Supplement 2 2023
Comparison of adnexal torsion in premenopausal and postmenopausal women and risk of malignancy
Osman Balci, Hasan Energin
Department of Obstetrics and Gynecology, Faculty of Meram Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.21165 Received: 2022-03-29 Accepted: 2022-06-06 Published Online: 2023-07-21 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S125-129
Corresponding Author: Hasan Energin, Department of Obstetrics and Gynecology, Faculty of Meram Medicine, Necmettin Erbakan University, 42080, Meram, Konya, Turkey. E-mail: hasanenergin@gmail.com P: +90 553 061 90 41 F: +90 332 223 61 81 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4089-403X
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2023-07-07, No: 4424)
Aim: Adnexal torsion is one of the rare causes of lower abdominal pain, however, it is a common gynecological surgical emergency. Its prevalence is 2.7%. The incidence of torsion may be lower in post-menopausal women because of decreased risk of benign ovarian cysts and benign teratomas. Adnexal masses in post-menopausal patients are more likely to be malignant. However, there is not enough study to know precisely the risk of malignancy in post-menopausal patients with adnexal torsion.
Material and Methods: This study was carried out in a tertiary center in Turkey. The study retrospectively analyzed 380 patients presented to our clinic with abdominal pain between January 2005 and January 2020 and underwent surgery for adnexal torsion.
Results: The data were collected from patients records at a tertiary center in Turkey over a 15-year period. Three hundred eighty patients underwent surgery for adnexal torsion; 288 patients were premenopausal and 92 patients were postmenopausal. Fourteen ovarian malignancies and 11 borderline serous and mucinous tumors were reported; 11 (11.9%) ovarian malignancies were reported in post-menopausal patients and 3 (1.1%) d in premenopausal patients. There were 6 serous cystadenocarcinoma, 4 mucinous cystadenocarcinoma, and 4 granulosa cell tumors that had been reported as malignancy histopathologic subtype.
Discussion: There is a longer delay in postmenopausal adnexal patients’ treatment since postmenopausal adnexal torsion is an uncommon and unexpected gynecological emergency. Malignancy prevalence is high in the postmenopausal group, and surgeons should suspect malignancy in post-menopausal adnexal torsion patients.
Keywords: Adnexal Torsion, Detorsion, Ovarian Malignancy
Introduction
Adnexal torsion is not a common cause of lower abdominal pain, however, it is a common gynecological surgical emergency. Its prevalence is 2.7% [1]. It has been seen most frequently seen in women of childbearing age. Any part of adnexa can undergo torsion. Neoplasia or hyperstimulation of ovaries may result in torsion.
Since adnexal torsion has non-specific clinical findings, diagnosis and surgery are usually delayed. Acute onset of abdominal pain with clinical findings of peritonitis can be related with adnexal mass. However, sometimes diagnosis of adnexal torsion is challenging, with common symptoms [1].
Ultrasound is the initial method of diagnosis, especially blood velocity loss in Doppler ultrasound is a possible finding, however precise diagnosis of adnexal torsion is made intra-operatively [2].
As most patients are of reproductive ages, the preferred treatment is a minimally invasive approach laparoscopic detorsion and preservation of adnexa [3]. Necrosis in ovaries may occur due to a delay in diagnosis or treatment [4].
In the literature, there are enough studies to feel secure to manage conservatively premenopausal patients with adnexal torsion. However, a more aggressive approach can be needed in postmenopausal patients due to the increased risk of malignancy. The risk of adnexal torsion may be lower in postmenopausal women since the incidence of benign ovarian cysts and benign teratomas in postmenopausal patients is low. In postmenopausal patients, there is an increased risk of malignancy in adnexal masses [2,5]. However, there are not enough studies to know precisely the risk of malignancy in post-menopausal patients with adnexal torsion.
In this study, we describe our experiences with patients with postmenopausal adnexal torsion and hypothesized that adnexal torsion in post-menopausal patients is more likely due to malignancy and the physician should consider the risk of malignancy.
Material and Methods
This retrospective study was conducted between January 2005 and January 2020 in a tertiary center in Turkey. The study retrospectively analyzed 380 patients who presented to our clinic with abdominal pain between January 2005 and January 2020 and had surgery for adnexal torsion. Three hundred eighty patients were analyzed according to demographic characteristics, menopausal status, preoperative signs and symptoms, preoperative and postoperative hemoglobin (Hb) values, postoperative fever, white blood cell (WBC) count, preoperation time, operation time, hospital stay, surgical findings and applied surgical procedures, and pathological results. The twist of the ovary/adnexa of at least 360 degrees was defined as ‘torsion’. Patients were defined as postmenopausal when patients reported 12 months of amenorrhea with or without menopausal symptoms. Data were compared between premenopausal and postmenopausal patients. All surgeries were performed by four gynecologists and staging surgeries were performed by two gynecologists specialized in gynecologic oncology.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The data were collected from patients records at a tertiary center in Turkey over a 15-year period; 380 patients underwent surgery for adnexal torsion; 288 patients were premenopausal and 92 patients were postmenopausal. Mean age, gravidity, parity, mass size, preoperative time, operation time, hospital stay were significantly higher in postmenopausal group. There were significantly more patients who had necrosis in specimens in the postmenopausal group (Table 1).
Abdominopelvic pain was the most common symptom (95.8% and 91.3%) in both groups, and adnexal mass was the most common sign in both groups (93.1% and 89.1). Doppler ultrasound was performed for all patients; velocity loss was seen in 84.0% in the premenopausal group and in 80.4% in the postmenopausal group, nausea and vomiting were seen in 184 patients (63.8%) in the pre-menopausal group and 56 (60.8%) in the post-menopausal group; 324 patients had peritoneal signs (85.2%) and 39 patients had a fever (10.2%) There was no significant difference in symptoms and signs in both groups (Table 2).
Surgical operation details (adnexal detorsion, cystectomy, oophorectomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) and staging surgery) and the histopathological findings were also noted (Table 2). Detorsion and detorsion with cystectomy was significantly higher in the premenopausal group. TAH-BSO and TAH-BSO and staging surgery were significantly higher in the postmenopausal group.
TAH-BSO was performed in postmenopausal patients. Unfortunately, out of working hours there was not any working pathologist, and there was also no chance of frozen pathological section in our center. Only in sixteen of post-menopausal patients, frozen sections could be taken since the operation was performed during working hours, 10 specimens were reported unidentified and 6 specimens were reported as benign. Other operations were performed during non-working hours, since patients had serious acute abdomen findings, therefore, additional staging surgery was performed in 52 (2 in premenopausal, 50 in postmenopausal) of these patients because of suspicion of malignancy based on the macroscopic appearance of the mass. The staging included pelvic wash for cytology, hysterectomy and adnexectomy, omentectomy and lymph-node sampling. The pathological results of these patients were malignant in 14 and borderline in 11 patients. Thus, the pathological result was consistent with malignancy in 48.0% of patients who underwent staging surgery.
Pathologic specimens were available for 322 of the 380 patients due to conservative surgery. Teratomas were the most common pathological finding in the premenopausal (n:92, 40.0%) and postmenopausal (n:26, 28.2%) groups. Fifty-two (22.6%) follicular cysts and 32 (13.9%) corpus luteum cysts were reported in pre-menopausal group, 9 (9.8%) fibromas were reported in postmenopausal group; 14 ovarian malignancies and 11 borderline serous and mucinous tumors were reported; 11 (11.9%) ovarian malignancies were reported in postmenopausal patients and 3 (1.3%) were reported in premenopausal patients. There were 6 serous cystadenocarcinomas, 4 mucinous cystadenocarcinomas, and 4 granulosa cell tumors were reported as malignancy histopathologic subtype. There were 3 (1.3%) borderline tumors in the premenopausal group and 8 (8.7%) in the postmenopausal group. There were significantly higher ratios of teratomas, follicular cysts, corpus luteum cysts in premenopausal patients’ pathological findings. In the postmenopausal group, the rates of serous cystadenomas, fibromas, ovarian malignancies, and borderline tumors were significantly higher (Table 2).
Discussion
Adnexal torsion is a gynecological emergency and should be diagnosed and treated as early as possible to save the ovarian tissue. In the differential diagnosis of acute pelvic pain in premenopausal patients, adnexal torsion comes to mind first. However, in postmenopausal patients, since it is a rare condition and there is no concern for fertility protection, diagnosis can be delayed.
In postmenopausal adnexal torsion patients, Ozcan et al. reported that there was no difference in symptoms and signs at the presentation from premenopausal patients, however they found a significant delay in surgical treatment for postmenopausal patients [6]. In our study, we found no significant difference in symptoms and signs between postmenopausal and premenopausal patients. But preoperative time was significantly lower in premenopausal patients. Surgery was performed on postmenopausal patients later than an excess delay of almost 50 hours. Although both groups had similar symptoms and clinical findings, this delay could be due to the fact that physicians usually do not suspect adnexal torsion in the differential diagnosis in older women.
We had found significantly more tissue necrosis in post-menopausal patients due to delay in surgery. However, there is no increased risk of thromboembolism due to necrosis of the tissue [7]. In our study, we also found that operation time and hospital stay were significantly longer in the post-menopausal group. Because in the postmenopausal group, more aggressive surgery was performed. In the premenopausal group, we performed two TAH-BSO and two staging surgeries, however, in the post-menopausal group, we performed forty-two TAH-BSO and fifty staging surgeries. Eitan et al. also reported significantly longer operation time and hospital stay in the postmenopausal group [6].
In adnexal torsion, ultrasound is the first-choice modality in imaging ovaries, because, when performed, especially with Doppler flow, it has good diagnostic performance and lower cost. However, a definite diagnosis of adnexal torsion is often made intra-operatively [2]. In our study, we found velocity loss on Doppler ultrasound in 84.0% in the premenopausal group and 80.4% in the postmenopausal group. There was no significant change between the two groups.
Pathological findings in both groups differ significantly; in the premenopausal group, the most common pathological diagnosis was benign teratoma. Respectively follicular cysts and corpus luteum cysts occupy the second and third place. In the postmenopausal group, teratomas are the most common pathological diagnosis. Respectively serous cystadenomas and malignancies are the second and third most common pathological diagnosis.
The incidence of malignancy in all patients was 3.7% (n=14), in the premenopausal group, it was 1.3% (n=3), in the postmenopausal group, it was 11.9% (n=11). There was a significant difference in malignancy incidence between both groups.
In previous studies, Hermann et al. found the risk of malignancy in 3% of 33 postmenopausal patients, whereas Ozan et al. found the risk of malignancy in 16% of 25 post-menopausal patients [6, 8]. In a study by Huchon C. et al., the incidence of malignancy was 25% in 37 women with torsion and older than 60 years [9]. Although in another study, Koonings et. al reported 19 adnexal torsions in postmenopausal patients and no malignancy was reported in their study.
We observed 6 serous cystadenocarcinomas, 4 mucinous cystadenocarcinoma, and 4 granulosa cell tumors among malignancies. In the literature, there are no studies reporting histopathological subtypes of malignancies, which were seen in ovarian torsions in postmenopausal patients.
In their studies, Spinelli et al. and Balci et al. reported that delays in the diagnosis of adnexal torsion in postmenopausal patients were caused by ovarian necrosis, which affects the reliability of frozen section results [10,13]. In our study, 16 frozen sections were taken from postmenopausal patients, since surgeries had been performed as an emergency in non-working hours, 10 specimens were reported unidentified due to necrosis, and 6 specimens were reported as benign. Fifty-two patients had staging surgery due to suspicion of malignancy on macroscopic appearance, and 14 malignant and 11 borderline tumors (48%) were reported. Staging surgeries were performed by gynecologists who specialized in oncologic surgery in suspicion of malignancy before the operation due to ultrasound findings (semi solid appearance, thick cysts wall, thick septations and size of the mass).
In staging surgery, we performed peritoneal washing cytology, TAH+BSO, omentectomy, lymph node dissection, and appendectomy. Fourteen malign cases were optimally cytoreduced. In 11 cases, capsule intact and the absence of lymph node metastases, malign cell negative peritoneal washing cytology (early stage) were reported. In 3 cases, the capsule was not intact, there were pelvic lymph node metastases and malign cell positive peritoneal washing cytology. There were no distant metastases or bowel implants or splenic metastases in all cases.
We observed that intra-operative pathological frozen section results were not helpful. Surgeons should make their decisions carefully, the suspicion of malignancy in the macroscopic appearance of mass and patient’s clinical findings should be considered carefully while deciding the aggressiveness of the surgery. The unreliability of the frozen section results in adnexal torsions could be due to necrosis of the tissue, which can be the result of a delay in diagnosis. If the delay in diagnosis could be shortened, this disadvantage could be prevented.
Our study is one of the largest studies examining postmenopausal adnexal torsions in the literature. Although the number of patients was high, this was a one-centered study, and four physicians performed surgeries, which decreases bias due to physicians’ different management styles.
The major limitation of our study is the retrospective nature of the clinical data. The study includes only women who were diagnosed with adnexal torsion, and there is a possibility that there was an underdiagnosis that have led to a diagnostic bias. Although this was a retrospective study, there are not enough published studies in the literature on this subject to date, which makes this work important, even its limitations.
Conclusion
There is a longer delayer in postmenopausal adnexal patients’ treatment because post-menopausal adnexal torsion is an uncommon and unexpected gynecologic emergency. Malignancy prevalence is high in the postmenopausal group, and surgeons should suspect malignancy in postmenopausal adnexal torsion patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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3. Cohen A, Solomon N, Almog B, Cohen Y, Tsafrir Z, Rimon E, et al. Adnexal Torsion in Postmenopausal Women: Clinical Presentation and Risk of Ovarian Malignancy. J Minim Invasive Gynecol. 2017;24(1):94-7.
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6. Ozcan A, Mumusoglu S, Gokcu M, Caypinar SS, Sagiroglu C, Inan AH, et al. Differentiated therapy in pre- and postmenopausal adnexal torsion based on malignancy rates: A retrospective multicentre study over five years. Int J Surg. 2016; 29:95-100.
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The influence of coccyx morphology on ganglion impar block treatment results in chronic coccydynia
Samet Sancar Kaya 1, Şeref Çelik 2, Erkan Yavuz Akçaboy 2, Hamit Göksu 3, Müge Baran 4, Şaziye Şahin 2
1 Department of Pain Medicine, Adıyaman University Training and Research Hospital, Adıyaman, 2 Department of Pain Medicine, University of Health Sciences, Ankara City Hospital, Ankara, 3 Department of Pain Medicine, University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, 4 Department of Pain Medicine, Ağrı Training and Research Hospital, Ağrı, Turkey
DOI: 10.4328/ACAM.21734 Received: 2023-04-26 Accepted: 2023-06-05 Published Online: 2023-06-20 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S130-134
Corresponding Author: Samet Sancar Kaya, Deparment of Pain Medicine, Adıyaman University Training and Research Hospital, 02100, Ziyaretpayamlı, Adıyaman, Turkey. E-mail: sametsancarkaya@hotmail.com P: +90 505 753 60 59 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4819-1128
This study was approved by the Ethics Committee of Ankara City Hospital (Date: 2022-01-26, No: E1-22-2338)
Aim: Coccydynia is usually managed conservatively; however, ganglion impar block (GIB) can be performed in patients who do not respond to conservative treatments. In this study, we aimed to investigate the effect of coccyx morphology on outcomes of GIB in coccydynia.
Material and Methods: A retrospective study included 101 patients with coccydynia who failed to respond to conservative treatments and underwent GIB. Patients were categorized as normal (Type 1), or abnormal (Type 2, 3, 4, and 5) based on the modified Postacchini and Massobrio classification. Pain scores before and after the injection at 1 and 3 months were compared. A more than 50% reduction in visual analogue scale (VAS) scores was defined as significant pain relief.
Results: According to the Postacchini-Massobrio classification, 42 patients had a normal coccyx (Group I) and 59 had an abnormal coccyx (Group II). VAS scores in both groups had improved significantly from baseline at 1 and 3 months (p <0.05). There were significantly greater decreases in VAS scores in the 1st and 3rd months in Group II than in Group I (p < 0.001). The 1st month VAS and 3rd month VAS scores were higher in the patient group without trauma history than in the patient group with trauma history (p = 0.008, and p = 0.040, respectively).
Discussion: GIB is safe and effective for the management of coccydynia. History of trauma and type of coccyx in patients with chronic coccydynia seem to affect treatment outcomes.
Keywords: Coccydynia, Ganglion Impar Block, Coccydynia Treatment, Coccyx Morphology, Postacchini-Massobrio Classification
Introduction
Coccydynia is described as pain and tenderness around the sacrococcygeal region [1]. Although its true incidence is unknown, it is more common in women [2]. Diagnosis is confirmed by clinical examination and imaging techniques. The first line of treatment is conservative such as non-steroidal anti-inflammatory drugs, modification of sitting style, sitting cushions, exercises, and physiotherapy; however, these treatments are ineffective in 10% of patients. In non-responsive patients, ganglion impar block (GIB) can be applied [3].
Ganglion impar block is the most widely used interventional therapy for coccydynia because it is easy and minimally invasive, significantly reduces pain, and the incidence of complications is low for GIB. The success rate of GIB in coccydynia is > 85% [4].
There are several articles reporting that the morphological features of the coccyx are important in the development of coccydynia [5, 6]. However, there are not enough data in the literature about which factors affect the therapeutic success of GIB. Therefore, the aim of our study was to investigate the effect of the morphology of the coccyx according to the modified Postacchini-Massobrio classification on outcomes of GIB in patients with chronic coccydynia.
Material and Methods
The medical records of patients with coccydynia who did not respond to conservative treatments, and then underwent GIB between June 2019 and June 2021 were retrospectively reviewed. The study was approved by the Ethics Committee of Ankara City Hospital (Date: 2022-01-26, No: E1-22-2338).
Inclusion criteria:
1. 18 years of age and over
2. Coccydynia patients unresponsive to conservative treatments for at least 3 months
3. Patients who underwent trans-sacrococygeal GIB under fluoroscopy and had routine coccyx radiographs and MRI scans before the procedure.
Exclusion criteria:
1. Previous surgery to the lumbar or coccygeal region
2. Coccydynia associated with cancer metastasis.
3. Coexisting chronic painful diseases such as fibromyalgia or psychiatric disorders
4. Not optimal fluoroscopy images during injection
5. Failure to block with appropriate doses of drugs
6. Missing information in the patient’s file
Imaging technique and analysis
The radiographs of all patients were classified according to the modified Postacchini and Massobrio classification [1, 7]. Coccyx curve was classified as follows: type 1: normal curve, type 2: coccyx more markedly curved and pointing anteriorly, type 3: very sharply angled anteriorly, type 4: anterior subluxation at the sacrococcygeal or intercoccygeal joint, type 5: coccygeal retroversion. The patients were categorized as normal (Type 1), or abnormal (Type 2, 3, 4, and 5) based on the modified Postacchini and Massobrio classification.
Fluoroscopic‑guided ganglion impar block
The injections were performed in an operating room. The patient was monitored and vital signs were observed throughout the entire procedure (blood pressure, heart rate, SpO2). After the intergluteal area was prepared with sterile aseptic precautions, while the patient was lying prone, the sacrococcygeal area was identified in the lateral position under C-arm fluoroscopy. The area was infiltrated with 2-3 mL 1% lidocaine using a 25-G needle. A 22-G spinal needle was inserted from the midline at the sacrococcygeal junction. In the lateral fluoroscopic view, when the tip of the needle was anterior to the coccyx, needle tip was confirmed by 1 mL non-ionic contrast spread in the shape of a “comma” (Figure 1). After confirmation, 3 mL of 0.25% bupivacaine and 2 mL of 8 mg dexamethasone were injected.
Data Collection
Initially, 118 patients who underwent a fluoroscopic‑guided GIB for coccydynia were included in the study. Thirteen of these patients were excluded from the study because their visual analogue scale (VAS) scores were not recorded, and 4 of them were excluded because the optimal block could not be performed.
Age, gender, body mass index (BMI), duration of pain, trauma history, and VAS scores before and after the procedure (1 month and 3 months) were obtained by retrospectively scanning of the medical records. Digital images of the coccyx were obtained with the picture archiving communication system.
The pain was assessed using the Visual Analogue Scale (VAS) (0 = “no pain” and 10 = “worst imaginable pain”), measured before the procedure, one and three months after the procedure. More than a 50% reduction in VAS scores was accepted as significant pain relief.
Statistical analysis
All analyses were carried out using IBM SPSS Statistics for Windows 25.0 (IBM Corp., Armonk, NY, USA). For analysis of normal distribution, the Kolmogorov-Smirnov test was used. Normally distributed quantitative data were presented as median ± standard deviation (SD), and quantitative data not normally distributed were expressed as the median and interquartile range (IQR). The chi-square test was used to analyze the relationship between the significant pain relief over time. The change in VAS scores and significant VAS reduction between groups according to time were demonstrated in graphics. P < 0.05 was accepted as statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The study included 101 patients, 42 of them had normal coccyx morphology (Group I) and 59 had abnormal coccyx morphology (Group II) based on the radiography of the coccyx. The average age of the subjects was 44.04 ± 13.73 years, and the average duration of pain was 22.52 ± 25.73 months. The groups were similar in terms of sex, age, BMI and duration of pain. However, trauma history was significantly higher in Group II than in Group I (p = 0.004) (Table 1).
According to the modified Postacchini-Massobrio classification, the most common type of coccyx among all patients was type 1 (41.6%), followed by type 2 (20.8%). Types 3, 4, and 5 frequencies were 10.9%, 14.9%, and 11.9%, respectively.
At baseline, there was no significant statistical difference between baseline mean VAS scores between groups (p = 0.787). Post-injection VAS scores were significantly decreased compared to baseline VAS scores in both groups (p < 0.05). VAS scores in Group II were significantly lower than in Group I in the 1st and 3rd months (p < 0.001) (Table 2).
Significant pain relief, which was accepted as ≥ 50% pain reduction on VAS scores had a lower prevalence in Group I than in Group II at 1and 3 months (respectively, p < 0.001 and p = 0.004) (Figure 2).
We assigned all patients into two groups according to a history of trauma: 46 patients with a history of trauma and 55 patients without a history of trauma and compared their preprocedural and postprocedural VAS scores. The mean age was significantly higher in patients without trauma history (p = 0.009). Duration of pain and VAS baseline were similar between groups with or without history (p > 0.05). The 1st-month VAS and 3rd-month VAS scores were higher in the patient group without trauma history (p = 0.008, and p = 0.040, respectively) (Table 3).
No complications were observed during or after the procedure in any of the patients.
Discussion
Although the etiology of coccydynia is not clearly known, it is accepted as having multifactorial origin, which can also be idiopathic [8]. Postacchini and Massobrio [7] suggested that coccyx morphology may have an important role in the etiology of coccydynia. They described a radiological classification system in which they identified 4 types of the coccyx and reported the relationship of these types with coccydynia. According to this classification, type II, III and IV patients have a higher risk of developing coccydynia. Later, a fifth type was described as retroverted angulation of the coccyx [1, 9]. Later studies generally focused on coccyx mobility and it was suggested that the majority of coccydynia cases had subluxation or hypermobile coccyx and chronic changes occurred because of this pathological instability [1, 8, 10]. However, no findings other than BMI, initiating trauma history and spicule are strongly associated with coccydynia, including instability [8, 11].
The only study in the literature on the effect of coccygeal morphology on GIB in patients with chronic coccydynia belonged to Sencan et al. [10] They assigned the coccydynia patients who had undergone GIB into two groups: those with normal and an immobile coccyx by performing dynamic radiographs. They did not find significant differences between the treatment outcomes of the normal and immobile groups. This result may support the claim that the role of instability in the etiology of coccydynia is weak. However, they did not evaluate the effect of subluxation and hypermobility on GIB outcomes. Postacchini and Massobrio [7] did not observe any relationship between the coccygeal morphology and treatment results in patients treated with coccygectomy. Ozkal [12] reported successful results in all 29 patients (13 type 1, 14 type 2, 2 type 3) who underwent coccyx excision resistant to conservative treatment. Kodumuri et al. [11] figured out that patients with coccydynia with a BMI below 30 and those with coccyx trauma responded better to treatment modalities such as manipulation, coccygectomy, and local steroid injections.
In most cases, there is a history of underlying trauma, and the decrease in pain with steroid injections around this area together with common trauma history is evidence that supports inflammation in the pericoccygeal region [13, 14]. It is thought that the overactivity or sensitivity of the ganglion impar also plays a role in the pain mechanism of coccydynia [15-17]. GIB seems reasonable in the treatment of chronic coccydynia, both in terms of inhibiting the excessive activity of the impar ganglion and suppressing possible inflammation in the pericoccygeal region. We found significant pain relief in 47.5% of patients at 1 month and 38.6% at 3 months in our study. This improvement was significantly lower in Group I than in Group II. There may be some reasons for this result. The severe angulation seen in patients with abnormal coccyx type may indicate that inflammation is more active in these patients than in patients with a coccyx without angulation. The fact that the history of trauma in patients with abnormal coccyx morphology is significantly higher than in patients with normal coccyx morphology, and the post-treatment VAS scores of patients with a history of trauma are significantly lower than those without a history of trauma supports our idea. Also, these advanced morphological disorders and inflammation may have led to overactivity of the ganglion impar in patients with abnormal coccyx type. The lack of difference between Group I and Group II in terms of significant improvement at 3 months can be attributed to the termination of the dominant effect of the steroid on inflammation.
In our study, a significant reduction in pain lasting up to 3 months was achieved in 38.6% of our patients. Similar to our study, Buttacı et al. [18] reported a 50-75% reduction in pain lasting weeks to months with GIB in patients. Malhotra et al. [13] observed that all patients reported pain relief that usually lasted for at least three months following GIB. Gunduz et al. [19] reported a success rate of 82% with a median duration of 6 months in patients with chronic coccydynia who had undergone GIB. Sir and Eksert [20] reported a significant improvement in pain scores at 3weeks and 3 months in patients with chronic coccydynia who underwent GIB. However, at 6 months, the pain levels were almost back to the baseline levels. Our success rates were lower than those reported by Malhotraet al. [13] and Gunduz et al [19]. The high success rates reported by Malhotra et al. [13] may be due to the use of 8 mL of 0.5% bupivacaine in contrast to other studies that have generally used lower volumes of 0.25% bupivacaine. Also the anatomical variability of the location of the ganglion impar may result in different success rates.
Similar to the literature, type I coccyx was most common, followed by type II in our study [2, 7]. However, in two studies, type 2 coccyx was reported to be more common [9, 21]. The majority of the patients in our study were female, and middle-aged, which was similar to other studies [10, 13, 20].
Malhotra et al. [13] observed the efficacy of both trans-sacrococcygeal and transcoccygeal approaches of GIB, but they did not report a significant difference between the two groups in terms of efficacy. Because of the demonstration that the sacrococcygeal joint can be a source of pain (secondary to inflammation or degenerative process) and its close proximity to the impar ganglion, we performed GIB with the trans-sacrococcygeal approach [16, 17, 22].
The major limitations of our study are the limited follow-up period of 3 months, retrospective nature, absence of dynamic radiography and functional parameters such as painless sitting time and Oswestry disability index. Nevertheless, we think that our study is valuable as the second study in the literature investigating the effect of coccygeal morphology on GIB in patients with chronic coccydynia.
Conclusion
GIB is an effective treatment procedure with a low complication rate for pain relief in coccydynia. In patients with chronic coccydynia, radiologically detected abnormal coccyx morphology and history of trauma appear to affect the treatment outcomes of GIB. Prospectively designed, controlled studies with a larger patient population are needed to determine the factors affecting the success of GIB in the treatment of chronic coccydynia.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Nathan S, Fisher B, Roberts C. A review of pathoanatomy, aetiology, treatment and outcome: Coccydynia. J Bone Joint Surg Br. 2010;92(12):1622-7.
2. Karadimas EJ, Trypsiannis G, Giannoudis PV. Surgical treatment of coccygodynia: an analytic review of the literature. Eur Spine J. 2011;20(5):698-705.
3. Lirette LS, Chaiban G, Tolba R, Eissa H. Coccydynia: an overview of the anatomy, etiology, and treatment of coccyx pain. Ochsner J. 2014;14(1):84-7.
4. Choudhary R, Kunal K, Kumar D, Nagaraju V, Verma S. Improvement in Pain Following Ganglion Impar Blocks and Radiofrequency Ablation in Coccygodynia Patients: A Systematic Review. Rev Bras Ortop. 2021;56(5):558-66.
5. Woon JT, Maigne J-Y, Perumal V, Stringer MD. Magnetic resonance imaging morphology and morphometry of the coccyx in coccydynia. Spine. 2013;38(23):E1437-45.
6. Hekimoglu A, Ergun O. Morphological evaluation of the coccyx with multidetector computed tomography. Surg Radiol Anat. 2019;41(12):1519-24.
7. Postacchini F, Massobrio M. Idiopathic coccygodynia. Analysis of fifty-one operative cases and a radiographic study of the normal coccyx. J Bone Joint Surg Am. 1983;65(8):1116-24.
8. Maigne J-Y, Doursounian L, Chatellier G. Causes and mechanisms of common coccydynia: role of body mass index and coccygeal trauma. Spine. 2000;25(23):3072-9.
9. Yoon MG, Moon M-S, Park BK, Lee H, Kim D-H. Analysis of sacrococcygeal morphology in Koreans using computed tomography. Clin Orthop Surg. 2016;8(4):412-9.
10. Sencan S, Cuce I, Karabiyik O, Demir FU, Ercalik T, Gunduz OH. The influence of coccygeal dynamic patterns on ganglion impar block treatment results in chronic coccygodynia. Interv Neuroradiol. 2018;24(5):580-5.
11. Kodumuri P, Raghuvanshi S, Bommireddy R, Klezl Z. Coccydynia–could age, trauma and body mass index be independent prognostic factors for outcomes of intervention? Ann R Coll Surg Engl. 2017;100(1):12-5.
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13. Malhotra N, Goyal S, Kumar A. Comparative evaluation of transsacrococcygeal and transcoccygeal approach of ganglion impar block for management of coccygodynia. J Anaesthesiol Clin Pharmacol. 2021;37(1):90-6.
14. Maigne J-Y, Pigeau I, Roger B. Magnetic resonance imaging findings in the painful adult coccyx. Eur Spine J. 2012;21(10):2097-104.
15. Foye PM. New approaches to ganglion impar blocks via coccygeal joints. Reg Anesth Pain Med. 2007;32(3):269.
16. Foye PM. Ganglion impar blocks via coccygeal versus sacrococcygeal joints. Reg Anesth Pain Med. 2008;33(3):279-80.
17. Kaya SS, Akcaboy EY, Celik S, Goksu H, Baran M, Yildiz G, et al. A comparative and retrospective study on the efficacy of caudal epidural steroid injection plus ganglion impar block versus ganglion impar block in patients with coccydynia. Ann Med Res. 2022;29(12):1413-7
18. Buttaci CJ, Foye PM, Stitik TP. Poster board 56: Coccydynia successfully treated with ganglion impar blocks: a case series. Am J Phys Med Rehabil. 2005;84(3):218.
19. Gunduz OH, Sencan S, Kenis-Coskun O. Pain relief due to transsacrococcygeal ganglion impar block in chronic coccygodynia: a pilot study. Pain Med. 2015;16(7):1278-81.
20. Sir E, Eksert S. Comparison of block and pulsed radiofrequency of the ganglion impar in coccygodynia. Turk J Med Sci. 2019;49(5):1555-9.
21. Przybylski P, Pankowicz M, Boćkowska A, Czekajska-Chehab E, Staśkiewicz G, Korzec M, et al. Evaluation of coccygeal bone variability, intercoccygeal and lumbo-sacral angles in asymptomatic patients in multislice computed tomography. Anat Sci Int. 2013;88(4):204-11.
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Download attachments: 10.4328.ACAM.21734
Samet Sancar Kaya, Şeref Çelik, Erkan Yavuz Akçaboy, Hamit Göksu, Müge Baran, Şaziye Şahin. The ınfluence of coccyx morphology on ganglion ımpar block treatment results in chronic coccydynia. Ann Clin Anal Med 2023;14(Suppl 2):S130-134
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Elizabethkingia meningoseptica: A new cause of ventilator-associated pneumonia in pediatric intensive care unit
Gultac Evren 1, Senem Akgul 2
1 Department of Pediatric Intensive Care Unit, 2 Department of Medical Microbiology, Manisa City Hospital, Manisa, Turkey
DOI: 10.4328/ACAM.21770 Received: 2023-06-01 Accepted: 2023-07-03 Published Online: 2023-07-10 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S135-139
Corresponding Author: Gultac Evren, Department of Pediatric Intensive Care Unit, Manisa City Hospital, Manisa, Turkey. E-mail: gultacevren@gmail.com P: +90 505 210 25 47 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0614-0894
This study was approved by the Ethics Committee of Bakırçay University (Date: 2022-10-05, No:720/2022-GOA)
Aim: Ventilator-associated pneumonia (VAP) is diagnosed by detecting bacterial microorganisms in addition to purulent tracheal secretions, fever, respiratory distress, leukocytes in the tracheal aspirate, and radiological findings of pneumonia in patients on mechanical ventilation for more than 48 hours. The objective of this study was to determine the effects of E. meningoseptica bacteria and other agents, which are infrequently detected in tertiary pediatric intensive care units, on clinical findings, demographic characteristics, and mortality in patients with VAP.
Material and Methods: In this retrospective study, patients who were intubated in a tertiary pediatric intensive care unit (PICU) and diagnosed with ventilator-associated pneumonia according to CDC criteria between 2021 and 2022 were evaluated. The study included 42 patients who met all inclusion criteria.
Results: The 42 participants in the study were diagnosed with VAP based on CDC criteria and positive microbiological test results. The average age of the patients was 38,5 months, and the bmales predominated. Nine patients had E. meningoseptica isolated from them. Eight of the forty-two patients included in the investigation perished, and three of them had VAP. Mechanical ventilation time (p = 0.017) and PICU hospitalization time (p = 0.017) were both prolonged in the E. meningoseptica-isolated group.
Discussion: In recent years, the prevalence of E. meningoseptica infection in pediatric intensive care units has increased rapidly. This infection causes fatal opportunistic infections in patients receiving broad-spectrum antibiotics, followed by central venous catheters, duration of mechanical ventilation, and length of PICU stay.
Keywords: Ventilator-Associated Pneumonia, Elizabethkingia Meningoseptica, Antibiotics, Pediatric Intensive Care Unit
Introduction
The term ventilator-associated pneumonia (VAP) refers to pneumonia that develops in patients who have been on mechanical ventilation for more than 48 hours [1]. The diagnosis is established clinically by detecting bacterial microorganisms along with purulent tracheal secretions, fever, respiratory distress, and white blood cells in the tracheal aspirate and detecting the radiological findings of pneumonia. It is one of the most important causes of hospital-acquired infections. Despite advances in asepsis techniques, antibiotic therapy, and supportive care, it is one of the causes of morbidity and mortality in intensive care patients. The incidence of VAP was found to be 9.62% in developed countries and 22.9% in developing countries [2,3]. Despite a better understanding of VAP risk factors, the incidence is still high. In a study conducted in developing countries, the mortality of VAP was 22%, 42.4%, and in studies conducted in developed countries, mortality was 18.4% [4,5,6].
Elizabethkingia meningoseptica (E.meningoseptica) is an oxidase-positive, non-glucose-fermenting, rod-shaped gram-negative bacterium commonly found in nature [7]. It is a rare pathogen that causes infections, especially in immunocompromised patients, such as neonatal meningitis, pneumonia, bacteremia, sepsis, soft tissue infections. The mode of transmission is not well known, it is stated that it is transmitted through contaminated water, and it usually causes hospital infections. The presence of invasive equipment, such as intravascular catheters, endotracheal tubes, and prosthetic devices, is most associated with prolonged treatment with broad-spectrum antibiotics, prolonged hospitalization, and nosocomial outbreaks [8].
Our aim in the study was to determine the effects of E. meningoseptica bacteria and other agents, which are rarely detected in a tertiary pediatric intensive care unit, on clinical findings, demographic characteristics, and mortality in VAP patients. E. meningoseptica is a rarely isolated agent that causes epidemics and is not frequently seen in pediatric intensive care units. The increase in the reporting of E.meningoseptica in adult intensive care units is a warning in terms of attention in terms of E.meningoseptica infections in PICUs in the future. There may be an increased risk for nosocomial infections in patients who are followed up in E.meningoseptica, PICUs, and who are usually immunosuppressed and undergo invasive intervention.
Material and Methods
Study Settings
The Institutional Ethical Committee of Bakırçay University, Türkiye, approved this retrospective, single-center study (approval number: 720/2022-GOA). Patients diagnosed with ventilator-associated pneumonia based on CDC criteria and followed as intubated in the tertiary pediatric intensive care unit (PICU) of Manisa City Hospital between 2021 and 2022 were evaluated retrospectively in this study. Our unit has twelve beds and admits more than 300 patients per year. All patient accommodations feature a single bed. On-call personnel include a pediatric intensive care specialist and a pediatrician. The ratio of nurses to patients is 1 to 1. The unit utilizes Maquet and Biovent-brand ventilators. Each patient uses a disposable active or passive humidifier circuit. Using an aerochamber device, patients receive inhaled therapy.
The investigation included patients who were followed in the intensive care unit between February 2021 and October 2022, were one month to eighteen years old, were on mechanical ventilation for more than 48 hours, and received endotracheal aspiration material. Patients who were mechanically ventilated for less than 48 hours and did not meet CDC criteria were excluded from the study.
Data gathering
PRISM score, laboratory data (maximum and minimum white cell count), duration of mechanical ventilation, length of stay in the pediatric intensive care unit, chest radiography results (new infiltration, consolidation, or cavity development), and culture results (endotracheal aspiration material) were collected retrospectively. All patients were monitored until discharge or exit for the development of ventilator-associated pneumonia.
Patients were diagnosed with VAP based on the following Centers for Disease Control and Prevention (CDC) criteria: 1-fever, leukopenia, or leukocytosis (any of them), 2-a-cough, dyspnea, or tachypnea; b-new onset; increasing or changing character of purulent secretion; c-lung on auscultation; ral or rhonchi; d-increased oxygen requirement or hypoxemia; 3-New onset or increased infiltration on radiography, consolidation (any of them), and 4-105 colony growth in endotracheal aspirate material (at least one of all four criteria is positive) [available from: https://www.cdc.gov]. Those with a positive endotracheal aspirate culture (ETA) below the threshold and those without clinical and radiological VAP findings were deemed colonized and excluded from the study.
Due to clinical findings, ETA was obtained from patients suspected of having VAP. In the interim, piperacillin-tazobactam was administered to the patients until their ETA results were determined. In ETA culture results, ceftazidime avibactam, or kinolon were added to patients with E. meningoseptica according to antibiogram results; inhaled antibiotics were added to some patients (especially gentamicin or colistin in patients with high renal function tests according to ETA antibiogram results); and intravenous antibiotic revision was performed on some patients. During the research period, 386 out of 962 intubated pediatric intensive care unit patients were followed up and included in the study. We excluded 198 intubated patients because they were connected to a mechanical ventilator for less than 24 hours and 24 patients because their medical records were insufficient. In 77 of 188 patients, VAP was considered, and ETA was sent. 105 colonies of colony growth were detected in the microbiological samples of 28 patients, and these patients were excluded from the study due to the possibility of ventilator-associated tracheitis. Twelve patients who met the CDC criteria were excluded from the study because the microbiological examination revealed no growth. The study included 42 patients who met all inclusion criteria.
Statistical analysis
For qualitative variables, data were analyzed using frequency and percentage (%), and for quantitative variables, mean standard deviation (SD), median, minimum, and maximum values were employed.E.meningoseptica and other microbiologic isolate groups were compared using the Mann-Whitney U test, Pearson Chi-square test, Fisher’s Exact test, and Fisher-Freeman-Alton test because the data did not exhibit a normal distribution. IBM-SPSS version 21.0 was used for statistical analyses, and p0.05 was considered significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Forty-two study participants were diagnosed with VAP based on CDC criteria and positive microbiological test results. The average age of the patients was 38,5 months, males predominated. Respiratory diseases were the leading cause of PICU hospitalization and the most prevalent underlying disease. Eight of the forty-two patients included in the investigation perished, and three of them had VAP (Table 1).
Pseudomonas aeruginosa and Elizabethkingia meningoseptica were the most frequently isolated microorganisms in VAP patients. P. aeruginosa was isolated twice from a single patient, while E. meningoseptica was isolated twice from three patients (Table 2).
Males comprised 4 of the 9 patients isolated with E. meningoseptica and 19 of the 33 patients isolated with other microorganisms. According to CDC criteria, there was no statistically significant difference between the two categories. Mechanical ventilation time (p = 0.017) and PICU hospitalization time (p = 0.017) were both prolonged in the E. meningoseptica-isolated group. All patients in the E. meningoseptica-isolated group received intravenous antibiotics, while 14 patients in the other group received inhaled antibiotics. One patient isolated with E.meningoseptica and seven patients isolated with other microorganisms perished (Table 3).
Discussion
In our study, we retrospectively analyzed 42 patients aged 0-18 years who were intubated in the PICU between 2021 and 2022 and diagnosed with ventilator-associated pneumonia according to CDC criteria. Patients’ demographic information, microbiological results, and treatments were evaluated.
In established nations, the incidence of ventilator-associated pneumonia is 15-17%, whereas in developing nations, this rate is 25-35% [9,10]. A study found that the incidence of VAP was 11.6% per 1000 ventilator days [11]. It has been shown that PRISM scores of 10 or higher increase the incidence of VAP in pediatric intensive care patients following cardiac surgery [12]. In our investigation, the VAP rate per 1000 ventilator days was 29.2%. The VAP mortality rate is 5% in advanced units utilizing the VAP prevention bundles and 47.43% in developing units not utilizing the VAP prevention bundles. This rate was discovered to be 19% in our study. The use of VAP prevention bundles has just begun in our unit. We believe this rate will decrease as a result of the implementation of VAP prevention packages.
P. aeruginosa (55%) and A. baumanni (31%) are the most frequently isolated microorganisms from cultures of endotracheal aspirate in pediatric intensive care units [13]. Similarly, P.aeroginosa was the most frequently detected microorganism in our study, followed by E.meningoseptica. Rarely detected in pediatric intensive care facilities, E. meningoseptica was isolated from 9 patients and 12 cultures in our study. Elizabethkingia meningoseptica is a gram-negative bacillus that causes nosocomial infections and is resistant to commonly used antibiotics in intensive care settings. The most prevalent clinical presentation of E.meningoseptica in children, according to a literature review spanning the years 1994 to 2017, was meningitis (73.9%), and admission with pneumonia was estimated to be 6.7% [14]. Premature infants, immunosuppressed patients, patients taking antibiotics, intensive care unit patients, and patients undergoing dialysis are susceptible to E. meningoseptica infections [15]. E. meningoseptiva was identified as a VAP agent among gram-negative bacteria in 8.66% of intensive care unit patients [16]. In our study, patients with VAP had a high prevalence of 21.4%.
Recent years have witnessed the emergence of E. meningoseptica infection as a global emergent infectious disease with poor prognoses. PICU length of stay, underlying comorbidities, and the use of central venous catheters are risk factors for E. meningoseptica infection [16]. Our patients stayed longer in the PICU, but this may be due to E. meningoseptica, a difficult-to-eradicate multidrug-resistant microorganism. Six out of eight patients had neurometabolic disease comorbidity. Both underlying comorbidity and prolonged ICU stay increased the risk of E.meningoseptica infection in patients. Six of the patients who stayed longer than 32 days in the PICU were fitted with central venous catheters.
The majority of reported epidemics of E.meningoseptica in children occur sporadically. Infection with E. meningoseptica is preventable, whether sporadic or concentrated. The causative agent for the E.meningoseptica outbreak, which was detected in 30 patients in the adult intensive care unit, was found in the unit’s water [17]. In our study, the majority of E.meningoseptica-isolated patients were admitted to the PICU at distinct times. E. meningoseptica was not detected in samples taken from areas where microorganisms can colonize, such as the water in the intensive care unit, aspiration materials, oxygen humidifiers, and distilled water used in mechanical ventilators.
E.meningoseptica is known to be antibiotic-resistant. In vitro, E.meningoseptica has been shown to be susceptible to fluoroquinolones, trimethoprim/sulfamethoxazole, and piperacillin/tazobactam [18]. In ETA culture, E. meningoseptica was isolated 12 times. In our study, three isolates were sensitive to quinolones, nine isolates were sensitive to ceftazidime-avibactam alone, and all other isolates in the culture antibiogram were resistant. In intensive care units, infection control measures must be rigorously implemented. In order to prevent infections, daily patients should have their VAP prevention bundles filled on a regular basis. In addition, antibiotic administration should adhere to a defined antibiotic management program.
In neonatal and pediatric patients, the mortality rate owing to E.meningoseptica ranged from 12.5% to 66.7% [19]. In an adult intensive care unit study, the mortality rate of VAP was 16.6%, 6.6% due to E.meningoseptica, and the cause of death in these patients was not found to be infection-related [17]. The agent was isolated from the tracheal aspirate cultures of nine out of nineteen patients who were ventilated mechanically, and four of these patients died [20]. In our study, VAP-related E. meningoseptica mortality was 2.3%, while VAP-related E. meningoseptica mortality was 19%. Even though mortality was not high in our study, inappropriate antibiotic use and the avoidance of superfluous central venous catheter placement are crucial for the eradication of E.meningoseptica infection. Given the prevalence of antimicrobial resistance, the lower mortality may be attributable to the increased use of newer antibiotic options, swift microbiological diagnostic tests, or antimicrobial susceptibility tests. Mortality may have decreased over time due to the enhanced conditions of pediatric intensive care units, rapid diagnosis, and early treatment. Healthcare professionals can play a crucial role in preventing and managing Elizabethkingia meningoseptica infections by maintaining infection control measures, improving antibiotic stewardship, and collaborating with infectious disease specialists to ensure appropriate diagnosis and treatment.
Our research had several limitations. The investigation was conducted retrospectively at a single center with a small sample size. There is a need for prospective and controlled investigations.
Conclusion
In recent years, the prevalence of E. meningoseptica infection has increased dramatically, producing fatal opportunistic infections in patients. In recent years, E. meningoseptica has been isolated more frequently in pediatric intensive care units from patients who use broad-spectrum antibiotics, are followed up with a central venous catheter, have prolonged mechanical ventilation, and have lengthy hospital stays. The high level of resistance to the majority of broad-spectrum antibiotics makes its management difficult. Emerging nosocomial pathogen E. meningoseptica is difficult to treat due to its high antimicrobial resistance, prolonged mechanical ventilation duration, and intensive care unit hospitalization in pediatric patients. A multifaceted strategy is required to prevent Elizabethkingia meningoseptica infections in critically ill pediatric patients. Proper hand hygiene and infection control measures, such as routine cleansing and disinfection of hospital surfaces and equipment, can aid in reducing the risk of transmission. Additionally, identifying and treating any underlying medical conditions or risk factors can aid in preventing infections. Future research should focus on the risk factors and treatment of E. meningoseptica infection.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Download attachments: 10.4328.ACAM.21770
Gultac Evren, Senem Akgul. Elizabethkingia meningoseptica: A New Cause of Ventilator-Associated Pneumonia in Pediatric Intensive Care Unit. Ann Clin Anal Med 2023;14(Suppl 2):S135-139
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Effect of tocilizumab treatment on intubation and mortality rates in patients with severe COVID-19: A retrospective cross-sectional study
Kubilay Issever 1, Mehmet Emir Arman 2, Deniz Cekic 3, Ahmed Cihad Genc 4, Ahmed Bilal Genc 5, Ali Muhtaroglu 6, Selcuk Yaylaci 7
1 Department of Internal Medicine, Faculty of Medicine, Giresun University, Giresun, 2 Department of General Practitioner, Sakarya University Research and Educational Hospital, Sakarya, 3 Department of Internal Medicine, Sakarya University Research and Educational Hospital, Sakarya, 4 Department of Internal Medicine, Sakarya University Research and Educational Hospital, Sakarya, 5 Department of Internal Medicine, Faculty of Medicine, Sakarya University, Sakarya, 6 Department of General Surgery, Faculty of Medicine, Giresun University, Giresun, 7 Department of Internal Medicine, Faculty of Medicine, Sakarya University, Sakarya, Turkey
DOI: 10.4328/ACAM.21833 Received: 2023-07-27 Accepted: 2023-08-28 Published Online: 2023-09-06 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S140-145
Corresponding Author: Kubilay Issever, Department of Internal Medicine, Faculty of Medicine, Giresun University, Merkez, Giresun, Turkey. E-mail: kubilayissever@gmail.com P: +90 531 381 74 75 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1376-1488
This study was approved by the Ethics Committee of Sakarya University Medical Faculty (Date: 2021-05-29, No: E-71522473-050.01.04-32203-320)
Aim: COVID-19 has impacted all health facilities worldwide since 2020. Thus, finding curative treatments is vital, especially for patients with severe disease. In this study, we aimed to evaluate the curative potential of Tocilizumab in patients with severe COVID-19.
Material and Methods: Retrospectively, we analyzed the files of 154 patients treated in the intensive care units (ICU) between October 2020 and October 2021. Tocilizumab was administered to the patients before intubation as soon as the signs of the severe disease were noticed. The groups were compared as “tocilizumab” (Group T) vs. “non-tocilizumab” (Group NT).
Results: No significant age and gender differences were found between the tocilizumab and non-tocilizumab groups. Intubation (31.2% vs. 45.5%) and mortality rates (33.8% vs. 45.5%) were lower in the tocilizumab group, but the difference was not statistically significant (p>0.05). Group T was more frequently treated with glucocorticoids, while this group contained fewer patients with diabetes mellitus and chronic kidney failure (p=0.01 and 0.004, respectively). Correlation analysis revealed a slightly and moderately positive correlation of mortality and intubation with CPAP (Continuous Positive Airway Pressure) therapy, uric acid, AST (Aspartate Aminotransferase), creatine kinase (CK), lactate dehydrogenase (LDH), troponin I, Vitamin D, and interleukin-6 (IL-6) (p=0.000, 0.001, 0.032, 0.015, 0.000, 0.000, 0.004, and 0.002, respectively).
Discussion: Our results revealed that Tocilizumab might prevent intubation and death if administered early in patients with severe COVID-19.
Keywords: Tocilizumab, COVID-19, Mortality, Intubation
Introduction
A novel Coronavirus disease caused by SARS-CoV-2 was first detected in China in December 2019 and has become a pandemic causing the fatality of millions of people so far. Thousands of studies have revealed that this disease might affect any body part, but severe disease is almost always associated with respiratory tract infection [1]. A relevant part of the infected patients might present with acute respiratory distress syndrome (ARDS) and should be treated in ICUs [1]. Since evolving data reported high mortality rates for intubated patients, delaying or avoiding intubation as much as possible with non-invasive mechanical ventilation (NIMV) methods such as high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP), especially with prone positioning, has been the management of choice for a long time for patients with severe respiratory failure [2]. Besides NIMV, treatment options that have been shown to avoid intubation would also reduce mortality rates due to this known fact. Remdesivir, dexamethasone, tocilizumab, baricitinib, and molnupiravir are in the frame of these treatments that show promising results [3]. Besides, tocilizumab is one of the most recommended drugs by the guidelines for severe COVID-19, along with dexamethasone [3,4].
Macrophage activation syndrome (MAS) is a dysfunctional, unproportional, exacerbated immune response to a pathogen or triggered by an autoimmune process. Cytokines and chemokines such as interleukin-1, interleukin-6, tumor necrosis factor-alfa, and interferon-gamma have been found to be triggered and activated significantly by SARS-CoV-2 in some patients [5]. The term “cytokine storm” can also describe this “cytokine madness.” MAS can cause acute respiratory distress (ARDS) and multiple organ failure. ARDS in severe COVID-19 can be described as hypoxic respiratory failure and is characterized by microvascular thrombosis, diffuse alveolar damage, and myeloid cell infiltrates [4]. Considering this pathophysiology underlying severe COVID-19, researchers focused on immunosuppressive agents to modify or control this hyperinflammatory state. Following the presentation of promising results from the dexamethasone study, immunomodulatory agents were the best candidates to prevent intubation and mortality in these patients [4].
As an immunomodulatory agent, Tocilizumab can reduce inflammation by inhibiting the binding of IL-6 to both membrane and soluble IL-6 receptors, thus blocking IL-6 signaling [4]. Tocilizumab can be used to treat not only rheumatoid arthritis but also giant-cell arthritis, systemic sclerosis, and juvenile idiopathic arthritis [6]. While the use of tocilizumab in patients with severe COVID-19 appears to be a logical hypothesis, clinical trials have revealed controversial results so far. Eight guidelines recommended its use in combination with dexamethasone in patients with severe disease whereas seven small trials reported no benefit in addition to a larger trial reporting a benefit only in patients requiring organ support [3]. These controversial results reveal that the literature still needs more studies to determine whether tocilizumab is effective in COVID-19 patients. Considering this fact, we aimed to analyze the effect of tocilizumab in patients with severe COVID-19 in this study.
Material and Methods
Our study was a retrospective cross-sectional study. The study included one hundred fifty-four patients treated in the Sakarya University Training and Research Hospital ICUs. This study was approved by Sakarya University Medical Faculty Ethical Committee (27/04/2020-E.4266). (Date: May 29, 2021, File number: E-71522473-050.01.04-32203-320). The authors have complied with the international guidelines, the “Regulations on Pharmaceutical Research,” enforced by The Ministry of Health of Turkey published in the 27089 numbered Official Journal dated 23 December 2008 and also with other regulations published at a later date.
Nasopharyngeal swab PCR test positivity was accepted as the gold standard for diagnosing COVID-19. Patients who were below the age of 18 and had negative PCR test results were excluded from the study.
During the first year of the pandemic, the standard treatment protocol in our institution for a patient with severe COVID-19 was favipiravir for 5 to 10 days (2x1600mg as loading dose, 2x600mg as maintenance dose) plus dexamethasone 24 mg IV for the first three days, 16 mg IV for the second three days and 8 mg IV for the third three days (or methylprednisolone ≥ 250 mg IV for the first three days, 80-250 mg IV for the second three days, and 80 mg IV for the third three days). After nine days, tapering the dexamethasone or methylprednisolone dose daily to prevent adrenal insufficiency, irrespective of the patient’s clinical status, was also part of our medical protocol. All patients included in the study were treated with this protocol during the first year of the pandemic. Standard Iv fluid resuscitation, anti biotherapy (if needed), standard oxygen support (nasal cannula, non-rebreather mask, HFNC, CPAP, intubation, respectively), prone positioning (PP) up to 16 hours if tolerated, low molecular weight heparin as an anticoagulant, proton pump inhibitors for stress ulcer prophylaxis were also part of the standard ICU treatment protocols for these patients. However, following the emerging studies suggesting the possible beneficial effects of tocilizumab in COVID-19 patients, the Ministry of Health started to provide tocilizumab only for a particular group of patients in the second year of the pandemic. Patients under 65 years of age who were in MAS were the candidates for tocilizumab treatment. Clinical findings associated with MAS were defined as ongoing resistant fever, constantly elevated or increasing levels of C-reactive protein (CRP), constantly elevated or increasing levels of ferritin (> 700 μg/L), elevated D-dimer levels, lymphopenia, thrombocytopenia, neutrophilia, and elevated liver enzymes in the guideline of the ministry of health. Patients who received or did not receive tocilizumab therapy were chosen randomly from the medical files except for the age and gender matching. We defined patients who received tocilizumab treatment at any time of their ICU stay as the “tocilizumab group” (T) and patients who received standard therapy as the “non-tocilizumab group” (NT). Demographic, laboratory, and clinical parameters were compared between these groups. Laboratory parameters obtained at the time of admission to the ICU were used for analysis. The collected data were analyzed in the biostatistical program.
Data analysis was performed using the Statistical Package for the Social Sciences (SPSS) 26.0 Statistics package program. The suitability of the patients’ numerical variables to the normal distribution was determined by looking at the skewness values. Only the values of Albumin, LDH, Fibrinogen, HB, and PLT of the patients corresponded to normal distribution rules. The reference value in the normal distribution is between ±1.5 7]. The chi-square test was used to compare the introductory characteristics of the patients, their use of various drugs, and the findings of comorbidities according to their tocilizumab drug use and discharge status. The Independent Sample T Test or Mann Whitney U test was used to compare laboratory parameters according to tocilizumab drug use and discharge status. Pearson or Spearman Correlation tests were used to examine the relationships between tocilizumab use, mortality, intubation status, and parameters. Correlation coefficient; A relationship between 0.00-0.30 was considered as low, between 0.30-0.70 as a medium level, and between 0.70-1.00 as a high-level relationship [8]. Logistic regression analysis was applied to estimate the mortality and intubation probability of the patients. The significance levels were carried out in the study considering the 0.05 and 0.01.[7]. The chi-square test was used to compare the introductory characteristics of the patients, their use of various drugs, and the findings of comorbidities according to their tocilizumab drug use and discharge status. The Independent Sample T- test or Mann-Whitney U test was used to compare laboratory parameters according to tocilizumab drug use and discharge status. Pearson’s or Spearman’ Correlation tests were used to examine the relationships between tocilizumab use, mortality, intubation status, and parameters. Correlation coefficient: a relationship between 0.00-0.30 was considered as low, between 0.30-0.70 as a medium level, and between 0.70-1.00 as a high-level relationship [8]. Logistic regression analysis was applied to estimate the mortality and intubation probability of the patients. The significance levels were carried out in the study considering the 0.05 and 0.01.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
There was no statistical age or gender difference between the groups. The median age was 55 for the non-tocilizumab group and 52 for the tocilizumab group. HFNC therapy was more frequently applied in group T (p=0.000). Although CPAP therapy was also more frequently applied in Group T (31.2% vs. 23.4%), the difference could not reach a statistically significant level. Patients in Group NT had higher intubation (45.5% vs. 31.2%) and mortality (45.5% vs. 33.8%) rates; however, these differences were not statistically significant. The average day after intubation was approximately 4.2 for Group NT and 2.2 for Group T. This difference was also insignificant Table 1 showsthat significantly more patients received dexamethasone 8 mg, methylprednisolone 80-250 mg, and methylprednisolone <80 mg in Group T (p=0.000, 0.026, and 0.02, respectively). In contrast, more patients in Group NT received plasmapheresis and convalescent plasma therapy (p=0.004 and 0.019, respectively). Significantly more patients in the NT group had DM and CRF as comorbidities (p=0.01 and 0.004, respectively). Other treatment modalities and comorbidities did not differ significantly between the groups (Table 1).
Laboratory parameters were analyzed and compared between the groups in Table 2. Patients in Group T had significantly higher levels of aspartate aminotransferase (AST), albumin, myoglobin, and Vitamin D (p=0.024, 0.000, 0.000, and 0.023, respectively), whereas lower levels of uric acid, troponin, and lymphocyte (p=0.037, 0.012, and 0.008, respectively). No other significant difference was found regarding lab parameters between the groups (Table 2).
Table 3 demonstrates the correlation of mortality and intubation rates with the factors affecting these rates. As expected, a strong positive correlation was determined between mortality and intubation rates and duration (p=0.000 for both). Slightly and moderately positive correlation was found between mortality and CPAP therapy, uric acid, AST, creatine kinase (CK), lactate dehydrogenase (LDH), troponin, Vitamin D, and interleukin-6 (IL-6) (p=0.000, 0.001, 0.032, 0.015, 0.000, 0.000, 0.004, and 0.002, respectively). Slightly and moderately positive correlation was found between intubation and CPAP therapy, uric acid, AST, CK, LDH, troponin, Vitamin D, and IL-6 (p=0.000, 0.008, 0.015, 0.025, 0.012, 0.001, 0.012, and 0.019, respectively). A slightly negative correlation was found between intubation and albumin levels (p=0.001) (Table 3).
Discussion
The results of our study revealed that Tocilizumab might be effective not only in reducing the risk of death but also in preventing intubation in patients with severe COVID-19. Although the difference between these groups seems insignificant statistically, the percentage difference is noticeable (31.2% vs. 45.5% for intubation and 33.8% vs. 45.5% for mortality). As authors, we are sure that the difference would be statistically significant if the number of patients were higher. This result is important when considering the literature’s disagreement regarding this agent’s benefit in COVID-19 patients. These kinds of studies are also critical for determining the place of immunomodulatory agents in treating autoimmune and infectious diseases, which can progress to cytokine storm and ARDS during their clinical courses. The agents that were shown to be effective against COVID-19 can also be used in future pandemics if the causative virus shows similar characteristics to SARS-CoV-2.
Stone et al. reported no benefit of Tocilizumab in their randomized-controlled trial (RCT) of 243 moderately ill COVID-19 patients [9]. Similarly, a phase 3 trial including 452 severe COVID-19 patients did not result in significantly better clinical status or lower mortality than the placebo at 28 days [10]. Another randomised-controlled phase 3 trial revealed that Sarilumab (an interleukin-6 antagonist similar to Tocilizumab) does not have an efficacy in hospitalized COVID-19 patients receiving supplemental oxygen [11]. Despite these heartbreaking results, most of the studies in the literature reported promising results for using IL-6 antagonists in COVID-19. The first results of the randomized controlled study that the RECOVERY Collaborative Group started in April 2020 suggested a beneficial effect of Tocilizumab in hospitalized COVID-19 patients with hypoxia and systemic inflammation when combined with systemic corticosteroids [12]. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group evaluated the place of IL-6 antagonists such as tocilizumab, sarilumab, and siltuximab in COVID-19 in their meta-analysis consisting of 27 trials and 10930 patients. This study showed that administration of IL-6 antagonists, compared with placebo or usual care, was associated with lower 28-day all-cause mortality [13]. Similarly, in a review that evaluated the recommendations of clinical guidelines for COVID-19, 10 of 12 guidelines recommended the use of tocilizumab in severe disease. Eight of these ten guidelines recommended its use combined with dexamethasone [3]. In a multicenter cohort study that included 3924 patients with severe COVID-19, the risk of in-hospital death was estimated to be lower with early tocilizumab treatment compared with no use of early tocilizumab 14]. [14].
Remarkably, most studies suggesting the beneficial effects of tocilizumab agree on its use in combination with dexamethasone and for patients, especially with severe disease. Table 2 reveals that more patients in group T received glucocorticoids during their treatments. While analyzing the results, it is vital to remember that group NT consisted of the patients treated in the first months of the pandemic, while group T contained patients from later phases. Thus, this difference can be explained by the late introduction of steroid treatment for severe COVID-19 and the strong recommendation of combination therapy by guidelines. Commonly usage of convalescent plasma therapy and plasmapheresis might also be explained by their experimental application during the first phases of the pandemic.
Our results reveal that tocilizumab might prevent intubation in patients with severe COVID-19. These results were in the same line with most of the reports in the literature. Arthur et al. reported a significant reduction in the need for mechanical ventilation in their review, analyzing the results of 10 RCTs [15]. Even in the phase 3 trial, which reported no beneficial effect of tocilizumab in COVID, as we mentioned above, ventilator-free days were 22 in the tocilizumab group, whereas it was 16 for the control group [10]. As a game-changer study for the treatment of COVID-19, the study of the RECOVERY group also reported a reduced intubation rate in the tocilizumab group [12]. However, in the study, Stone et al. conducted, the need for mechanical ventilation or death before intubation was similar between tocilizumab and the control group [9]. The potential reasons behind the increased incidence of HFNC therapy application in group T were the increased frequency of HFNC application in the later phases of the pandemic and the higher application rate of the tocilizumab to the patients with the severe disease before the intubation in which NIMV techniques are highly used. Considering the positive correlation between comorbidities and mortality in patients with severe COVID-19, it was unsurprising to determine a higher incidence of CRF and DM in the group NT since this group had a higher mortality rate. 0]. As a game-changer study for the treatment of COVID-19, the study of the RECOVERY group also reported a reduced intubation rate in the tocilizumab group [12]. However, in the study by Stone et al., the need for mechanical ventilation or death before intubation was similar between tocilizumab and the control group [9]. The potential reasons behind the increased incidence of HFNC therapy application in group T were the increased frequency of HFNC application in the later phases of the pandemic and the higher application rate of the tocilizumab to the patients with the severe disease before the intubation in which NIMV techniques are highly used. Considering the positive correlation between comorbidities and mortality in patients with severe COVID-19, it was unsurprising to determine a higher incidence of CRF and DM in the NT group since this group had a higher mortality rate.
We compared the laboratory data between the groups in Table 3. Albumin, vitamin D, AST, and myoglobin levels were significantly higher in the T group. In contrast, uric acid, troponin I, and lymphocyte levels were significantly higher in the NT group. In this study, we chose the control group of similar age and gender as the patient group to rule out the mortality effects of these parameters. Nevertheless, laboratory parameters that are famously known to be associated with mortality in COVID-19, such as higher uric acid and troponin I, lower albumin, and vitamin D, were more frequently seen in the NT group [12,16,17,18]. These findings were compatible with the higher mortality rate in the NT group. Exceptional laboratory parameters at this point are the lymphocyte count, AST, and myoglobin. Lower lymphocyte levels are associated with an increased risk of death in COVID-19; however, higher levels of this parameter were found in the NT group, which is a more mortal group. Likewise, myoglobin and AST levels are reported to be associated with higher mortality in severe COVID-19 in the literature, although they were detected at higher levels in the T group, where the mortality rate was lower. Surprisingly, the levels of some laboratory parameters reported as mortality biomarkers in COVID-19 so far in the literature, such as CK, CRP, IL-6, platelets, ferritin, neutrophile count, D-dimer, fibrinogen, and LDH, did not differ significantly between the groups. Especially the similarity between the groups regarding acute phase reactants such as IL-6, CRP, and ferritin showed us that the clinical severity of the patients included in the study was close to each other. This characteristic of the groups can be considered as a healthy sign of objective comparison between the groups.
Analyses evaluating the correlation levels of some significant parameters with mortality and intubation revealed a slightly and moderately positive correlation with CPAP therapy, uric acid, AST, CK, LDH, troponin, Vitamin D, and IL-6. These results were compatible with the literature since these parameters were reported to be associated with increased mortality and intubation rates. The only exceptional parameter is vitamin D since its lower levels are generally associated with higher mortality and intubation rate in COVID-19 patients [19].
Limitations
Our study has some limitations. It was a retrospective study with a small patient group. Additionally, patients receiving different therapies could not be distinguished and presented in small groups for subgroup analysis. Finally, it would be better to obtain the patients’ laboratory test results and follow-up data after the treatments and compare them as “before vs. after”. Despite these limitations, our study could contribute to the “controversial” literature regarding the beneficial effects of tocilizumab.
Tocilizumab can prevent intubation and death if administered early in patients with severe COVID-19. More randomized controlled studies with larger patient populations are needed to better clarify the effect of tocilizumab treatment on COVID-19 patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Download attachments: 10.4328.ACAM.21833
Kubilay Issever, Mehmet Emir Arman, Deniz Cekic, Ahmed Cihad Genc, Ahmed Bilal Genc, Ali Muhtaroglu, Selcuk Yaylaci. Effect of tocilizumab treatment on intubation and mortality rates in patients with severe COVID-19: A retrospective cross-sectional study. Ann Clin Anal Med 2023;14(Suppl 2):S140-145
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Two-stage revision of infected knee replacement in patients with antibiotic-loaded spacer
Kemal Kayaokay 1, Kemal Aktuğlu 2
1 Department of Orthopaedics and Traumatology, Izmir Katip Çelebi University, Atatürk Research and Training Hospital, 2 Department of Orthopaedics and Traumatology, Ege University, Izmir, Turkey
DOI: 10.4328/ACAM.21841 Received: 2023-08-02 Accepted: 2023-09-06 Published Online: 2023-09-21 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S146-149
Corresponding Author: Kemal Kayaokay, Department of Orthopaedics and Traumatology, Izmir Katip Çelebi University, Atatürk Research and Training Hospital, 35150, Karabağlar, Izmir, Turkey. E-mail: kemalkayaokay@gmail.com P: +90 532 201 16 11 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1655-0587
This study was approved by the Non-Interventional Clinical Research Ethics Committee of Izmir Katip Celebi University (Date: 2023-04-27, No: 0199)
Aim: Prosthetic infections after total knee arthroplasty (TKA) are the most important cause of early failure in TKA, despite advances in diagnosis and treatment. In our study, we aimed to evaluate the results of a two-stage total knee arthroplasty using an antibiotic-loaded spacer.
Material and Methods: Two-stage revision was performed in all patients who were diagnosed with infected TKA. A prefabricated antibiotic-loaded articulating polymethylmethacrylate spacer or a vancomycin + gentamicin-loaded spacer to fill the gap was placed following debridement and irrigation. The patients were evaluated in terms of laboratory, clinical and radiographic findings at postoperative months 1, 3, 6 and in the following months. The recorded American Knee Society (AKS) Knee Scores of the patients before surgery and at the final follow-up were included in the evaluation.
Results: The mean patient age was 71.38 (range: 56-85) years. Culture was positive in 10 (47.6%) and negative in 11 (52.4%) of the 21 patients. The mean time from the most recent surgery (primary or revision) until removal of the prosthetic implant was 30.38 months (range: 0.5-96 months) and the mean time between the first and second stages was 6.2 months (range: 3-16 months). The mean AKS knee score increased from 39.1 points (range: 31-48) prior to the first stage to 74.95 points (range: 63-86) after the second stage (p<0.001).
Discussion: The two-step revision arthroplasty technique is a reliable and effective method in the treatment of infected TKA. The use of antibiotic-loaded spacers gives satisfactory results in increasing joint range of motion(ROM).
Keywords: Antibiotic-Loaded Spacer, Periprosthetic Joint Infection, Total Knee Arthroplasty
Introduction
Primary prosthetic joint infection (PJI) is among the most severe complications after total knee arthroplasty (TKA). It remains to be the most frequently reported cause of early failure in TKA, despite advancements in the prevention, diagnosis and treatment of prosthetic joint infections encountered after TKA [1]. In spite of the widespread use of antibiotic prophylaxis in the preoperative and postoperative periods, improved operating room conditions (such as laminar flow) and preoperative examination of patients for the causes of infection, the rate of PJI after primary total joint replacement ranges between 1-3% [2]. Although rare, primary prosthetic joint infections have a significant impact on patients’ quality of life. Rapid diagnosis and identification of the causative agent are of utmost importance in achieving a successful outcome in the treatment of infected TKA. The goal of revision surgery is to eradicate the infection and create a pain-free, functional and stable joint. Majority of patients with prosthetic joint infection require treatment with a single- or two-stage revision surgery. In single-stage revision surgery, thorough irrigation, debridement and reimplantation are performed within a single session. Indications for the use of a single-stage revision in infected knees are as follows: identification of the causative organism, the absence of a polymicrobial infection and availability of sufficient soft and bone tissue. On the other hand, two-stage revision is considered the gold standard in the treatment of infected TKAs. A two-stage revision surgery requires the removal of all indwelling components, radical debridement of the medullary canal and synovial membrane and abundant irrigation. This is followed by placement of an antibiotic-loaded cement or spacer. Prolonged intravenous and oral antibiotic therapy should be administered in the postoperative period [3-5].
This study aimed to evaluate the outcomes of the two-stage revision of infected knee replacement in patients who had an antibiotic-loaded spacer.
Material and Methods
Patients who underwent revision knee replacement between January 2008 and January 2016 in the orthopedics clinic of Ege University were retrospectively evaluated. Thirty five patients had undergone revision knee replacement for various reasons within the specified time interval. Of these patients, 21 underwent a two-stage revision TKA due to infection. Demographic data of the patients and treatment outcomes were retrospectively evaluated. Demographic data including age, gender, affected side and etiology of arthritis as well as joint ROM were evaluated. Growth of the same microorganism in two or more cultures or in intraoperative cultures obtained from the synovial fluid or growth of a virulent microorganism such as S. aureus in one culture or the presence of a sinus tract that communicates with the prosthesis were considered indicators of infection. In patients who did not meet these major criteria, the presence of three of the following five minor criteria was also considered an indicator of prosthetic infection [6].
The five minor criteria are: (I) Elevated Serum Erythrocyte Sedimentation Rate (ESR) and Serum C-Reactive Protein (CRP) concentration (II) Increased White Blood Cell (WBC) count in synovial fluid or a ++ Leukocyte Esterase Strip Test (III) Increased polymorphonuclear neutrophil (PMN) percentage (%) in synovial fluid (IV) Positive histological analysis of periprosthetic tissue (V) A single positive culture.
A two-stage revision was performed in all patients who were diagnosed with infected TKA. A prefabricated antibiotic-loaded articulating polymethylmethacrylate spacer or a vancomycin + gentamicin-loaded spacer to fill the gap was placed following debridement and irrigation. The patients were evaluated in terms of laboratory, clinical and radiographic findings at postoperative months 1, 3, 6 and in the following months. The recorded American Knee Society (AKS) Knee Scores of the patients before surgery and at the final follow-up were included in the evaluation. In this scoring system, a score of less than 60 was considered a poor outcome, a score between 60-69 was considered a fair outcome, a score between 70-84 was considered a good outcome and a score between 85-100 was considered an excellent outcome [7].
Descriptive characteristics were determined. Dependent t-test was used to compare the preoperative and postoperative measurements. p<0.05 was considered statistically significant.
Informed consent was obtained from each patient. The study protocol was approved by the local ethics committee (Approval number/date 0199/27.04.2023).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The mean patient age was 71.38 (range: 56-85) years. The culture was positive in 10 (47.6%) and negative in 11 (52.4%) of the 21 patients. The identified microorganisms in the preoperative and intraoperative cultures were as follows: coagulase-negative staphylococci in 2 patients, methicillin-sensitive Staphylococcus Aureus in 7 patients and Enterococcus Faecalis in 1 patient.
The mean WBC count dropped from 12.200/µL prior to the first stage (range: 9.350-20.600 µL) to 7.150/µL (range: 4.500 -10.910 µL) prior to the second stage. The mean ESR dropped from 75.38 mm/h prior to the first stage (range: 36 -110 mm/h) to 23.57 mm/h prior to the second stage (range: 8-41 mm/h). The mean CRP level dropped from 13.34 mg/dL prior to the first stage (range: 2.94-40 mg/dL) to 0.74 mg/dL prior to the second stage (range: 0.06-3.13 mg/dL).
The mean time from the most recent surgery until removal of the prosthetic implant was 30.38 months (range: 0.5-96 months) and the mean time between the first and second stage was 6.2 months (range: 3-16 months). Nine patients underwent delayed reimplantation after 6 months. The delays were due to cellulitis in three patients, redness in four patients and superficial wound infection in two patients. Ten patients who had positive cultures after the first-stage surgery were treated with intravenous antibiotics to which the organisms that were identified in culture were sensitive. The remaining 11 patients who had negative cultures were administered intravenous or oral cephalosporins.
The mean ROM increased from 52.4° (range: 40°-70°) prior to the first stage to 90° (range: 80°-100°) after the second stage (p<0.001). The mean AKS knee score increased from 39.1 points (range: 31-48) prior to the first stage to 74.95 points (range: 63-86) after the second stage (p<0.001). The mean AKS function score increased from 14.5 points (range: 5-50) prior to the first stage to 69.76 points (range: 60-75) after the second stage (p<0.001). The mean time until partial weight bearing was 5.6 days (range: 2-6 days). According to the clinical examination and results of the blood tests at the final follow-up, 19 patients did not have any findings of infection recurrence, whereas 2 patients (9.5%) required long-term antibiotherapy and repeat debridement due to recurrent infection. Of the 21 patients, 11 (52.4%) had been diagnosed with diabetes mellitus (DM) and 3 had rheumatoid arthritis (RA). One of the two patients who had a recurrent infection and underwent debridement had DM and RA. This patient had a prolonged recurrence of infection.
Discussion
Treatment of infected TKAs is a challenging process. The surgeon treating an infected TKA aims to eradicate the infection and maximize long-term function and quality of life. The two-stage revision TKA is considered the gold standard in achieving these goals. Radical surgical treatments such as arthrodesis, resection arthroplasty and amputation are preferred in the presence of a treatment-resistant infection when the extensor mechanism is destroyed and soft tissue coverage is not sufficient. The timing of reimplantation is of utmost importance for treatment success in two-stage revision TKA [8,9]. Therefore, the proper use of antibiotics and the duration of antibiotherapy should be thoroughly planned after proper irrigation and debridement. Mahmud et al. recommended at least 6 weeks of intravenous antibiotic therapy prior to reimplantation [10]. In making the decision to perform second-stage revision surgery, it is recommended to discontinue antibiotherapy for at least two weeks and perform a knee joint aspiration for culturing and biochemical testing [11,12]. We treated our patients with intravenous antibiotherapy for 6 weeks followed by oral antibiotic therapy for 4 weeks depending on the bacterial growth in culture. We stopped administering antibiotic therapy in the following 2 weeks and performed revision TKA in the presence of 3 consecutively negative CRP tests after IV and oral antibiotherapy, improvement in clinical symptoms and sufficient quality of soft tissue. While Insall et al. recommended performing the second stage when soft tissue is in good condition and joint aspirate does not show any findings of infection, Mont et al. emphasized the importance of preoperative evaluation of sensitivity and cultures through biopsy and joint aspiration [13,14]. On the other hand, other authors have also claimed that the decline in ESR and CRP levels as well as the improvement observed in the clinical examination would suffice without the need for another aspiration, similar to the present study [15]. In terms of treatment success, the rate of infection eradication was 90.4% with the method used in this study. Although it seems like performing joint aspiration and culture prior to the second stage would lead to increased treatment success, it is known that most of the infected TKAs do not even manifest with a positive culture. We believe that the method we used is much more preferable in clinical practice.
A short time interval between the first and second stages would also complicate the eradication of infection in the revision of infected TKAs, thereby leading to an increase in the frequency of of recurrence of infection. On the other hand, a long-time interval between the first and second stages would have a negative effect on joint ROM. In contrast, some studies have also reported an increased rate of recurrent infections with a longer time between the two surgeries [9]. In addition, it is known that a longer time between the two surgeries leads to decreased bone mineral density and a higher degree of muscle atrophy, which both render rehabilitation more difficult after the second stage. More successful outcomes have been obtained in revisions performed after a minimum of 6 weeks [13]. In a study by Hoffman AA et al., they reported a mean time interval of 3 months (1-15 months) between the first and second stages [16]. In the present study, the mean time interval between the two stages was 6.76 months (3-16 months). However, the second stage was delayed in some patients due to several reasons such as the need to ensure that the infection was eradicated in patients who were administered empiric antibiotherapy despite negative cultures and to wait for skin problems to resolve in patients who had an active draining fistula.
The results of a two-stage revision performed on a large series consisting of 253 patients were reported by Mahmud et al. in 2012. It was stated that 16 patients (7%) developed reinfection within a mean follow-up of 48 months. The clinical AKS scores were found to be 60 and 129 before and after surgery, respectively. The rate of infection-free cases following two-stage revision has been reported to be 85% within 5 years and 78% within 10 years [10]. In a study by Haleem et al. conducted with 96 knees of 94 patients, it was reported that implant removal was performed due to reinfection in 9 patients during a mean follow-up of 7.2 years [12]. Freeman et al. studied 76 revision cases in 74 patients, wherein static spacers were used in 28 patients and articulating spacers in 48 patients, wherein the success rates were 92.1% and 94.7%, respectively [17]. In a study by Westrich et al., 75 knees of 72 patients were studied and infection eradication rate was reported to be 90.7%[18]. Two-stage revision procedures performed for antibiotic-resistant organisms were investigated in one study. It was reported that the eradication rate of antibiotic-resistant organisms was 91.2%. In the present study, 2 patients (9.6%) developed reinfection throughout a mean follow-up of 31 months. During follow-up after reimplantation, these two patients who presented with pain, localized heat as well as infection findings, i.e., elevated white blood cell count, ESR and CRP, underwent repeated debridement and received intravenous antibiotics. However, the symptoms did not improve and therefore we had to remove the polyethylene filler with cement and the femoral component implanted in the first stage and perform a second stage to manage the infection.
According to the literature, vancomycin, tobramycin, teicoplanin and gentamicin have been utilized as antibiotics in cement [3,4]. In our patients, we used antibiotic cement prepared with 4g of vancomycin in a cement containing 40 g of gentamicin. None of the patients exhibited toxicity. The infection was eradicated within 3 to 6 months in 13 patients, within 7 months in 4 patients, within 9 months in 1 patient, within 14 months in 1 patient and within 16 months in 1 patient. One patient exhibited a recurrent infection. An extensive debridement should be performed to eradicate the infection while performing surgery for infected TKA. However, large bone defects can be formed and collateral ligament insufficiency can be observed while removing the implant at this stage. While using a thick cement to fill the void after debridement leads to decreased instability, it also leads to a larger bone defect and increased ligament laxity. These risks would be minimized with the use of antibiotic-loaded cement spacers. On the other hand, use of spacers with proper antibiotics prepared by a surgeon can also lead to similar results. Articulating cement spacers can be preferred to prevent joint contracture and increase ROM, particularly in two-stage revision surgeries. There are studies reporting that articulating spacers provide better functional outcomes compared to static spacers, allowing for early rehabilitation and ROM exercises between the two stages.
In our patients, the clinical AKS knee scores were 39.1 and 74.9 and function scores were 14.5 and 69.8 before the treatment and at the end of follow-up, respectively. There is still no clear consensus on the superiority of articulating and static spacers over one another in the two-stage surgical treatment procedure for infected TKA [19]. Vasarhelyi et al. reported better ROM and AKS scores in 104 patients in whom they used articulating spacers compared to static spacers in a study conducted with 176 patients with PJI [20]. Voleti et al. published a systematic review comparing two types of spacers and reported that there was no significant difference between the spacers in terms of reinfection rates (7% for articulating and 12% for static spacers, p=0.2) or functional scores. They also found that the articulating spacer group had improved ROM (101 vs. 91 degrees, P = 0.002)[21]. Similarly, Pivec et al. conducted a systematic review of 48 studies and reported a higher ROM in the articulating spacer group (100 vs. 92 degrees, p=0.001) [22]. However, there was no difference in terms of reinfection rates or functional scores. The ROM of the joint in our study was significantly increased (p <0.001).
This study had some limitations. First of all, the study was retrospective. Second, it was difficult to perform definitive statistical analyses due to the small sample size of the reinfection group after two-stage reimplantation. There is a need for further multicenter and prospective studies with a larger sample size for clearer results. We do not recommend set diagnostic standards for infection eradication in patients with an infected prosthetic joint. We believe that each patient should be evaluated individually.
Conclusion
Two-stage revision arthroplasty is a reliable and effective technique in the treatment of infected TKA. This procedure enhances treatment success with soft tissue evaluation, culturing and identification of the causative pathogen.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
References
1. Parvizi J, Jacovides C, Antoci V, Ghanem E. Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme. J Bone Joint Surg Am. 2011; 93(24):2242-8.
2. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):104.
3. Davey PG, Rowley DR, Phillips GA. Teicoplanin–home therapy for prosthetic joint infections. Eur J Surg Suppl. 1992; (567):23-5.
4. Eisen DP, Denholm JS. Recommendations for rifampicin therapy of staphylococcal infection in Infectious Diseases Society of America prosthetic Joint Infection Guidelines are not supported by available literature. Clin Infect Dis. 2013; 57(1):159-60.
5. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56(1):1-25.
6. Parvizi J, Gehrke T, Chen AF. Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone Joint J. 2013;95-B(11): 1450-2.
7. Insall JN, Dorr LD, Scott RD, Scott WN. Rationale of the Knee Society clinical rating system. Clin Orthop Relat Res. 1989; (248):13-4.
8. Restrepo C, Schmitt S, Backstein D, Alexander BT, Babic M, Brause BD, et al. Antibiotic treatment and timing of reimplantation. J Arthroplasty. 2014; 29(2 Suppl):104-7.
9. Burnett RS, Kelly MA, Hanssen AD, Barrack RL. Technique and timing of two-stage exchange for infection in TKA. Clin Orthop Relat Res. 2007; (464): 164-78.
10. Mahmud T, Lyons MC, Naudie DD, Macdonald SJ, McCalden RW. Assessing the gold standard: a review of 253 two-stage revisions for infected TKA. Clin Orthop Relat Res. 2012; 470(10): 2730-6.
11. Durbhakula SM, Czajka J, Fuchs MD, Uhl RL. Antibiotic-loaded articulating cement spacer in the 2-stage exchange of infected total knee arthroplasty. J Arthroplasty. 2004; 19(6): 768-74.
12. Haleem AA, Berry DJ, Hanssen AD. Mid-term to long-term followup of two-stage reimplantation for infected total knee arthroplasty. Clin Orthop Relat Res. 2004; (428): 35-9.
13. Insall JN, Thompson FM, Brause BD. Two-stage reimplantation for the salvage of infected total knee arthroplasty. J Bone Joint Surg Am. 1983; 65(8): 1087-98.
14. Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am. 2000; 82(11): 1552-7.
15. Wyatt MC, Beswick AD, Kunutsor SK, Wilson MJ, Whitehouse MR, Blom AW. The Alpha-Defensin Immunoassay and Leukocyte Esterase Colorimetric Strip Test for the Diagnosis of Periprosthetic Infection: A Systematic Review and Meta-Analysis. J Bone Joint Surg Am. 2016; 98(12): 992-1000.
16. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005; (430): 125-31.
17. Freeman MG, Fehring TK, Odum SM, Fehring K, Griffin WL, Mason JB. Functional advantage of articulating versus static spacers in 2-stage revision for total knee arthroplasty infection. J Arthroplasty. 2007; 22(8): 1116-21.
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19. Samelis PV, Papagrigorakis E, Sameli E, Mavrogenis A, Savvidou O, Koulouvaris P. Current Concepts on the Application, Pharmacokinetics and Complications of Antibiotic-Loaded Cement Spacers in the Treatment of Prosthetic Joint Infections. Cureus. 2022; 14(1): 20968.
20. Vasarhelyi E, Sidhu SP, Somerville L, Lanting B, Naudie D, Howard J. Static vs Articulating Spacers for Two-Stage Revision Total Knee Arthroplasty: Minimum Five-Year Review. Arthroplast Today. 2022; (13): 171-5.
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22. Pivec R, Naziri Q, Issa K, Banerjee S, Mont MA. Systematic review comparing static and articulating spacers used for revision of infected total knee arthroplasty. J Arthroplasty. 2014; 29(3): 553-7.
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Kemal Kayaokay, Kemal Aktuğlu. Two-stage revision of infected knee replacement in patients with antibiotic-loaded spacer. Ann Clin Anal Med 2023;14(Suppl 2):S146-149
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Effect of clinical characteristics on terminal ileum length in right hemicolectomy for primary right colon adenocarcinoma
Yunushan Furkan Aydoğdu 1, Emre Gülçek 2, Çağrı Büyükkasap 3, Hasan Bostancı 3, Osman Yüksel 3
1 Department of General Surgery, Bandırma Research and Training Hospital, Balıkesir, 2 Department of General Surgery, Polatlı Duatepe State Hospital, Ankara, 3 Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
DOI: 10.4328/ACAM.21845 Received: 2023-08-06 Accepted: 2023-09-06 Published Online: 2023-09-13 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S150-153
Corresponding Author: Yunushan Furkan Aydoğdu, Department of General Surgery, Bandırma Training and Research Hospital Balıkesir, Turkey. E-mail: yfaydogdu92@gmail.com P: +90 537 561 66 81 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2418-2393
This study was approved by the Ethics Committee of Gazi University Faculty of Medicine (Date: 2023-01-23, No: 079)
Aim: Although the severity of diarrhea, the number of defecations, disturbances in the absorption of bile salts in right hemicolectomy theoretically depend on the resected length of the terminal ileum, there is no international guideline on how much the terminal ileum can be resected. The aim of this study was to determine the length of the ileum removed in patients undergoing right hemicolectomy for primary right colon adenocarcinoma and to evaluate whether surgical urgency, tumor localization and patient characteristics affect the length of the ileum.
Material and Methods: We evaluated 145 patients who underwent right hemicolectomy for primary colon adenocarcinoma.
Results: The median resected ileum length of the patients included in the study was 6 cm (min:2-max:73). When ileum lengths were evaluated by subgroups according to T stage (p=0.005) and N stage (p=0.005), there was a significant relationship between them. When N stages were also evaluated, there was no significant relationship between N0-N1 stages, while there was a significant difference in ileum lengths between N1-N2 (p=0.008) and N0-N2 (p=0.001) stages.
Discussion: In this descriptive study, we investigated the factors that may explain the variability of ileum length in patients who underwent right hemicolectomy for primary right colon adenocarcinoma, with the idea that the length of the ileum resected during surgery does not have a certain standard.
Keywords: Right Colon Adenocarcinoma, Terminal Ileum, Tumor Invasion, Regional Lymph Nodes, Distant Metastases
Introduction
According to current information, colorectal cancers represent 10% of all cancer cases and contribute to mortality in a large patient population with 9.4% of cancer-related deaths [1]. Metabolic and physiologic events occurring in the gastrointestinal tract after colorectal adenocarcinoma surgeries have long been evaluated and screened with many assessment scales in the postoperative period and quality of life has been evaluated [2,3,4]. However, the changes and metabolic disorders in the human gastrointestinal system caused by left colon and rectal cancers in the foreground have been repeatedly screened and evaluated in the literature [5,6,7].
The right colon and terminal ileum segments of the gastrointestinal tract are the leading segments of the gastrointestinal tract in terms of absorption of enterohepatic circulation, vitamin B12 and minerals that are important for the vital functions of the human body [8]. In addition, bile acid reabsorption, which is one of the primary functions of the distal segment of the ileum adjacent to the ileocecal valve, causes diarrhea and disruption of bowel regularity in patients after surgery [9]. Resection of the ileocecal valve after surgery for right colon adenocarcinoma also contributes to this condition. Both of these conditions reduce the quality of life of these patients, affect their social life and impair their psychosocial status [8,10].
Literature on the length of the ileum to be included in right hemicolectomy for right colon cancer is restricted [11,12].
In this study, we aimed to evaluate the length of the ileum segment resected during surgery for right colon adenocarcinoma and the factors affecting this length, which we think have not been adequately evaluated in the literature and have remained in the background.
Material and Methods
In this study, 145 patients who underwent right hemicolectomy for primary colon cancer in the last five years at a tertiary health center were evaluated. This study was planned as a retrospective, cross-sectional and single-center experience study. The aim of the study was to determine the length of the terminal ileum removed after right hemicolectomy and to evaluate whether patient characteristics, surgical method and tumor localization affect this length. Patients who underwent right hemicolectomy for benign reasons and patients who underwent right hemicolectomy due to non-colon cancer invasion and metastasis were excluded from the study (Figure 1). The resected ileum lengths of the patients were scanned and surgical approach methods of the patients were revealed. The lengths of the resected ileum segments were compared according to the TNM staging system of the American Joint Committee on Cancer (AJCC) [13].
Study approval was obtained from the Gazi University Faculty of Medicine Ethics Committee with the decision dated 23-01-2023 and numbered 079. The study protocol complies with the Declaration of Helsinki.
Statistical Analysis
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) (version 26.0, SPSS Inc, Chicago, IL, USA) program. Besides descriptive statistical methods (median, frequency, rate), the Kruskal-Wallis test was used to compare quantitative data, and the Mann-Whitney U test was used for two-group comparisons. Pearson’s chi-squared test and Fisher’s exact test were used to compare qualitative data. P<0.05 was considered statistically significant. Fisher’s exact post-hoc test was used to determine differences between groups.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
There were a total of 145 patients, 87 males (60%) and 58 females (40%), who met the inclusion criteria. The median age of the patient population was 66 years (min:29-max:91). The length of the ileum specimen included in the specimen was 6.0 (min:2-max:32.5) cm in the female group and 6.2 (min:2-max:73) cm in the male group, with no significant difference (p=0.745).
Patients were evaluated according to the localization of colon adenocarcinoma, TNM stages and tumor differentiation. According to the localization of colon adenocarcinoma, in patients with caecum localization (43.4%), the median length of ileum specimen included in the specimen was 7.0 (min:2 max:73) cm, those localized in the ascending colon (n=44 (30.3%)) were 5.0 (min:2-max:13) cm, and those located in the hepatic flexure (26.2%) were 6.0 (min:2-max:55) cm. When these groups were evaluated with the Kruskal-Wallis test, a significant difference was observed (p=0.012). When divided into T1 (n=7), T2 (n=22), T3 (n=75) and T4 (n=41) groups according to T stages, there was a significant difference between the ileum lengths included in the specimen (p=0.005) (Table 1). When we divided into N0 (n=73), N1 (n=46) and N2 (n=26) groups according to N stages, a significant difference was observed between the ileum lengths included in the specimen (p=0.005). Then, when the N stage groups were evaluated post-hoc within themselves with the Mann-Whitney U test, there was no significant difference between the ileum lengths included in the specimen in the N0 (median 6.0 (min:2-max:73) cm) and N1 (median 6.0 (min:2-max:55) cm) groups (p=0.73). There was a significant difference between N1 and N2 (median 8.5 cm) groups (p=0.008) and between N0 and N2 groups (p=0.001) (Table 2). When we divided the tumor into three groups according to tumor differentiation as good, moderate and poor differentiation, there was no significant difference between the resected terminal ileum lengths according to the degree of differentiation (p=0.029).
Patients were then classified according to surgical method and the urgency of surgery. According to the surgical method, the patients were divided into three groups: robotic (n=1), laparoscopic (n=9) and open (n=135) surgery. There was no significant difference between the length of ileum included in the specimen in patients who underwent robotic (median 16 cm), laparoscopic (median 7.0 cm) and open (median 6.0 cm) surgery (p=0.317). When classified according to surgical urgency, 35 (24.1%) patients were included in the emergency surgery group and 110 (75.9%) patients were included in the elective surgery group. The median ileum length included in the specimen in the emergency surgery group was 8.0 (min:2-max:73) cm, while the median ileum length in the elective surgery group was 6.0 (min:2-max:67) cm. There was a significant difference between both groups in terms of ileal length (p=0.007) (Table 1).
Discussion
In this descriptive study, we investigated the factors that may explain the variability of ileum length in patients who underwent right hemicolectomy for primary right colon adenocarcinoma, with the idea that the length of the ileum resected during surgery does not have a certain standard.
A review of the current literature did not reveal extensive and well-validated data on the length of the resected ileum. The literature was mostly related to B12 malabsorption due to resection of the ileocecal valve, magnesium malabsorption, bile acid malabsorption, diarrhea, which affects the long-term quality of life and has an impact on the social status of postoperative patients, and impaired defecation patterns compared to the preoperative period [8,9,10,14]. These studies evaluating malabsorption were representative of studies on Chron’s disease rather than primary right colon adenocarcinomas [15].
In the literature, we encountered a study with ideas close to our hypothesis. Ismail FQ et al., [12] evaluated all patients who underwent right hemicolectomy and found a significant relationship between the length of resected ileal specimens and BMI only. However, no significant association was found with surgical approach. In our data, we found no correlation between surgical approach and resected ileal specimen length (p=0.317). In the aforementioned study and in our study, tumor localization was found to be a factor affecting ileal specimen length. This may be explained by the fact that surgeons prefer to resect more ileum segments as the tumor localization approaches the ileum.
We think that one of the most important parameters for the surgeon to determine the resection margins in the intraoperative period and to achieve negative surgical margins in oncologic surgery is the characteristics of the tumor itself. In our hypothesized study, when we subdivided the primary adenocarcinomas of the right colon according to the TNM staging system [13] of the AJCC group, which is accepted in the literature, and evaluated the length of the ileum specimen, we found that T stage (p=0.005) and N stage (p=0.005) were significant, but M stage (p=0.349) was not significant.
However, when we evaluated according to surgical urgency, there was a significant difference between the ileum specimen lengths of patients who underwent resection for urgent reasons (median value 8.0 (min:2-max:73) cm) and patients who underwent oncologic surgery under elective conditions (median value 6.0 (min:2-max:67) cm) (p=0.007).
Conclusion
In conclusion, we found that tumor T stage, tumor N stage and type of surgical urgency are the factors that may affect the length of ileum specimens included in the specimen in primary right colon adenocarcinomas. If future studies can determine the interaction of the change in ileum specimen lengths with functional evaluations in patient follow-up, this may contribute to the current literature regarding the length of the ileum specimen to be resected.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
References
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12. Ismail FQ, Öberg S, Wozniak AB, Oggesen BT, Rosenberg J. Variation in the length of terminal ileum specimen in right hemicolectomy: a descriptive study. ANZ J Surg. 2023;93(4):951-5.
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15. Duerksen DR, Fallows G, Bernstein CN. Vitamin B12 malabsorption in patients with limited ileal resection. Nutrition. 2006;22(11-12):1210-3.
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Yunushan Furkan Aydoğdu, Emre Gülçek, Çağrı Büyükkasap, Hasan Bostancı, Osman Yüksel. Effect of clinical characteristics on terminal ileum length in right hemicolectomy for primary right colon adenocarcinoma. Ann Clin Anal Med 2023;14(Suppl 2):S150-153
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Evaluation of age-related surgery in congenital scoliosis
Dilek Arslan, Osman Fikret Sönmez
Department of Neurosurgery, Health Sciences University, Izmir Tepecik Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.21851 Received: 2023-08-09 Accepted: 2023-09-12 Published Online: 2023-09-21 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S154-159
Corresponding Author: Dilek Arslan, Department of Neurosurgery, Health Sciences University, Izmir Tepecik Training and Research Hospital, Konak, Izmir, Turkey. E-mail: dilekozenc@gmail.com P: +90 532 397 85 50 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7463-4389
This study was approved by the Ethics Committee of University of Health Sciences Izmir Tepecik Training and Research Hospital (Date: 2023-05-04, No: 2023/03-48)
Aim: In deformity surgeries performed on pediatric, adolescent and adult patients with congenital scoliosis, age-related goals, techniques and results change. In this study, we aimed to guide patient management and surgical planning and avoid possible complications in 5 pediatric (0-12 years), 5 adolescent (13-19 years) and 5 adult (>20 years) patients operated for congenital scoliosis.
Material and Methods: A retrospective review of patients operated for congenital scoliosis between 2017 and 2022 in a single center was performed. The characteristics and measurement values of 15 congenital scoliosis patients who were operated using bilateral pedicle screw system were compared in relation to age. Scoliosis Research Society 22-question questionnaire was applied.
Results: The length of hospital stay of the pediatric group was statistically higher than of the adult group (p=0.021). There was no significant difference in the SRS-22 questionnaire of the groups. According to intragroup comparisons, the final postoperative values of the pediatric and adolescent groups were statistically lower than the preoperative values (p=0.001; p=0.042). The amount of decrease in thoracic kyphosis values in the pediatric group was statistically higher than in the adult group (p=0.038).
Discussion: Congenital scoliosis is a complex spinal problem associated with many abnormal findings. When a surgeon decides to perform congenital scoliosis surgery, the more important criterion than the patient’s age is the severity of the segmentation defect present in the patient. In proportion to the damage caused by the deformity to the patient’s quality of life, it should be decided whether to perform the surgery or to delay surgery.
Keywords: Adult Congenital Scoliosis, Adolescent Congenital Scoliosis, Pediatric Congenital Scoliosis, Congenital Scoliosis, Surgical Technique
Introduction
Scoliosis is defined as a lateral curvature of the spine of at least 10° measured by the Cobb angle. It is divided into neuromuscular, congenital and idiopathic [1]. There is not much literature information about adult congenital scoliosis [2]. Congenital scoliosis was first classified in 1968 by Winter et al. based on x-ray images [3-4]. In principle, congenital scoliosis has two possible forms of malformation. Failures of formation or failures of segmentation, or a combination of both, lead to a mixed deformity. Congenital scoliosis is associated with a high frequency of anomalies inside and outside the spine [5].
Lumbar hemivertebrae progress more slowly than thoracic vertebrae [5,6]. Segmentation defects involve multiple blocks of vertebrae [3]. Scoliosis curves are complex three-dimensional deformities involving the coronal, sagittal and rotational planes. In adolescents, if the Cobb angle cannot be reduced below 25° on side bending radiographs, it is defined as structural and usually progresses by 1 degree per year as the patient matures. Non-structural curves usually do not progress as the patient matures [1].
Since congenital scoliosis varies greatly from patient to patient, the indications, patterns and complications of surgery also vary greatly, and there are no clear guidelines that could be used [7,8]. Scoliosis surgery may also be preferred for cosmetic and psychological reasons [9].
Material and Methods
Data Collection
Ethics committee approval for the study was obtained from University of Health Sciences Izmir Tepecik Training and Research Hospital (Decision no: 2023/03-48). Patients who underwent surgery for congenital scoliosis between 2017 and 2020 in a single center were retrospectively analyzed. Three groups of congenital scoliosis patients: 5 pediatric (0-12 years), 5 adolescent (13-19 years) and 5 adult (>20 years) patients were included in the study. Patients with incomplete medical records and patients with irregular follow-up were excluded. Radiologic images taken before and after the operation, physical examination findings, pathways followed in the diagnosis and treatment of the cases, demographic data, age, gender, number of comorbidities, follow-up period, deformity level, SVA% (sagittal vertical axis), PI-LL mismatch % (pelvic incidence- lumbar lordosis), PT% (pelvic tilt), sagittal and coronal radiographic data, SVA(mm) (sagittal vertical axis), TK (°) (thoracic kyphosis), LL (°), PI-LL mismatch (°), PJA (proximal junctional angle), PT(°), PI (°), SS(°)(sacral slope), Thoracic Cobb angle (°)(TCA), Lumbar Cobb angle (°)(LCA), Coronal balance (mm)(CI), sagittal balance (mm)(SI) were measured. Operative and systemic complications were evaluated. The Scoliosis Research Society 22-question questionnaire [SRS-22r] was administered to each patient postoperatively.
Operative procedure: All operations were performed by senior surgeons. The lowest transpedicular screw vertebra was selected according to the last vertebra intersected by the central sacral vertical line. The selection of the upper instrumented vertebra (UIV) was performed according to the laterally tilted radiographs [10]. Three or four pedicle screws were placed on the proximal and distal foundation. Pedicle screws were placed wherever necessary to obtain additional correction. Ponte osteotomies were performed when kyphosis correction was required. Rods were corrected by applying reduction and extension.
Measurement Method
Segment angles kyphosis/lordosis: measured from the upper endplate to the lower endplate of the hemivertebra. SVA (°): the distance of the vertical line tangent to the anterior C7 vertebra in the sagittal plane from the posterior superior edge of the sacrum.TK (°): Sagittal cobb angle measured from the superior endplate of T5 to the inferior plate of T12. LL (°): Sagittal cobb angle measured from the upper plate of T12 to the end plate of the sacrum.
PI-LL mismatch (°):PI°-LL° PJA: proximal junction angle (sagittal Cobb angle between UIV and UIV+2 level (UIV+2)),PT (°): angle between the vertical line passing through the axis of the femoral head and the line joining the femoral head to the sacral endplate midpoint PI (°): The angle between a line perpendicular to the upper endplate of S-1 and the line joining the upper endplate SS (°): The angle between the upper endplate of S1 and the horizontal line TCA (°): The angle of lateral deviation of the curve on a standing spine x-ray in the frontal plane; parallel lines are drawn on the superior surface of the uppermost vertebra forming the curve and on the posterior surface of the lowest vertebra forming the curve, the angle between the uprights lowered to these lines is measured as the Cobb angle [11]. LCA (°): TCA (°) measurement method was applied. CI (mm): Deviation of the standing C7 plumb line from the mid-sacral vertical line was considered significant if it exceeded 20 mm. SI(mm): Measured as the distance from the C7 plumb line to a plumb line. Vertical line drawn and determined from the posterosuperior corner of the sacrum. Positive (+) sagittal balance was considered when the C7 plumb line was anterior to the posterosuperior corner of the sacrum and negative (-) when the C7 plumb line was posterior to the posterosuperior corner. Deviation greater than 20 mm in the sacrum was considered decompensation. Junctional kyphosis was defined as an angle of more than 10° between the lower endplate of the uppermost instrumented vertebra and the upper endplate of the vertebra two levels higher. Coronal imbalance: The distance between the C7 plumb line and the central sacral vertical line is more than 2 cm [1]. Transfusion threshold: A hemoglobin level <8 g/dL was considered the transfusion threshold.
Statistical Method
Data were analyzed using the statistical package program IBM SPSS Statistics Standard Concurrent User V 26 (IBM Corp., Armonk, New York, USA). Descriptive statistics were expressed as number of units (n), percentage (%), mean ± standard deviation (x_ ±ss), median (M), minimum (min), maximum (max) and intercartillary distance (IQR) values. The normal distribution of the numerical variables was evaluated by the Shapiro- Wilk normality test. The hHomogeneity of variances was evaluated by Levene’s test. Fisher’s exact test was used to compare the groups with categorical variables. Comparisons of the groups with numerical variables were made by One-way analysis of variance if the data were normally distributed and by Kruskal-Wallis analysis if the data were not normally distributed. If the result of one-way analysis of variance was found to be significant, the Tukey test was used as a multiple comparison (post hoc) test. In the Kruskal-Wallis analysis, the Dunn-Bonferroni test was used as a multiple comparison test. In the comparison of preop and final postop sagittal and coronal radiographic values according to the measurement times, two-way analysis of variance in repeated measures was used if the data were normally distributed. The Bonferroni correction was applied for all pairwise comparisons in two-way repeated measures analysis of variance. For Sacral slope (°) and Lumbar Cobb angle (°) where assumptions were not met, intergroup comparisons were made by the Kruskal-Wallis analysis and intragroup comparisons were made by the Wilcoxon test. p<0.05 was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The mean follow-up period was 41.2 months (8-60 months). The mean patient age was 10.2±2.2 years in the pediatric group, 16.0±1.4 years in the adolescent group and 26.0±6.9 years in the adult group. The mean age of the adult group was statistically higher than of the pediatric and adolescent groups (p<0.001). The number of male patients was 2 (40.0%) in the pediatric group, 1 (20.0%) in the adolescent group and 3 (60.0%) in the adult group (p=0.800) (Table 1).
The reasons for surgery were mostly lower back and leg pain and curvature in the lower back in lumbar scoliosis, back pain and pressure sores at the level of kyphosis in thoracolumbar scoliosis. In one patient with advanced deformity, operation was decided due to shortness of breath and development of clubfoot. The number of patients with increased curvature was one in the pediatric group (20.0%) and 2 in the adolescent group (40.0%). The number of patients with low back pain was 2 in the adolescent and adult groups (40.0%) (p=0.145), (Table-1).
The number of patients with SVA≤5cm was 3 in all three groups (60.0%). The number of patients with PI-LL mismatch ≥20° was one (20.0%) in the pediatric group, 2 (40.0%) in the adolescent group and 3 (60.0%) in the adult group. The number of patients with PT≤20° was 2 (40.0%) in the pediatric group, 5 (100.0%) in the adolescent group and 3 (60.0%) in the adult group (p=0.765, p=0.251), (Table 1).
According to intergroup comparisons, there was no statistical difference between preoperative and postoperative SVA values of the groups (p=0.474, p=0.750). Thoracic kyphosis (°) final postop values of the pediatric and adolescent groups were statistically lower than the preop values (p=0.001; p=0.042). The decrease in the values of the adult group was not statistically significant (p=0,999), and the amount of decrease in the Thoracic kyphosis (°) values in the pediatric group was statistically higher than in the adult group according to the difference comparisons (p=0,038). According to intra-group comparisons, the final postop LL (°) values of the three groups were statistically lower than the preop values (p=0.007; p=0.009; p=0.049). According to within-group comparisons, the final postop PI-LL mismatch (°) values of the pediatric and adult groups were statistically higher than the preop values (p=0.010; p=0.010). According to within-group comparisons, final postop PJA (UIV-UIV+2) (°) values in the pediatric group were statistically lower than preop values (p=0.021). According to intra-group comparisons, the final postop PT (°) values of the pediatric group were statistically higher than the preop values (p=0,017) (Table 2).
According to intra-group comparisons, the final postop Thoracic Cobb angle (°) values of the adult group were statistically lower than the preop values (p=0,048). According to intra-group comparisons, the final postop Lumbar Cobb angle (°) values of the three groups were statistically lower than the preop values (p=0,049; p=0,038; p=0,033) (Table 3).
The mean blood loss during the operation was between 277-2000ml. Five patients received allogeneic blood transfusion. The mean operation time was 510 min in the pediatric group, 525 min in the adolescent group and 400 min in the adult group (p=0.538). The mean hospital stay was 19 days in the pediatric group, 13 days in the adolescent group and 9 days in the adult group. The length of hospital stay in the pediatric group was statistically higher than that in the adult group (p=0.021) (Table 1).
Patients were evaluated postoperatively with the Scoliosis Research Society 22-question questionnaire [SRS-22r]. There was no statistically significant difference between the groups in pain, self-image, function activity, mental health, satisfaction with treatment and total scores. Thoracolumbar rotoscoliosis was present in 2 patients in the pediatric group, 3 in the adolescent group and 2 in the adult group. 2 adolescent patients had thoracic butterfly vertebrae. One adult patient had cervicothoracolumbar scoliosis. Hemivertebrae were observed at T2, T3, T9, L1, L2, L3, L4 vertebral levels. One pediatric patient had diastomyelia at the T11-T12 level. None of the patients had a syrinx.
Postoperative revision was performed in 2 pediatric patients, 1 adult patient due to pedicular screw malposition and 1 pediatric patient due to rod fracture (Figure-1). One pediatric patient with second degree mitral regurgitation developed postoperative hemopneumothorax. An adolescent with restrictive lung disease and limited cervical extension developed pneumothorax, pulmonary atelectasis and external iliac vein thrombosis. One hepatitis B carrier adult patient developed postoperative hyperbilirubinemia. Two pediatric patients developed postoperative systemic infection. In 1 pediatric and 1 adult patient, it was observed that the screw came out of the skin of the kyphosis region (Figures –2 and 3), approximately one year after the operation and they were operated again for this reason. The complication rate was 3/5 in pediatric patients, 1/5 in adolescents and 3/5 in adults. No operation-related deficit was observed in any patient.
Discussion
Various spinal deformities are classified into three categories: formation defects, segmentation defects or mixed spinal defects [12]. Surgical treatment for congenital scoliosis is complex [13]. Currently, in situ fusion, convex growth arrest and hemivertebra excision via a combined anterior and posterior approach in one or two stages are the surgical methods used [14]. Single-stage posterior hemivertebra resection combined with bilateral transpedicular screw instrumentation has become the widely adopted procedure for the correction of congenital scoliosis. The use of pedicle screws is a powerful method that allows excellent deformity correction in the coronal and sagittal planes and is safe even in very young children [15]. Pedicle screw instrumentation can effectively transmit the correction torque to the anterior and middle columns of the spine, increasing the pressure resistance of the anterior and middle columns, helping to retard the growth of the vertebrae and preventing the crankshaft phenomenon [16,17]. Posterior unilateral transpedicular screw fixation may be a recommended alternative in children to further minimize trauma and reduce growth arrest of the concave side. In addition, short-segment fusion can be performed to preserve more growing segments and motor units. This allows the non-fused concave side of the spine to grow [18]. The use of pedicle screws has a much better correction rate than other instrumental methods [19]. Pedicle screw instrumentation has no negative effect on the growth of vertebral bodies [20,21]. In one of the pediatric patients in our series, we performed osteotomy and unilateral instrumented fusion. In the 1st year of postoperative follow-up, we found that the rod and the lowest screw were fractured and we operated again.
Surgical options for congenital scoliosis in pediatric, adolescent and neglected and treated adult patients vary depending on several factors such as the type of anomaly, degree of deformity, vertebral type and age of the patient [13, 22-24]. An increase in the Cobb angle indicates an increased load on the spine, which may result in lower back and back pain. Surgical treatment options in pediatric and adolescent patients include growth-allowing systems or fusions. Typically, early surgical intervention before the age of three is the recommended treatment for young patients with congenital scoliosis. However, no evidence has been found in long-term studies to support this. Once a patient has reached skeletal maturity, surgical options such as in situ fusion, epiphysiodesis, vertical expandable prosthesis titanium rib implant and growth-guided devices may not be appropriate [12]. Procedures involving osteotomies such as pedicle removal osteotomy, hemivertebrectomy and vertebral column resection are technically more challenging and have higher complication rates than posterior spinal fusion [13]. In the correction of deformity in congenital scoliosis we preferred to perform hemivertebrectomy in our adult patients. There was no statistically significant difference in complication rates between the groups.
In pediatric and adolescent patients, long-term deformity correction is provided with posterior column resection and posterior fixation with pedicular screws. However, when we investigate the relevance of this information for adult patients, we can see that the literature is focused on the pediatric population and there is a lack of data and information about adult congenital deformity in the diagnosis and treatment process [2].
Limitations
In this group study, the small sample size limited the clarity of the statistical analysis. Larger sample sizes are needed.
Conclusions
Congenital scoliosis is a complex spinal problem associated with many abnormal findings. When a surgeon decides to perform surgery for congenital scoliosis, more important criterion than the patient’s age is the severity of the segmentation defect present in the patient. Both for neglected adult patients and the adult population of treated pediatric patients, it is necessary to determine the decision and method of surgical treatment by defining the characteristics and complaints of adult congenital spinal deformity patients seeking medical attention.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Dilek Arslan, Osman Fikret Sönmez. Evaluation of age-related surgery in congenital scoliosis. Ann Clin Anal Med 2023;14(Suppl 2):S154-159
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Demographics and inflammatory features correlate in lumbar disc hernia
Mahmut Özden
Department of Neurosurgery, Memorial Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21858 Received: 2023-08-11 Accepted: 2023-09-12 Published Online: 2023-09-18 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S160-164
Corresponding Author: Mahmut Özden, Department of Neurosurgery, Memorial Hospital, Bahcelievler, 34180, Istanbul, Turkey. E-mail: drmahmut2023@gmail.com P: +90 532 227 32 07 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2441-0015
This study was approved by the Ethics Committee of Memorial Bahcelievler Hospital (Date: 2023-01-05, No: 74)
Aim: In patients with lumbar disc hernia, the demographic and inflammatory factors that are mutually associated with each other and radicular pain are not entirely clear. This study aimed to determine these correlations.
Material and Methods: This retrospective investigation evaluated 124 lumbar disc hernia patients selected according to detailed inclusion and exclusion criteria to minimize bias factors. The study determined the patient’s demographic and clinical features, comorbid diseases, pain intensity, disc hernia side and levels, extent of paresis, and inflammatory indices (neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio). Pain intensity was assessed with Visual Analogue Scale (VAS) scores. Inflammation indices are calculated from blood counts. NCSS (Number Cruncher Statistical System, 2020, USA) software was utilized for statistical analysis.
Results: Patient’s age, extent of paresis, and disc hernia side correlated with pain intensities. Patients with disc hernias at the L1-L2 and L5-S1 levels had shorter preoperative pain duration than the cohort’s median pain duration, while the reverse was true for L2-L3 and L4-L5 level disc hernias. Twelve patients (9.7%) had comorbid diabetes, demonstrating a lower reduction of immediate postoperative pain. There was a slight negative correlation between the neutrophil-to-lymphocyte ratio and the preoperative pain duration.
Discussion: This current study provides additional insights regarding demographics, anatomy, and inflammatory components of disc hernia.
Keywords: Lumbar Disc Hernia, Microdiscectomy, Demographics, Inflammation
Introduction
Lumbosacral disc hernia is the most common cause of lower back and leg pain. Lumbosacral radiculopathy is an impairment of nerve roots causing any blend of motor paresis, sensory disturbance, and pain depending on the compression degree on nerve roots [1]. The most common causes of lumbar radiculopathy are disc hernia and spondylosis. Less-defined aspects of disc hernia exist, including inflammation, comorbid diseases, and their association with pain. Also, determining the mutual interactions of these factors with hernia anatomy and the extent of paresis would provide novel insights into the disc hernia. These factors are overlooked in the daily practice of surgeons performing spine surgery. However, despite successful surgery, a recurrence of patient’s pain complaints in the absence or presence of newly protruded discs is encountered in several cases. Hence, in this retrospective study, we investigated these parameters and their associations in a patient cohort (n=124) with single-level lumbar disc hernia treated with microdiscectomy.
Material and Methods
Study Design and Treatment
This clinical study complied with the Helsinki Declaration’s rules and the latest amendments. All participating patients gave consent forms after obtaining information about the study. The local ethics committee permitted the study (Decision Number: 74, 2023-01-05). The study involved 124 participants, 68 men and 56 women, operated at the same institution, Memorial Bahçelievler Hospital (Istanbul, Turkey). Patients were between 19 and 78 years old and had radiological features of single-level lumbar disc hernias compatible with lumbar radicular pain. In all patients, radicular pain or neurogenic claudication accompanied spinal stenosis on imaging. The main criteria to define the surgical timing were either the patient’s declaration that the pain is unbearable or the extent of motor paresis, which may cause irreversible neurological damage if left untreated. The exclusion criteria were prior fractures in the hernia region, primary and metastatic tumors, degenerative vertebral disease, and spinal malformations. The patients with previous lumbar disc operations or other pain-related neural, osteological, and muscular diseases were also excluded. The diabetic patients in the study cohort were confirmed not to suffer from diabetic neuropathy by a consultant neurologist. All patients underwent single- level simple lumbar microdiscectomy with partial hemilaminectomy + flavectomy and foraminotomy under the surgical microscope.
Data Collection
The assessed information included demographic data (gender, age, comorbid diseases), herniation level and sides, intensity and duration of preoperative pain, postoperative pain alleviation, paresis, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Visual Analogue Scale (VAS) was used to evaluate pain intensity at preoperative, immediate postoperative, and in the 3rd and 6th months of the postoperative period. Clinical examinations determined the extent of paresis semi-quantitatively using a scale between 0 to 5, reflecting motor deficit and loss of muscle strength from absent to complete. The current study analyzed mutual associations of all the assessed parameters and compared inflammatory and demographic features stratified according to the median duration of preoperative pain, which was 14.5 days in the cohort. Lastly, the study revealed NLR and PLR associations with demographic features, extent of paresis, and pain intensity.
Statistics
NCSS (Number Cruncher Statistical System, 2007, Utah, USA) was utilized for statistics. Student’s –T-test and the Mann-Whitney U test were used to compare quantitative variables with normal and non-normal distribution, respectively. Fisher’s Exact and Fisher-Freeman-Halton tests were used for chi-square analysis. The Kruskal-Wallis test was utilized to determine the significance of the difference between the means of three or more groups in non-normally distributed groups. Lastly, Spearman’s correlation analysis was performed to evaluate the relationships between quantitative variables. Statistical significance was accepted as p<0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Demographic, Anatomical and Pain Features
The total number of participants was 124 (68 males, 56 females). The median age of patients was 45 (19-78). While the preoperative pain of 63 patients (50.8%) lasted for 14 days or less, it lasted for 15 days or more in 61 patients (49.2%). The median and mean pain durations were 14.5 (1-365) and 46,62±12,71 days, respectively. Fifty-two patients (41.9%) had right-sided, and 72 patients (58.1%) had left-sided disc hernia. The number and percentages of patients with diabetes mellitus, coronary disease, thyroid diseases, and other different pathologies were 12 (9.7%), 5 (4.0%), 4 (3.2%), and 13 (10.5%), respectively. Two (1.6%), 3 (2.4%), 9 (7.3%), 67 (54.0%), and 43 (34.7%) patients had disc hernias at the levels L1-L2, L2-L3, L3-L4, L4-L5, and L5-S1, respectively. All patients had pain and paresis at the ipsilateral side of the disc hernia. Thirty-nine patients (31.5%) had no paresis, while the remaining 85 (68.5%) had paresis at different degrees. Forty-one (33.1%), 27 (21.8%), 10 (8.1%), and 7 (5.6%) patients had an extent of paresis (motor deficit) defined as 1, 2, 3, 4, respectively. There were no patients with complete paresis. The mean preoperative VAS score of the patients was 9.10±0.69. These values reduced to 1.53±1.07, 1.35±1.12, and 1.24±1.16 at the immediate postoperative, 3rd and 6th postoperative months, respectively. All these pain reductions were statistically significant (p<0.0001) at all time points. Preoperative pain in patients without paresis was significantly higher than in those with 1 (p=0.036). Postoperative 6th month VAS pain values in those without paresis were significantly higher than in those with 3 (p=0.017). Patients younger than the median age of the patient cohort tended to have higher preoperative pain than patients older than the median age (p=0.051). Patients with left-sided disc hernias had higher preoperative pain intensity (p=0.028).
Patient’s Features According to Preoperative Pain
Table 1 summarizes the characteristics of disc hernia patients stratified according to the preoperative pain duration. The percentages of patients both without paresis (39.7%) and level 4 paresis (9.5%) were significantly higher in patients with shorter duration (≤14 days) of pain. NLR values differed among different pain durations; those with shorter preoperative pain duration had higher NLR levels (p=0.034). A lack of significant difference was noted for PLR when stratified according to preoperative pain duration (p=0.281).
NLR and PLR Correlations With Clinical Features
NLR values of the cases ranged from 0.9 to 16 with a median of 3.15±1.79. The PLR values of the cases ranged from 15.1 to 294.9 with a median of 115.7. Table 2 demonstrates the associations of NLR and PLR values with pain intensity. NLR and PLR values did not correlate with preoperative and postoperative pain except for a tendency of negative correlation between NLR and immediate postoperative pain (r=-0.183, p=0.051). A slight statistical correlation also existed between the pain duration and NLR values (r=-0.191, p=0.042; not shown in Table). Table 3 demonstrates comparisons of NLR and PLR values stratified according to demographics, hernia anatomy, and the extent of paresis.
Effects of Diabetes
Diabetes was present in 9.7% of the study cohort. Preoperative VAS scores did not differ between patients with or without diabetes (p>0.05), but the immediate postoperative pain scores were higher in diabetic patients (p=0.002). The change in VAS scores in the immediate postoperative period also highly differed according to the presence of diabetes (p=0.001).
Discussion
Demographics, paresis and disc hernia level
The lower preoperative pain in older patients is likely attributable to the aging-associated chronic disc degeneration and subsequent increase in pain thresholds. Lower preoperative pain observed in patients with paresis may be associated with the denervation, where intense damage on nerve root fibers transmitting pain signals may alleviate pain. Postoperative 6th month pain in patients without paresis was higher than in those with level 3 paresis. Pain recurrence at a relatively later period may be associated more with inflammation, as reduced long-term pain control after disc hernia surgery is associated with lower circulating cortisol and higher inflammatory IL-6 [2]. The extent of paresis statistically differed according to the preoperative pain. Peculiarly, the percentage of patients without paresis (39.7%) and with level 4 paresis (9.5%) was higher among patients with shorter preoperative pain duration. This feature may be associated with diverging patient types requiring immediate surgery: patients with no motor deficit but not tolerating pain and patients who may partially cope with pain but present with significant motor deficits. L1-2 and L5-S1 level disc hernia cases accumulated more in the group with a shorter duration of preoperative pain, while the reverse was true for L2-3 and L4-5 disc hernia cases. This finding may be incidental due to the low number of patients or the mid-lumbar region hernias causing more intense pain and earlier surgeries. The patients with right-sided hernia had higher preoperative pain, but postoperative pain did not correlate with the lesion side. This observation is consistent with findings suggesting that right-sided disc hernias were usually more extensive in patients with radicular pain [3].
Diabetes in disc hernia patients
In this cohort, a notable proportion of cases had diabetes mellitus, which showed a reduced decline in the VAS scores during the immediate postoperative period. The association of diabetes with disc hernia is explicable with inflammatory cytokines, subchondral vertebral endplate microangiopathy, senescence, apoptosis, autophagia of intradiscal chondrocytes, and advanced glycation end products (AGEs) [4]. In disc hernia surgery, higher pain positively correlates with circulating IL-6, an inflammatory cytokine related to diabetic hyperalgesia [5]. Thus, diabetes-induced inflammation may have contributed to disc disease and lesser pain alleviation.
Blood inflammatory indices
The extruded nucleus pulposus attracts leukocytes and induces neural root inflammation [1]. In rats, depletion of leukocytes with nitrogen mustard prevented nucleus pulposus-induced hyperalgesia [6]. The neutrophil-to-Lymphocyte Ratio (NLR) is an inflammatory marker obtainable from blood counts. In 20 patients receiving lumbar disc hernia surgery, a positive correlation existed between the NLR values and VAS scores measured at the preoperative and postoperative periods [7]. A study examined lumbar magnetic resonance imaging (MRI) features, NLR values, and usage of nicotine products in 87 lumbar disc hernia patients [8]. Mutual positive correlations existed between the level of nicotine consumption, inflammation, and the extent of disc hernia [8]. An analysis of 126 patients with neck pain revealed that MRI-demonstrated cervical hernia patients had higher NLR and CRP levels than healthy controls and those with pain without MRI pathology [9]. Another study defined inflammatory indices MI-1 and MI-2, by multiplying PLR and NLR values with CRP values, respectively, and found that MI-1 and MI-2 correlated positively with lumbar pain [10]. This current study’s results differ from those of previous studies since NLR values were higher in patients with shorter preoperative pain duration. This feature may be associated with a higher inflammatory state in these patients. NLR values and immediate postoperative pain scores had a slight negative correlation, likely due to higher surgical benefits for patients with increased inflammation who achieved pain relief after the excision of the inflammatory disc material.
The current study has limitations as it is retrospective, and the VAS method is subjective. The data regarding the pain duration by disc level are limited since the patient’s numbers were low except for L4/5 and L5/S1 hernias. The association of diabetes with disc disease needs to be assessed in larger cohorts as the data pertains to a small number of patients. Nonetheless, the current study also has strengths. Detailed inclusion and exclusion criteria allowed reliable analyses in a homogenous cohort. All the patients were treated in the same institution, eliminating heterogeneities regarding surgery decisions and timing criteria, VAS assessments, and physical examination.
Conclusion
The pain and paresis in disc hernia occur due to a blend of anatomical and inflammatory factors, which may differentially contribute to disease among different age groups. More extensive studies with prolonged assessments of blood indices are necessary to prove the proposals of this study. Also, the role of diabetes in hernia pathogenesis needs further investigation. A better understanding of the contribution degree of anatomical characteristics and inflammation in disc hernia will help to achieve better patient management.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
References
1. Dower A, Davies MA, Ghahreman A. Pathologic Basis of Lumbar Radicular Pain. World Neurosurg. 2019; 128: 114-121.
2. Geiss A, Rohleder N, Kirschbaum C, Steinbach K, Bauer HW, Anton F. Predicting the failure of disc surgery by a hypofunctional HPA axis: evidence from a prospective study on patients undergoing disc surgery. Pain. 2005; 114(1-2): 104-17.
3. Carragee EJ, Kim DH. A prospective analysis of magnetic resonance imaging findings in patients with sciatica and lumbar disc herniation. Correlation of outcomes with disc fragment and canal morphology. Spine (Phila Pa 1976). 1997; 22(14): 1650-60.
4. Alpantaki K, Kampouroglou A, Koutserimpas C, Effraimidis G, Hadjipavlou A. Diabetes mellitus as a risk factor for intervertebral disc degeneration: a critical review. Eur Spine J. 2019; 28(9): 2129-44.
5. Haddadi K, Abediankenari S, Alipour A, Ghazvini HRG, Jafarpour H, Asadian L, et al. Association between Serum Levels of Interleukin-6 on Pain and Disability in Lumbar Disc Herniation Surgery. Asian J Neurosurg. 2020; 15(3):494-8.
6. Kawakami M, Tamaki T, Matsumoto T, Kuribayashi K, Takenaka T, Shinozaki M. Role of leukocytes in radicular pain secondary to herniated nucleus pulposus. Clin Orthop Relat Res. 2000; (376):268-77.
7. Bozkurt H, Arac D, Cigdem B. Effect of Preoperative Uric Acid Level and Neutrophil / Lymphocyte Ratio on Preoperative and Postoperative Visual Analogue Pain Scores in Patients with Lumbar Disc Herniation: A Cross-Sectional Study. Turk Neurosurg. 2019; 29(5): 705-9.
8. Doğan A, Doğan K, Taşolar S. Magnetic resonance imaging evaluation of the effects of cigarette and maras powder (smokeless tobacco) on lumbar disc degeneration. Clin Neurol Neurosurg. 2019; 186:105500.
9. Ethemoğlu KB, Erkoç YS. Is There Any Relationship Between Cervical Disc Herniation and Blood Inflammatory Response? Cureus. 2020; 12(8):e10161.
10. Firidin MN, Akyüz ME. Preoperative and postoperative diagnostic efficiency of multi-inflammatory index on pain scoring of degenerated intervertebral disc. Adv Clin Exp Med. 2022; 31(9): 947-52.
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Mahmut Özden. Demographics and inflammatory features correlate in lumbar disc hernia. Ann Clin Anal Med 2023;14(Suppl 2):S160-164
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Comparison of suicide attempt cases admitted to emergency services during COVID-19 and before
Mehmet Göktuğ Efgan, Osman Sezer Çınaroğlu, Umut Payza, Efe Kanter, Serkan Bilgin
Department of Emergency Medicine, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.21867 Received: 2023-08-13 Accepted: 2023-09-16 Published Online: 2023-09-21 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S165-170
Corresponding Author: Mehmet Göktuğ Efgan, Department of Emergency Medicine, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey. E-mail: goktugefgan@gmail.com P: +90 232 243 43 43 F: +90 232 243 15 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0794-1239
This study was approved by the Non-Invasive Clinical Research Ethics Committee of Izmir Katip Çelebi University (Date: 2022-06-16, No: 0309)
Aim: COVID-19 infection did not remain isolated in China, where it originated, but spread all over the world and caused a pandemic. It is known that people’s mental health may deteriorate in situations such as pandemics that create a global impact. Deterioration in people’s mental health can affect the number and general characteristics of suicide attempt cases admitted to the emergency department. The aim of this study was to compare the number of suicide attempts in the emergency department in two periods before and during COVID-19.
Material and Methods: The study was planned as a retrospective, observational study. Suicide attempt cases admitted to our emergency department 2 years before and 2 years during COVID-19 infection were analyzed. Patients were divided into two groups.
Results: A total of 900 patients were included in the study. The mean age was 41.44±14.97 years. The number of admissions before COVID-19 infection was higher. Statistically significant differences were found between both groups in marital status, previous diagnosis of psychiatric illness, educational status and age.
Discussion: The number of patients admitted to our emergency department with suicide attempts decreased in the 2-year period following the pandemic. Statistically significant changes were found in patient characteristics. Especially patients who were single, unemployed and had a history of depressive mood disorder presented to the emergency department with suicide attempts more frequently during COVID-19. We argue that preventive and preventive health services should be expanded in epidemic situations such as pandemics.
Keywords: COVID-19, Suicide, Emergency Department
Introduction
Suicide, which refers to ending one’s life by one’s own will and whose Latin meaning is “killing oneself” (suicide), is considered a fatal act [1]. According to the World Health Organization, the number of deaths due to suicide is more than 700,000 every year [available at: Organization WH. Preventing suicide: a global imperative. Luxemburg: World Health Organization. 2014. s. 07-08]. Suicidal behavior can be observed in individuals with severe mental disorders as well as in normal individuals reacting to challenging life conditions [2].
Durkheim argued in 1897 that suicide should be considered a purely social phenomenon [3]. Positive or negative changes in the social structure lead to an increase in suicide rates and a decrease in social peace and welfare. The fact that suicide rates and forms vary from one society to another, and even that the methods and numbers of suicides differ in different segments of the same society, indicates that social phenomena affect suicides [available at: Odağ C: Suicide. Izmir: Izmir Psychiatry Association Publications. 1995,4]. Problems related to marriage, unemployment, low socioeconomic level, living alone, migration history and stressful social events can be listed as determinants of suicide rates [5,6].
In December 2019, the COVID-19 outbreak in China caused global concern. All health systems around the world have been helpless in combating the pandemic [7]. Unpredictable outcomes, uncertainty, and information pollution about COVID-19, especially on social media, can affect people’s mental state and health. Restrictive practices related to the pandemic such as social isolation and quarantine may cause sadness, anxiety, fear, panic, irritability, anger, distress, frustration, guilt, helplessness and loneliness. Such symptoms, which many individuals may experience during or after a crisis, can lead to serious mental problems and suicidal behavior [8,9,10].
Previous studies have reported an increase in the prevalence of depression, anxiety and sleep disorders and the number of suicide attempts in COVID-19 patients [11,12,13]. In our study, we aimed to compare the number, demographic characteristics and characteristics of pre-COVID-19 and COVID-19-era suicide attempt cases admitted to our emergency department.
Material and Methods
Study Design
This study was designed as a retrospective observational study. After the pandemic was declared, strict health measures were taken in our country as in the whole world. These measures were actually eased approximately 2 years after the onset of the pandemic. For this reason, all patients admitted to the emergency department with suicide attempts or suspicion between March 2018 and March 2022, covering 2 years before and 2 years after the period of March 2020, when COVID-19 infection started, were included in the study. Before starting the study, ethics committee approval was obtained from Izmir Katip Çelebi University Ethics Committee for Non-Invasive Clinical Research dated 16.06.2022 and decision number 0309.
Patients and Setting
All patients aged 18 years and older who presented to the emergency department with a suicide attempt or suspicion between the specified dates were included in the study. The records of patients with suicide attempts or suspicion were verified from the hospital data system and psychiatry consultations. Patients with incomplete data and patients referred to an external center were excluded from the study.
Data Collection
The data of the patients who met the study criteria were collected through the hospital data registry system. Age, gender, marital status, occupation, known diagnosis of psychiatric illness, number of suicide attempts, method of suicide attempt, educational status, family history and outcome information were recorded. Patients were divided into two groups: before and during the pandemic. The data obtained were compared between the two groups.
Statistical Analysis
Data were analyzed using the statistical package program IBM SPSS Statistics Standard Concurrent User V 26 (IBM Corp., Armonk, New York, USA). Descriptive statistics were given as number of units (n), percentage (%), mean ± standard deviation, median, minimum and maximum values. Normal distribution of numerical variables was evaluated by the Shapiro-Wilk normality test. Numerical variables according to the time of diagnosis were compared with independent samples t-test if the data were normally distributed and with the Mann-Whitney U test if the data were not normally distributed. The relationship between categorical variables was evaluated by Pearson’s chi-square and Fisher’s exact test. p<0.05 was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 900 patients were included in the study and 426 (47.3) of them were females. The mean age was 41.44±14.97 years. When all patients were divided into two groups before and during the pandemic and compared, there was a statistically significant difference between the categories of marital status, occupation, psychiatric diagnosis, method, educational status, family history and outcome variables (p<0.05).
In the marital status variable, single patients accounted for 55% (305 people) and married patients accounted for 45% (45) before the pandemic. During the pandemic, single patients accounted for 64.3% (222) and married patients accounted for 35.7% (123). Comparison of Suicide Cases Before and During the Pandemic with Categorical Variables is presented in Table 1 and Table 2.
There is a statistically significant difference between the variables of age and number of attempts and suicide cases before and during the pandemic (p<0.05). Regarding the age variable, the mean age of the patients before the pandemic is higher. In the number of interventions variable, the average number of attempts in patients before the pandemic is higher. The Comparison of Suicide Cases Before and During the Pandemic with the Variables of Age and Number of Attempts is presented in Table 3.
Discussion
It is known that pandemics, which cause global effects as a result of epidemic diseases such as the COVID-19 pandemic, have effects on mental health. WHO has predicted an increase in the number of mental health problems due to the pandemic. They brought this situation to the agenda through various messages and publications aimed at mental health awareness and prevention (available at: https://www.who.int/publications-detail-redirect/9789240003927). Suicide attempts are one of the frequent presentations of mental health problems to the emergency room. In this study, we aimed to investigate the effects of mental disorders that occur during the pandemic on suicide attempts in our society. We compared changes in the number of suicide cases and other characteristics of patients who presented with a suicide attempt during the pre-pandemic and 2-year period when the pandemic measures were lifted. Our results show that the number of patients admitted to our hospital with suicide for 2 years during the pandemic has decreased. Some of the studies investigating drug use and deaths related to COVID-19 disease focused on patients using antidepressant drugs. In the study conducted by Bora et al., it was determined that the use of antidepressants reduces mortality [14]. This situation has been associated with the fact that the pituitary hormone balance is affected by pandemic situations such as COVID-19 and the stress hormone levels are high. The difference in the number of suicide attempts admitted to the emergency department before and during COVID-19 may be due to the drug effect. However, we found that there was a statistically significant increase in the rates of patients who were single, unemployed, diagnosed with known depressive disorder and had not completed their basic education, and presented to the emergency service with suicide attempts concurrently with the pandemic (p=0.005, p=0.002, p=0.001, p= 0.001).
When the patients were examined according to their gender, there was no statistically significant difference between the patients who applied to the emergency department with a suicide attempt before and during the COVID-19 outbreak. It was found that the male gender was more common in both periods. In the study conducted by Kang et al. in which suicide cases admitted to the emergency department after the COVID-19 pandemic were examined, no statistically significant difference was found in gender distribution before and during the pandemic [15]. The results are similar to our study, but the gender distribution was predominantly female in both periods. This can be explained by the fact that the studies were conducted in different societies. However, it should be noted that the effect of epidemic situations such as pandemics on patients who applied to the emergency department with a suicide attempt is independent of gender.
Again, in the study by Kang et al., the rate of admission to the emergency department with suicide is higher among those who were single in both periods [15]. In the study by Kang et al., no statistical significance was reported between the two periods in terms of single or other marital status. In our study, it was found that single patients increased statistically during the pandemic, while married patients decreased statistically. Our result may be due to the decrease in social interaction of single patients with the restrictions on staying at home, and the decrease in social communication, which is an important condition in the prevention of mental disorders.
The mean age of patients who attempted suicide during the pandemic was found to be statistically significantly lower. In the study conducted by Shrestra et al., no statistical significance was found between the ages of patients who presented to the emergency department with a suicide attempt in the pre- and post-COVID-19 periods [16]. Their study reported that the average age was 32 years. In our study, while the mean age was 39 years before COVID-19, it was found to be 33 years during COVID-19, and the difference between them is statistically significant.
While the number of suicide attempts with medication and incision decreased statistically significantly, the number of attempts with jumping, hanging and firearms increased statistically. In the study by Kang et al., it was determined that the number of suicide attempts by taking drugs increased statistically significantly after the pandemic. This may be due to social differences and existing comorbid conditions of the patients and the different access to drugs.
While the rates of discharge from the emergency department and mortality rates with the pandemic did not differ statistically significantly, it was found that the rates of hospitalization and referral increased statistically significantly. They reported that mortality rates increased, hospitalization rates increased, and referrals out of hospital decreased during the COVID-19 period. They explained this by the effect of emptying beds as a result of increased mortality. However, in our study, the rates of hospitalization and referral increased, while the rates of mortality and discharge from the emergency room did not change before and during COVID. The decrease in the number of patients in the rooms due to the measures may have been the main reason for out-of-hospital referrals.
Limitations
The study has some limitations. The first limitation is that it was retrospectively reviewed and the accuracy of the information written on the data recording system and in the consultation note was taken as basis. The second limitation is that the study was conducted in a single center. Although it was conducted in a large hospital, the fact that it reflects the population of a single region constitutes a limitation. Since we have a relatively young patient population, it may not be correct to generalize the study results to all age groups. There is a possibility that death after hospitalization and intensive care unit hospitalization may be due to reasons other than suicide and this may also be considered as a limitation.
Conclusion
The results of our study show that although the number of patients admitted with suicide attempts decreased in the 2-year period with the pandemic, the general characteristics of the patients changed. Particular attention should be paid to emergency room admissions of patients who are single, unemployed and have a history of depressive mood disorder. In epidemic situations such as pandemics, it may be useful to expand preventive and preventive health services.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
References
1. Sadock BJ, Sadock VA, editors. Kaplan & Sadock’s comprehensive textbook of psychiatry. Philadelphia: Lippincott Williams & Wilkins Publishers; 2000. p. 1978-81.
2. Sayıl I. Crisis intervention and suicide prevention. Ankara: Ankara University Press; 2008. p. 98-105.
3. Durkheim E, Ozankaya Ö. Suicide. Ankara: İmge Bookstore; 1992. p. 62-7.
4. Langford RA, Ritchie J, Ritchie J. Suicidal behavior in a bicultural society: a review of gender and cultural differences in adolescents and young persons of Aotearoa/New Zealand. Suicide Life Threat Behav. 1998;28(1):94-106.
5. Stack S. Suicide: a 15-year review of the sociological literature. Part II: modernization and social integration perspectives. Suicide Life Threat Behav. 2000;30(2):163-76.
6. Heikkinen A, Aro H, Lonnqvist J. Recent life events, social support and suicide. Acta Psychiatrica Scandinavica. 1994;377(Suppl.):65-7.
7. Zandifar A, Badrfam R. Iranian mental health during the COVID-19 epidemic. Asian J Psychiatr. 2020;51:101990.
8. Banerjee D. The COVID-19 outbreak: crucial role the psychiatrists can play. Asian J Psychiatr. 2020;50:102014.
9. Peng EY, Lee MB, Tsai ST, Yang CC, Morisky DE, Tsai LT, et al. Population-based post-crisis psychological distress: an example from the SARS outbreak in Taiwan. J Formos Med Assoc. 2010;109(7):524-32.
10. Xiang YT, Yang Y, Li W, Zhang L, Zhang Q, Cheung T, et al. Timely mental health care for he 2019 novel coronavirus outbreak is urgently needed. Lancet Psychiatry. 2020;7(3):228-9.
11. Deng J, Zhou F, Hou W, Silver Z, Wong CY, Chang O, et al. The prevalence of depression, anxiety, and sleep disturbances in COVID-19 patients: a meta-analysis. Annals of the New York Academy of Sciences. 2020;Special issue:1-22.
12. Sher L. COVID-19, anxiety, sleep disturbances and suicide. Sleep medicine. 2020;70:124-32.
13. Dragovic M, Pascu V, Hall T, Ingram J, Waters F. Emergency department mental health presentations before and during the COVID-19 outbreak in Western Australia. Australasian Psychiatry. 2020;28(6):627-31.
14. Bora ES, Arıkan C, Yurtsever G, Acar H, Delibaş D H, Topal F E. Is it possible that antidepressants protect against COVID-19? Ann Clin Anal Med. 2021;12(9):991-4.
15. Kang JH, Lee SW, Ji JG, Yu JK, Jang YD, Kim SJ, et al. Changes in the pattern of suicide attempters visiting the emergency room after COVID-19 pandemic: an observational cross sectional study. BMC Psychiatry. 2021; 21(1): 1-7.
16. Shrestha R, Siwakoti S, Singh S, Shrestha AP. Impact of the COVID-19 pandemic on suicide and self-harm among patients presenting to the emergency department of a teaching hospital in Nepal. PLoS one. 2021; 16(4): e0250706.
Download attachments: 10.4328.ACAM.21867
Mehmet Göktuğ Efgan, Osman Sezer Çınaroğlu, Umut Payza, Efe Kanter, Serkan Bilgin. Comparison of suicide attempt cases admitted to emergency services during COVID-19 and before. Ann Clin Anal Med 2023;14(Suppl 2):S165-170
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Relationship between perceived stress level with menstruation symptoms and quality of life in women
Aybüke Ersin, Sena Öndeş
Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Atlas University, Istanbul, Turkey
DOI: 10.4328/ACAM.21870 Received: 2023-08-14 Accepted: 2023-09-16 Published Online: 2023-09-21 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S171-175
Corresponding Author: Sena Öndeş, Department of Physiotherapy and Rehabilitation, Faculty of Medicine, Atlas University, 34408, Istanbul, Turkey. E-mail: sena.ondes@atlas.edu.tr P: +90 538 709 45 35 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9715-3083
This study was approved by the Non-Interventional Scientific Research Ethics Committee Istanbul Atlas University (Date: 2022-03-30, No: E-22686390-050.01.04-13570)
Aim: The aim of the study is to investigate the relationship between perceived stress level, menstrual symptoms and quality of life in women aged between 18-50 years.
Material and Methods: This study was carried out with the participation of 172 volunteers. The Perceived Stress Scale was used to evaluate the stress levels of the participants, the Menstruation Symptom Scale was used to evaluate the menstrual symptoms, and the Short Form-36 was used to evaluate the quality of life. Simple Linear Regression Analysis was used to examine the effects of demographic characteristics of the participants on menstrual symptoms, and Pearson’s or Spearman’s Correlation Analyzes were performed in accordance with the distribution of the data to determine the relationship between perceived stress level, menstrual symptoms, and quality of life.
Results: The results of our study show that smoking increases menstrual symptoms (p=0.022). Perceived stress level was found to be correlated with all sub-parameters of the Menstruation Symptom Scale at a low level (p<0.05). It was found that there was a moderate and negative correlation with all Short Form-36 sub-parameters, except for the Short Form-36 physical function sub-parameter (p<0.05).
Discussion: Our study showed that menstrual symptoms tend to increase as the perceived stress level in women increases. In addition, it has been revealed that the increase in stress level and menstrual symptoms negatively affects the quality of life of women. According to the results of our study, it is recommended that future studies examine the effects of stress reduction practices on women’s menstrual symptoms and quality of life.
Keywords: Perceived Stress Level, Menstruation Symptoms, Quality of Life
Introduction
The physiological changes that occur regularly every month with the changes in hormones during the period from menarche to menopause to provide reproductive functions in women are called the menstrual cycle [1]. Premenstrual symptoms are generally defined as irritability, moodiness, breast tenderness, and skin disorders. Besides, the most common symptoms seen during menstruation are abdominal pain, lower back pain, and cramps. These symptoms are accompanied by fatigue, weakness, nausea, and vomiting [2]. These symptoms are referred to as an umbrella term, dysmenorrhea, which consists of severe painful cramping in the lower abdomen, often concomitant with sweating, tachycardia, headache, nausea, vomiting, diarrhea, and tremulousness occurring just before or during the menses. Its prevalence is between 20% and 90% [3].
Dysmenorrhea alters body awareness and daily life activities, reduces work efficiency, work quality, and self-confidence, causes economic losses and risk of work accidents, influences negatively social relations, attendance to classes, and reaching educational goals [4]. Menstruation symptoms are one of the main reasons for absenteeism from school among young women [5]. A study conducted with adolescent women has shown that increased depression, anxiety, and stress levels and symptoms such as low back pain, early fatigue, muscle pain, and dizziness increased one week before, during, and one week after the menstrual period [2]. The level of stress was found to be related with premenstrual symptoms, menstrual pain, and menstrual cycle irregularities, which limited the functional activities of the university students [6]. The need for hours of rest and difficulty in studying have been revealed. Menstrual symptoms affect the women’s quality of life negatively [7]. Furthermore, menstrual irregularity, dysmenorrhea, and premenstrual syndrome, which impair the quality of life, and are also risk factors for future health problems, may occur as a result of the increased stress levels in university students [8,9].
According to the literature, determining the physical, psychological, and social effects of stress-related symptoms associated with menstruation may provide information to prevent a reduction in the quality of life. Therefore, the aim of our study is to investigate the effect of perceived stress levels on menstrual symptoms and to determine the effect of perceived stress levels and menstrual symptoms on the quality of life in women.
Material and Methods
Participants
This cross-sectional study was conducted in Istanbul in March 2022. The sample of the study consisted of non-menopausal women between the ages of 18-50. The needed sample size was calculated by using G*Power software. For the correlation analyses, a medium effect size of 0.3 was hypothesized, with α =0.05 and a sample size of 114, resulting in a power of .906 [10]. Post hoc power was calculated using the effect size of the study and the power was found to be 95%. The study involved 192 women. Women who have been diagnosed with pregnancy, polycystic ovary syndrome, thyroid dysfunction, psychological disorders, fibromyalgia, neurological deficit, reproductive system diseases such as endometriosis, ovarian cysts, chronic pelvic pain, and pelvic inflammatory disease were excluded. The status of the participants is shown in Figure 1.
Study Design
All the assessment forms were delivered to the participants via e-mail, social media platforms such as Facebook, Instagram, LinkedIn, and networks via Google surveys. All participants who voluntarily participated in the study were informed about the purpose and content of the study with a voluntary consent form, and their consent was obtained. Ethical approval was obtained for this study from the Non-Interventional Scientific Research Ethics Committee with the date 30-03-2022 and the decision number E-22686390-050.01.04-13570.
Outcome Measurements
Demographic information was collected via a form that includes questions about age, occupation, body mass index, number of births, chronic illness, and existing reproductive system diseases.
The Perceived Stress Scale (PSS) was used to measure the perceived stress levels of the participants. This scale was developed by Cohen, Kamarck, and Mermelstein in 1983. Turkish validity and reliability of PSS were performed by Eskin et al. The scale contains 14 questions in a 5-likert type. Scoring for each question varies from “never (0)” to “very often (5)”. Seven questions are scored in reverse. There are also short forms consisting of 10 and 4 questions. The scale has two subgroups, namely self-efficacy and stress perception. The questions measure people’s perception of stress experienced in different situations in the last month. On this scale, questions 4-5-6-7-9-10 and 13 are scored in reverse order. The lowest and highest scores a participant can obtain on this scale are 0 and 56, respectively. A high total score means a high perceived stress level. [11,12].
The Menstruation Symptom Scale (MSS) was used to determine menstrual symptoms. The Turkish validity and reliability study of the scale, which was developed by Chesney and Tasto in 1975, was performed by Güvenç et al. in 2014. The scale consists of 22 questions in a 5-likert type. Scoring ranges from “never (1)” to “always (5)”. It has 3 sub-dimensions: Negative Effects/Somatic Complaints, Menstrual Pain, and Methods of Coping with Menstrual Pain. The MSS score is calculated by taking the total average score of the questions. An increase in the mean score indicates an increase in the severity of menstrual symptoms. [3,13].
The Short Form-36 (SF-36) Quality of Life Questionnaire was used to evaluate the quality of life. This questionnaire was developed by Ware in 1999. The Turkish validity and reliability study was performed by Koçyiğit et al. in 1999. The scale consists of 36 questions and 8 subgroups. These are physical functioning, role-physical, role-emotional, vitality, mental health, social functioning, pain, and general health. The scale does not have a total score. For each subgroup, a score varying between 0 and 100 is available. The higher the score, the higher the quality of life [14,15].
Statistical Analysis
Statistical analyzes were performed using the SPSS program (Statistical Package for the Social Sciences, version 26.0. SPSS Inc, Chicago). The distribution of the data was determined by the Kolmogorov-Smirnov test. All data collected from participants were presented with mean and standard deviation values. The effects of the demographic characteristics of the participants on menstrual symptoms were determined via Simple Linear Regression Analysis. The relationship between perceived stress level, menstruation symptoms and quality of life was examined by Pearson’s or Spearman’s Correlation analysis, in accordance with the distribution of data. The significance level p was defined as 0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 192 women aged between 18-50 years were included in the study. The demographic characteristics of the participants are shown in Table 1. Thirteen individuals were excluded from the study because of polycystic ovary syndrome, 1 had neurological deficit, 1 had fibromyalgia, and 6 had thyroid dysfunction. Statistical analysis was performed for 171 individuals. 34% of the individuals were smokers. In the analysis, it was determined that only smoking among demographic characteristics affected menstrual symptoms (p=0.022) (Table 1).
A statistically significant relationship was found between the negative effects of perceived stress level on menstrual symptoms, menstrual pain, methods of coping with menstruation and general menstruation symptoms (p<0.05). The relationship between perceived stress level and menstrual symptoms and quality of life is given in Table 2.
The relationship between the Menstruation Symptoms Scale total score and SF-36 Short Form sub-parameters, role-physical, role-emotional, vitality, mental health, social functioning, bodily pain, and general health perception was statistically significant (p< 0.05) (Table 2).
There was also an association between perceived stress level and SF-36 Short Form sub-parameters, role-physical, role-emotional, vitality, mental health, social functioning, bodily pain and general health. There was no statistically significant correlation between physical functioning score, which is the SF-36 Short Form sub-parameter, with perceived stress level and menstrual symptoms (p>0.05) (Table 2).
Discussion
As a result of this study, a significant relationship was found between perceived stress level and menstrual symptoms. The increase in stress level also causes an increase in menstrual symptoms. In addition, according to our study, both the stress level and the increase in menstrual symptoms affect the quality of life negatively.
Dysmenorrhea is one of the leading menstrual symptoms and its prevalence is between 45-95% among women of reproductive age in the world. The strongest risk factors associated with dysmenorrhea are heavy menstrual bleeding and family history [16]. Bauman et al. express that women soldiers with heavy menstrual bleeding and dysmenorrhea have limitations in daily living activities and have reduced quality of life. It has been recommended that every woman should be at the most appropriate level both physiologically and psychologically to commence their career and therefore it is essential to increase awareness of menstrual symptoms and provide effective treatment [17]. On the other hand, studies show that menstrual symptoms of military women are more severe than those of university students [7,18,19]. In our study, it was revealed that perceived high stress increased the severity of menstrual symptoms. We speculated that the stress levels of military women may be higher due to the working conditions. Also, our study revealed that higher stress levels caused worse menstrual symptoms.
There is a reported positive bidirectional relationship between dysmenorrhea and bad mood. Anger at the beginning of menstruation increases the incidence of dysmenorrhea [20]. Demir et al. revealed that the anxiety and stress level, which was quite high during the COVID-19 pandemic, affected the menstrual cycle characteristics of the woman [21]. In line with these studies, we also found that menstrual symptoms get worse according to bad mood such as anxiety, depression, and anger, the results of our study match the results we found in the literature. On the other hand, there is a limited number of studies investigating the relationship between perceived stress levels and menstrual symptoms in the literature.
Menstrual symptoms adversely affect the quality of life and health status of women. Menstrual symptoms lead to some problems such as depressive mode, lethargy, and lack of concentration, which causes social and economic losses. A study investigating the relationship between menstrual symptoms and the quality of life of 6048 working women in Japan reported that increased menstrual symptoms caused a reduced quality of life. They suggested to take this situation into account when regulating work and health policies [22].
A study in which 184 adolescents were volunteered, revealed that 39% of the participants had dysmenorrhea and 8% of these adolescents had amenorrhea due to the limitation of their physical functioning, which led to a decrease in the psychosocial quality of life [23]. Another study reported that 77% of the participants had dysmenorrhea, 10% had oligomenorrhea, and 5% had heavy menstrual bleeding. Women who had menstrual symptoms presented a poor quality of life, besides, women with oligomenorrhea had a worse quality of life than other women [24]. Similarly, our study shows that a high stress level also increases the severity of menstrual symptoms and negatively affects the quality of life.
There is arguable evidence regarding the effect of smoking on dysmenorrhea. While some studies in the Turkish population reported that smoking is not associated with dysmenorrhea, some studies claim that it increases dysmenorrhea [25,26]. Although it is thought that smoking is not a variable that affects dysmenorrhea alone as a result of the studies, the results of our study showed that smoking increases menstrual symptoms.
The small number of participants is a limitation of our study. In the future, it will be important to strengthen our results by increasing the number of participants, providing general data for women in our country, and shedding light on the development of policies that will reduce the negative effects of menstrual symptoms on women’s work and social lives.
Limitations
Our study has a limitation. The use of drugs in general or during menstruation was not questioned and it was not taken into account whether these drugs changed menstruation symptoms.
Conclusion
Our study concluded that excessive perceived stress levels lead to an increment in menstrual symptoms and reduced quality of life among women. In addition, menstrual symptoms negatively affect women’s quality of life. According to the results of our study, it is recommended that future studies investigate the effects of stress reduction practices on women’s menstrual symptoms and quality of life.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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3. Güvenç G, Seven M, Akyüz A. Menstrüasyon semptom ölçeği’nin Türkçe’ye uyarlanması (Adaptation of the Menstruation Symptom Scale into Turkish). TAF Preventive Medicine Bulletin. 2014;13:367-74.
4. Yılmaz T, Nuraliyeva Z, Dinç H. Genç kadınların dismenore ile baş etme yöntemleri (Methods of young women coping with dysmenorrhea). Jaren. 2020;6(2):294-9.
5. Fernández-Martínez E, Onieva-Zafra MD, Parra-Fernández ML. Lifestyle and prevalence of dysmenorrhea among Spanish female university students. PLoS One. 2018;13(8):e0201894.
6. Yamamoto K, Okazaki A, Sakamoto Y, Funatsu M. The relationship between premenstrual symptoms, menstrual pain, irregular menstrual cycles, and psychosocial stress among Japanese college students. J Physiol Anthropol. 2009;28(3):129-36.
7. Karlsson TS, Marions LB, Edlund MG. Heavy menstrual bleeding significantly affects quality of life. Acta Obstet Gynecol Scand. 2014;93(1):52-7.
8. Sharma A, Taneja DK, Sharma P, Saha R. Problems related to menstruation and their effect on daily routine of students of a medical college in Delhi, India. Asi Public Health. 2008;20(3):234-41.
9. Kollipaka R, Arounassalame B, Lakshminarayanan S. Does psychosocial stress influence menstrual abnormalities in medical students? J Obstet Gynaecol. 2013;33(5):489-93.
10. Eskin M, Harlak H, Demirkıran F, Dereboy Ç. Algılanan stres ölçeğinin Türkçeye uyarlanması: güvenirlik ve geçerlik analizi (Turkish adaptation of the perceived stress scale: reliability and validity analysis). New/Yeni Symposium Journal. 2013;51:132-40.
11. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983; 24(4):385-96.
12. Chesney M A, Tasto D L. The development of the menstrual symptom questionnaire. Behav Res Ther. 1975;13(4): 237-44.
13. Kosinski M, Keller SD, Hatoum HT, Kong SX, Ware Jr JE. The SF-36 Health Survey as a generic outcome measure in clinical trials of patients with osteoarthritis and rheumatoid arthritis: tests of data quality, scaling assumptions and score reliability. Med Care. 1999;37( Suppl.5):S10-22.
14. Koçyiğit H, Aydemir Ö, Fişek G, Ölmez N, Memiş AK. Form-36 (KF-36)’nın Türkçe versiyonunun güvenilirliği ve geçerliliği (Reliability and validity of the Turkish version of Form-36 (SF-36)). İlaç ve Tedavi Dergisi. 1999;12(2):102-6.
15. Karout S, Soubra L, Rahme D, Karout L, Khojah HM, Itani R. Prevalence, risk factors, and management practices of primary dysmenorrhea among young females. BioMed Research International. 2021;21:1-14.
16. Bauman D, Sommer A, Hamer T, Noy D, Elami M, Yogev SS, et al. Reduced activity and quality of life in women soldiers with heavy menstrual bleeding and dysmenorrhea. J Pediatr and Adolesc Gynecol. 2022;35(1):53-8.
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18. Armour M, Parry K, Manohar N, Holmes K, Ferfolja T, Curry C, et al. The prevalence and academic impact of dysmenorrhea in 21,573 young women: a systematic review and meta-analysis. J Womens Health. 2019;28(8):1161-71.
19. Türkmen H. Üniversite öğrencilerinde dismenore görülme sıklığı ve dismenoreye etki eden faktörler (Prevalence of dysmenorrhea in university students and factors affecting dysmenorrhea). Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi. 2019;6(1):39-46.
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Aybüke Ersin, Sena Öndeş. Relationship between perceived stress level with menstruation symptoms and quality of life in women. Ann Clin Anal Med 2023;14(Suppl 2):S171-175
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The role of PAPP-A and free B-HCG, which are among the first trimester tests, in predicting pregnancy complications
Fatih Şahin 1, Fatma Yazıcı Yılmaz 2
1 Department of Obstetrics and Gynecology, Prof. Dr. Cemil Tascıoglu City Hospital, Istanbul, 2 Department of Obstetrics and Gynecology, Private Clinic, Ankara, Turkey
DOI: 10.4328/ACAM.21877 Received: 2023-08-16 Accepted: 2023-09-18 Published Online: 2023-09-23 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S176-179
Corresponding Author: Fatih Şahin, Department of Obstetrics and Gynecology, Prof. Dr. Cemil Tascıoglu City Hospital, Istanbul, Turkey. E-mail: fatih_sahin67@hotmail.com P: +90 544 743 01 67 F: +90 212 230 35 35 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1621-5896
This study was approved by the Ethics Committee of Sişli Etfal Training and Research Hospital (Date: 2014-09-02, No: 356)
Aim: In our study, we aimed to evaluate the predictive value of first-trimester maternal serum PAPP-A (Pregnancy Associated Plasma Protein-A) and B-HCG (human chorionic gonadotropin) levels in predicting pregnancy complications.
Material and Methods: The study included 489 singleton pregnancies undergoing first-trimester screening at the antenatal clinic, with perinatal records examined both before and after birth. Cases with PAPP-A <0.4 MoM and B-HCG <0.5 MoM values were investigated for associations with miscarriage, ectopic pregnancy, fetal death, preeclampsia, gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR), small for gestational age (SGA), large for gestational age (LGA), preterm labor, premature rupture of membrane (PROM), preterm premature membrane rupture (PPROM), cholestasis, and newborn requirements.
Results: In our study, patients with low PAPP-A values had a 2.6 times higher prevalence of preeclampsia, while in the B-HCG group, the prevalence was 2 times higher. Additionally, there was no significant association between the high-risk group and GDM, SGA, IUGR, and PROM.
Discussion: It has been observed that PAPP-A and HCG levels examined in the first trimester are associated with adverse pregnancy outcomes in the later weeks of pregnancy.
Keywords: PAPP-A, B-HCG, Obstetric Ultrasound
Introduction
Serum concentrations of free human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) are used as indicators of chromosomal abnormalities in the context of first-trimester screening tests [1]. Placental insufficiency could result in a low PAPP-A outcome; PAPP-A and free hCG levels are produced in the placenta shortly after implantation, and low PAPP-A levels have been associated with conditions such as preeclampsia, stillbirth, preterm birth, and fetal growth restriction in investigations. However, debate continues regarding the findings of studies using free hCG [2].
Today, the combination of nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A) and free β-human-derived chorionic gonadotropic (β-hCG) and serum levels is one of the most effective methods for screening in pregnancy [3]. However, maternal and pregnancy-related characteristics such as maternal age, ethnicity, smoking habits, weight, and conception procedures influence these tests. Multiples of the median (MoM) are calculated using each of these variables [4].
The screening method used in weeks 9-14 of pregnancy is not only employed for diagnosing chromosomal abnormalities, but also has the potential to predict adverse pregnancy outcomes based on the levels of these biomarkers [5].
In our study, we aimed to assess the predictive value of first-trimester maternal serum PAPP-A and B-HCG values in predicting pregnancy complications.
Material and Methods
The study was conducted between January 1, 2014, and July 1, 2014, at Sisli Hamidiye Etfal Training and Research Hospital Antenatal Clinics. It included a total of 489 singleton pregnancies with ages ranging from 18 to 40 years, who presented for first-trimester prenatal screening tests. Perinatal records before and after birth of these patients were examined. The study commenced after obtaining approval from the hospital’s ethics committee. Demographic information of all patients, results of the dual screening test, and serum free B-HCG and PAPP-A MoM values were scanned, recorded, and included in the study. Out of the 489 patients, those with normal first-trimester test results and those with values outside the normal range were compared in terms of the week of delivery, mode of delivery, newborn gender, birth weight, miscarriage, ectopic pregnancy, 1st minute APGAR, 5th minute APGAR, neonatal intensive care requirement, neonatal death, cholestasis, preeclampsia, gestational diabetes, placenta previa, placental abruption, fetal death, intrauterine fetal growth restriction, small for gestational age (SGA), large for gestational age (LGA), preterm labor, and preterm premature rupture of membrane. An analysis was undertaken to ascertain whether notable disparities existed in pregnancy complications between PAPP-A levels falling below or above the threshold of 0.4 MoM, as well as for free B-HCG levels below or above the threshold of 0.5 MoM. Maternal serum PAPP-A and B-HCG were measured using the IMMULITE 2000 system analyzers. The data were statistically evaluated using the SPSS 16.00 program. This study was approved by the Istanbul Sisli Etfal Hospital Clinical Research Ethics Committee on 02.09.2014 with approval No.356. In addition, written permission and informed consent were obtained from the pregnant women. The study was conducted in accordance with the Principles of the Declaration of Helsinki
Statistical Analysis
The data obtained for our study were analyzed using the IBM SPSS software (version 20.0) within a computational environment. The socio-demographic features of the research group were presented through cross-tabulations and descriptive statistical presentations, involving percentages and numerical representations. Mean values and standard deviations were provided for continuous variables. The conformity of data to a normal distribution was assessed using the Kolmogorov-Smirnov test. The chi-square analysis was employed to contrast categorical variables. A t-test was executed to assess normally distributed data between the two cohorts, while for non-normally distributed data, the Mann-Whitney U test was implemented; in instances with more than two groups, the Kruskal-Wallis test was utilized. To explore interconnected variables, correlation analysis was conducted. A logistic regression analysis was employed to estimate the need for Neonatal Intensive Care Unit (NICU) based on pertinent factors. Prediction of NICU necessity associated with PAPP-A value was accomplished using ROC analysis. The threshold for statistical significance was established at a p-value of less than 0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The demographic characteristics and obstetric histories of the patients included in our study are summarized in Table 1.
Table 2 examines the relationship between PAPP-A and perinatal complications. There were 123 newborns with an APGAR score below 7 at the 5th minute. Among them, 22 newborns had PAPP-A values below 0.4 MoM, constituting 31% of the population. There were 101 newborns with APGAR scores below 7 at the 5th minute and PAPP-A values above 0.4 MoM, representing 24% of the entire population. There was no significant relationship between PAPP-A values and the 5th minute APGAR score. The number of newborns requiring intensive care was 117. Among them, 24 newborns had PAPP-A values below 0.4 MoM, making up 33.3% of the population. There were 93 newborns with PAPP-A values above 0.4 MoM requiring intensive care, representing 22.3% of the population. There was a significant relationship between PAPP-A and the need for newborn intensive care. The need for newborn intensive care was higher at 33% in the high-risk group (p: 0.045).
There was a significant relationship between PAPP-A values and preeclampsia. The rate of preeclampsia was 2.6 times higher in the high-risk group with PAPP-A values below 0.4 MoM (p: 0.001). There was no significant relationship between PAPP-A values and GDM. There was a significant relationship between PAPP-A values and preterm birth. The rate of preterm birth was 3.2 times higher in the high-risk group with PAPP-A values below 0.4 MoM (p: 0.0001). There was no significant relationship between PAPP-A and SGA or PROM. The findings are summarized in Table 3.
In our study, there was no significant relationship between B-HCG values and 5-minute APGAR scores. There was a significant relationship between B-HCG values and preeclampsia. The rate of preeclampsia was 2 times higher in the high-risk group with B-HCG values below 0.5 MoM (p: 0.023). There was no significant relationship between B-HCG values and GDM, also between B-HCG values and preterm birth. There was no significant relationship between B-HCG MoM values and SGA, PROM, and the need for neonatal intensive care. The findings are summarized in Table 3.
Discussion
PAPP-A is produced by syncytiotrophoblasts and is the largest glycoprotein associated with pregnancy [6]. PAPP-A is a metalloproteinase that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4) and serves as an important regulator of IGF bioavailability and cell growth. Concentrations of PAPP-A in the blood of pregnant women often decrease in fetal aneuploidy, and low concentrations can be associated with intrauterine growth restriction, preterm birth, preeclampsia, and placental abruption [7]. PAPP-A has been characterized as an IGF-dependent IGFBP-4 protease. In a study, IGFBP-4 was identified as a potent IGF inhibitor in vitro, and the cleavage of IGFBP-4 eliminated the inhibitory effect of IGF on various systems. This suggests that IGFBP-4 proteolysis functions as a positive regulator of IGF bioavailability [8].
Due to the intriguing nature of the topic, there are numerous articles available in the literature. In a recent study, uterine artery Doppler pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A), and free beta-human chorionic gonadotropin (fβ-hCG) levels were investigated individually or in combination for predicting the development of preeclampsia. However, the addition of these markers to first-trimester screening tests was not found to be beneficial for predicting preeclampsia [9]. Similarly, in another recent study, it was concluded that placental growth factor (PlGF) is a more useful marker for predicting preeclampsia in the first-trimester screening compared to PAPP-A [10]. Another study found that low maternal serum PAPP-A in the first trimester is associated with adverse pregnancy outcomes, but the predictive values are weak [11]. In another study, the addition of placental volume to first-trimester screening tests has been found to be useful in predicting the risk of small for gestational age (SGA) [12]. In our study, PAPP-A values below 0.4 MoM and B-HCG values below 0.5 MoM were found to be associated with preeclampsia, miscarriage, and preterm delivery.
Limitation
The limitations of the study stem from its retrospective nature; however, the complete patient records within the hospital system strengthened our study. Over the years, the discovery of new biomarkers will contribute to further advancements in research. Undoubtedly, the quest for markers that can predict the later weeks of pregnancy during the intrauterine course has always intrigued researchers. It is expected that in the coming years, with the continuous advancement of technology, these topics will diversify.
Conclusion
It has been observed that PAPP-A and HCG levels examined in the first trimester are associated with adverse pregnancy outcomes in the later weeks of pregnancy
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Elmas B, Laleli Koç B, Tuğrul Ersak D, Zorlu U, Aydoğdu E, Yılmaz G, et al. The relationship between the first trimester maternal serum PAPP-A and β-hCG values and newborn intensive care needs in low-risk pregnancies. Turk J Obstet Gynecol. 2022;19(4):287-94.
2. Guo X, Wang F, Li J, Guo Z, Wang J. Prediction performance of serum placental growth factor (PLGF) human chorionic gonadotropin β (β-hCG) and PAPP-A levels in early pregnancy for pregnancy outcomes. Pak J Med Sci. 2022;38(7):1877-82.
3. Honarjoo M, Zarean E, Tarrahi MJ, Kohan S. Role of pregnancy-associated plasma protein A (PAPP-A) and human-derived chorionic gonadotrophic hormone (free β-hCG) serum levels as a marker in predicting of Small for gestational age (SGA): A cohort study. J Res Med Sci. 2021;26:104.
4. Caron L, Fillion A, Giguère Y, Audibert F, Forest JC, Gasse C, et al. First-trimester screening for Down syndrome using quadruple maternal biochemical markers. Clin Chem Lab Med. 2023;61(9):1630-5.
5. Genc S, Ozer H, Emeklioglu CN, Cingillioglu B, Sahin O, Akturk E, et al. Relationship between extreme values of first trimester maternal pregnancy associated plasma Protein-A, free-β-human chorionic gonadotropin, nuchal translucency and adverse pregnancy outcomes. Taiwan J Obstet Gynecol. 2022;61(3):433-40.
6. Pasińska M, Balcerek E, Repczyńska A, Łazarczyk E. The Levels of Pregnancy-Associated Plasma Protein (PAPP-A) and Chorionic Gonadotropin (β-hCG) in the Blood Serum of Women with Hypothyroidism in the 1st Trimester of Pregnancy. Int J Womens Health. 2023;15:167-76.
7. Cruañes-Monferrer J, Gil Liñan A, Ramírez Andreo A. [Translated article] Edematous Infraumbilical Plaque in a Pregnant Woman. Actas Dermosifiliogr. 2023;114(3):T257-8.
8. Oxvig C, Conover CA. The Stanniocalcin-PAPP-A-IGFBP-IGF Axis. J Clin Endocrinol Metab. 2023;108(7):1624-33.
9. Khanam Z, Mittal P, Suri J. Does the Addition of Serum PAPP-A and β-hCG Improve the Predictive Value of Uterine Artery Pulsatility Index for Preeclampsia at 11-14 Weeks of Gestation? A Prospective Observational Study. J Obstet Gynaecol India. 2021;71(3):226-34.
10. Mazer Zumaeta A, Wright A, Syngelaki A, Maritsa VA, Da Silva AB, Nicolaides KH. Screening for pre-eclampsia at 11-13 weeks’ gestation: use of pregnancy-associated plasma protein-A, placental growth factor or both. Ultrasound Obstet Gynecol. 2020;56(3):400-7.
11. Morris RK, Bilagi A, Devani P, Kilby MD. Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. Prenat Diagn. 2017;37(3):253-5.
12. Kim YR, Park G, Joo EH, Jang JH, Ahn EH, Jung SH, et al. First-trimester screening model for small-for-gestational-age using maternal clinical characteristics, serum screening markers, and placental volume: prospective cohort study. J Matern Fetal Neonatal Med. 2022;35(25):5149-54.
Download attachments: 10.4328.ACAM.21877
Fatih Şahin, Fatma yazıcı yılmaz. The role of PAPP-A and free B-HCG, which are among the first trimester tests, in predicting pregnancy complications. Ann Clin Anal Med 2023;14(Suppl 2):S176-179
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Genetic spectrum of familial hypertriglyceridemia from the southeastern region of Turkey
Ayse Ergul Bozaci 1, Aysel Tekmenuray Ünal 2, Fatma Demirbaş 3, İbrahim Taş 1, Mehmet Nuri Ozbek 4
1 Department of Pediatric Metabolism, Diyarbakır Children’s Hospital, 2 Department of Medical Genetics, Gaziyasargil Research and Training Hospital, 3 Department of Pediatric Gastroenterology and Hepatology, Diyarbakır Children’s Hospital, 4 Department of Pediatric Endocrinology, Gaziyasargil Research and Training Hospital, Diyarbakir, Turkey
DOI: 10.4328/ACAM.21880 Received: 2023-08-17 Accepted: 2023-09-21 Published Online: 2023-09-23 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S180-185
Corresponding Author: Ayse Ergul Bozaci, Department of Pediatric Metabolism, Diyarbakır Children’s Hospital, Diyarbakir, Turkey. E-mail: ergul.acar@yahoo.com.tr P: +90 236 229 26 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9783-1016
This study was approved by the Ethics Committee of Diyarbakır Gazi Yaşargil Research and Training Hospital (Date: 2021-12-31, No: 966)
Aim: The disorders of lipid metabolism that cause primary hypertriglyceridemia result from genetic defects in triglyceride synthesis and metabolism. Although primary causes are rare in hypertriglyceridemia, they should be considered in severe hypertriglyceridemia cases. Identified genetic mutations are LPL, APOC2, APOA5, LMF1 and GPIHBP1 mutations.
Material and Methods: This descriptive cross-sectional study was conducted in Diyarbakir Children’s Hospital pediatric metabolism clinic on 60 patients from 41 unrelated families who were followed and diagnosed with severe hypertriglyceridemia based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis. The LPL, APOC2, APOA5, LMF1, GPIHBP1 genes were sequenced in 60 patients. Patients with initial triglyceride levels >885mg/dL were included in the study. Patients with a secondary cause were excluded from the study.
Results: Rare DNA sequence variants were identified in 49 patients (81.66%), including variants LPL (n=15), APOC2 (n=32), and APOA5 (n=2). No mutations were found in 11 patients (21%). The mean initial triglyceride level was 4322.8±4483mg/dL. Acute pancreatitis occurred in 38.33% (n=23) of the patients. The incidence of eruptive xanthoma was 28.33%, organomegaly was 23.33%, and failure to thrive was 21.66%. 69.23% of the patients with failure to thrive were patients with pancreatitis. Two different variants, c.55+6T>G and c.55+1G>C were detected in the APOC2 gene, seven different variants one of which is novel, c.557G>A, c.953A>G, c.296T>C, c.662T>C, c.1262G>A, c.644G>A and c.679G>C, were detected in the LPL gene, and two different variants one of which is novel, c.334_399dup65bp and c.16_39del24bp were detected in the APOA5 gene. Six patients were homozygous for both c.557G>A and c.953A>G variants.
Discussion: The frequency of mutations in APOC2 was 50%, LPL was 25% and APOA5 was %3.33. The relatively high prevalence of APOC2 mutations in our cohort may be due to regional frequency. The development of new therapeutic options for this rare disease requires awareness and screening among these patients. These findings highlight the need for molecular analysis in patients with severe HTG. It is anticipated to guide future individualized therapeutic strategies.
Keywords: Hypertriglyceridemia, Lipoprotein Lipase, APOC2, Acute Pancreatitis
Introduction
Severe hypertriglyceridemia is characterized by plasma triglyceride levels > 885mg/dL (>10.0 mmol/L) in the fasting state (>12 hours) [1]. It is known that the genetic etiology is extremely complex, and both common and rare variants are effective. Moderate elevation of triglyceride (177-885 mg/dL or 2.0-10.0 mmol/L) may be a condition resulting from the polygenic effect of multiple genes and secondary causes [2]. However, it has been determined that mutations in six genes (LPL, APOC2, APOA5, LMF1, GPIHBP1 and GPD1) show severe hypertriglyceridemia (HTG) due to disruption of chylomicron removal pathways. Dietary fats are absorbed from the intestine and transported as triglycerides (TG) in chylomicrons [3]. Chylomicrons that enter the blood begin to degrade when the APOC2 they carry is recognized by lipoprotein lipase (LPL, EC 3.1.1.34). When this process is impaired or insufficient, chylomicron particles accumulate in the plasma and cause hypertriglyceridemia [4]. It has been determined that familial hypertriglyceridemia occurs in the presence of biallelic mutations in the LPL, APOC2, APOA5, LMF1 and GPIHBP1 genes. Clinical features include recurrent pancreatitis, organomegaly, growth retardation, eruptive xanthomas and lipemia retinalis [2]. General circulating persistence of chylomicron is associated with free fatty acid toxicity and, together with its proinflammatory properties, is a trigger for pancreatitis [5]. Pancreatitis due to hypertriglyceridemia is more serious and has a higher complication rate compared to other causes [4]. Lipoprotein electrophoresis was not performed due to technical incompetence. Also, Fredrickson’s classification is not useful in daily practice.
In patients with severe HTG, omega-3, medium chain triglyceride (MCT) and fenofibrates are used in the treatment [6]. However, since therapeutic interventions to reduce TG levels are often ineffective, individualized therapeutic strategies targeting its molecular basis are being developed. Therefore, we aim to evaluate the coexistence of severe HTG and pancreatitis and to define the variants that cause monogenic HTG in our center.
Material and Methods
Study design and data acquisition
This descriptive cross-sectional study was conducted at Diyarbakır Children’s Hospital pediatric metabolism clinic on 60 patients from 41 unrelated families who were followed and diagnosed with severe hypertriglyceridemia based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis. Patients with initial triglyceride levels >885 mg/dL were included in the study. Patients with body weight <-2 SDS under 2 years of age, and patients with body mass index <-2 SDS over 2 years of age were considered as failure to thrive. Patients with a secondary cause were excluded from the study. Inclusion criteria were rare biallelic variants in LPL, APOC2, APOA5, LMF1, GPIHBP1 genes classified as likely pathogenic or pathogenic according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.
Molecular Analyses
All exons and exon-intron junctions of the genes were evaluated by the next-generation sequencing method. Genomic DNA was extracted from peripheral blood samples using a QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Standardized PCR pools were prepared using NexteraXT sample preparation kit for next-generation sequencing analysis with the Miseq device (Illumina, Inc.). Sanger sequencing of genomic variants identified by exome sequencing or targeted gene sequencing was performed for all patients and their families. Sanger sequencing was used to validate pathogenic variants within families on 3500 genetic analyzer (Applied Biosystems, Foster City, USA). The sequencing results were analyzed using CLC genomic workbench software. For clinical interpretation of variants, allele frequency data were obtained from various databases, including gnomAD (http://gnomad.broadinstitute.org/) and ExAc (http://exac. broadinstitute.org/). The pathogenicity of variants was assessed using in silico prediction tools, such as PolyPhen-2 (http://genetics.bwh. harvard.edu/pph2), SIFT (http://sift.jcvi.org), and MutationTaster (http: // www. mutationtaster.org) and Human Splicing Foundation (http://www.umd.be/hsf/).
Ethical Approval
The study involving the use of human subjects was conducted in accordance with all the relevant national regulations, institutional policies and in accordance with the tenets of the Helsinki Declaration and has been approved by the the local Diyarbakır Gaziyaşargil Research and Training Hospital Ethics Committee (Date: 31-12-2021/No966).
Statistics
Statistical analyses of the data were performed using the SPSS software package for Windows software package (ver.18.0; SPSS Inc., Chicago, IL, USA). As descriptive statistics, numbers, and percentages for categorical variables, mean±standard deviation or median (minimum-maximum) were used for numerical variables. The distribution of data was evaluated using the Shapiro-Wilk test. For numerical comparisons, Student’s t-test or Mann-Whitney U- test was used to assess differences between two groups according to the normal distribution of the measured parameters.
Results
A total of 60 patients, 26 female and 34 male, from 45 different families were included in the study. None of the patients have been previously published. The consanguinity rate was 96.66%. The mean age at the time of the data collection was 5.31±4.37 years (min: 6 months max: 14 years). The mean age at diagnosis was 2.62±3.90 years (min: 7 days max: 13 years). The total duration of follow-up of the cohort was three years, individually ranging from 4 to 46 (median = 12.1) months.
Rare DNA sequence variants were identified in 49 patients (81.66%), including variants LPL (n=15), APOC2 (n=32), APOA5 (n=2). No mutation was detected in 11 patients (21%). The mean age at diagnosis of APOC2 patients was 2.95±4.18 years, LPL patients was 2.97±4.33 years. There was no significant difference between the mean age at diagnosis between genetic defects. 15/23 patients had recurrent pancreatitis. Initial TG levels in patients with APOC2 were significantly higher than in those with LPL (p<0.05). The clinical and laboratory characteristics according to the gene defects are shown in Table 1. The mean age of the patients with pancreatitis in patients with pancreatitis was 2.62±3.81 years, and of patients without pancreatitis it was 2.73±4.03 years. Triglyceride levels of the patients with pancreatitis at the time of diagnosis were found significantly higher (p<0.05). Failure to thrive was observed more frequently in patients with pancreatitis. The clinical and laboratory characteristics of patients with pancreatitis and without pancreatitis are presented in Table 2.
Dietary treatment was applied in all patients. The recommended fat intake for patients was 10–15% of their total caloric intake. MCT oil was recommended to be 50-80% of total fat. Low-fat, medium chain triglyceride (MCT) oil-rich formula was used in infants under 1 year old. Lipid restriction and MCT oil supplementation were performed in patients older than 1 year. Omega 3 was given to 54 patients older than three months old. Fenofibrate was received by six patients. When the mean undertreatment TG levels were evaluated, no significant difference was found between the groups.
A total of 47 pancreatitis episodes were recorded. Therapeutic apheresis was performed in six patients due to severe pancreatic episodes. Three sessions of TA were performed in 2/6 patients, and one session in 4/6 patients. Triglyceride levels were measured after each TA and continued until <1000 mg/dL. Necrotizing pancreatitis was observed in two patients. In the follow-up, pancreatic enzyme supplementation was started due to exocrine pancreatic insufficiency.
Two different variants, c.55+6T>G and c.55+1G>C were detected in the APOC2 gene. A c.55+6T>G (IVS2+6T>G) intronic variant was detected in 22 patients from 11 families. This variant has so far been considered a “variant of uncertain significance (VUS)” because it is extremely rare (PM2) in healthy population databases and deleterious (PP3) in in-silico prediction tools. The c.55+1G>C (IVS2+1G>C) splice-site variant was detected in the APOC2 gene in 10 patients. Seven different variants, c.557G>A, c.953A>G, c.296T>C, c.662T>C, c.1262G>A, c.644G>A and c.679G>C were detected in the LPL gene. Both c.557G>A p.Gly186Glu (G186E) and c.953A>G p.Asn318Ser (N318S) (double homozygous variants) variants in the LPL gene were homozygous in six patients. In the F30, c.644G>A p.Gly215Glu(G215E) heterozygous and c.679G>C p.Val227Leu(V227L) heterozygous variants were found as compound in two siblings. c.679G>C p.Val227Leu variant is novel. In P48, the c.334_399dup p.Ala112_Thr133dup variant was homozygous in the APOA5 gene. This variant is a novel variant. Molecular analysis results are shown in Table 3.
Discussion
Familial hypertriglyceridemia is a rare cause of severe triglyceride elevation, which is seen with a prevalence of 1 in 1.000.000 [2]. The LPL, APOC2, APOA5, LMF1, GPIHBP1 genes have been identified as the causative genes of monogenic chylomicronemia [7]. These genes are necessary for the normal functioning of the LPL enzyme. Loss-of-function mutations in the LPL pathway could be detected in less than 30-40% of familial HTG patients [8,9]. In patients without genetic mutation, the underlying cause may be the development of autoantibodies against proteins in the LPL pathway or additional genetic factors. In our study group, LPL, APOC2, APOA5, LMF1 and GPIHBP1 genes were analyzed in 60 patients. A total of 11 different variants were detected in 81.66% (n=49) of patients, including two novel variants. The reason why this rate is higher than in other studies may be due to very high consanguinity rates (96.66%) or very strict inclusion criteria.
In familial HTG, the LPL gene was the most commonly affected gene in the literature [8-10]. The most commonly affected gene was APOC2 in our study group and the prevalence of APOC2 variants was high compared to previous observations [8,9]. The c.55+6T>G (IVS2+6T>G) intronic variant was detected in 22 patients in our study. This variant has so far been considered a “variant of unsignificant (VUS)” because it is extremely rare (PM2) in healthy population databases and deleterious (PP3) in in-silico prediction tools. This mutation was detected in a Turkish infant and three Turkish adult patients with hypertriglyceridemia [11,12]. Since it was detected in 22 familial HTG cases in our study, it was thought that it would be appropriate to classify it as a “likely pathogenic/pathogenic”. Additionally, the higher proportion of cases with this variant in our Turkish cohorts could reflect ascertainment bias or possible founder effect of this variant.
In our study, the LPL gene was the second most affected gene. The c.557G>A p.Gly186Glu (G186E) and c.953A>G p.Asn318Ser (N318S) variants were found double homozygous in the LPL gene in six patients. The c.557G>A p.Gly186Glu variant is a pathogenic variant that has been previously reported [13]. The c.953A>G p.Asn318Ser variant has been reported in the ClinVar database with different classifications as pathogenic, VUS, and benign. Although, this variant was evaluated as a polymorphism but associated with increased cardiovascular risk. In addition, this variant has also been shown to reduce LPL activity [14,15]. The c.953A>G p.Asn318Ser variant, which was detected as a double homozygous mutation in six patients, the clinical significance of this variant cannot be commented on since the c.557G>A p.Gly186Glu variant is pathogenic. The c.644G>A variant was previously reported as pathogenic [15,16]. The c.1262G>A p.Trp421Ter (W421*), c.644G>A p.Gly215Glu (G215E) variants in the LPL gene has also been reported previously and are classified as pathogenic [13]. The c.679G>C p.Val227Leu variant is novel. The amino acid valine at position 227 is a conserved amino acid in protein; previously reported as c.679G>T p.Val227Phe (V227F) in a patient as a pathogenic in the form of different amino acid conversion with different nucleotide change. In another patient, it was reported as likely pathogenic as c.680T>C p.Val227Ala conversion to a different aminoacids (ClinVar#2441229). The c.334_399dup p.Ala112_Thr133dup variant in APOA5 gene is novel variant. This variant was classified as likely pathogenic because the patient had hypertriglyceridemia, although it was evaluated as VUS in databases such as Varsome and Franklin, but not found in healthy population databases. The c.16_39del p.Ala6_Ala13del (A6_A13del) variant in the APOA5 gene was previously reported. Initial TG levels of patients with APOC2 gene defect were significantly higher than those with LPL gene defect (p<0.05). The significant difference in mean initial triglyceride levels of the APOC2 and LPL genes may be due to the different sample size and small number of subgroups.
Severe HTG is an independent risk factor for pancreatitis. TG level ≥1000 mg/dL is usually indicated as the threshold for the development of pancreatitis [17]. However, some studies argue that TG>500mg/dL increases the risk of pancreatitis [6]. Acute pancreatitis was observed in 38.33% of the patients, and recurrent pancreatitis was observed in 65.21% of them. Triglyceride levels of the patients with pancreatitis at the time of diagnosis were found significantly higher than the without pancreatitis patients (p<0.05). Consistent with the literature, the frequency of pancreatitis was higher in patients with higher triglyceride levels in our study. To prevent pancreatitis, therapeutic plasmapheresis has been included in the guidelines as an option [18-20]. We also performed TA in six patients because of severe pancreatitis unresponsive to medical treatment and poor general condition. In our study, triglyceride levels were measured after each TA and continued until <1000 mg/dL. In most of our patients, triglyceride levels decreased after one session.
MCT-rich low-fat diet, fenofibrates are not effective enough to reduce TG levels in patients with severe HTG [21]. Recently, LPL gene therapy (Alipogene tiparvovec), APOC3 inhibitors (Volanesorsen), ANGPTL3 and ANGPTL4 inhibitors have been developed and evaluated in clinical trials [22]. The development of new therapeutic options for this rare disease requires awareness and screening among these patients. These findings highlight the need for molecular analysis in patients with severe HTG. It is anticipated to guide future individualized therapeutic strategies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Ayse Ergul Bozaci, Aysel Tekmenuray Ünal, Fatma Demirbaş, İbrahim Taş, Mehmet Nuri Ozbek. Genetic spectrum of familial hypertriglyceridemia from the southeastern region of Turkey. Ann Clin Anal Med 2023;14(Suppl 2):S180-185
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Key variables in managing femoral pathological fractures and search for objective parameters for decision-making
Hüseyin Kaya, Arman Vahabi, Dündar Sabah
Department of Orthopedics and Traumatology, Faculty of Medicine, Ege University, Izmir, Turkey
DOI: 10.4328/ACAM.21884 Received: 2023-08-18 Accepted: 2023-09-20 Published Online: 2023-09-23 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S186-191
Corresponding Author: Arman Vahabi, Department of Orthopedics and Traumatology, Faculty of Medicine, Ege University, Izmir, Turkey. E-mail: armanvy@gmail.com P: +90 530 876 03 31 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8937-6658
This study was approved by the Ethics Committee of Ege University Faculty of Medicine (Date: 2021-10-15, No: 21-10T/4)
Aim: Bone invasion in advanced cancers represents later stages and requires individualized treatment strategies based on patient related variables. The objective of this study is to ascertain the significance of age, location, serum levels of Ca, urea, albumin, and accordingly calculated MEP (Metastatic Early Prognostic) score, in planning the treatment of femoral impending and pathological fractures. The secondary aim was to compare complication rates between osteosynthesis and prosthetic replacement and to place this analysis on the time axis.
Material and Methods: This retrospective cohort was conducted at a tertiary care hospital with a dedicated orthopedic oncology team. The database search was performed for surgically treated femoral pathological/impending fractures between 2010 and 2020. Demographic data, mortality, fracture location, levels of Ca, urea, albumin, and follow-up X-rays were collected. Surgical procedures were categorized as prosthetic replacement or osteosynthesis for comparative analysis. Complications and the necessity of secondary interventions were noted accordingly.
Results: A total of 109 patients met the inclusion criteria. The average follow-up period was 9.1 months, with a mean survival time of 12.96 months. High serum urea levels, low albumin levels, high calcium levels were associated with increased one-year mortality. Osteosynthesis procedures had a higher need for secondary surgeries compared to prosthetic reconstruction. A threshold of one year has shown to be the critical limit before mechanical complications related to osteosynthesis occur.
Discussion: Secondary surgery rates were higher in the fixation group with survival exceeding one year, suggesting a greater consideration for prosthetic replacement in that group. Markers such as urea, albumin, and calcium levels can provide insights into mortality rates when evaluating surgical treatment options.
Keywords: Metastatic Bone Disease, Bone Metastasis, Orthopaedic Oncology, MEP Score, Mortality, Life Expectancy
Introduction
Bone invasion is the third most prevalent site of metastatic disease, following the lung and liver. While it is worth noting that axial skeletal involvement is generally more prevalent than appendicular skeletal involvement, discussions regarding the treatment of pathological fractures often focus on the lower extremities since most of the patients requiring surgical intervention are in this group. Pelvis and proximal femur are the most frequently involved localizations after the spine. [1,2].
Femoral lesions often result in pathological fractures, significantly impacting the patient’s ability to mobilize and increasing mortality rates. Despite the prevalence of bone metastases, comprehensive knowledge regarding the most appropriate treatment methods remains incomplete. To enhance the treatment process for patients with bone metastases, it is crucial to identify objective data that can guide physicians in making informed decisions and optimizing treatment options at critical junctures [3].
The incidence of metastatic bone lesions requiring treatment in patients with malignancy is increasing due to advances in early diagnosis and effective treatment modalities, as well as the implementation of new treatment and screening programs. Managing these fractures necessitates approaches that go beyond general trauma principles and require more individualized strategies. Factors such as the life expectancy, age, tumor type, extent or number of metastatic diseases, fracture location, and overall patient condition play a crucial role in determining the treatment strategy [4].
The primary objective of the study was to identify the survival rate and its correlation with the various variables (Ca, Albumin, Urea) and MEP (Metastatic Early Prognostic) score in patients who underwent surgery for pathologic fractures due to metastatic femoral lesions. The secondary objective was to compare complication rates among cases undergoing different surgical procedures, and to analyze these results over an axis of time (osteosynthesis versus prosthetic replacement).
Material and Methods
This retrospective cohort study was conducted at a tertiary care hospital that boasts a dedicated multidisciplinary orthopedic oncology team with a longstanding tradition spanning over thirty years. Ethical approval from the institutional board was obtained (21-10T/4).
The database search was conducted regarding femoral pathological fractures or impending fractures treated surgically between January 2010 – December 2020. The search was conducted through operation records so that patients that did not receive the surgical intervention were not included in the scope of this study. Exclusion criteria were cases with pathological fractures related to primary bone lesions, pathological fractures that are not related to the femur, and those with insufficient medical records. Data of patients who did not attend their follow-up visits in the 1st month, despite no mortality, were deemed insufficient and therefore excluded from the study. A total of 220 patients were identified initially. After exclusion, a total of 109 cases were eligible for final analysis.
Demographic variables, such as age, gender, side, follow-up period, and the time between operation and exitus, were collected. Data on mortality were also obtained from the national health database. Additionally, the original tumor sites were noted for patients with confirmed pathological diagnoses.
Lesions were classified into two main groups according to their location: proximal, and diaphyseal femoral fractures. Fractures occurring between the subtrochanteric region and the distal diaphyseal metaphyseal region were categorized as diaphyseal fractures. Furthermore, cases were labeled as impending fractures or pathological fractures.
Serum urea, albumin, calcium, and corrected calcium values from the latest preoperative control were obtained. The Metastatic Early Prognostic (MEP) scores were calculated accordingly using these parameters as previously described [5]. Assigned scores regarding MEP score were as follows: Albumin below 35g/l received one point, urea level above 46.8 mmol/l received one point and corrected calcium above 10.2 mg/dl received two points.
Due to the specific nature of this population, strict follow-up protocols could not be implemented. However, efforts were made to obtain postoperative follow-up X-rays at the 2nd, 6th, 12th, and 24th weeks. These X-rays were evaluated for lysis, fracture healing, implant failure, tumor progression, and periprosthetic fracture. Overall complications, secondary surgeries and surgery-related complications were also recorded.
Among the performed surgeries, proximal femur replacement, osteosynthesis with plate, cephalomedullary nailing, and intramedullary nailing with or without cement application were noted. The analyses were conducted by comparing two groups: prosthetic replacement and osteosynthesis.
Efforts have been made to describe mortality risk, specifically focusing on one-year mortality rates. Independent risk factors assigned for analysis included age, serum calcium (Ca) levels, albumin levels, and urea levels. Regression analyses were employed in this group, utilizing data from 62 eligible patients who had a complete dataset for studied variables.
Statistical Analysis
The statistical software package SPSS 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) was utilized for the analysis. A significance level of 0.05 was chosen for determining the statistical significance. Variables were compared using the Kaplan-Meier method in univariate analyses. For multivariate analysis, assessment was performed using Cox-regression analysis. The Pearson’s chi-square test was employed to examine the relationship between categorical variables. Continuous variables underwent ROC analysis, with the appropriate cutoff value was determined based on the Youden index.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The average follow-up period was 9.1 months, ranging from 1 to 125 months. The mean survival time was determined to be 12.96 months with a 95% confidence interval.
Regarding the demographic characteristics, the mean age was 63 (+/-5.5) years, there were a total of 56 female and 53 male patients. Among them, 29 had breast cancer metastases, 21 had metastases of hematological malignancies, 20 had metastases of lung cancer, and 16 had metastases from urinary system malignancies. The distribution of femoral fractures based on location was as follows: 27 cases of neck/trochanteric fractures, 54 cases of subtrochanteric fractures, and 28 cases of diaphyseal fractures. Among these patients, 16 underwent surgery due to impending fractures, while 93 patients underwent surgery for pathological fractures (Figure 1).
The survival times of patients who underwent planned surgery for impending lesions, were found to be longer compared to those who underwent surgery after the fracture. However, due to heterogeneity between the groups, this difference could not be statistically demonstrated (p:0,252).
Analyzing the cases in terms of prognostic biochemical markers, it was observed that preoperatively obtained high serum urea levels (p:0.005), low albumin levels (p:0.002) and high serum corrected calcium levels (p:0.053) were significantly associated with one-year mortality. Based on individuals with a MEP (Metastatic Early Prognostic) score of 0, the risk for those with a score of 2 was found to be 2.3 times higher (p: 0.035). However, for individuals with a score of 1, the risk was 1.7 times higher, but this difference was not statistically significant (p: 0.159).
There were no significant difference in mortality rates between two groups (osteosynthesis (n=44, 40.3%) and prosthetic reconstruction (n=65, 59.6%)), the need for secondary surgical intervention was significantly higher in the osteosynthesis group (p:0.003). There was no difference between the groups in terms of the diagnosis of the primary tumor.
Out of a total of 109 patients, 39 patients died within the first year. Among the 70 remaining survivors, 20 cases had a follow-up period exceeding 2 years. Among the 39 patients who died in the first year, 12 had metastases of lung carcinoma, 12 had metastases from other carcinomas, 4 had hematological malignancies, 7 had breast malignancies, and 3 had prostate malignancies. Out of these 39 patients, 23 received prosthetic implants, while 16 received osteosynthesis. Among the 39 patients, 22 deaths occurred within the first 4 months, and 28 deaths occurred within the first 6 months.
Secondary interventions were required for 9 out of 16 patients who survived beyond 1 year and had received osteosynthesis initially. Secondary surgeries were required within the timeframe of 1 to 4 years. Among the patients who received osteosynthesis, 56% of cases with a lifetime exceeding one year required secondary surgical intervention. Among the patients who required secondary surgery, 6 had breast cancer, 3 had renal cell carcinoma (RCC), and 1 had lung cancer. Cases with complications are listed in Table 1.
Among the 62 patients included in the regression analysis, the mean age was 65.98 years with a standard deviation of 12.3. Out of these patients, 29 (46.8%) were female, and 33 (53.2%) were male. Among the cases, 52 were classified as actual fractures, while 10 were categorized as impending fractures. Osteosynthesis was performed on 27 (43.5%) patients, whereas 35 (56.5%) patients underwent prosthetic replacement (Figure 2).
The MEP scores are categorized into four groups: 0, 1, 2, and 3-4, as originally defined. However, when compared according to original categorization, it was observed that the MEP score did not provide a reliable prediction for 3-month and 1-year mortality (p:0.736 p:0.47). To predict mortality based on the MEP score, the grouping was modified as follows: 0-1 were combined into one category, and 2-3-4 were considered as a separate category. Unfortunately, no meaningful data could be derived from this grouping either (p:0.413, p:0.091). Again, the grouping was modified as 0 and 1 and 2-3-4. Regarding this grouping technique, one-year mortality prediction was significant (p:0.042). Again, when grouped with 0 vs. 1-2-3-4, 1-year mortality risk prediction was successful (p:0.013), while 3 months mortality prediction was not achieved (p: 0.305). (Table 2).
We could not find any ground for the utilization of MEP Score as its current form for pathological fractures and moved on with establishing threshold values for calcium, albumin, and urea in our study population. We then analyzed the impact of these variables on mortality prediction, using the Youden index, we identified a threshold value of 40.9 (Sen: 90 CI:73.5-97.9 Spe: 59.4 CI:40.6-23.7) for serum albumin, 54 (Sen: 36,7 CI:19.9-56.1 Spe:90.6 CI: 75-98) for urea, and 10.5 (Sen:26.67 CI:12.3-45.9 Spe:93.75 CI:79.2-99.2) for corrected calcium and threshold of age of 60 years (Sen:80 CI:61.4-92.3 Spe:46.98 CI: 29.1-65.3). The values exhibited high concordance with the internationally recognized standard ranges.
Further analysis was conducted after categorical classification, using these threshold values. The Kaplan-Meier survival analysis on one-year mortality risk revealed that age, serum albumin, corrected calcium urea level were independent risk factors. Cox-regression analysis after the univariate model revealed that elevated urea and corrected calcium levels and lowered albumin levels independently emerged as risk factors for one-year mortality (Table 3) (Figure 3).
Discussion
One of the major findings of this study was the importance of considering the patient’s one-year survival expectation as a primary consideration in determining the treatment approach, particularly regarding the ongoing debate of osteosynthesis versus prosthetic replacement. Factors such as the patient’s anticipated life expectancy, overall health condition, and fracture location along with the soft tissue involvement emerged as the primary determinants for selecting the appropriate surgical treatment. The primary goal is to accomplish all these objectives simultaneously, without necessitating any secondary interventions, which could be a big insult to patient’s well-being. The aim is to provide better function, palliate pain, and improve or protect the quality of life [6]. In cases with a short survival expectation, minimally invasive surgeries or radiation therapy may be preferred. However, predicting mortality risk is not an easy task and additional objective parameters could be useful in the decision-making process [7].
The MEP score was described by Downie et al. and has been proven to predict risk of early mortality rate after admission with metastatic proximal femoral lesion. In this retrospective cohort study, we have tried to test the adaptability of this scoring system in the decision-making process for metastatic bone disease of the femur. Although we have failed to demonstrate the strong correlation with MEP scores and mortality rates, all three examined markers (Ca, Urea, Albumin) were found to have predictive value over 1-year mortality risk. Although the MEP scoring system was identified as a mortality predictor in proximal femoral metastatic diseases, our findings indicate that these markers can also be utilized as a one-year mortality predictor, which can strongly influence treatment decision.
The correlation between serum markers and mortality has been proposed in various fields of medicine, suggesting that it generally reflects the overall condition of the patient and impairments should be addressed prior to interventions when feasible [8,9]. However, the significance and importance of these variables in relation to pathological fracture treatment have not been fully elucidated. Despite the utilization of diverse classification and scoring systems and various clinical or laboratory variables to enhance the management of pathological fractures, the underlying principle remains consistent: personalized treatment [10–12]. Therefore, it appears reasonable to incorporate these serum variables into the decision-making process, along with consideration of the critical one-year survival threshold.
When compared with prosthetic replacement, minimally invasive osteosynthesis has a number of advantages. This technique has been shown to be characterized by shorter operation time, less blood loss, and smaller surgical incisions [13]. However, it is important to consider the potential requirements for postoperative weight-bearing restrictions and the risk of complications in cases where the fracture fails to achieve bony union as disadvantages of this approach [14]. On the other hand, prosthetic replacement has some other advantages. These include removal of tumor tissue, which reduces the tumor burden, facilitates early mobilization, and allows for follow-up protocol without the need for fracture union. However, it is important to note that prosthetic replacement has certain drawbacks that should be avoided in these already vulnerable patients, such as longer operation time, greater blood loss, and wider surgical incisions [15]. Overall, reported treatment failure rates in prosthetic treatment are lower with increased implant longevity [16,17].
It is important to note that some of these issues related to prosthetic replacement could be prevented through effective preoperative preparation and the use of proper surgical techniques, thus bringing this option forth. At our center, when dealing with femoral pathological fractures, our primary approach involves employing prosthetic replacement in most of cases. This approach is based on our center’s longstanding tradition and extensive experience with femoral proximal resection prostheses. In contrast to the literature, which has reported prosthetic dislocations in up to 20% of cases, our series showed a significantly lower rate of only 3% [18]. This outcome can be attributed to our mastered technique employed during femur proximal resection prostheses. This technique involves performing an osteotomy of the trochanter major and subsequently securing it back to the prosthesis while securing the iliopsoas muscle on the prosthesis.
Patients treated with plate osteosynthesis in our series were selected with certain characteristics such as relatively intact bone stock, relatively long life expectancy, and sufficient bone stock. However, despite these careful patient selection considerations, we observed a high incidence of complications among patients treated with plating techniques. As a result, our clinical practice has gradually shifted towards two alternative options: intramedullary nailing and prosthetic replacement. In line with our clinical experience, the current literature also emphasizes the superiority of intramedullary nail applications as an effective method of osteosynthesis in pathological fractures, particularly for cases involving the proximal and midshaft regions of the femur. We have adopted this approach in parallel with our own observations, except in cases of distal diaphyseal fractures, where alternative strategies may be more suitable [19].
Bone invasion frequently indicates advanced stages of various cancers, as the median survival rates for several malignancies are less than one year. For instance, the overall median survival following a diagnosis of bone invasion is approximately 6 months for lung cancer, and 6-9 months for bladder cancer. However, certain cancers exhibit relatively longer median survival rates, such as 12 months for renal cell carcinoma, 12-53 months for prostate cancer, and 19-25 months for breast cancer. Notably, thyroid cancers can achieve median survival rates as high as 48 months following bone invasion [20].
Limitations
This study had several limitations, primarily stemming from its retrospective design and high rate of missing data. Additionally, evolving treatment and follow-up protocols over time in this patient group could have biased our results to some extent. Another limitation is the inability to present a standardized surgical protocol due to the significant inter-patient variables and the requirement for personalized treatment approaches. Furthermore, an additional limitation is the absence of consideration for non-surgical adjuvant treatments received by the patients as a variable. This oversight could be regarded as a limitation in terms of comprehensively assessing the impact of different treatment modalities.
Conclusion
The need for secondary surgery is considerably higher in cases that have undergone osteosynthesis for pathological femur fractures, particularly among individuals with a life expectancy exceeding one year. In such cases, mprosthetic replacement should be kept in mind as treatment of choice.
Furthermore, when evaluating surgical treatment options based on anticipated survival time, certain biochemical markers such as urea and albumin and corrected calcium levels may provide insights into one-year mortality rates. These variables can be employed either individually or as a component of a comprehensive approach to aid in this assessment. We find it unlikely that the MEP scoring system, in its current form, is practically adaptable for clinical use.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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2. Hage WD, Aboulafia AJ, Aboulafia DM. Incidence, location, and diagnostic evaluation of metastatic bone disease. Orthop Clin North Am. 2000 ;31(4):515-28, vii.
3. Jacofsky DJ, Haidukewych GJ. Management of pathologic fractures of the proximal femur: state of the art. J Orthop Trauma. 2004 ;18(7):459-69.
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5. Downie S, Lai FY, Joss J, Adamson D, Jariwala AC. The Metastatic Early Prognostic (MEP) score. Bone Joint J. 2020;102-B(1):72-81.
6. Cappellari A, Trovarelli G, Crimì A, Pala E, Angelini A, Berizzi A, et al. New concepts in the surgical treatment of actual and impending pathological fractures in metastatic disease. Injury. 2023;54(Suppl.1):S31-5.
7. Zacherl M, Gruber G, Glehr M, Ofner-Kopeinig P, Radl R, Greitbauer M, et al. Surgery for pathological proximal femoral fractures, excluding femoral head and neck fractures: resection vs. stabilisation. Int Orthop. 2011;35(10):1537-43.
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13. Zhou S, Liu J, Zhen P, Shen W, Chang Y, Zhang H, et al. Proximal femoral nail anti-rotation versus cementless bipolar hemiarthroplasty for unstable femoral intertrochanteric fracture in the elderly: a retrospective study. BMC Musculoskelet Disord. 2019 29;20(1):500.
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Hüseyin Kaya, Arman Vahabi, Dündar Sabah. Key variables in managing femoral pathological fractures and search for objective parameters for decision-making. Ann Clin Anal Med 2023;14(Suppl 2):S186-191
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The impact of parity on sexual function in Somali women: A prospective study
Adil Barut, Deka Omer Mohamud
Department of Obstetrics and Gynaecology, Somali-Mogadishu Recep Tayyip Erdoğan Research and Training Hospital, Mogadishu, Somalia
DOI: 10.4328/ACAM.21886 Received: 2023-08-21 Accepted: 2023-09-21 Published Online: 2023-09-23 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S192-196
Corresponding Author: Adil Barut, Department of Obstetrics and Gynaecology, Somali-Mogadishu Recep Tayyip Erdoğan Research and Training Hospital, Mogadishu, Somalia. E-mail: dradilbarut@gmail.com P: +252 610267232 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1121-4923
This study was approved by the Ethics Committee of Mogadishu Somali Turkey Training and Research Hospital (Date: 2022-05-09, No: MSTH/10163/09.05.2022/558)
Aim: Childbirth is considered a celebrated and respected event in almost all societies, particularly in developing and underdeveloped countries. This study aimed to document the sexual problems of Somali women in multiparous or grand multiparous women.
Material and Methods: This prospective study included 363 consecutive women who had presented to the Department of Gynaecology. Data included age, number of parities, delivery method, education, and residence area. The participants were asked to complete the Female Sexual Function Index (FSFI).
Results: Of the 363 participating women, 12.1%, 16.8%, 34.7% and 36.4% were classified as nulliparous, primiparous, multiparous (2-4 deliveries) and grand multiparous women, respectively. The overall mean age was 30.1±7.8 years. The overall incidence of sexual dysfunction was 57.3%, 38.6%, 54.1%, 61.2%, and 65.9% among nulliparous, primiparous, multiparous (2-4 deliveries), and grand multiparous women, respectively.
Total FSFI and orgasm scores were significantly higher among nulliparous, primiparous, and multiparous (2-4 deliveries) women than among grand multiparous women (p<0.05). In addition, grand multiparous women had a significantly higher incidence of sexual dysfunction as compared with nulliparous women (65.9% vs 38.6%, p=0.014). Grand multiparous status showed a significant inverse association with the orgasm score. Multiparous (2-4 deliveries) and grand multiparous status had significant associations with sexual dysfunction (OR:2.05, p=0.045; OR:3.07, p=0.002, respectively).
Discussion: Our findings showed an incremental rise in the incidence of sexual dysfunction through the forms of parity from nulliparity to grand multiparity, with the latter showing a significant difference from the former.
Keywords: Multiparous Women, Grand Multiparous Women, Sexual Dysfunction, Somalia
Introduction
Female sexual function is an important component of quality of life, affected by a wide range of factors in an individual’s psychological, relational, and physical life. Although motherhood represents a celebrated event in a woman’s life, in physical and psychosocial terms, it can potentially negatively impact female sexual function [1].
Similarly, childbirth is also considered a celebrated and respected event in almost all societies, particularly in developing and underdeveloped countries. This is particularly true among African populations. On the one hand, women who are not able to conceive are often underestimated and disgraced, while on the other hand, they are expected to give birth to as many children as possible, mainly because of the preference for large families on economic grounds and due to very limited availability to contraception. However, multiparity or even grand multiparity (≥5 births) are associated with adverse obstetrical outcomes, resulting in weakening of the pelvic floor and/or a urogenital prolapse, both of which may affect sexual function [2].
The number of studies assessing the relationship between multiparity/grand multiparity and sexual function among healthy women has been very limited, with none reported from Sub-Saharan African (SAA) countries.
This study sought to examine the adverse effects of multiparity/grand multiparity on women’s sexual function in a relatively large sample of Somali women, in comparison with their nulliparous married counterparts.
Material and Methods
Study design and participants
This prospective study included 363 consecutive married women (nulliparous, primiparous, multiparous) who had presented between May 10 and August 1, 2022 to the Department of Gynaecology of Mogadishu Somali Turkey Training and Research Hospital in Mogadishu, the capital city of Somalia. Data included age at marriage and at presentation, the number of parities, delivery methods, education status, and residency of area (rural or urban).
Participants were asked to complete the Female Sexual Function Index (FSFI). For those who were illiterate, the FSFI was completed by a gynecology specialist (AB or DOM), consistent with responses given by the participants.
Inclusion criteria were age of at least 18 years, being in a monogamous marriage and sexually active. Exclusion criteria included polygamous marriage, pregnancy, comorbid conditions, history of a previous major pelvic trauma, psychiatric or neurological disorders, alcoholism, illicit drug use, and use of drugs that might affect sexual function.
Female Sexual Function Index
The FSFI was developed by Rosen and colleagues to assess six domains of female sexual function (sexual desire, sexual arousal, lubrication, orgasm, satisfaction, and pain) and has become one of the most widely used measures of female sexual function . The 19-item FSFI is easy to understand and has been adapted to a number of languages. The items are scored on a five-point (1 to 5) Likert scale, with lower scores corresponding to lower levels of sexual functioning and a score of less than 26.55 indicating sexual dysfunction. Fifteen items also include a sixth response option scored with zero, indicating no sexual activity in the past four weeks [3, 4]. Cronbach’s α for the reliability of the FSFI in the Somalian language was found to be 0.79.
The study was approved by the Ethics and Research Committee of Mogadishu Somali Turkey Training and Research Hospital (Permission number: MSTH/10163/09.05.2022/558) and was performed in accordance with the principles and guidelines of the Declaration of Helsinki [5]. All participants were informed about the study and gave consent to publication of the results. Analysis and reporting of the results are in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.
Definitions
Nullipara and primipara were used for a woman who has not yet given birth to a child and for a woman who has been pregnant and given birth once, respectively.
Multiparity was defined as giving birth more than once, and grand multiparity was defined as giving birth ≥5 times (live or stillbirth). Sexual dysfunction was defined by a total FSFI score of less than 26.55 [6].
Data processing and analysis
Data were collected using a structured format, including relevant socio-demographic features and were processed using the Statistical Package for Social Sciences (SPSS) version 21 (IBM Corp., Armonk, N.Y.; USA). Quantitative data were expressed as means, standard deviation (SD), median, minimum, and maximum, and qualitative data as frequencies and percentages. Homogeneity was checked using Levene’s test, where a p-value of >0.05 was considered in favor of homogeneity. The Shapiro-Wilk normality test was used to check whether continuous variables were normally distributed.
Numerical variables were found to be normally distributed using the Kolmogorov-Smirnov test. For pairwise comparisons, numerical variables were compared using the independent t-test and multigroup comparisons were performed using the one-way ANOVA test. The post hoc multiple comparisons (Bonferroni) were used to determine between-group differences. Nominal variables were analyzed with Pearson’s chi-squared test. Univariate analysis was performed to determine the effect of various types of parity on the subdomains of sexual function, and binary regression analysis was performed to determine the association of parity types with sexual dysfunction. A p-value of less than 0.05 was accepted as statistically significant. All variables were expressed with 95% confidence intervals (CI).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
During the study period, a total of 1106 women presented to the gynecology outpatient clinic. Due to physical limitations and the time required for the completion of the FSFI, every third presenting patient was selected. As a result, 482 women were asked to participate in the study, and 363 women (75.3%) gave consent and completed the FSFI. The questionnaires of 114 illiterate women (31.4%) were completed by the investigators in compliance with the responses obtained. Completion of the FSFI took 10-15 minutes for literate women and 20-25 minutes for illiterate women.
Socio-demographic characteristics
The socio-demographic data of the participants are summarised in Table 1. Of 363 participating women, 44, 61, 126 and 132 were classified as nulliparous, primiparous, multiparous (2-4 deliveries) and grand multiparous women, respectively. The overall mean age was 30.1±7.8 years (range 19-56). The overall mean age at marriage was 19.9±3.9 years (range 11-30). There were no significant differences in total FSFI and subdomain scores between women having normal vaginal delivery and C-section.
Incidences of sexual dysfunction
The overall mean FSFI total score was 25.0±4.8, which was below the cut-off value of 26.55, indicating sexual dysfunction in 205 women. The overall incidence of sexual dysfunction was 57.3%, being 38.6%, 54.1%, 61.2%, and 65.9% among nulliparous, primiparous, multiparous (2-4 deliveries), and grand multiparous women, respectively.
Between-group comparisons
For group comparisons, multiparous women were further classified into two groups, i.e., multiparous women having 2-4 deliveries (n=126) and grand multiparous women (n=132). Comparisons of the four groups with respect to sociodemographic features and FSFI scores are presented in Table 2. Illiteracy rates were significantly higher among grand multiparous women than among primiparous. The four groups were similar with respect to age at marriage, education status, and area of residency (p>0.05). Total FSFI and Orgasm scores were significantly higher among nulliparous, primiparous, and multiparous (2-4 deliveries) women than among grand multiparous women (p<0.05). In addition, grand multiparous women had a significantly higher incidence of sexual dysfunction compared to nulliparous women (65.9% vs 38.6%, p=0.014). Nulliparous, primiparous, and multiparous (2-4 deliveries) women had similar total FSFI and subdomain scores as well as similar incidences of sexual dysfunction (Table 2).
Univariate and binary regression analysis
The results of univariate and binary regression analyses are summarised in Table 3. Grand multiparous status showed a significant inverse association with the orgasm score. Multiparous (2-4 deliveries) and grand multiparous status were in significant associations with sexual dysfunction (for multiparity with 2-4 deliveries, OR:2.05, 95% CI 1.02-4.14, p=0.045; for grand multiparity OR:3.07,95% CI 1.52-6.22, p=0.002).
Discussion
We evaluated the impact of parity on sexual dimensions as determined by the FSFI scores among Somali women. To our knowledge, this is the first study in Somalia to examine the sexual impacts of parity in monogamous marriages. Similar studies are extremely rare and have been conducted in regions other than Africa [1, 7, 8], with none addressing sexual dysfunction among grand multiparous women. Previous studies on sexual dysfunction have primarily been performed in the presence of conditions that may adversely affect sexual function, such as cancer, diabetes, menopause, infertility, and pregnancy [9-12].
In our sample, grand multiparous women accounted for more than a third of the participants (36.4%) and had significantly lower total FSFI and orgasm scores than each of the other parity groups (nulliparity, primiparity, and multiparity with 2-4 deliveries), as well as a significantly higher incidence of sexual dysfunction compared to nulliparous women. These findings were consistent with the results of univariate and binary regression analyses, where grand multiparity showed a significant inverse association with orgasm in univariate analysis, and both multiparity with 2-4 deliveries and grand multiparity showed significant associations with sexual dysfunction in binary regression analysis. Importantly, the overall incidence of sexual dysfunction was considerably high (57.3%) in the cohort, representing the third highest incidence across all sub-Saharan Africa (SAA) countries, following Nigeria (80%) [13] and Ethiopia (68%) [7]. No studies from Africa investigated sexual dysfunction based on parity. Moreover, we found a remarkably increased incidence of sexual dysfunction at 38.6% among nulliparous women, which merits further studies in this population.
Our findings showed an incremental rise in the incidence of sexual dysfunction through the forms of parity from nulliparity to grand multiparity, with the latter showing a significant difference with the former. However, a study from Iran reported an inverse relationship; hence, the greater the parity, the greater sexual activity compared with primiparous women [8]. This discrepant finding may be due to the fact that the FSFI was completed by the participants between 2 and 12 months’ postpartum. Another study from Finland compared multiparous and nulliparous women and found orgasm and pain problems to a lesser extent and more satisfaction with sexual activity among multiparous women [14].
Limitations
Although our study provides clear-cut data with a considerably large sample size about the levels of sexual dysfunction among Somali women in a wide spectrum of parity, it reflects a single-centre experience. It thus may not be representative of the general population.
Conclusion
Our study points to a relatively overlooked issue concerning sexual dysfunction, the effects of parity on sexual function. Our findings suggest that particularly grand multiparous women experience more adverse effects as to orgasm and sexual function. Further studies are needed on the relationship of parity with sexual function.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Adil Barut, Deka Omer Mohamud. The impact of parity on sexual function in Somali women: A prospective study. Ann Clin Anal Med 2023;14(Suppl 2):S192-196
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Incidental bilateral synchronous invasive breast cancer in a patient with low back pain
Berrin Papila Kundaktepe 1, Vedat Durgun 1, Ergin Erginoz 1, Meltem Pekpak 2, Sennur Ilvan 3
1 Department of General Surgery, 2 Department of Internal Medicine, 3 Department of Pathology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey
DOI: 10.4328/ACAM.20890 Received: 2021-10-09 Accepted: 2021-11-27 Published Online: 2023-09-23 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S197-199
Corresponding Author: Berrin Papila Kundaktepe, Department of General Surgery, Cerrahpaşa Tıp Fakültesi Yerleşkesi, İstanbul Üniversitesi, Kocamustafapaşa Caddesi, No:53, 34098, Fatih, İstanbul, Turkey. E-mail: papilaberrin@yahoo.com P: +90 532 493 34 74 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4394-3976
Bilateral synchronous invasive breast cancer is rare with an incidence of less than 3%. In the majority of the patients, the contralateral breast tumor is often diagnosed when noticing the lesion in the other breast during the physical examination due to a mass. Infrequently, the patient may be totally asymptomatic, as seen in this presented case. In this report, we present a rare case presenting with low back pain, which was then incidentally diagnosed as bilateral breast carcinoma.
Keywords: Invasive Ductal Carcinoma, Bilateral Breast Cancer, Synchronous Tumor
Introduction
Breast cancer is the most frequently occurring cancer and the second leading cause of cancer death in women worldwide. Coping with the burden of breast cancer necessitates a deep understanding of the underlying etiology and a special focus on community screening programs. Various risk factors have been associated such as advanced age, female gender, personal or a family history of breast cancer, histological abnormalities such as lobular carcinoma in situ and proliferative changes with atypia, BRCA mutations, early menarche, late menopause, nulliparity, and exogenous hormone use [1]. Although it has been attributed to be the most common cancer type in women, bilateral breast cancer is rare and occurs in 1 to 2.6% of all patients with breast carcinoma [2]. In this report, we present a rare case presenting with lower back pain without any breast-related complaints, which was later incidentally diagnosed as bilateral breast carcinoma. This case is unique because a synchronous tumor in the breast is rare, especially when it is diagnosed incidentally in the search for another pathology.
Case Report
A 67-year-old female patient presented to the outpatient clinic for lower back pain. She was multiparous with 6 children, and her past medical history was unremarkable. There was no known disease in her family history, and there was no genetic disease running in the family. Complete physical examination was normal and laboratory parameters were within normal limits. Lumbar magnetic resonance imaging (MRI) revealed a focal lesion with suspected metastasis within the L5 vertebra corpus (Figure 1). Positron emission tomography/computerized tomography (PET/CT) did not show any F-18 fluorodeoxyglucose (FDG) uptake in the vertebra, however, lesions with FDG uptake were observed in both breasts (Figure 2). The patient underwent breast ultrasonography and mammography, which revealed solid lesions with high suspicion of malignancy (BIRADS 4C), and histopathological examination was recommended (Figure 3). Tru-cut biopsy from the lesion in the right inner lower and left inner lower quadrants of the breasts revealed bilateral invasive ductal carcinoma. Bilateral modified radical mastectomy was performed. The pathological specimen was consistent with invasive ductal carcinoma in the right inner lower quadrant of the right breast with a diameter of 0.9 cm. Axillary lymph nodes were negative for cancer cells (0 out of 19 lymph nodes). In the left breast, an invasive ductal carcinoma 0.7 cm in diameter and an accompanying ductal carcinoma in situ were detected in the inner lower quadrant. Axillary lymph nodes were also negative in the left breast (0 out of 15 lymph nodes). Estrogen and progesterone receptors were reported positive and Cerb-B2 (Her2/neu) was negative for both tumors. After the operation, the patient used tamoxifen as an adjuvant therapy for two years. After five years of follow-up, the patient was disease-free without any complaints.
Discussion
Bilateral synchronous invasive breast cancer is rare with an incidence of less than 3% [2]. The most common presenting symptoms are usually a breast lump, pain in the breast, and nipple discharge. A lump in the breast is the most common complaint and has a high predictive value for malignancy [3-5]. Physical examination is crucial, and imaging modalities such as breast ultrasonography and mammography are key in guiding the clinician for further patient management. Given the rare presentation of this patient, however, the initial diagnosis was established with a PET/CT, unlike the traditional imaging modalities used in breast cancer diagnosis.
Cross-sectional studies estimate that by the year 2040, breast cancer will be the most common cancer [6]. Despite this increasing breast cancer incidence trends, death from breast cancer alone is expected to decline, which is attributed to improved screening and treatment modalities such as the increased usage of mammography and the adoption of endocrine therapy. [7-9] There still exists a window of opportunity to decrease breast cancer-related deaths by increasing access to high-quality prevention programs and offering better care through various treatment services.
The incidence of a carcinoma presenting in both breasts is nearly 3%, where the presence of a synchronous tumor is 0.6% and the presence of a metachronous tumor is 2.2% [10]. They may result from genetic predisposition, environmental risk factors, or an accumulation of various events throughout the lifetime [11]. A patient with a history of breast cancer is almost five times more likely to develop contralateral breast cancer than those who are unaffected [12]. Therefore, it is essential to continue screening individuals with a history of breast cancer who have already received treatment and who were already cured.
Treatment of breast cancer is stage-dependent and should be patient-tailored to meet the needs of each individual. Nonmetastatic cancers are usually treated with surgical resection and sampling or removal of the axillary lymph nodes, and postoperative radiation therapy can be considered. Neoadjuvant or adjuvant systemic therapies may be administered where hormone-positive tumors are treated with endocrine therapy, ERBB2 positive tumors are treated with the monoclonal antibody trastuzumab, and triple-negative tumors are treated with chemotherapy alone [13]. Treatment of metastatic breast cancer is mostly palliative, but the same principles apply [13].
Conclusion
Breast cancer is the most common type of cancer among women and a common cause of cancer death. Studies suggest an increasing trend in the incidence of breast cancer in the future but a decrease in mortality due to improved screening programs and treatment modalities. Clinicians should keep in mind that not all women will present with typical symptoms of breast cancer, which were all absent as seen in this case. Rarely, a bilateral carcinoma can be detected. Hence, a thorough history taking, performing a complete physical examination, and choosing the correct radiological imaging modality can help a physician manage a patient and be able to detect tumors at an early stage.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
Funding: None
References
1. Arif S, Baloch Q, Zaheer F, Agheem R, Ariff M, Ahmed M. The adequate breast cancer knowledge assessment: A cross-sectional study done among nonmedical women of Karachi. J Educ Health Promot. 2018;7:169.
2. Khairy GA, Guraya SY, Ahmed ME, Ahmed MA. Bilateral breast cancer. Incidence, diagnosis and histological patterns. Saudi Med J. 2005 Apr;26(4):612-5. Erratum in: Saudi Med J. 2005;26(8):1316.
3. Koo MM, von Wagner C, Abel GA, McPhail S, Rubin GP, Lyratzopoulos G. Typical and atypical presenting symptoms of breast cancer and their associations with diagnostic intervals: Evidence from a national audit of cancer diagnosis. Cancer Epidemiol. 2017;48:140-6.
4. Walker S, Hyde C, Hamilton W. Risk of breast cancer in symptomatic women in primary care: a case-control study using electronic records. Br J Gen Pract. 2014;64:e788–93.
5. Redaniel MT, Martin RM, Ridd MJ, Wade J, Jeffreys M. Diagnostic intervals and its association with breast, prostate, lung and colorectal cancer survival in England: historical cohort study using the clinical practice research datalink. PLoS One. 2015;10(5):e0126608.
6. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708.
7. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
8. Jamal A, Phillips E, Gentzke AS, Homa DM, Babb SD, King BA, et al. Current cigarette smoking among adults: United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(2):53-9.
9. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Sauer AG, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438-51.
10. Megaro G, Rossi L, Ceddia S, Sinjari M, Mannino A, Gozzi E, et al. Synchronous and Metachronous Metastatic Breast Cancer, with Different Histology and Opposite Immunophenotype, Treated with Combination of Chemotherapy, Anti-Her2, and Endocrine Therapy: A Case Report. Case Rep Oncol 2020;13:544-549.
11. Dawson PJ, Maloney T, Gimotty P, Juneau P, Ownby H, Wolman SR. Bilateral breast cancer: one disease or two? Breast Cancer Res Treat. 1991;19(3):233–44.
12. Vaittinen P, Hemminki K. Risk factors and age-incidence relationships for contralateral breast cancer. Int J Cancer. 2000;88(6):998–1002.
13. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019;321(3):288–300.
Download attachments: 10.4328.ACAM.20890
Berrin Papila Kundaktepe, Vedat Durgun, Ergin Erginoz, Meltem Pekpak, Sennur Ilvan. Incidental bilateral synchronous invasive breast cancer in a patient with low back pain. Ann Clin Anal Med 2023;14(Suppl 2):S197-199
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Gaucher disease and SARS-CoV-2 infection: A case report
Nafiye Urgancı 1, Nazan Dalgıc 2, Dilek Guller 1, Merve Usta 1
1 Department of Pediatric Gastroenterology, 2 Department of Pediatrics Infectious Diseases, Health Sciences University, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21229 Received: 2022-05-15 Accepted: 2023-04-29 Published Online: 2023-08-08 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S200-202
Corresponding Author: Nafiye Urganci, Department of Pediatric Gastroenterology, Health Sciences University, Sisli Hamidiye Etfal Training and Research Hospital, Sariyer, Istanbul, Turkey. E-mail: nafiyeurganci@yahoo.com P: +90 212 338 63 00 F: +90 212 338 63 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4854-507X
Gaucher disease is an autosomal recessive genetic disorder, caused by deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of glucosylceramide in macrophages. It causes splenomegaly, hepatomegaly, cytopenia, and bone lesions associated with infiltration of bone marrow, spleen, and liver by Gaucher cells. A new coronavirus named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causing severe acute respiratory disease, emerged in China in December 2019. Most of the infected children appear to be asymptomatic or have a milder clinical course in contrast with adults. Herein, we report a pediatric case of Gaucher disease with SARS-CoV-2 infection.
Keywords: Gaucher, SARS-CoV-2, Enzyme Therapy
Introduction
Gaucher disease (GD), the most common sphingolipidosis, is an autosomal recessive genetic disorder, caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of glucosylceramide in macrophages [1].
Three clinical forms have been identified as type 1 (adult or non-neuronopathic type),which is the most common (95%) and typically causes no neurological damage [1].
Although most of the infected children with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) appear to be asymptomatic or have a milder clinical course in contrast with infected adults [2], severe cases have been reported in children with underlying chronic diseases, comorbidity, immunosuppression, and in the younger pediatric age group [3]. Currently, there is no sufficient data if patients with GD have a higher risk of SARS-CoV-2 infection or whether it causes a more severe clinical course. A pediatric case of Gaucher disease with SARS-CoV-2 infection was presented in this report.
Case Report
An eleven-year-old boy has been followied with the diagnosis of GD type 1 in the department of pediatric gastroenterology since 2013. He received enzyme replacement treatment (ERT) (60 U/kg/2 weeks). In his routine follow-up, he had a cough and when questioned we learned that his mother had a SARS-CoV-2 infection.
In his physical examination, his weight was 24 kg (<3rd centile) and his height was 126 cm (3-10th centile). The fever was 36˚C. His oropharyngeal examination was normal. His abdomen was soft. He had no dyspnea and auscultation revealed.
Nasopharyngeal swabs were obtained for the detection of SARS-CoV-2 RNA. The laboratory examinations revealed positive reverse real-time polymerase chain reaction (rRT-PCR) for SARS-CoV-2. The complete blood count revealed low hemoglobin (Hb), low mean corpuscular volume (MCV), elevated red cell distribution width (RDW), and increased platelet count. Biochemical parameters were within normal limits except for decreased creatinine, increased ferritin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Coagulation tests were within normal limits. D-dimer was elevated. The laboratory findings are shown in Table 1.
Computed tomography (CT) of the chest revealed increased emphysematous aeration in both lungs, accompanying sequelae fibrotic densities, and band-style atelectatic areas. The patient was out of follow-up for the last two years and thus could not take ERT. Due to lack of treatment, lungs were affected, and these CT findings were attributed to GD itself not SARS-CoV-2 infection.
ERT was not delayed. In the observation period after ERT, no clinical decompensation was observed. Second rRT-PCR for SARS-CoV-2 from nasopharyngeal swabs in the second week was negative. D-dimer decreased. The patient was asymptomatic and no change was detected in his physical examination. Written informed consent was taken.
Discussion
The standardized birth incidence of GD in the general population varied from 0.39 to 5.80 per 100 000, and the prevalence ranged from 0.70 to 1.75 per 100 000, higher among the Ashkenazi Jewish population [4], and 2.3/1000000 in our country [5]. The most common type of GD, type 1 is characterized by hepatomegaly, splenomegaly, anemia, thrombocytopenia and bone involvement. Treatment consists of intravenous ERT (imiglucerase, velaglucerase, or taliglucerase) and oral inhibitors of glucosylceramide biosynthesis (miglustat or eliglustat) [1]. Our patient had dispnea, hepatosplenomegaly and bicytopenia on admission in 2013. Examinations revealed Gaucher cells in bone marrow aspiration and deficient beta-glucosidase enzyme activity in leukocytes (200-2000pmolspot.20h- Hamburg University Medical Center). He had homozygous c. 1448T>C (rs421016) (p.L483P) mutation. He was started on (60 U/kg/2 weeks) ERT.
Patients with several rare metabolic and genetic diseases are likely to be at risk of life-threatening acute metabolic decompensation and severe clinical course in case of SARS-CoV-2 infection [6]. It has been proposed that both GD and SARS-CoV-2 appear to be characterized by lysosomal involvement or disruption, and both share the central role of proinflammatory responses, triggering autoinflammatory cascades involving a wide spectrum of myeloid cells, cytokine/chemokine secretion and NLRP3 inflammasome activation, and elevation of cytokines (IL-2R, IL-6, IL-10, MIP1-α and TNF-α) [7].
Mistry et al. [7] recommended that ERT should be continued without prolonged interruption, which could trigger hyperinflammation and potentially exacerbate the severity of SARS-CoV-2 infection. ERT was postponed only 3 days in our patient. In the observation period after ERT, no clinical decompensation and worsening of laboratory parameters were observed.
A link has been reported between SARS-CoV-2 and pediatric multi-system inflammatory syndrome disease causing cardiogenic or vasogenic shock requiring intensive care, and it is not yet established whether patients with GD have a risk of severe SARS-CoV-2 infection.
Conclusion
Physicians should consider these patients at risk and be alert about early testing and diagnosis. Although a definite interpretation can not be made with a single case, we think that ERT should not be interrupted, with close follow-up in order not to disrupt treatment of disease.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017;18(2):441.
2. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663-65.
3. Çokuğraş H, Önal P. SARS-CoV-2 infection in children. Turk Pediatri Ars. 2020;55(2):95-102.
4. Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology. 2017;22(2):65-73.
5. Ozkara HA, Topcu M. Sphingolipidoses in Turkey. Brain Dev. 2004;26(6): 363-6.
6. Brunetti-Pierri N, Fecarotta S, Staiano A, Strisciuglio P, Parenti G. Ensuring continuity of care for children with inherited metabolic diseases at the time of COVID-19: the experience of a metabolic unit in Italy. Genet Med. 2020;22(7):1178-80.
7. Mistry P, Balwani M, Barbouth D, Burrow TA, Ginns EI, Goker-Alpan O, et al. Gaucher disease and SARS-CoV-2 infection: Emerging management challenges. Mol Genet Metab. 2020;130(3):164-9.
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Nafiye Urgancı, Nazan Dalgıc, Dilek Guller, Merve Usta. Gaucher disease and SARS-CoV-2 infection: A case report. Ann Clin Anal Med 2023;14(Suppl 2):S200-202
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Reconstruction with hamstring autograft of atraumatic simultaneous ruptures of the bilateral quadriceps tendons: A novel technique
Burak Kuscu 1, Fatih Dogar 2, Duran Topak 2, Yakup Ekinci 3, Kaan Gürbüz 3
1 Department of Orthopaedics and Traumatology, Kahramanmaras Pazarcık State Hospital, Kahramanmaras, 2 Department of Orthopedics and Traumatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, 3 Department of Orthopaedics and Traumatology, Kayseri City Education and Research Hospital, Kayseri, Turkey
DOI: 10.4328/ACAM.21569 Received: 2023-01-01 Accepted: 2023-04-29 Published Online: 2023-05-04 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S203-206
Corresponding Author: Burak Kuscu, Department of Orthopaedics and Traumatology, Kahramanmaras Pazarcık State Hospital, 46700, Pazarcık, Kahramanmaras, Turkey. E-mail: dr.burakkuscu@hotmail.com P: +90 507 192 73 13 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1082-2206
Bilateral spontaneous quadriceps tendon rupture is a very uncommon phenomenon recorded in a few cases, but unilateral traumatic quadriceps tendon rupture is a rather common orthopedic pathology. In addition, it is related to systemic (e.g., diabetes mellitus, hyperparathyroidism, gout, pseudogout, obesity, steroid usage) and autoimmune diseases as well as most chronic renal failure (CRF). The occurrence of bilateral atraumatic simultaneous quadriceps tendon ruptures in CRF is most likely associated with the duration of renal disease and the duration of dialysis. Here we present an atraumatic spontaneous rupture of both quadriceps tendons with tendon hamstring autograft in a previously diagnosed male patient with CRF repaired using a novel reconstruction technique. This technique, which we use in quadriceps tendon repair, is an easy and effective method that shows excellent results in early rehabilitation and knee joint movements and prevent early re-rupture.
Keywords: Quadriceps Tendon, Rupture, Reconstruction, Chronic Renal Failure, Novel Technique
Introduction
Bilateral spontaneous simultaneous rupture of the quadriceps tendon is very rare and almost always related to comorbidities although unilateral quadriceps tendon rupture is a relatively common injury [1]. Spontaneous tendon ruptures, characterized by uremic tendinopathy, were seen in about 15% of patients with CRF. Bilateral concurrent atraumatic quadriceps tendon ruptures in chronic kidney disease are almost certainly related to the duration of the renal disease and the duration of dialysis [2].
Here we present a case of a previously diagnosed CRF male patient, repaired with the new reconstruction technique, an atraumatic spontaneous rupture of bilateral quadriceps tendons with tendon autografting.
Case Report
A 40-year-old male patient who had been on dialysis for 10 years due to CRF was standing after a routine dialysis session without any known trauma. As a result, a crunch from both knees was heard, as was an immediate beginning of pain. The patient was then unable to stand or ambulate after that. On physical examination at the emergency department, a severe effusion was noted in the suprapatellar space in both knees. Moreover, no active extension against gravity was feasible, and patellar reflex could not be induced on either side. A 1–1.5 cm gap was found at the attachment site of the quadriceps tendons to the superior patella on palpation in the suprapatellar region of the bilateral knees (Figure 1a). X-ray findings showed a patella Baja image in both knees. Both knees had radiographic indications of osteoarthritis, including restricted joint space, osteophyte forms, and subchondral sclerosis (Figure 1b). In both knee joints, T2-weighted magnetic resonance imaging (MRI) revealed a discontinuity between the distal quadriceps tendon and the upper pole of the patella, with the intervening region filled with hyperintense signal intensity in stark contrast to the tendon’s hypointense signal intensity. Additionally, on both sides, a minor joint effusion was observed in the suprapatellar region (Figure 1c).
Surgical Technique
The patient was applied spinal anesthesia and was placed in the supine position. Consequently, preoperative surgical preparations were performed. Approximately 3- to 4-cm longitudinal incision was made first through the proximal and distal of the right knee patella superior pole (Figure 2a). A massive hematoma in the suprapatellar space was cleared after the dissection (Figure 2b). A large gap with full-thickness quadriceps tendon rupture at the enthesis region on the proximal pole of the patella was observed (Figure 2c). A 2- to 3-cm incision was performed at pes anserinus muscle insertion region area, and the semitendinosus and gracilis tendon grafts were removed. Both tendons were augmented with a 2/0 vicryl suture with the Krackow suture technique, and their proximal and distal ends were sutured with the Krackow technique. The distal end of the quadriceps tendon rupture line was debrided and refreshed. The central medial and lateral parts of the ruptured quadriceps tendon were sutured with 1/0 vicryl using the Krackow suture technique. These threads were tunneled to the superior center of the patella with two 1.2-mm K-wires and passed through the patella bone. These suture threads were pulled to the patella superior to the distal part of the quadriceps tendon, and tight knots were tied at the superior margin of the patella (Figure 2d). Afterward, a 4.5-mm transverse tunnel was then opened from the superior central part of the patellar bone (Figure 2e, f). A semitendinosus autograft was passed through this tunnel (Figure 2g). Moreover, the sutured ends of this autograft were passed through the distal medial and lateral portions of the quadriceps tendon and were tightly stitched on themselves (Figure 2 h, i). The same procedures were performed on the left knee using a gracilis tendon autograft.
Postoperative rehabilitation
The patient recovered without incident following surgery, which included an initial phase of continuous passive movement from 0 to 30 and then complete weight-bearing mobilization with a locking knee brace. The knee brace’s flexion angle increased day by day as the patient gained control. At the end of the second month, he was able to flex the knee to 120 degrees and resumed his quadriceps-strengthening workouts. The patient was mobilized on crutches for 2 months before active weight-bearing was allowed.
Postoperative outcomes
At the end of the 12-month follow-up, the patient was nearly pain-free except for some mild discomfort while ascending or descending stairs, which was consistent with the arthritic changes, and he was able to walk without assistance. His quadriceps strength was rated 4+/ 5, and he was able to do a straight-leg lift with a range of motion of 0 to 130. He was able to perform an active extension of both knees with less than <5° of extension lag in either knee (Figure 3a, b) with a healing view on the X-rays (Figure 3c). In addition, the Lysholm score was 91points (limp=5, support=5, locking= 15, instability=20, pain=20, swelling=10, stairs=10 squatting=6), and based on the Lysholm criteria, it was an excellent result.
Discussion
In this case, in addition to the primary repair of bilateral quadriceps tendon rupture by opening a hole in the patella with a parallel double-row Krackow suture technique, unlike the literature the hamstring autograft was passed through a transverse tunnel in the patella and reconstructed end-to-end to the quadriceps tendon. We used this technique to prevent quadriceps tendon rupture and to start early knee movements of the patient.
The quadriceps tendon rupture mechanism occurs most frequently as a result of a fast, eccentric contraction of the quadriceps muscle when standing on one foot and partially flexing the knee, as a result of a fall or direct blow [3]. Moreover, bilateral simultaneous ruptures are extremely rare and strongly associated with systemic illnesses. In the patient of the current study, the diagnosis of CRF and quadriceps tendons were detached from the upper pole of the patella, which is similar to situations in the literature.
Surgical treatment and subsequent immobilization followed by physiotherapy protocol are the most used and recommended treatment protocols. Moreover, this treatment protocol reduces the risk of tendon rupture and the time required to return to a functional range of motion [3].
In the literature, the transosseous suture method, which is passed through the tunnels opened in the patella, is the preferred choice for use, although different methods are defined in surgical treatment. Krackow described the transosseous method in which a single thread is used [4].
Several augmentation procedures for quadriceps tendon regeneration include wire reinforcement, Mersilene tape, and Dacron vascular and carbon fiber grafts [5]. Alternatively, autologous tissues have been used [6].
In the study by Leopard et al. [7], the m. semitendinosus and m. gracilis tendons were sutured together because end-to-end repair could not be performed for the quadriceps tendon. This obtained tendon was passed through the transverse tunnel in the patella and passed several times to bridge this defect in the quadriceps tendon. In another study carried out by Unlu et al. [8], two autograft tendons were used, and the quadriceps tendon was sutured end-to-end, then passed through the patella in the same way and sutured to the patellar tendon differently after passing through the quadriceps tendon. In our case report, different from the above study, after the quadriceps tendon was sutured to the patella with the end-to-end Krackow suture technique, a single autograft tendon was used, passed transversely through the patella, and passed through the quadriceps tendon medially and laterally, and then sutured onto itself.
The Lysholm score was determined by Unlu et al. as a mean value of 89 points (good results) [8]. In addition, the range of motion (ROM) at flexion and lack of extension of the knees were 120° and 10° in the study by Unlu et al. [8]. In our case, the Lysholm score was 91 points (excellent result), and ROM at flexion and lack of extension of the knees were 130° and < -5°, respectively.
The current surgical method, which was applied to the patient of this study with a diagnosis of CRF and bilateral quadriceps tendon rupture, did not have a re-rupture after 2 years of follow-up, and nearly a full range of motion was reached. However, there are no studies in the literature with long-term results, although several repair methods have shown excellent results for bilateral quadriceps tendon ruptures.
As a result, bilateral spontaneous quadriceps tendon rupture is an extremely rare condition and can be seen in patients with systemic disease. Reinforcement with the Krackow suture method with the help of hamstring autograft has shown that this technique is an easy and effective method, which shows excellent results in early rehabilitation and knee joint movements and helps avoid early re-rupture.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Ellanti P, Davarinos N, Morris S, Rice J. Bilateral synchronous rupture of the quadriceps tendon. Ir J Med Sci. 2012;181(3):423-5.
2. Lim CH, Landon KJ, Chan GM. Bilateral Quadriceps Femoris Tendon Rupture in a Patient with Chronic Renal Insufficiency: A Case Report. J Emerg Med. 2016;51(4):e85-e87.
3. Garner MR, Gausden E, Berkes MB, Nguyen JT, Lorich DG. Extensor Mechanism Injuries of the Knee: Demographic Characteristics and Comorbidities from a Review of 726 Patient Records. J Bone Joint Surg Am. 2015;97(19):1592-96.
4. Krackow KA. The Krackow suture: how, when, and why. Orthopedics. 2008;31(9):931-3.
5. Pocock CA, Trikha SP, Bell JS. Delayed reconstruction of a quadriceps tendon. Clin Orthop Relat Res. 2008;466(1):221-4.
6. Okay E, Turgut MC, Tokyay A. Quadriceps reconstruction with suture anchor and Achilles allograft combination in quadriceps tendon re-rupture after primary surgical repair: A novel technique. Jt Dis Relat Surg. 2021;32(3):798-803.
7. Leopardi P, Vico Gd, Rosa D, Cigala F, Maffulli N. Reconstruction of a chronic quadriceps tendon tear in a body builder. Knee Surg Sports Traumatol Arthrosc. 2006;14(10):1007-11.
8. Unlu MC, Kaynak G, Caliskan G, Birsel O, Kesmezacar H. Late repair of quadriceps tendon ruptures with free hamstring autograft augmentation and tension relief in patients with predisposing systemic diseases. J Trauma. 2011;71(4):1048-53.
Download attachments: 10.4328.ACAM.21569
Burak Kuscu, Fatih Dogar, Duran Topak, Yakup Ekinci, Kaan Gürbüz. Reconstruction with hamstring autograft of atraumatic simultaneous ruptures of the bilateral quadriceps tendons: A novel technique. Ann Clin Anal Med 2023;14(Suppl 2):S203-206
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Aortic valve replacement due to infective endocarditis in a 24-week pregnant patient
Ali Akdogan 1, Ahmet Coskun Ozdemır 2, Engin Erturk 1
1 Department of Anaesthesiology and Intensive Care, 2 Department of Cardiovascular Surgery, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
DOI: 10.4328/ACAM.21696 Received: 2023-03-18 Accepted: 2023-05-05 Published Online: 2023-05-14 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S207-209
Corresponding Author: Ali Akdogan, Department of Anaesthesiology and Intensive Care, Faculty of Medicine, Karadeniz Technical University, 61080, Trabzon, Turkey. E-mail: draliakdogan@yahoo.com P: +90 462 377 57 41 F: +90 462 325 53 98 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7592-3844
Infective endocarditis in pregnant women is mostly associated with a history of rheumatic or congenital heart disease and is very rare. Surgical mortality is high both for the mother and the fetus. In most cases, infective endocarditis in pregnancy has a subacute course and includes the mitral valve, but it may also rarely involve the aortic valve, as in our case. Hypothermia and rewarming during the cardiopulmonary bypass period may trigger fetal hypoxia and uterine contraction in these patients, which may adversely affect both the mother and the fetus. We present a 28-year-old female patient with extensive vegetations on the aortic valve due to infective endocarditis, who applied to the emergency department with complaints of dyspnea and consciousness at the 22nd week of her pregnancy.
Keywords: Cardiopulmonary Bypass, Infective Endocarditis, Aortic Valve Replacement, Pregnancy, Pulsatile Flow
Introduction
Infective endocarditis (IE) in pregnant patients lead to high maternal and fetal mortality [1,2]. Symptoms and findings that occur due to physiological changes during pregnancy may mask the findings of IE and challenge the diagnosis. Surgical mortality is high both for the mother and the fetus. In this article, an aortic-valve replacement of a 24-week pregnant patient who was diagnosed with aortic valve endocarditis is reported.
Case Report
A 22-week pregnant patient was admitted to the emergency room due to shortness of breath and exhaustion. The patient was transferred to the intensive care unit upon the detection of hemorrhage and infarction in brain MRI as she developed unconsciousness, disorientation and cooperation disorder on the second day. Upon the detection of the bicuspid valve, moderate aortic regurgitation and aortic valve vegetation on the patient’s Transthoracic Echocardiography, a Transesophageal echocardiography was performed. Two large vegetations, one at the tip of the non-coronary leaflet and one just beneath the aortic annulus were seen. Streptococcus gordonii was detected in the series of blood cultures. Surgery was recommended due the existent cerebral embolism and the vegetation that is larger than 1 cm. Heparinization of the patient was found risky by the Department of Neurology and it was decided to continue antibiotic treatment. Transesophageal echocardiography that was performed a week later showed that the vegetation on the ventricle surface reached 20×8 mm. Surgery was recommended again. The patient was informed about the maternal and fetal risks and she was operated on the following morning.
After median sternotomy and routine cannulation extracorporeal circulation was established. The patient was not cooled and the body temperature was not allowed to drop below 34 degrees Celcius. After x-clamping of the ascending aorta, the flow was switched to pulsatile flow. Magnesium-free isothermic blood cardioplegia was given in a retrograde fashion. The bicuspid aortic valve and destroyed tips of the cusps were seen. There was a large vegetation at the tip of the non-coronary leaflet and another one holding onto the endocardium extending into the left ventricle just beneath the right coronary cusp. Vegetations were excised (Figure 1). Below the right coronary and non-coronary commissure was a cavity about the size of 2×1 cm, filled with destructed myocardial tissue. These tissues were excised. A 23 Medtronic Hancock II (Medtronic Inc., Minneapolis, MN, USA) bioprosthesis valve was implanted using 16 pledgeted 2/0 polyester sutures. The surgical procedure was completed in routine fashion. The patient was extubated on the 5th postoperative hour. Fetal movements were normal in the fetal ultrasonography performed on the first postoperative day. The prosthetic aortic valve was found to be functioning normally during postoperative echocardiography. The patient was transferred to the infectious diseases department where the patient would be receiving further antibiotherapy. She was discharged uneventfully on postop 2st day.
A preoperative consent form was obtained from the patient.
Discussion
IE is rarely seen in pregnant patients and the incidence is reported to be 6/100000. Cardiac diseases during pregnancy are seen in 1-3% frequency and are responsible for 10-15% of maternal mortality [1,2].
Cardiac diseases that develop and generate during pregnancy can generally be treated medically as they have high maternal and fetal mortality. However, surgical treatment is sometimes needed in patients with IE. Treatment options for pregnant women with IE should be selected according to the intensity of endocarditis and the gestational age. Continuing without surgery should be a priority in cases where valve functions and structures are preserved, when the vegetation is in regress and when the risk of embolization is low. Criteria that are used in making a decision to operate should be the same as in a non-pregnant patient. The surgical option should always be considered to prevent maternal mortality.
Surgery was preferred in this case due to recurrent systemic embolization. Since the 24th week of the pregnancy is a critical stage for the fetus, the operation took place during pregnancy.
Hypothermia during cardiopulmonary bypass has been shown to cause uterine contractions and reduce placental blood flow. Moreover, hypothermia reduces the placental oxygen exchange [3]. Similarly, the warming phase after hypothermia causes contractions in the uterus, which initiates preterm labor [4]. For this reason, in this case, hypothermia was not applied, and the body temperature of the patient was kept above 33 degrees by using a heater blanket to tolerate the loss of heat from the surgical field. Magnesium was not added to the cardioplegia as it may reduce the heart rate of the fetus.
The pulsatile flow was used to increase fetal survival by creating physiological conditions. Even though this method is widely used in open heart surgeries during pregnancies nowadays, the superiority of pulsatile flow other than its theoretical advantages has not yet been proved [5]. Fetal bradycardia, which is formed during cardiopulmonary bypass, is prevented by increasing the pump flow. Fetal heart rate was monitored during surgery.
The delivery of the fetus in the last trimester of the pregnancy before the operation is seen a safe option. In this case, the cardiac operation was done during pregnancy as the patient was at the 24th week of the pregnancy.
In IE during pregnancy, one should be dynamic to prevent maternal mortality and the decision to operate should not be delayed due to pregnancy. Avoiding hypothermia during the operation and not adding magnesium in the cardioplegia is important to prevent uterine contractions. Besides that, the use of pulsatile flow has theoretical advantages.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Rex S, Devroe S. Cardiac disease in pregnancy. Best Pract Res Clin Anaesthesiol. 2022;36(1):191-208.
2. Meller CH, Grinenco S, Aiello H, Córdoba A, Sáenz-Tejeira MM, Marantz P, et al. Congenital heart disease, prenatal diagnosis and management. Cardiopatías congénitas, diagnóstico y manejo prenatal. Arch Argent Pediatr. 2020;118(2):e149-e61.
3. Kapoor MC. Cardiopulmonary bypass in pregnancy. Ann Card Anaesth. 2014;17(1):33-9.
4. Becker RM. Intracardiac surgery in pregnant women. Ann Thorac Surg. 1983;36(4):453-8.
5. Parry AJ, Westaby S. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg. 1996;61(6):1865-9.
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Ali Akdogan, Ahmet Coskun Ozdemır, Engin Erturk. Aortic valve replacement due to infective endocarditis in a 24-week pregnant patient. Ann Clin Anal Med 2023;14(Suppl 2):S207-209
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Genetic and immunological biomarkers in the diagnosis of pulmonary tuberculosis: A literature review for miRNA and cytokine characterization
Umit Karadeli 1, Meliha Merve Cicekliyurt 1,2
1 Department of Medical System Biology, School of Graduate Studies, 2 Department of Medical Biology, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey
DOI: 10.4328/ACAM.21502 Received: 2022-11-20 Accepted: 2022-12-31 Published Online: 2023-05-05 Printed: 2023-09-25 Ann Clin Anal Med 2023;14(Suppl 2):S210-214
Corresponding Author: Meliha Merve Cicekliyurt, Department of Medical Biology, Faculty of Medicine, Canakkale Onsekiz Mart University, 17100, Canakkale, Turkey. E-mail: mervemeliha@comu.edu.tr P:+90 286 218 0018 F: +90 286 218 37 38 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4303-9717
There is a sensitive interaction in the relationship between the Mycobacterium tuberculosis that causes tuberculosis disease (TB) and its host. This interaction significantly affects the course of the infection. Unfortunately, scientific studies continue without slowing down this disease, which remains popular among the infectious diseases with the highest mortality rate. Although the importance of genetics and the immune system in the host-bacteria relationship is emphasized, immunopathological events still need to be fully elucidated.
The molecular events between Mycobacterium tuberculosis and the host dictate the course of infection. Different expression levels of miRNAs in this infection continue until the polarization of macrophages. In addition, studies have shown that miRNAs also affect cytokine release in this cellular immune process.
This review aimed to reveal how M. tuberculosis affects the course of host miRNAs during active infection and how cytokine levels change due to this interaction by reviewing the recent literature. This study will discuss the implications of using miRNA profiles and cytokine levels as biomarkers for the onset, maintenance, and termination of active TB.
Keywords: Cytokine, Immunity, miRNA, Pro-Inflammation,Tuberculosis
Introduction
According to data from the World Health Organization, TB still ranks in the top 10 leading causes of death centuries after its discovery. Its popularity is maintained because 10 million people were still diagnosed with Tuberculosis in 2019 (available at: https://www.who.int/teams/global-tuberculosis-programme/tb-reports). However, Turkey’s 2020 Tuberculosis Control Report shows that the incidence has decreased to 14.1 per 100,000 (available at: https://hsgm.saglik.gov.tr/tr/tuberkuloz-istatistikler). This decline in incidence in Turkey and worldwide indicates that saving one life can prevent hundreds of thousands of people from becoming infected.
It is crucial to rapidly improve current diagnostics and treatments apart from the traditional ones through more technological and individualized approaches and to continue this fight against TB in a determined manner [1-3]. Despite the astonishing progress in diagnosing and treating TB since its inception and the decline in incidence, it seriously threatens public health.
M. tuberculosis is a bacillus-shaped bacterium that grows slowly in culture and can be stained with acid-alcoholic dyes thanks to the mycolic acid in its cell walls. Although this type of bacteria can infect many mammalian species, humans are the only reservoir, and, with some exceptions, the only transmission is from person to person [4].
M. tuberculosis can direct its relationship with its host through its many structural components. These structural components have formed a specific pathogenesis system for the bacterium. In fact, the extent of infection and the localization of the bacteria depend on the interactions between the bacteria and its host [5]. This pathogenesis manifests itself as an innate and acquired immune response.
The innate immune response is the initial response following recognition of the tubercle bacillus by host macrophages. This event triggers the host gene expressions and release of cytokines. Acquired immune response is the control and enhancement of an existing immune response [8]. CD4 and T helper cells play a major role in the adaptive immune response [6,7].
Cytokines and subgroups of cytokines are effective molecules that increase inflammation and proinflammation events and recruit other subgroups for cellular immunity. Studies have shown that TB’s cytokine levels are unevenly distributed [8,9]. This profile of cytokines can be used as diagnostic biomarkers and determination of the stage of the disease [8,10,11].
MicroRNAs (miRNAs) play a role in biological mechanisms, primarily through their control at the transcription level. The relationship of miRNAs, which came to the fore with cancer research and was later developed and studied in many diseases and agents in infectious diseases such as Tuberculosis, which has a high mortality rate, has been revealed [10,12,13,14].
miRNAs are generally 20-22 nucleotides long and are conserved across species [15]. Studies have shown that miRNAs have a role in immune system regulation against many pathogens, including M. tuberculosis [10,16]. miRNAs follow a similar pathway to macrophages in regulating the innate immune response. It also has significant roles in rearranging the host transcriptome to inhibit bacteria effectively [17].
Studies have also shown that M. tuberculosis predisposes to pathogenicity by restricting host-mediated antibacterial signalling pathways by using miRNAs. In contrast, the host response attempts to inhibit bacterial proliferation by increasing processes such as autophagy. The host provides this protection using miRNA [18].
Aim of the work
Despite advances in health technology, TB remains a threat today; it is evident that early diagnosis and treatment of this disease require quick steps to prevent contagion. Therefore, the purpose of this article is to present the successful results of early diagnosis and treatment in TB disease, based on the literature in addition to standard definitions and procedures, or even just recent developments, according to the cytokine and miRNA profiles in the host.
Tuberculosis immunology and cytokines
M. tuberculosis is an obligate intracellular bacterium. When bacteria enter the cell, they can escape from the immune system’s fighters thanks to their virulence factors and use the host’s defence system to their advantage. TB, a classic example of infection, can progress from latent to active disease according to the response of the host immune system [19].
Innate immune response and acquired immune response play a role in TB infection. The most critical step of the innate immune response is the early immune response. Bacteria, which overcome the host’s physical barriers, such as mucosa, and reach the alveoli, encounter macrophages here. The Toll-Like Receptor (TLR) in macrophages recognizes the bacteria, creates a signal against it, and invites other immune system elements to the environment [20]. “Pathogen-associated molecular patterns” (PAMP) released by bacteria stimulate the dendritic cells (DC) of the host [20,21]. Mycolic acids in bacteria can stimulate natural killer cells (NK). B and T cell-mediated systems have developed in the acquired immune response. Monoclonal antibodies released from B cells and CD4/CD8 released from T cells are primary molecules of the system [22,23]. IFN-γ, TNF-α, IL-6, and Interleukin1 beta (IL-1β) are major molecules in the early pro-inflammatory process. While IL-2 acts as an NK activator, IL-12 is the protective element of the immune system; IL-6 is involved in forming T and B-cell-mediated immune systems [23].
Cellular immunity together with cytokines are mediators of the inflammatory response in TB. It has been shown in studies that lymphocytes released from T cells stop infection by limiting bacterial growth [24]. In addition, activated oxygen radicals produced from macrophages are released into the environment with the help of cytokines released from T cells, especially IFN-γ and TNF-α [25]. Thanks to these radicals, bacterial death becomes inevitable. In addition, IL-13, IL-10, IL-5, and IL-4, which are T-helper two cytokines, affect the course of the disease (Figure 1) [24, 25].
Contrary to this system developed by the host, bacteria have developed a system according to themselves. M. tuberculosis has serious strategies to protect itself from the host’s defence system. They stimulate the release of IL-10 by T cells, and IL-10 release works inversely proportional to IFN-γ release. In this way, they develop a protective mechanism [26].
Seyedhosseini et al. [27] have determined the plasma levels of IL-17, IL-6, and TGF-β in healthy control groups, newly diagnosed active tuberculosis, and TB patients being treated. As a result, IL-6 plasma level was found to be higher in patients newly diagnosed when compared with both healthy subjects (P = 0.002) and TB patients receiving treatment (P<0.0001) [27]. For that reason, new therapeutic approaches against Tuberculosis aim to neutralize IL 6-induced cellular activation by lowering the IL 6 level via monoclonal antibodies. In addition, Adanwah and colleagues showed that IL-6 levels could be used as a marker for tuberculosis classification due to specific differences in IL-6 levels between tuberculosis patients and asymptomatic contacts [28].
IL-17 and TGF-β were significantly overexpressed in patients with active tuberculosis (newly diagnosed) compared to those on TB treatment and healthy individuals [28]. In addition, a study has shown that active and latent TB patients express elevated levels of IL-17 in their lung tissue samples, which is not shown in blood samples [29].
Mirzaei et al. [30] investigated TNF-α serum levels between the healthy control group and TB patients. According to these findings, they reported that TNF-α concentration was considerably higher in TB patients compared to the healthy group (P<0.05) [30].
MicroRNAs and biogenesis
In the miRBase online database, 38589 precursor and 48860 mature miRNAs are listed and available to researchers (Version 22.2, September 2022). miRNA maturation proceeds in stages. First, Drosha (RNA polymerase III) and a hairpin-shaped pre-miRNA are formed with a cofactor (DGCR8) and pri-miRNA. The pre-miRNA is then transported GTP-bound from the nucleus to the cytoplasm, where it continues to be processed. The pre-miRNAs in the cytoplasm bind to the Dicer enzyme, and this enzyme cuts to form mature miRNAs. This cut initiates the formation of RISC (RNA-induced silencing complex). As a result, one strand of this double-stranded mature miRNA is broken down, and the other strand joins with RISC. This splicing directs the miRNA to bind to the 3’ UTR region of the mRNA, and mRNA degradation occurs [31,32].
miRNAs and M. tuberculosis
miRNAs’ functions are increasing daily thanks to new-generation sequencing and advanced molecular techniques. Scientific studies have demonstrated the roles of miRNAs in metabolic diseases, infectious diseases, and even neurodegenerative diseases, especially in cancer. miRNA expression levels in host body fluids have been used in the early diagnosis and determination of the course of the disease in infectious agents. It is a drug target in viral infectious diseases such as hepatitis C [31].
The immune system works perfectly against factors such as Mycobacterium tuberculosis, an intracellular pathogen. Likewise, these intracellular pathogens have developed excellent mechanisms to ignore the host immune system. A situation that can be called a war of powers has arisen. As a result of the research, it has been shown that the most potent strategy implemented in this war is the miRNA mechanism [33].
miRNAs play critical roles in activating cytokine signaling, triggering immune system cells, developing, and even proliferation. It has been reported that miRNA varieties, including miR-155, miR-21, and miR-146a play significant roles in this immune response mechanism (Figure 2) [34].
miRNA-Cytokine Characterization in Tuberculosis Disease
During a bacterial infection, bacterial recognition by macrophages and phagocytosis are the most basic steps. M. tuberculosis is aware that this step is dangerous. This awareness has taught it to block the level of actin that promotes phagosome maturation. They developed this mechanism in the form of inhibition of proteins involved in the formation of actin. They achieve this inhibition by increasing miR-142-3p [35].
Cavusoglu C. et al. [36] investigated miRNA and cytokine characterization in TB disease by grouping them into active and latent Tuberculosis. They have contributed extensively to the literature by including M. tuberculosis genotyping, pre-treatment, and post-treatment follow-ups in their study group. Their study showed a statistically significant decrease in the expression of miR-449a, miR-38, miR-590-5p, miR-15a-5p, and miR-454-3p in the comparison of miRNA expressions between the patient group and the healthy control group before treatment. Compared to healthy controls, the cytokine expressions of the patient group before treatment decreased significantly. In contrast, no significant change in miRNA expression was obtained between the post-treatment and pre-treatment groups. After treatment, up to two-fold decreases in the expression levels of CCL8, CXCL10, IL17A, IFNG, TNF, IL2RG, TNFRSF1A and IL4 cytokines were detected in the case groups. These results suggest that increased virulence may indicate a delay in early pro-inflammatory response due to the complex activity of host immunity. When all groups were evaluated together, it was revealed that there was no clinically significant relationship between the course of the disease, miRNA and cytokine expressions and bacterial genotypes [36].
Ulger M. et al. [37], in a study comparing plasma levels of miRNA and some cytokines in TB and healthy control groups, detected significant upregulation of miRNAs mir-1, miR-7-5p, miR-10a-5p, miR-9-5p, miR-10b-5p, miR-15b-5p miR-16-5p, miR-25-3p, miR-100-5p, miR-106b-5p, miR-128 -3p, miR-133a-3p, miR-193a-5p, miR-210-3p, miR-143-3p, miR-200b-3p, miR-205-5p, and miR-296-5p in the patient group (p<0.05). In addition, IL-10, IL-1β, TNF-α, IFN-γ, and IL-8 levels were significantly higher in the TB group (p<0.05). These results indicate a correlation between miRNA and cytokine levels in forming the immune response against bacteria in TB disease. Only IL-4, IL-6, and IL-12/P40 levels were not significantly different (p>0.05). For rapid diagnosis of TB infection, combinations of miR-296-5, -5p, miR-10a-5p, miR-15b-5p, miR-10b-5p, miR-100-5p, miR-143-3p, miR-9, miR-200b-3p, miR-193a-5p, miR-210-3p and miR-1 were identified as potential noninvasive markers that consistent with immunological response [37].
In mycobacterial infections, bacteria have developed negative regulators to inhibit the immune response. Bacteria perform this negative regulatory mechanism through miRNAs. Thanks to these mechanisms, they can use macrophages as their main reservoir. They inhibit the production of pro-inflammatory cytokines from turning the immune response of macrophages positive for themselves. This critical balance between macrophages and mycobacteria determines the course of infection [38].
In a study investigating the role of miR-21 in M. bovis BCG and M. tuberculosis infections in mice, it was reported that miR-21 upregulation inhibited the production of proinflammatory cytokines and increased the production of the anti-pro-inflammatory (IL-10 and IL-12) cytokines. This result is cited in the literature as an effective strategy used by miR-21 to escape Mycobacteria’s host immune response and establish chronic infection [39].
Numerous studies describe the role of miRNAs in the regulation of inflammatory responses in M. tuberculosis-infected macrophages (Table 1).
Some miRNA species are listed in the literature and play a role in many different steps of the immune system. These miRNAs play a role in many immune events from lipid metabolism to apoptosis, from immune response to macrophage maturation and autophagy, as shown in Table 1.
Conclusion
TB is still one of the deadliest diseases, according to the criteria set by the WHO. Since it is a contagious disease that requires long-term treatment, it continues to be a “global health problem.” M. tuberculosis, the causative agent of TB, can maintain its life in macrophages for a long time by disrupting the host’s immune system. miRNAs are non-coding nucleotide sequences involved in many vital events and control mechanisms in the cell. It is evident that miRNAs, which have come to the fore with cancer studies, also have important roles in infectious diseases. Pro-inflammatory cytokines are essential in functioning cytokines and many other immune system mechanisms. Depending on the bacterium’s ability, the release of pro-inflammatory cytokines from host cells can be stopped, thus increased cytokines increase the likelihood that the bacteria will remain inside the macrophage.
According to the results, determining host mRNA levels in the early inflammation period may be a guide for meeting cytokine levels, preventing disease development, and therapeutic strategies. Studies on this subject are available in the literature. However, developing and conducting in vivo studies, increasing the number of case-control groups, and establishing multicenter research units will prevent early diagnosis and treatment of the global problem of TB.
Scientific Responsibility Statement
The authors accept full scientific responsibility for designing the study, collecting, analyzing, and interpreting data, writing the manuscript, preparing and scientifically reviewing the content, and approving the final version.
Animal and human rights statement
As the study is a review, it does not involve the use of laboratory/ other animals. This review includes studies previously recognized in the literature as having been published according to the statement, “All procedures performed in studies involving human participants conform to the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards”. Studies were not conducted by adding human participants again.
Funding: None
Conflict of interest
The authors declare that there is no conflict of interest.
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Umit Karadeli, Meliha Merve Cicekliyurt. Genetic and immunological biomarkers in the diagnosis of pulmonary tuberculosis: A literature review for miRNA and cytokine characterization. Ann Clin Anal Med 2023;14(Suppl 2):S210-214
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