December 2024
Comparison of community-acquired and nosocomial legionella pneumonia cases in Konya, Turkey
Hale Turan Ozden 1, Keziban Ucar 2
1 Department of Infectious Diseases and Clinical Microbiology, Health Sciences University, İzmir Tepecik Education and Research Hospital, İzmir, 2 Department of Emergency, Baskent University, Konya Application and Research Hospital, Konya, Turkey
DOI: 10.4328/ACAM.22058 Received: 2023-11-22 Accepted: 2024-04-02 Published Online: 2024-10-23 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):812-816
Corresponding Author: Keziban Ucar, Department of Emergency, Baskent University,, Konya Application and Research Hospital, Konya, Turkey. E-mail: dr_kezi@hotmail.com P: +90 505 740 09 83 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9188-0266
Other Authors ORCID ID: Hale Turan Ozden, https://orcid.org/0000-0003-1359-6205
Aim: Legionella pneumophila is an important cause of community and hospital-acquired pneumonia. The aim of this study was to compare the clinical findings, risk factors, and laboratory and radiological data of 20 nosocomial and 26 community-acquired cases with the diagnosis of L. pneumophila pneumonia between April 2017 and October 2019 retrospectively.
Material and Methods: Twenty patients with nosocomially acquired Legionella pneumonia (NALP), and twenty-six patients with community-acquired Legionella pneumonia (CALP) were included in the study. We applied the Centers for Disease Control (CDC) and World Health Organization (WHO) criteria for the diagnosis both of nosocomial infection and Legionella pneumonia. The diagnosis was based on the positivity of urinary antigen test for Legionella pneumonia (Acro Biotech, USA). Statistical analysis was performed using chi-square and independent student t-test using SPSS Statistics 25.0 program.
Results: Among the risk factors, older age was more common in the NALP group than in the CALP group, whilst chronic lung disease and cancer were more common in the NALP group than in the CALP group. The radiological features at presentation and during the evolution were similar in both groups. While CRP level was found to be high in the CALP group, ALT, AST, total and direct bilirubin levels, prothrombin time and INR values were significantly higher in the NALP group. Statistical analysis showed that myalgia was more common in the CALP group than in the NALP group. When both groups were compared in terms of mortality rates and SOFA and APACHE scores, no statistically significant difference was detected.
Discussion: As a result of our study, radiological and laboratory findings of the cases with community-acquired and nosocomial Legionella pneumonia in our region were found to be similar to previous studies.
Keywords: Legionella, Pneumonia, Nosocomial
Introduction
Legionella is a facultative, intracellular bacterium that penetrates and proliferates in the phagosomes of alveolar macrophages and serum monocytes [1]. Legionella pneumophila is one of the causative agents of hospital-acquired pneumonia, which can progress from a mild clinical picture to severe multiple organ failure and show a wide clinical spectrum in the population. It can cause epidemics, especially by colonizing water systems and being transmitted via aerosol in environments such as hotels and hospitals [2]. Legionella pneumophila is an important cause of community-acquired and hospital-acquired pneumonia. This infection, which can have both social and nosocomial origins, was first detected in 1976 [3]. Legionella Disease (LD), which is still often referred to as lung infections that present with different symptoms, is characterized by interstitial patterns on chest X-ray and typical bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus) [4, 5].
Although LD is transmitted from the environment through inhalation of aerosol containing the bacteria, outbreaks occur more frequently in sporadic form. Person-to-person transmission does not occur [2]. It is reported that the frequency of LD in community-acquired pneumonia requiring hospitalization in adults varies between 5-10% [2]. Diagnosis cannot be made easily due to nonspecific clinical findings, radiological features and the need for special laboratory tests. The most specific tests for diagnosis are the detection of Legionella antigen in culture and urine [6].
In this study, we aimed to compare the risk factors, clinical findings, and laboratory and radiological imaging findings in community-acquired and hospital-acquired Legionella pneumonia cases that we diagnosed and hospitalized in our hospital.
Material and Methods
This study was carried out at Başkent University Konya Application and Research Hospital between April 2017 and October 2019. Başkent University Konya Application and Research Center Hospital is a 200-bed hospital with Internal Medicine, Surgery, Gynecology and Pediatrics services, Hemodialysis, Kidney Transplantation unit and Intensive Care units. Patients hospitalized with the diagnosis of pneumonia and positive urine Legionella antigen test (Acro Biotech, USA) were included in the study. The study was conducted retrospectively by scanning patient files. A total of 46 patients were included in the study. 20 patients with nosocomially-acquired Legionella pneumonia (NALP), and 26 patients with community-acquired Legionella pneumonia (CALP) were included in the study. We applied the Centers for Disease Control (CDC) [7] and the World Health Organization (WHO) [8]. criteria for diagnosis both of nosocomial infection and Legionella pneumonia. Demographic information, extrinsic and intrinsic risk factors (Chronic lung disease, cancer, cardiopathies, steroid use, smoking habits, chronic renal failure, diabetes mellitus), clinical, radiological and laboratory findings of the selected patients were recorded. The patients’ hemogram, CRP, AST, ALT, LDH, prothrombin time, INR (International Normalized Ratio), total bilirubin, direct bilirubin, sodium potassium, procalcitonin, phosphorus levels and complete urinalysis were examined. The data were compared statistically. PA chest radiography and/or thorax computed tomography were taken from all patients. Mortality rates, APACHE (Acute Physiology and Chronic Health Evaluation) and SOFA (The Sequential Organ Failure Assessment) scores of the patients were calculated.
Statistical analysis
Collected data were recorded into the previously prepared forms. Statistical analysis was performed using chi-square and independent student t test using SPSS Statistics 25.0 program. Numeric values were reported as mean±standard deviation (SD). p<0.05 was accepted as significant.
Results
Among the risk factors, old age was more common in the NALP group than in the CALP group, whilst chronic lung disease and cancer were more common in the NALP group than in the CALP group. The difference for other risk factors, such as cardiopathies, chronic renal failure, diabetes, smoking habit, and corticosteroid therapy was not statistically significant (Table 1, p>0.05).
Some of the most common clinical manifestations are shown in the table. Statistical analysis showed that myalgia was more common in the CALP group than in the NALP group (p<0.05). The difference for other common clinical manifestations, such as fever, cough, sputum, chest pain, headache, confusion, dyspnea, abdominal pain, fatigue, anorexia, diarrhea was not statistically significant (Table 2, p>0.05).
Laboratory findings of both groups of patients were evaluated. (white blood cell count, CRP, hemoglobin, hematocrit, platelet count, AST, ALT, total bilirubin, direct bilirubin, prothrombin time, INR, sodium, potassium, LDH; CK; procalcitonin, phosphorus, hematuria). While CRP and CK levels were found to be significantly higher in the CALP group than in the NALP group; ALT, AST, total bilirubin, direct bilirubin, prothrombin time, and INR levels were found to be significantly higher in the NALP group compared to the CALP group (Table 3).
No significant statistical difference was detected between the two groups in terms of radiological findings (right lung infiltration, left lung infiltration, bilateral infiltration, pleural effusion and empyema) (Table 3). When both groups were compared in terms of mortality rates and SOFA and APACHE scores, no statistically significant difference was detected (Table 3).
Discussion
Clinically, community-acquired pneumonia (CAP) and hospital-acquired pneumonia are very similar and difficult to distinguish. Legionella pneumonia is more common in the elderly. However, CAP can be seen in all age groups [9]. In the first 24-48 hours, weakness, malaise, muscle aches and severe headache occur, then suddenly rising fever, patchy infiltration in the lung radiogram, dry cough, sometimes side pain, nausea, vomiting and diarrhea are detected as a factor in the atypical pneumonia table. Legionella pneumonia should be considered. Fever above 39-40°C, relative bradycardia, confusion, presence of hyponatremia, extrapulmonary symptoms and unresponsiveness to beta-lactam antibiotic therapy are other clues for Legionella pneumonia [2]. Legionella is a deadly pneumonia agent with a high mortality rate [6].
Unlike classical pneumococcal pneumonia, the symptoms of atypical pneumonia are insidious. Diagnosis is difficult because the clinical, radiological and laboratory findings are not as distinct as those of typical pneumonia, and the causative agents are intracellular microorganisms and do not grow in sputum culture. Diagnosis cannot be made easily because it has nonspecific clinical findings, radiological features, and the need for special laboratory tests [10].
PCR in sputum and bronchoalveolar lavage samples is the preferred diagnostic method in the diagnosis of Legionella pneumonia. PCR has a high diagnostic value and detects all Legionella serogroups [11]. In the diagnosis, an antigen test is performed in the urine, only L. pneumophila shows serogroup 1 and develops due to serogroup 1 in 85% of cases of pneumonia. The sensitivity of this test is 70%, and the specificity is 100 %. It should not be forgotten that Legionella antigen positivity in urine may last more than 300 days and other factors that may cause the current clinic should be excluded in the differential diagnosis [12]. In our study, we diagnosed Legionella with urine antigen, which has high specificity, since we could not access PCR test.
Patients with severe immunodeficiency and oncological/hematological malignancies are particularly at risk for the development of Legionella infection and the serious prognosis of the disease. Other malignancies, diabetes mellitus, chronic lung disease, smoking, old age (over 50 years of age) and male gender are also among the risk factors [13]. Determining risk factors is important in this sense, as the clinical course varies depending on the patient’s immune system, the presence of additional diseases, early treatment at the appropriate time and whether complications develop [14]. In our study, it was found that there was a difference in these risk factors between the NALP and CALP groups. In the NALP group, advanced age, malignancy and chronic lung disease frequency were determined as risk factors compared to the CALP group.
LD has a wide clinical spectrum that can range from mild cough, and fever to coma and affects many systems. It has been reported that the incubation period is 2-10 days, although the period is generally short in immunosuppressed people and can extend up to 20 days. The disease first begins with nonspecific findings such as fever, malaise, myalgia, headache, and nonproductive cough [6]. The most common clinical findings in our patients were fever, cough, shortness of breath, loss of appetite, fatigue, muscle pain, and chest pain and no difference was detected between the two groups in terms of symptoms other than myalgia. Myalgia was significantly higher in the CALP group. Diarrhea is a frequently observed gastrointestinal system symptom and is seen in 25-50% of cases [6]. Diarrhea complaints were less frequent on average in our cases and no statistically significant difference was detected between the two groups. In another study comparing the CALP and NALP groups, cough, chest pain, neurological symptoms (headache, confusion), and gastrointestinal symptoms (nausea, vomiting, diarrhea) were found to be significantly higher in the NALP group [15].
Studies have shown that LD most often appears as an airspace consolidation involving one of the lower lobes on lung radiographs, while pleural effusion and mediastinal lymphadenopathy are less common [5, 16].
It has also been suggested that the resolution of pulmonary infiltrates on chest radiographs takes longer than pneumonia caused by other pathogens [17]. In a more recent study, Poirier et al. showed that the early radiographic and tomographic signs of LD were similar to those found in community-acquired pneumonia of other bacterial origin [16]. In our study, when the chest radiographs of the patients were evaluated, it was seen that there was infiltration in all patients. When the regions where infiltrations were observed between the two groups were compared, no significant difference was detected between the groups. In the study conducted by Pedro-Botet et al., similar to our findings, no difference was detected between the two groups in terms of radiological findings [15].
In laboratory tests for Legionella pneumonia, elevated transaminases, creatinine phosphokinase and LDH, hyponatremia and hypophosphatemia may be observed [18]. In our study, CRP, AST, ALT, Prothrombin time and total bilirubin values were found to be higher in the NALP group. In the study conducted by Pedro-Botet et al., ALT elevation was found to be statistically significant in the NALP group [15].
Legionnaires’ disease ranges from mild to severe. In a case series of 214 patients hospitalized for Legionnaires’ disease, 47 percent had moderate/severe pneumonia (Pneumonia Severity Index IV to V) and 18 percent required intensive care unit (ICU) admission [19]. In other case series, 44 percent required ICU admission. Even in tertiary care centers, the mortality rate ranges from approximately 1 to 10 percent [19-21]. After ICU admission, mortality can be over 30 percent and some patients require extracorporeal membrane oxygenation [22]. In a recent study in which 50 patients were included in the study, the mortality rate was found to be 73% in cases in which 26% were diagnosed with hospital-acquired LD, and the SOFA score was found to be high in hospital-acquired cases [23]. However, in our study, we did not detect a statistically significant difference in mortality rates, SOFA and APACHE scores between the NALP and CALP groups.
As a result, since L. pneumophila pneumonia can progress with severe complications such as ARDS, tests for early diagnosis should be requested and treatment should be started without delay in cases where Legionella pneumonia is suspected based on anamnesis, clinical and laboratory findings. L. pneumophila can be both community and hospital acquired. In this study, we concluded that there may be differences in laboratory, clinical, risk factors and radiological imaging between community- and hospital-acquired Legionella pneumonia. We think that randomized, more comprehensive studies should be conducted to investigate the differences between community-acquired and hospital-acquired Legionella pneumonia.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Hale Turan Ozden, Keziban Ucar. Comparison of community-acquired and nosocomial legionella pneumonia cases in Konya, Turkey. Ann Clin Anal Med 2024;15(12):812-816
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Impacts of respiratory support methods on the prognosis of COVID-19 patients treated in the intensive care unit.
Nevin Aydın 1, Umut Karayalçın 2, Osman Esen 3
1 Department of Anaesthesiology and Reanimation, Faculty of Medicine, University of Health Science, Kanuni Sultan Süleyman Training and Research Hospital, 2 Department of Emergency, Faculty of Medicine, University of Health Science, Dr. Sadi Konuk Training and Research Hospital, 3 Department of Anaesthesiology and Reanimation, Faculty of Medicine, İstinye University, İstanbul, Turkey
DOI: 10.4328/ACAM.22063 Received: 2023-12-03 Accepted: 2024-03-19 Published Online: 2024-10-21 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):817-821
Corresponding Author: Nevin Aydın, Department of Anaesthesiology and Reanimation, Faculty of Medicine, Health Science University, Kanuni Sultan Süleyman Training and Research Hospital, 34303, İstanbul, Turkey. E-mail: nevinaydin4334@gmail.com P: +90 532 524 14 08 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0189-5865
Other Authors ORCID ID: Umut Karayalçın, https://orcid.org/0000-0002-7920-8693 . Osman Esen, https://orcid.org/0000-0001-6280-5064
This study was approved by the Ethics Committee of Clinical Research (Date:2020-10-27, No: 278)
Aim: The goal of this study was to investigate the impacts of respiratory support methods and duration of intubation on the prognosis in COVID-19 patients treated in a tertiary care center’s intensive care unit (ICU).
Material and Methods: The data was gathered from the medical files of 106 adult COVID-19 patients treated in the ICU of our tertiary care center for this retrospective analysis.
Results: The average age was 65.4 ± 14.9 years (24 to 93), and the rate of mortality was 64 .1 % (68 /106) in our series. The duration of ICU stay was 16.9±11.41 days (range: 1 to 60). The respiratory support methods used included continuous positive airway pressure (CPAP) (n=42, 39,6%), high flow nasal oxygen HF (n=28, 26.24%), urgent intubation (n=26, 24.5%), nasal oxygen support (n=6, 5,6%), and both CPAP and high flow nasal oxygen (n=4, 3,7%), respectively. No significant relationship was detected between prognostic outcome and duration of intubation (p=0.349), and duration of ICU stay (p=0.272).
Discussion: Critically ill patients with COVID-19 pneumonia have a high fatality rate. A well-established ICU and awareness of the implications of clinical data can maintain clinical standards and continue evidence-based practices that keep fatality rates low.
Keywords: COVID-19, Treatment, Prognosis
Introduction
Around the world, the COVID-19 epidemic continues to be a major public health problem. Although the scientific understanding of COVID-19 is expanding by the day, there is a paucity of data on the characteristics and outcomes of patients who require ICU admission [1]. Several studies have found that certain factors may be linked to an increased risk of hospitalization and fatality in COVID_19 patients. Advanced age (>60 years), obesity (BMI > 30 kg/m2), diabetes, hypertension, cardiovascular disease, a history of smoking, and chronic obstructive pulmonary disease (COPD) are just a few of them [2, 3].
At a high cost, the COVID-19 epidemic has taught us many significant medical, social, political, economic, and humane lessons. With a limited understanding of the virus, its transmission, community spread, and medical therapy of the disease at the time, our worldwide community’s response was reactive and cautious. Non-peer-reviewed publications, case reports, and case series with insufficient and non-standardized data resulted in techniques and clinical management that were not scientifically sound, thus exposing patients to potentially nonbeneficial or even hazardous treatment strategies [4, 5].
Application of sound scientific evidence-based management principles distilled from decades of research in the past, with some adjustments in practices specific to COVID-19, mitigation strategies, and the careful application of disaster management principles in times of surge has resulted in better and superior outcomes. This is supported by the fact that, while outcomes have varied significantly amongst centers, they have generally improved over time, particularly when healthcare delivery systems are not overburdened [6, 7, 8 ].
Our expertise and comprehension of the virus, as well as the disease’s therapy, are still evolving. We attempt to outline the progress made in a succinct yet thorough manner, as well as our predictions for future paths. The current study aimed to investigate the implications and correlation between prognostic outcomes and demographic, clinical, and laboratory features in critically ill COVID-19 patients admitted to ICU.
Material and Methods
This study was conducted utilizing data acquired from an electronic hospital database of a tertiary care facility. This study comprised a total of 106 adult COVID-19 patients (aged 24 or older) who were diagnosed with COVID-19 and admitted to the hospital’s ICUs.
In addition to specific computed thoracic tomography findings, reverse transcriptase-polymerase chain reaction (RT-PCR) was used in all patients to confirm the diagnosis of COVID-19 disease.
Patients were admitted to our ICU if they met WHO criteria for severe pneumonia, which included a fever or suspected respiratory infection, as well as one of the following: a respiratory rate >30 breaths per minute, severe respiratory distress, or oxygen saturation of less than 90% on room air [9]. The researchers used evidence-based guidelines for acute respiratory distress syndrome (ARDS) and evolving consensus statements for COVID critical care management [10, 11, 12]. Based on procedures from small case series that have indicated short-term physiological increases in oxygenation, non-intubated oxygen-dependent patients were requested to adopt prone positioning (PP) for as long as tolerated [13, 14, 15].
Chronic comorbidities were chosen based on previously reported data utilizing pre-existing International Classification of Diseases classifications (ICD-10). Among the conditions were cardiovascular disease, lung disease, hypertension, diabetes, renal disease, liver disease, and a history of a solid malignant tumor. Our hospital was designated as a pandemic institution by the Turkish Ministry of Health ( Sahra Hospital Affiliated with Dr Sadi Konuk Training and Research Hospital).
In this study, only COVID-19 patients who required an ICU stay were looked at. The study did not include patients under the age of 18, and pregnant women. The study followed the principles of Good Clinical Practice outlined in the Declaration of Helsinki. On admission and discharge, data on baseline demographic factors, comorbidities, interventions delivered, and hospital outcomes were collected. Patients were treated per local medical standards. All of the patients had either been discharged alive from the ICU or had died by the time the data was processed and the study conclusions were published.
Statistical analysis
Data were analyzed using Statistical Package for Social Sciences program version 21.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as means (standard deviations) and categorical variables were demonstrated as frequencies and percentages. Missing data were not imputed. Independent Samples and Kruskal-Wallis tests were used to compare variables between groups.
Outcome parameters
Age, BMI (kg/m2), comorbidities, smoking habits, vaccination history, prognostic outcomes, duration of ICU stay, and respiratory supportive methods were all collected from the hospital database.
Ethical Approval
This study was approved by the Ethics Committee of Clinical Research (Date: 2020-10-27, No: 278)
Results
In this study, we enrolled 106 patients treated in ICU who tested positive or negative for COVID-19. Baseline demographics, patient comorbidities and respiratory support methods interventions are summarized in Table 1. The average age was 65.4 ± 14.9 years (24 to 93), and the average BMI was 30.1 ± 6.6 kg/m2 (17.6 to 57.5). In this series, 74 patients (69.8%) had comorbidities while 32 cases (30.2 %) did not have any systemic diseases. Smokers constituted 15 % of the COVID-19 patient population (n=16) in ICU. 36 cases (33.9 %) had received at least one dose of the COVID-19 vaccine. The respiratory support methods used included continuous positive airway pressure (CPAP) (n=42, 39.6%), high flow nasal oxygen (n=28, 26.24%), urgent intubation (n=26, 24.5%), nasal oxygen support (n=6, 5.6%), both CPAP and high flow nasal oxygen (n=4, 3.7%), respectively.
Table 2 presents blood gas and monitor values at admission to the intensive care unit, duration of ICU stay, duration of ICU stay and mortality rate. The rate of mortality was 64.1 % (68/106) in our series. The duration of ICU stay was 16.9±11.41 days (range: 1 to 60). No significant relationship was detected between prognostic outcome and duration of intubation (p=0.349), and duration of ICU stay (p=0.272). Table 3 shows no statistically significant difference was found in the average ICU hospitalization days of patients with or without comorbidities, smokers or non-smokers, vaccinated or non-vaccinated, positive or not detected in any PCR result, pathology detected in tomography or not.
Discussion
We aimed to compare the duration of intubation, duration of ICU stay and respiratory parameters in severe COVID-19 patients treated in the ICU with different prognostic outcomes. We noted that the duration of ICU stay was not affected remarkably by the respiratory supportive method.
COVID-19 pneumonia has a wide clinical spectrum, ranging from mild to life-threatening. Patients with COVID-19 pneumonia have only had their broad epidemiological results, clinical presentation, and clinical outcomes documented in previous investigations [16]. However, there is still a lack of information about critically ill patients. Data on the clinical features and outcomes of critically sick individuals infected with COVID-19 are sparse, yet they are crucial for lowering mortality.
Because there is currently no specialist medicine to treat COVID-19 infection, supportive care has remained the mainstay of treatment. Patients were being treated in isolation, and their immediate family and acquaintances were being quarantined. Individuals who are critically ill, on the other hand, require aggressive therapy and close monitoring. The patient numbers in three prior critically ill patient studies were insufficient to summarize the characteristics and mortality of these COVID-19 pneumonia patients [2, 17, 18].
Severe ARDS is the basic pathophysiology of severe viral pneumonia. Men and people older than 65 years of age are more likely to acquire ARDS. As a result, it’s plausible to assume that the death rate of severe COVID-19 pneumonia at 28 days is similar to that of severe ARDS, which is around 50% [19].
Critically sick patients with COVID-19 pneumonia have a significant fatality rate. Non-survivors are expected to live for 1–2 weeks after being admitted to the ICU. Patients over 65 years old with comorbidities and ARDS have a higher chance of death. The severity of COVID-19 pneumonia puts a strain on hospital critical care services, particularly if they are understaffed or under-resourced [16].
In our series, the ICU mortality rate was 64.1 %. This contrasts with ICU fatality rates reported in major case series from several countries varying from 30.9% to 49%. [20]. The disparities in ICU outcomes could be due to a variety of factors. To begin with, many patients remain in the ICU at the time of reporting 58% of patients in the Lombardy cohort [21] and 56.1 percent of patients in the New York case series [22]. Attempts to measure mortality early in the pandemic based on a limited set of patients with completed outcomes and a short follow-up period may skew statistical interpretation in favor of greater fatality rates.
In a more recent systematic evaluation of 15 trials, the pooled ICU mortality rate was found to be 25.7% which is comparable to the normal ARDS mortality rate of 35–45 percent [23].
Second, when compared to data from several major case series, our patients exhibited a decreased risk profile for severe disease. This could be due to discrepancies in ICU admission requirements. For ICU admission, we used the WHO criteria for severe pneumonia, although ICUs in overburdened healthcare systems may have used more strict admission criteria as part of rationing [24].
Graselli et al. found that older age, male sex, a high fraction of inspired oxygen, high positive end-expiratory pressure, or low PaO2:FiO2 ratio on ICU admission and a history of chronic obstructive pulmonary disease, hypercholesterolemia, and type 2 diabetes mellitus were all independent risk factors for mortality [21].
Having enough ICU staff was also crucial in ensuring that all patients got standard ICU care in accordance with ARDS and COVID-19 evidence-based guidelines. Prone positioning, a time-consuming procedure, was also performed on more than half of the ICU patients, which could not have been done due to a lack of ICU personnel [24].
Conclusion
Our study demonstrated the relationship between clinical and therapeutic characteristics and prognostic outcomes of COVID-19 patients admitted to an ICU in a tertiary care center. Even if powerful antiviral medicines are not yet widely available, low ICU mortality rates can be attained with good access to the ICU, early intubation, lung-protective ventilatory methods, and good general supportive care in the ICU. Severe COVID-19, on the other hand, has a high morbidity rate and can quickly deplete ICU resources in a pandemic. A well-established ICU and awareness of the implications of clinical data can maintain clinical standards and continue evidence-based practices without resorting to resource rationing, keeping fatality rates low.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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4. Walkey AJ, Kumar VK, Harhay MO, Bolesta S, Bansal V, Gajic O, et al. The viral ınfection and respiratory ıllness universal study (VIRUS): An ınternational registry of Coronavirus 2019-related critical illness. Crit Care Explor. 2020;2(4):0113.
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6. Domecq JP, Lal A, Sheldrick CR, Kumar VK, Boman K, Bolesta S, et al. Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: The International Viral Infection and Respiratory Illness Universal Study Registry. Crit Care Med. 2021;49(3):437-48.
7. Anesi GL, Jablonski J, Harhay MO, Atkins JH, Bajaj J, Baston C, et al. Characteristics, outcomes, and trends of patients with COVID-19-related critical ıllness at a learning health system in the united states. Ann Intern Med. 2021;174(5):613-21.
8. Bravata DM, Perkins AJ, Myers LJ, Arling G, Zhang Y, Zillich AJ, et al. Association of Intensive Care Unit Patient Load and Demand With Mortality Rates in US Department of Veterans Affairs Hospitals During the COVID-19 Pandemic. JAMA Netw Open. 2021;4(1):2034266.
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The role of heat shock protein 27 and 60 levels in the follow-up of thalassemia patients
Alper Gok 1, Mehmet Almacioglu 2, Ayse Binnur Erbagci 3, Ali Bay 4
1 Department of Pediatrics, Private Güzelyalı Hospital, Adana, 2 Department of Pediatrics, Faculty of Medicine, Sanko University, Gaziantep, 3 Department of Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep, 4 Department of Pediatrics, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
DOI: 10.4328/ACAM.22107 Received: 2024-01-14 Accepted: 2024-08-12 Published Online: 2024-10-21 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):822-826
Corresponding Author: Mehmet Almacioglu, Department of Pediatrics, Faculty of Medicine, Sanko University, Gaziantep, Turkey. E-mail: mehmet.almacioglu@sanko.edu.tr P: +90 532 798 79 84 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9882-6649
Other Authors ORCID ID: Alper Gok, https://orcid.org/0000-0001-6874-4151 . Ayse Binnur Erbagci, https://orcid.org/0000-0002-8248-5376 . Ali Bay, https://orcid.org/0000-0001-9153-9682
This study was approved by the Ethics Committee of Gaziantep University (Date: 2013-10-01, No: 01.10.2013/336)
Aim: It was aimed to measure the levels of the heat shock proteins 27 and 60 as mediators to show hypoxia and tissue injury in thalassemia major and thalassemia intermedia patients followed in our clinic.
Material and Methods: 53 patients who had the diagnosis of thalassemia major (n=38) and thalassemia intermediate (n=15) and who presented to the Department of Pediatric Hematology at Gaziantep University were evaluated. 50 healthy children aged between 1-16 attending to general pediatric examination for routine control were taken as a control group (n=50). The relationship between clinical findings and laboratory parameters, and HSP 27 and HSP 60 were evaluated.
Results: The mean age was 9.2 ± 4.4 years in thalassemia major patients, 5.6 ± 3.8 years in thalassemia intermediate patients and 9.1 ± 3.7 years in control group patients. The level of HSP 27 was 5 ± 3 in thalassemia major, 4.2 ± 1.7 in thalassemia intermediate, 0.93 ± 0.76 in control group and the difference between patients and control group was significant (p<0.05). When the splenectomy status and HSP levels of the patients were compared, HSP 27 level was 7.5 ± 5 in patients who had undertaken splenectomy and was 3.7 ± 2.4 in patients who had not undertaken splenectomy and it was statistically significant (p<0.05). HSP 60 levels were 13.6 ± 20 in patients who had undertaken splenectomy and were 8.3 ± 32.4 in patients who had not undertaken splenectomy and it was statistically significant.
Discussion: Measuring HSP 27 and HSP 60 levels could be used as evaluation criteria in following of thalassemia major and in thalassemia intermediate patients the evaluation of complications.
Keywords: Anemia, Children, Heat Shock Protein, Thalassemia
Introduction
Heat shock proteins are primarily involved in the transport, folding, binding and degradation of intracellular polypeptides, called chaperones, assembly and separation of oligomeric proteins within the cell [1, 2]. Some molecular chaperones attach to unfolded proteins, preventing them from being degraded and forming protein aggregates (for example: HSP70, HSP40). Some molecular chaperones capture damaged protein structures and ensure that these proteins are broken down with the help of chemical energy (for example: HSP60), that is, as a chaperone, HSP ensures that cell proteins are present in the right way, in the right place, at the right time [3, 4].
High HSP levels are only seen during the initial stages of stress. Even if the cell continues to be exposed to high temperatures after the initial shock, HSP levels begin to decline and return to normal levels. As a result, HSP contributes to the cell’s adaptation to stressful conditions [5, 6].
HSP27 is located in both the cytoplasm and nucleus. In addition to thermotolerance, this protein plays a role in regulating the differentiation of epithelial cells, migration of keratinocytes during wound healing, preventing apoptosis and protecting cells from the cytotoxicity of inflammatory mediators. It also has a limited ability to protect enzymes against heat denaturation. HSP27 prevents apoptosis by inhibiting caspase activation, regulating the signaling pathway, or acting as a chaperone to protect cells [7].
HSP60, adhesion molecule E-selection, ICAM-1 and VCAM-1 expression from vascular endothelial cells; It also induces IL-6 release from vascular endothelial cells, muscle cells and macrophages. It is a protein known to be present in inflammatory events [8].
Thalassemias are autosomal recessive hemolytic anemias that occur due to the inability to produce one or more of the globin chains in the structure of hemoglobin in erythroblasts or to produce them in small amounts. Beta thalassemia, which presents with varying degrees of anemia, is the result of the inability to synthesize the chain required for adult hemoglobin as a result of mutation of the beta globin gene on the short arm of chromosome 11. Since alpha globin chains, which must combine with β globin chains, cannot form sufficient tetramers, they cause hemolysis by collapsing in erythrocyte precursors and erythrocytes [9].
Anemias generally progress with tissue hypoxia. Hypoxic conditions lead to increased synthesis of heat shock proteins (HSP) [10].
Especially in recent years, it has been reported that ischemia and thrombosis are more common in β thalassemia intermedia patients. A previous study found a 25% rate of silent cerebral infarction. In addition, iron accumulation occurs due to transfusions in thalassemia patients, and this iron causes damage to many organs such as the heart, liver and pancreas. Many parameters such as ferritin, oxidative stress indicators, antioxidant capacity, liver and heart MRI and T2 star measurements have been previously studied to evaluate tissue damage in thalassemia patients [11].
In this study, the importance of heat shock proteins as a new mediator in detecting tissue damage caused by hypoxia and iron accumulation in thalassemia major and thalassemia intermedia patients was discussed.
Material and Methods
Our study started in Gaziantep University Faculty of Medicine Hospital, Department of Child Health and Diseases, in accordance with the Declaration of Helsinki Decisions, Patient Rights Regulation and ethical rules, after the approval of the local ethics committee, Gaziantep University Ethics Committee, dated 01.10.2013 and numbered 01.10.2013/336. Additionally, the study was supported by Gaziantep University Scientific Research Projects Commission.
In this study, 53 patients who applied to Gaziantep University Pediatric Hematology Clinic and were diagnosed with Thalassemia major and Thalassemia intermedia were evaluated. Fifty healthy children, aged between 1 and 16 years, who applied to the general pediatric clinic for routine check-up, were included as the control group. The study and control groups were composed of subjects with similar age and gender. The patients were diagnosed with β-thalassemia by complete blood count, peripheral smear findings, maternal and paternal hemogram parameters, hemoglobin electrophoresis, and in some cases, molecular genetic analysis.
The files of the cases were examined retrospectively and their ages, gender, physical examination findings, laboratory parameters, abdominal ultrasonography and echocardiography findings were recorded and analyzed. HSP 27 and HSP 60 levels were read at 450 nm with an ELISA reader (Biotek Instruments, USA).
Statistical analysis
Kolmogorov Smirnov test was used to check the suitability of continuous variables for normal distribution. Student’s t test was used to compare variables with normal distribution between 2 independent groups, and Mann Whitney U Test was used for variables with non-normal distribution. Kruskal Wallis test and Dunn multiple comparison tests were used to compare more than 2 independent groups. The relationship between categorical variables was tested with chi-square analysis. Descriptive statistics are frequency, percentage and mean ± std. deviation values are given. SPSS for Windows version 22.0 package program was used for statistical analysis and P<0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Gaziantep University University (Date: 2013-10-01, No: 01.10.2013/336).
Results
In this study, HSP 27 and HSP 60 levels were studied in a total of 103 children, including 38 thalassemia major, 15 thalassemia intermedia and 50 healthy control groups. The relationship between HSP levels and clinical and laboratory findings was investigated. Among the individuals included in the study, there were 19 females and 19 males in thalassemia major patients, 7 females and 8 males in thalassemia intermedia patients, and 23 females and 27 males in the control group. There was no statistically significant difference in terms of gender in all 3 groups (p = 0.90).
The average age of thalassemia major patients was 9.2 ± 4.4 years, the average age of thalassemia intermedia patients was 5.6 ± 3.8 years, and the average age of the control group was 9.1 ± 3.7 years.
HSP 27 level was 5 ± 3.9 in thalassemia major, 4.2 ± 1.7 in thalassemia intermediary, and 0.93 ± 0.76 in the control group. Accordingly, there was a statistically significant difference between the thalassemia major, thalassemia minor and control groups (p = 0.01). When the groups were evaluated separately among themselves, the following values were found for thalassemia major and thalassemia intermedia (p1-2 = 0.10), for thalassemia major and control group (p1-3 = 0.001), and for thalassemia intermedia (p2-3 = 0.001). HSP 60 level was 10.1 ± 28.5 in thalassemia major, 2.7 ± 3.1 in thalassemia intermediary, and 0.35 ± 0.49 in the control group. Accordingly, there was a statistically significant difference between the thalassemia major, thalassemia minor and control groups (p = 0.01) (Table 1). When the groups were evaluated separately among themselves in terms of HSP 60, it was determined for thalassemia major and thalassemia intermedia (p1-2 = 0.10), for thalassemia major and control group (p1-3 = 0.001), and for thalassemia intermedia (p2-3 = 0.001) (Table 1).
There was a statistically significant difference in platelet counts between the thalassemia major and control groups (p = 0.015). However, there was no statistically significant difference in platelet counts between thalassemia major, thalassemia intermedia and the control group (p > 0.05).
While splenectomy was performed in 13 of 38 patients with thalassemia major among the cases included in the study, there were no patients with splenectomy in the thalassemia intermedia and control groups. When the patients’ splenectomy status and HSP values were compared, the HSP 27 value was 7.5 ± 5 in the splenectomy group and 3.7 ± 2.4 in the non-splenectomy group (p = 0.016). The HSP 60 value was 13.6 ± 20 in the splenectomy group and 8.3 ± 32 in the non-splenectomy group (p = 0.038). Accordingly, HSP 27 and HSP 60 were statistically significantly higher in patients who underwent splenectomy (Table 2.).
Discussion
In our study, there were a total of 103 cases: 38 with thalassemia major, 15 with thalassemia intermedia and 50 in the healthy control group. Considering the cases, the K/E ratio was 7/8 in thalassemia intermedia patients, 19/19 in thalassemia major patients, and 23/27 in the control group. Accordingly, in our study, no statistically significant difference was found in terms of gender in all three groups. According to the literature, the F/M ratio is generally reported to be equal in thalassemia major and thalassemia intermedia patients [12]. When the average age of all individuals included in the study was examined, it was found to be 9.2 ± 4.4 years in thalassemia major patients, 5.6 ± 3.8 years in thalassemia intermedia patients, and 9.1 ± 3.7 years in the control group, and it was noted that the average age of thalassemia intermedia patients was younger.
Studies have been conducted evaluating the relationship between iron load and oxidative stress in thalassemia major patients. In their study on 56 thalassemia major pediatric patients, Fatima et al. showed that the substance, which is an indicator of lipid peroxide, increased compared to the control group, and the determinants related to the antioxidant system decreased significantly [13]. According to this result, they suggested that non-transferrin-bound iron in serum and the intracellular iron pool induce peroxidative damage.
Heat shock proteins are molecular chaperones that assist in protein folding and translocation. The term molecular chaperone is defined as the ability of stress proteins to bind to cellular proteins to aid their transport or migration. Under cellular stress, proteins denature and can form aggregates. This event will ultimately result in cell death. Heat shock proteins bind to cellular proteins and protect them from aggregation during cell stress. The degradant helps heal damaged cells by binding to poorly folded polypeptides. It has been observed by various studies that heat shock proteins are induced by physiological thermal changes similar to fever. The fact that fever uses HSPs in important pathways that protect the organism against infection and other disease conditions and interacts with these pathways suggests that fever and HSPs developmentally protect the organism in the long term [14, 15].
Anemias generally progress with tissue hypoxia. Hypoxic conditions lead to increased synthesis of heat shock proteins [16]. Especially in recent years, it has been reported that ischemia and thrombosis are frequently seen in thalassemia intermedia patients. In a recent study conducted in patients with thalassemia intermedia, silent cerebral infarction was detected in a rate of 25% [17]. Again, tissue hypoxia generally occurs in thalassemia major patients, and this research aims to investigate whether HSP 27 and HSP 60 levels of thalassemia major and thalassemia intermedia patients can be measured and used as biomarkers in follow-up [17].
There was a statistically significant difference in platelet counts between the thalassemia major and control groups, and no statistically significant difference in platelet counts was detected between the thalassemia major, thalassemia intermedia and control groups. However, we found a slightly positive and significant correlation between platelet counts and HSP 27 and HSP 60 levels in thalassemia major patients. Consistent with the information in the literature [18], we found a statistically significant difference between the ferritin levels of thalassemia major and thalassemia intermedia patients and the control group. A study found that markers related to oxidative damage showed a strong correlation with ferritin [19]. Based on this information, we expected a positive correlation between ferritin elevation and heat shock proteins. On the contrary, in our study, we did not find a statistically significant relationship between ferritin levels and HSP 27 and HSP 60 levels in the thalassemia major, thalassemia intermedia and control groups.
In our study, 13 of 38 patients with thalassemia major underwent splenectomy, while there were no patients with splenectomy in the thalassemia intermedia and control groups. When the patients’ splenectomy status and HSP values were compared, the HSP 27 value was found to be 7.5 ± 5 in the splenectomy group and 3.7 ± 2.4 in the non-splenectomy group. The HSP 60 value was found to be 13.6 ± 20 in the splenectomy group and 8.3 ± 32 in the non-splenectomy group. Accordingly, we found HSP 27 and HSP 60 levels to be statistically significantly higher in patients who underwent splenectomy. Eldor et al. showed that there is platelet activation in both thalassemia major and thalassemia intermedia and that this condition is unrelated to splenectomy [20]. In a prospective study of 563 patients who underwent splenectomy in a study conducted in the Netherlands, portal vein thrombosis was found to develop in 9 patients (2%) and it was stated that these were mostly patients with hemolytic anemia [21]. In our study, the high values of HSP 27 and HSP 60 in patients with splenectomy can be speculated as splenectomy in thalassemia major has a negative effect on oxidative stress and tissue damage.
When the HSP 27 level of the cases was examined, it was found to be 5 ± 3.9 in thalassemia major, 4.2 ± 1.7 in thalassemia intermediary, and 0.93 ± 0.76 in the control group. According to this; HSP 27 levels of thalassemia major and thalassemia intermedia patients were found to be statistically significantly higher than the control group. HSP 60 level was found to be 10.1 ± 28.5 in thalassemia major, 2.7 ± 3.1 in thalassemia intermedia and 0.35 ± 0.49 in the control group. Accordingly, a statistically significant difference was detected between the thalassemia major, thalassemia intermedia and control groups in terms of HSP 60. The relationship between thalassemias and HSP 27 has been previously evaluated in two studies. Firstly, in parallel with the results of our study, in a study conducted in Iran with 140 thalassemia major and 140 healthy controls, serum HSP 27 level was significantly higher in the patient group than in the control group [22]. Some of the 64 patients aged between 8 and 18 years were given 30 mg zinc supplements daily, and a significant decrease in HSP 27 levels was detected in the 9th month of the treatment group compared to the pre-treatment period. In the group not given zinc supplementation, an increase in HSP 27 levels was observed at the end of the 9th month, and based on this, it was thought that serum HSP 27 levels could be reduced in thalassemia patients with the potential antioxidant and anti-inflammatory effects of zinc [22].
Limitation
This study has some limitations. First, we did not investigate the potential roles of these proteins in disease progression, hypoxia prediction, or tissue damage assessment. Second, we did not assess disease susceptibility or predict follow-up complications. However, the strength of our study that we established an association between HSP27 and HSP60 levels and general features of thalassemia.
Conclusion
Our study is important as it is the first to measure serum HSP 27 and HSP 60 levels together in thalassemia major and thalassemia intermedia patients, and also to evaluate their relationship with hemogram parameters, liver function tests, ferritin, CRP and splenectomy. Measuring HSP 27 and HSP 60 levels in patients with thalassemia major and thalassemia intermedia can be used as a tool to determine susceptibility to the disease and follow up complications. Our results need to be supported by reproducing similar studies.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Alper Gok, Mehmet Almacioglu, Ayse Binnur Erbagci, Ali Bay. The role of heat shock protein 27 and 60 levels in the follow-up of thalassemia patients. Ann Clin Anal Med 2024;15(12):822-826
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Investigation of the treatment efficiency with mandibular advancement appliance therapy on snoring and mild obstructive sleep apnea
Handan Tuğçe Oğuz 1, Neslihan Üçüncü 2
1 Department of Orthodontics, Mamak Oral and Dental Health Center, 2 Department of Orthodontics, Faculty of Dentistry, Gazi University, Ankara, Turkey
DOI: 10.4328/ACAM.22114 Received: 2024-01-20 Accepted: 2024-04-02 Published Online: 2024-10-09 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):827-832
Corresponding Author: Handan Tuğçe Oğuz, Department of Orthodontics, Mamak Oral and Dental Health Center, Ankara, Turkey. E-mail: htugce@gmail.com P: +90 505 827 88 31 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7123-2453
Other Author ORCID ID: Neslihan Üçüncü, https://orcid.org/0000-0001-8690-3937
This study was approved by the Academical Board of Gazi University, Dentistry Faculty, Department of Orthodontics (Date: 2004-07-23, No: 21.33.1335).
Aim: The correct repositioning of the mandible and the design feature of the appliance have a key role in the success of mandibular advancement device (MAD) therapy in obstructive sleep apnea (OSA) treatment. There is still a dilemma on the most effective mandibular advancement and vertical opening amount, titratability, material and piece number of the MAD appliances. This study was performed to identify the treatment efficiency of a modified monobloc style, untitrable MAD constructed from silicone material, which has 75% of the maximum protrusion mandibular advancement amount and a 6 mm vertical opening.
Material and Methods: 15 snoring and mild OSA patients were included in this study. Polysomnography tests and cephalometric analysis were done during pretreatment and after 8 weeks of ordinary MAD use, with MAD in mouth. Linear and area measurements were done on the lateral cephalometric films. The results were analyzed with a paired comparison t-test.
Results: Significant reductions occurred in Total Apnea Hypopnea Index, Total Hypopnea Index, Arousal+Awakening Number (p ‹ 0.05) and Awakening
Number (p< 0.01) Significant increases were found in Oropharyngeal and Hypopharyngeal Airway Dimensions (p< 0.05) , the narrowest sagittal dimension of the pharyngeal airway (p< 0.01), Tongue Area, Oral Area, Oropharyngeal Area and Nasooropharyngeal Area (p< 0.01).
Discussion: Modified monobloc style, unadjustable MAD, constructed from dental silicone material, with 6 mm vertical opening and 75% of the maximum protrusion mandibular advancement amount was found to be an effective treatment alternative for snoring and mild obstructive sleep apnea.
Keywords: Obstructive Sleep Apnea, Snoring, Mandibular Advancement Appliance Therapy
Introduction
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder which is characterized by recurrent episodes of partial or complete upper airway obstructions, blood oxygen desaturation, sleep arousal and/or awakening during sleep. It leads to severe long-term health problems as a result of the decrease in blood pressure during apnea and hypopnea episodes. Apnea is the cessation of breathing for 10 seconds or more. Hypopnea is a decrease of 30-90% of normal airflow in breathing, for at least 10 seconds. Increased risk of high blood pressure, heart diseases, heart attacks, heart failure, pulmonary hypertension and stroke can be seen in OSA patients. People from all ages, even pediatric and adolescent ages can be affected, but middle ages have the highest prevelence. OSA prevelence is estimated at 3-7% in men and 2-5% in women. Snoring, excessive daytime sleepiness, morning headache, mood changes like nervousness or depression and difficulty concentrating are the symptoms of OSA. Snoring is the most evident symptom of OSA. Every OSA patient snores, but every snoring person is not an OSA patient. The etiology of OSA is multifaceted involving genetic, craniofacial, anatomical, neuromuscular and inflammatory factors whose contributions differ from patient to patient [1, 2, 3].
OSA treatment is performed by a multidicipliner team consisting of medical doctors and dentists. Treatment approach should be chosen according to the severity of the disorder. OSA is classified as mild, moderate or severe depending on the Apnea-Hypopnea Index (AHI). AHI<5 is considered normal. AHI between 5-20 represents mild, AHI between 21-40 represents moderate and AHI >40 represents severe OSA [4].
The American Sleep Disorders Association reported that oral appliance therapy is the primary treatment option for snoring and mild OSA patients. There are three kinds of oral appliances for snoring and OSA treatment. They are Mandibular Advancement Devices, Tongue Retaining Devices and Palate Lifting Devices. Mandibular Advancement Devices (MAD) are the most popular and the most effective type of oral appliance. MADs, reposition the mandible to a more forwarded position. This advancement stretch and stabilize the attached soft tissues and tongue, which increases the tension of the genioglossus, supra and infrahyoid muscles, In doing so, it enlarges the airway in the oropharyngeal and hypopharyngeal regions. However, the design feature and the correct repositioning amount of the mandible have a key role in the success of MAD therapy. Inadequate positioned mandible and incorrectly designed MAD decrease treatment efficiency and patient cooperation. The literature does not provide consensus on the most effective mandibular advancement and vertical opening amount, piece number, titrable or non-titrable choice and construction material of MAD appliances [4, 5, 6].
The aim of this study is to identify an effective mandibular protrusion amount, vertical opening amount and design feature for MAD therapy in mild OSA treatment.
Material and Methods
This study includes 15 patients, aged 31 to 69 years, ( mean age 49.07, SD 9.88; 8 females and 7 males) who were diagnosed with mild OSA at Gazi University Faculty of Medicine, Sleep Disorders Center. They were referred to the Gazi University Faculty of Dentistry, Department of Orthodontics for oral appliance therapy.
The inclusion criteria were: (1) Snoring and Mild OSA patients with AHI= 5-15; (2) Subjects with good oral hygiene and periodontal health; (3) Subjects who have at least 8 teeth at one jaw. The exclusion criteria were: (1) Moderate to severe OSA patients, with AHI › 20; (2) Patients with severe health problems; (3) Subjects with TMJ disorders.
The sample comprised lateral cephalometric films and polysomnography reports obtained pretreatment and after 8 weeks of ordinary use of appliance with MAD in mouth. Linear and area measurements were done on the lateral cephalometric films.
Oral Appliance
A modified monobloc type, teeth and tissue supported, one pieced, soft silicone materialed, unadjustable MAD appliance was applied to the subjects included in this study. The mandibular advancement amount was 75% of the maximum protrusion and the vertical opening amount was 6 mm. Silasto 70 ( Dr. Hinz Dental,97-406) dental silicone material was used to construct the appliance ( Figure 1).
When MADs were applied to the patients they were informed how to use the appliance and instructed to use the MAD every night. Control appointments were given to the patients after 1 and 2 weeks of use of MAD. At control appointments, the patients were investigated for tissue irritations, TMJ pain, tooth hypersensitivity and compliance.
The 8 weeks of ordinary use of MAD, after patient compliance observation, were regarded as the outcome measuring time for this current study.
Cephalometric Investigation
All films were obtained in natural head position, by the same radiology technician, with the same Orthopantomograph Instrumentarium device. Pretreatment cephalograms were taken in centric occlusion. Posttreatment cephalograms were taken with MAD in mouth. Linear and area measurements were done on each radiograph for investigation of the changes in airway dimensions and airway areas. Figure 2 shows the linear measurements and Figure 3 shows the area measurements. Both linear and area measurements were performed by the same orthodontist. The area measurements were done with Placom KP-90N digital planimeter.
Polysomnographic Investigation
The patients undergone polysomnographic analysis at Gazi University Faculty of Medicine, Sleep Disorders Center. The tests were performed with Somnostar computer aided PSG device with Alpha programme by the same sleep technician. 9 polysomnographic parameters was taken into consideration in this study. Total sleep time, Sleep efficiency, Arousal Number, Awakening Number, Arousal+Awakening Number, Total Apnea Index, Total Hypopnea Index, Total Apnea+Hypopnea Index and Minimum oxygen saturation were evaluated in PSG tests. Total Sleep Time is the total amount of sleep time scored during the total PSG recording time. Sleep Efficiency is the ratio of total sleep time to time in bed. Arousal Number is the number of shifting from deep sleep (REM sleep) to light sleep ( non-REM sleep) during the total PSG recording time. Awakening Number is the number of shifting from sleep to awakening during the PSG total recording time. Arousal+Awakening Number is the sum of arousal and awakening numbers during the total PSG recording time. Total Apnea Index is the index obtained by dividing the apnea index to sleeping hour. Total Hypopnea Index is the index obtained by dividing the hypopnea index to sleeping hour. Total Apnea+ Hypopnea Index is the index obtained by dividing the sum of apnea and hypopnea numbers to sleeping hour. Minimum Oxygen Saturation is the minimum oxygen level detected during the total PSG recording time.
Statistical Analysis:
The statistical analysis performed on the parameters obtained from cephalometric films and polysomnograpy reports. The statistical analysis performed with SPSS 15.0 programme. Paired samples t-test was used to analyze the differences in cephalometric and polysomnographic parameters, before MAD therapy and with MAD. The inter-examiner reproducibility on cephalometric investigation for airway area and airway dimension measurements were done too. Repeating cephalometric analysis were done on random selected 10 patients, by the same orthodontist , one week apart from the first measurement. Random selected 3 linear and 3 area measurements inter-class confidence coefficients were calculated. Inter-class confidence coefficients were calculated between 0.95-0.99.
Ethical Approval
This study was approved by the Academical Board of Gazi University, Dentistry Faculty, Department of Orthodontics (Date: 2004-07-23, No: 21.33.1335).
Results
Linear Measurement Results
Linear cephalometric investigations showed that the horizontal and superoinferior position of the hyoid bone changed significantly (p< 0.05), the vertical position of the hyoid bone changed significantly (p< 0.01) with MAD in mouth. The vertical position of vallecula did not change significantly, but the horizontal position change was statistifically significant (p< 0.05) with MAD. Significant increases were found in airway dimensions with MAD in mouth. Oropharyngeal Airway Dimension (p< 0.05), Hypopharyngeal Airway Dimension (p< 0.05) and the narrowest sagittal dimension of the pharyngeal airway (p< 0.01) increased significantly (Figure 2) (Table 1). The definitions of the linear measurement parameters and cephalometric referance planes are written below.
1) 1-NA 2) 1-NB 3) Overjet 4) Overbite 5) Tongue Lenght ( VT): The linear distance between V point and tip of the tongue.6) Tongue Height: A line drawen perpendicular from the most superior point of tongue dorsum to the VT line. 7) PM’-U: Soft palate lenght 8) SPT: The maximum thickness of the soft palate 9) PM’-UPW: Nasopharyngeal airway dimension 10) U-MPW:Oropharyngeal airway dimension 11) V-LPW: Hypopharyngeal airway dimension. 12) PASmin: The narrowest sagittal dimension of the pharyngeal airway 13) V┴FH: The vertical position of the Vallecula 14) V-CV: The horizontal position of the Vallecula 15) H┴FH: The vertical position of hyoid bone according to FH plane, 16) H-CV: The horizontal position of the hyoid bone 17) H┴MP: The vertical position of hyoid bone according to mandibular plane 18) Rgn-H: The horizontal position of the hyoid bone according to mandibula 19) H┴C3Rgn: The superoinferior position of hyoid bone, Reference Planes: SN Plane: The line between S and N points. FH Plane: The line between Po and Or points. CV Plane : The line between the most anteroinferior points of the second and the third cervical vertebras. MP : The line between Go and Gn points.
Area Measurement Results
The area measurements performed on lateral cephalometric films showed that significant changes occurred in airway areas with MAD type oral appliance therapy. Tongue Area (p < 0.01), Oral Area (p < 0.01), Oropharyngeal Area (p < 0.01), and Nasooropharyngeal Area (Total Airway Area) (p < 0.01) demonstrated a significant increase (Figure 3) (Table 2). The definitions of the area measurements are written below
1. Tongue Area (TA): The cross-sectional area outlined by the dorsum of the tongue surface and the lines that connect T, Rgn, H and V points. 2. Residuel Oral Area (ROA): The cross-sectional area outlined by the superior contour of the tongue and the external contours of hard and soft palate. 3. Oral Area (OA): The sum of tongue area and residuel oral area. 4.Soft Palate Area (SPA): The cross-sectional area outlined by the anterior and posterior contours of the soft palate. 5. Oropharyngeal Area (OA): The cross-sectional area outlined by the PNS, UPW, LPW and V points. 6.Nasooropharyngeal Area (NOPA):The sum of the tongue area, residuel oral area, soft palate area and oropharyngeal area.
Polysomnographic Analysis Results
Respiratory evaluations showed that significant reductions were found in Total Apnea Hypopnea Index, Total Hypopnea Index, Arousal+Awakening Number (p ‹ 0.05) and Awakening Number (p‹ 0.01) ( Table 3).
Discussion
MADs were regarded as the most effective therapy for snoring and mild OSA, but the design feature of the appliance changed the success rate and patient compliance. The success rate of the MAD is affected by the material, piece number, titratability and horizontal-vertical mandibular replacement amounts of the appliance.
Tissue and tooth supported oral appliances are more stable in mouth due to occupying greater oral areas and spreading the oral forces homogeneously. MAD appliances constructed from soft dental materials have better patient compliance because they occur less destructive oral forces, tooth hypersensitivity and tissue irritations. [5, 6, 7, 8]
One-pieced or two-pieced appliance design does not affect the treatment success significantly. Many studies have shown that if the oral appliance has good stability, the piece number of the appliance does not affect the treatment result [5, 6, 7, 8, 9, 10].
The titratability of the appliance was found insignificant too in the treatment success of the oral appliance therapy. The literature review has shown that when the oral appliance prevents the airway obstruction and enlarges the airway properly it shows treatment efficiency regardless of titrability option [5, 6, 7, 8, 9, 10, 11].
The mandibular replacement amount is the most important criteria on MAD treatment efficiency. Especially the mandibular protrusion amount is very important in treatment success. However, there is no consensus on both the maximum protrusion and the vertical opening amount.
The literature has shown that the ideal mandibular advancement amount should be between 50% and 75% of the maximum protrusion amount of the mandible [5, 6, 7, 8, 9, 10, 12, 13, 14]. The researches prefer different vertical opening amounts, varying from 1 mm to 14 mm. The literature review has shown that if the vertical opening amount of the mandible is greater than the protrusion amount, there will be inefficient hypopharyngeal airway enlargement. Because increased vertical dimension causes posterior mandibular rotation which reduces the pharyngeal airway area [14, 15, 16, 17]. Mayoral et al. [17] reported that every 1 mm of vertical increase, up to 8 mm of interincisal distance, leads 0.3 mm reduction in mandibular advancement amount. In this current study 6 mm mean vertical opening amount was selected in order to obtain an effective vertical opening, without any reduction in mandibular protrusion.
Modified monobloc style, one-pieced, tooth and tissue supported, unadjustable , MAD appliance with 6 mm vertical opening and sagittal advancement amount of %75 maximum protrusion, constructed from dental silicone material was used in this current study in order to use all recommended MAD design features in literature.
Our results demonstrated that both airway dimensions and airway areas increased significantly with MAD in mouth. Statistifically significant changes was found in the horizontal, vertical and superoinferior position of the hyoid bone. This changes can be explained by the forward and downward position of the mandible with MAD. The vertical position of vallecula did not change significantly but the horizontal position change was found to be significant. (p < 0.05) The insignificant vertical position change and significant horizontal position change of vallecula is due to our MAD appliance design. The MAD appliance used in this current study aimed for more effective mandibular protrusion than vertical opening of the mandible. Significant increases occurred in the Oropharyngeal Airway Dimension (p < 0.05), Hypopharyngeal Airway Dimension (p < 0.05) and the narrowest sagittal dimension of pharyngeal airway (p < 0.01) with MAD appliance. Our results showed similarity with other studies [18, 19, 20, 21, 22, 23, 24, 25]. These findings are also important to identify the enlargement levels of the pharyngeal dimensions. The MAD appliance with 6 mm vertical opening and 75% maximum protrusion amount used in this current study enlarged the pharynx at retropalatal and retroglossal levels.
In the present study, significant changes occurred in airway areas with MAD in mouth. Tongue Area (p < 0.01), Oral Area (p < 0.01), Oropharyngeal Area (p < 0.01), and Nasooropharyngeal Area (Total Airway Area) (p < 0.01) demonstraded a significant increase. The changes in tongue area vary in literature. Statistifically significant increase, unsignificant increase or statistifically significant decrease can occur in tongue area. The statistifically significant increase in tongue area in this current study can be explained by the forward movement of V,H and Rgn points with mandibular protrusion occurring with MAD in mouth. The statistifically significant increases occurred in Oral Area (p < 0.01), Oropharyngeal Area (p < 0.01), and Nasooropharyngeal Area (Total Airway Area) (p < 0.01) shows similarity with the literature [18, 19, 20, 21, 22, 23, 24, 25]. These increases in airway areas are due to mandibular protrusion. The mandibular protrusion increases the distance between the soft palate and the posterior pharyngeal wall and enlarges the space between the tongue root and the posterior region of the oropharynx. Also, the vertical opening amount of 6 mm was chosen in order to prevent excessive posterior rotation of mandible and reduction in mandibular protrusion amount.
Beneficial changes occurred in the respiratory parameters of the patients included in this study. Significant reductions were found in Total Apnea Hypopnea Index, Total Hypopnea Index, Arousal+Awakening Number (p ‹ 0.05) and Awakening Number (p‹ 0.01). The minimum blood oxygen saturation amount of the patients treated with MAD in this study increased insignificantly.
This study has some limitations. The first limitation is the small number of participants. Because of the small participant number, the difference between genders was not investigated. Another limitation is the long term effects of the appliance could not be able to investigate because the participants did not come to post-treatment control appointments and control polisomnographic analysis tests at the 6th and 12th months.
Conclusion
The modified monobloc type, one pieced, unadjustable MAD appliance with 6 mm vertical opening and sagittal advancement amount of %75 maximum protrusion, constructed from dental silicone material was found to be an effective treatment option for snoring and mild OSA. Airway dimensions, airway areas and narrowest sagittal dimension of pharyngeal airway increased significantly. A statistifically significant beneficial respiratory changes occured in PSG tests. The life quality of the patients increased significantly with MAD therapy. Patient cooperation and satisfaction were also provided.
Acknowledgment
We would like to express our sincere thanks and gratitude to Professor Doctor Oğuz Köktürk, the Head of Gazi University Faculty of Medicine Sleep Disorders Center.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Handan Tuğçe Oğuz, Neslihan Üçüncü. Investigation of the treatment effıciency with mandibular advancement appliance therapy on snoring and mild obstructıve sleep apnea. Ann Clin Anal Med 2024;15(12):827-832
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Investigation of the utility of dynamic contrast MRI in predicting pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer
Selim Özdemir 1, Hüseyin Akkaya 2, Okan Dilek 2, Gökhan Söker 2, Zeynel Abidin Taş 3, Ahmet Gülmez 4, Bozkurt Gülek 2
1 Department of Radiology, Düziçi State Hospital, Osmaniye, 2 Department of Radiology, University of Health Sciences, Adana City Training and Research Hospital, Adana, 3 Department of Pathology, University of Health Sciences, Adana City Training and Research Hospital, Adana, 4 Department of Medical Oncology, University of Health Sciences, Adana City Training and Research Hospital, Adana, Turkey
DOI: 10.4328/ACAM.22224 Received: 2024-04-18 Accepted: 2024-05-20 Published Online: 2024-10-08 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):833-838
Corresponding Author: Hüseyin Akkaya, Department of Radiology, University of Health Sciences, Adana City Training and Research Hospital, Adana, Turkey. E-mail: dr.hsynakkaya@gmail.com P: +90 534 845 42 17 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5821-670X
Other Authors ORCID ID: Selim Özdemir, https://orcid.org/0000-0002-0989-9732 . Okan Dilek, https://orcid.org/0000-0002-2144-2460 . Gokhan Soker, https://orcid.org/0000-0002-5369-4769 . Zeynel Abidin Tas, https://orcid.org/0000-0002-5504-4487 . Ahmet Gülmez, https://orcid.org/0000-0002-3353-344X . Bozkurt Gülek, https://orcid.org/0000-0003-1510-6257
This study was approved by the Ethics Committee of University of Health Sciences, Adana City Training and Research Hospital (Date: 2021-12-30, No: 1709)
Aim: The study aimed to evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived semi-quantitative perfusion parameters obtained before treatment in predicting pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.
Material and Method: The study included 93 patients with locally advanced rectal cancer who underwent DCE-MRI before treatment and whose pathological response to treatment was recorded. Rectal MRIs were evaluated retrospectively and simultaneously by two radiologists based on consensus. The mesorectal fascia (MRF) invasion and extramural vascular invasion (EMVI) of the tumors were assessed. Tumor length was measured in the sagittal or coronal plane using the T2-weighted sequence, considering the longest diameter of the tumor. The correlation of semi-quantitative parameters obtained from DCE-MRI and other MRI findings with pathological response to neoadjuvant chemoradiotherapy was also investigated.
Results: EMVI findings were observed in 28 (30.1%) patients, and MRF involvement in 15 (16.1%). The rates of T3 and T4 in T staging and those of N2 in N staging were found to be higher in groups with no response to neoadjuvant therapy compared to responders. Among the dynamic MRI parameters evaluated, the best diagnostic test performance for responders belonged to wash-out, followed by wash-in. The AUC values were calculated respectively at %96.4 [%95 CI (0.903-0.992)] and % 94.3 [ %95 CI (0.903-0.992)].
Discussion: Wash-in and wash-out rates, semi-quantitative parameters of dynamic MRI taken before neoadjuvant chemoradiotherapy, can be used to predict pathological response to treatment.
Keywords: Rectal Cancer, Dynamic MRI, Pathological Response, Neoadjuvant Chemoradiotherapy
Introduction
In rectal cancer, appropriate staging is important for both treatment planning and prognosis [1]. Magnetic resonance imaging (MRI) is the most commonly used modality for local staging of rectal cancer and determining appropriate treatment. Studies have shown that dynamic contrast-enhanced MRI (DCE-MRI) is effective in evaluating the presence of malignant neovascularity with varying diffusion and perfusion properties [2, 3]. The early identification of pathological outcomes using non-invasive, quantitative, and semi-quantitative measures is crucial for cost savings in the development of new target drugs [4]. Neoadjuvant chemoradiotherapy (CRT) has become standard in locally advanced stages of rectal cancer (T3c-d, T4, or N involvement) and mesorectal fascia (MRF) invasion [5]. Predicting the response to treatment in patients given neoadjuvant CRT is important in treatment planning and disease prognosis [6]. Although MRI is used as the standard method in the primary staging of rectal cancer in many centers, its role in examining treatment response is not yet clearly understood. With the widespread use of MRI in cancer patients, regression in tumor size and stage has been achieved, as well as a decrease in recurrence and an increase in life expectancy [7, 8]. European criteria are applied in the definition of locally advanced rectal cancer. The perfusion parameters of DCE-MRI have an important place in this process since the hemodynamics of the contrast medium may reflect both vascular fraction and permeability [5, 9].
This study aimed to evaluate the utility of semi-quantitative perfusion parameters derived from DCE-MRI taken before treatment in predicting pathological response to neoadjuvant CRT in patients with locally advanced rectal cancer.
Material and Methods
Patient Selection and Study Design
This retrospective study was carried out in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The requirement for informed consent from the patients was waived due to the retrospective nature of the study.
In this study, patients who were pathologically diagnosed with rectal cancer at the oncology or surgical oncology departments between January 2018 and November 2022 were screened, and 291 patients were identified.
Capecitabine (2×825 mg/m2) was administered to the patients, as the chemotherapeutic agent. The dose required for radiotherapy in rectal cancer to treat microscopic disease with conventional fractionation is 45–50.4 Gy. These standard neoadjuvant chemoradiotherapy protocols recommended in the literature were applied to all patients [7,8]. All patients underwent surgery 12 weeks after the end of neoadjuvant therapy. All of the patients included in the study were patients with locally advanced rectum ca, and cases with distant metastases were not included in the study. The modified Ryan scoring system was utilized for pathological evaluation (8). When pathological response scores of 0 and 1 were combined, these patients were considered responders in a single group [2-4].
Imaging Technique
The following imaging protocol was used to create images: matrix, 268×259; field of view (FOV), 350 mm; slice thickness, 5 mm, slice distance, 0.8 mm; and repetition time (TR)/echo time (TE), 4,608/100 ms for the T2-weighted axial sequence; matrix, 220×205; FOV, 220 mm; slice thickness, 3 mm; slice distance, 0.5 mm; and TR/TE, 3,299/110 ms for the T2-weighted sagittal sequence; matrix, 312×186; FOV, 250 mm; slice thickness, 4 mm; slice distance, 0.4 mm; and TR/TE, 5,760/100 ms for the T2-weighted coronal sequence; matrix, 312×224; FOV, 250 mm; slice thickness, 4 mm; slice distance, 0.4 mm; and TR/TE, 514/8 ms for the pre- and post-contrast x T1-weighted axial and sagittal sequences; and matrix, 220×223; FOV, 240 mm; TR/TE, 6.0/1.88; dynamic scanning time, 00:10.5 s; and k0 time 00:03.0 s for the dynamic T1-weighted axial sequence.
In all patients, 0.1 mmol/kg of gadoteric acid (Dotarem®) was intravenously administered at a rate of 2 ml/sec via an antecubital vein with an automatic injector. After the intravenous contrast agent injection, 15 ml of physiological saline was administered at the same rate. Semi-quantitative parameters were obtained by calculating the contrast agent concentration. The evaluation was performed by retrospectively screening the images from the picture archiving and communication systems of the hospital. For imaging, a 1.5T MRI device (Philips Ingenia, Best, Eindhoven, Netherlands, 2017) and a phased array superficial body coil were used.
MRI Evaluation
In our center, considering the time required for the tumor to regress, in accordance with the clinical guidelines of the European Society for Medical Oncology, the best time for total mesorectal excision (TME) is considered to be six to eight weeks after the end of CRT; therefore, TME surgery was performed according to this schedule. The patients’ rectal MRIs taken before neoadjuvant therapy were evaluated. The evaluation was carried out simultaneously and retrospectively by two radiologists, one with four and the other with 20 years of experience in radiology. Tumor localization was divided into three groups: low (0-5 cm from the anal verge), middle (5-10 cm from the anal verge), and high (10-15 cm from the anal verge). The staging of the patients was undertaken based on the T and N evaluation criteria using the MRI images. Lymph nodes larger than 5 mm in diameter were evaluated pathologically in terms of lymph node involvement. Thoracoabdominal computed tomographic (CT) examinations were performed to evaluate distant organ metastases. MRF invasion and extramural vascular invasion (EMVI) of the tumor were evaluated using conventional images. Tumor volume was measured in sections where the tumor was best visualized on T2-weigted sequences. Volumetric evaluation was performed using regions of interest (ROI) and measuring the tumor area separately for each section. Tumor length was measured in the sagittal or coronal plane in the T2-weighted sequence, considering the longest diameter of the tumor. The images were evaluated on a workstation (Intelli Space Philips, the Netherlands).
Statistical Analysis
The Statistical Package for the Social Sciences (SPSS) v. 25.0 software package was used for the statistical analyses of the data. Categorical measurements were summarized as numbers and percentages, and continuous measurements as mean and standard deviation (median and minimum-maximum where appropriate). The Shapiro-Wilk test was used to determine whether the parameters in the study showed a normal distribution. The chi-square and Fisher’s exact tests were used to compare categorical variables. The one-way analysis of variance test was conducted for the analysis of the differences between the groups in the presence of normally distributed variables, and the Kruskal-Wallis test was used in those that did not show a normal distribution. The post hoc Bonferroni test was employed to examine the source of the difference between the groups. Lastly, a receiver operating characteristic (ROC) curve analysis was applied to determine the power of the investigated parameters to predict pathological response. The statistical significance level was taken as 0.05 in all tests.
Ethical Approval
This study was approved by the Ethics Committee of University of Health Sciences Turkey, Adana City Training and Research Hospital and the Turkish Ministry of Health (Date: 2021-12-30, No: 1709).
Results
After excluding patients who were not suitable for evaluation, 93 patients with locally advanced rectal cancer who underwent DCE-MRI before treatment and whose pathological response to treatment was recorded were included in the study (Figure 1).
The mean age of the patients was 62.0 ± 11.3 years, and 59 (63.4%) were male. Tumor localization was found to be low in 25 (26.9%) patients, middle in 44 (47.3%), and high in 24 (25.8%). EMVI findings were observed in 28 (30.1%) of the patients, and MRF involvement in 15 (16.1%). The mean tumor length was 5.13 ± 1.4 cm, and the mean tumor volume was 30.2 ± 8.7 cm3. Of all patients, 64 (68.8%) were included in the non-responder group, and 29 (31.2%) in the responder group. Minimal response was detected in 34 (36.6%) of the 64 patients evaluated in the non-responder group (Table 1). There was no significant difference between the tumor localization of the responder and non-responder groups (p = 0.269). In T staging, the rates of T3 and T4 were higher in the non-response and minimal response groups compared to the responders (p < 0.001). In N staging, the rate of N2 was higher in patients with no response and minimal response compared to responders (p = 0.014). The rates of EMVI and MRF involvement were found to be higher in the groups with no response and minimal response than in responders (p = 0.003 and p = 0.007, respectively) (Table 2). There was a significant difference between the groups in terms of tumor length and tumor volume (p < 0.001 for both). When the source of significance was examined with the post hoc Bonferroni test, it was determined that tumor length and tumor volume were lower in responders than in patients with no response and those with minimal response (p < 0.05) (Table 2).
Table 3 presents the diagnostic test performances of T stage, N stage, EMVI, and MRF involvement for pathological response. In this analysis, at their respective cut-off points, the AUC values of T stage, N stage, EMVI, and MRF involvement were calculated to be 80.3, 56.1, 66., and 61.7, respectively. Accordingly, the best diagnostic test performance belonged to the T stage. The following perfusion parameters were evaluated: (1) maximum enhancement, (2) maximum relative enhancement; (3) T0 (s), (4) time to peak (s), (5) wash-in rate (s-1), and (6) wash-out rate (s-1) (Figure 2 ). In the examination of the diagnostic test performances of maximum enhancement, Maximum enhancement ratio (%), time to peak (s), T0 (s), wash-in rate (s-1), and wash-out rate (s-1) for pathological response, the AUC values of these parameters were determined to be 91.5%, 89.2%, 87.3%, 51.4%, 94.3%, and 96.4%, respectively, at their respective cut-off points. Accordingly, the best diagnostic test performance belonged to wash-out rate, followed by wash-in rate (Figure 3).
Discussion
It has been reported that the degree of angiogenesis in a tumor is associated with tumor grading and aggressiveness, which are associated with prognosis and treatment response [12-14]. According to the results of the study, among dynamic MRI parameters, maximum enhancement, maximum enhancement ratio, time to peak, and wash-in and wash-out rates were lower in patients with complete response than in those with no response or minimal response to CRT. In addition, the ROC curve analysis revealed the best diagnostic test performance for the wash-out rate at 96.4%, followed by the wash-in rate at 94.3%. Since highly differentiated tumors have denser vascular structures, they permit a greater exchange between the blood bed and the interstitial space due to the more efficient passage and permeability of various substances, including MRI contrast [14-16]. Therefore, as tumor aggressiveness increases, parameters measured in dynamic MRI are lower than in non-aggressive tumors [17, 18]. In a study including 51 cases, Ciolina et al. [14] found these parameters to be low in those with pathological complete response. In addition, the authors noted the best diagnostic test performance in the wash-out value at 95%. In another study evaluating 90 patients, Phongkitkarun et al. [5] reported that the maximum enhancement and time to peak values were lower in the group with pathological response to neoadjuvant therapy with a sensitivity of 95%. In a study of 95 cases, Oberholzer et al. [16] found that the time to peak value obtained from dynamic contrast MRI was successful in predicting pathological response with 95% sensitivity. Consistent with the literature, our results demonstrated that the wash-out and wash-in rates were the most successful parameters in predicting response to neoadjuvant therapy.
In a study including 34 cases, Gollub et al. [8] reported that T and N stages were lower in the group with pathological response. In another study of 71 cases, Sengul et al. [18] determined that tumors with low T and N stages showed a higher rate of pathological response compared to those with high T and N stages. Similarly, Johnston et al. [19] found that a low T stage was associated with pathological response at a sensitivity of 78.9% in 44 patients. Our results support the literature data in that when T and N staging was performed according to conventional MRI findings before CRT, the rates of T3, T4, and N2 were found to be higher in patients with no response and those with minimal response (p = 0.014).
In a study conducted by Tong et al. [20] with 38 patients, it was determined that as tumor length increased, pathological response to neoadjuvant CRT decreased. In a comprehensive study covering 405 cases, Yeo et al. [21] reported that as tumor volume increased, pathological response to neoadjuvant CRT decreased, and the cut-off value of tumor volume was 23.1 cm3 with 95% sensitivity. Similarly, Palmisano et al. [22] observed that pathological response decreased as tumor volume increased, and the cut-off value of tumor volume was 21.55 cm3 with 92% sensitivity. Our results are in agreement with those reported in the literature. The ROC curve test revealed the cut-off values of tumor length and tumor volume to be >4.4 cm and >23.8 cm3, respectively. Accordingly, the sensitivity of tumor volume was found to be 95.31% in predicting pathological response.
In a study found EMVI positivity before CRT to be higher among patient groups with no pathological response at a sensitivity of 95% in a total of 100 cases [23]. The authors also noted that the rate of patients with MRF involvement was higher among non-responders. This has been proven to be an indicator of poor prognosis in patients with rectal cancer presenting with EVMI and MRF involvement, as well as showing the biological aggressiveness of cancer [22]. In the current study, the rates of EMVI and MRF involvement were higher in patients with no response and those with minimal response compared to the responders, which is consistent with the literature.
Limitation
There are some limitations to our study. First, although measurements were performed by two radiologists using ROI, individual differences that might occur due to manual measurements cannot be overlooked. Second, in the current literature, ktrans, ve, and kep calculations have been used to describe DCE-MRI parameters, where ktrans correlates with the initial slope (wash-in rate) of the time intensity curve, ve correlates with the peak height and time to peak of the time intensity curve, and kep controls the shape of the curve (reflected in the relative contributions of its independent components, Ktrans and ve); however, we were not able to use these quantitative parameters since there is no software in our hospital that could calculate these values. This can be considered a limitation in terms of the inability to compare related data with the existing literature. Lastly, due to the single-center and retrospective design of the study, the generalizability of our findings is limited.
Conclusion
Wash-in and wash-out rates, which are semi-quantitative parameters of dynamic MRI taken before neoadjuvant CRT, are successful in predicting pathological response to treatment. Patients with locally advanced stage rectal cancer who have high T and N stages, as well as those with EMVI and MRF involvement, tend to have a lower pathological response to neoadjuvant CRT.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Selim Özdemir, Hüseyin Akkaya, Okan Dilek, Gökhan Söker, Zeynel Abidin Taş, Ahmet Gülmez, Bozkurt Gülek. Investigation of the utility of dynamic contrast MRI in predicting pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. Ann Clin Anal Med 2024;15(12):833-838
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Retrospective evaluation of 92 cases on the diagnosis and treatment of interstitial lung diseases
Elif Açar 1, Suat Konuk 2, Emine Özsarı 2, Orhan Kayakıran 2
1 Department of Allergy and Immunology, Kayseri Erciyes University Hospital, Kayseri, 2 Department of Pulmonology, Bolu Abant Izzet Baysal University Hospital, Bolu, Turkey
DOI: 10.4328/ACAM.22233 Received: 2024-04-28 Accepted: 2024-08-07 Published Online: 2024-10-03 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):839-844
Corresponding Author: Orhan Kayakıran, Department of Pulmonology, Bolu Abant Izzet Baysal University Hospital, Bolu, Turkey. E-mail: orhankayakiran.7@gmail.com P: +90 538 236 10 11 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8419-7039
Other Authors ORCID ID: Elif Açar, https://orcid.org/0000-0002-4669-5034 . Suat Konuk, https://orcid.org/0000-0002-8240-4775 . Emine Özsari, https://orcid.org/0000-0001-5842-7849
This study was approved by the Ethics Committee of Bolu Abant Izzet Baysal University Clinical Research (Date: 2019-12-19, No: 2019/323)
Aim: Interstitial lung diseases (ILDs) constitute a group of over 200 diseases affecting gas exchange, characterized by inflammation and fibroproliferation. The approach of a tertiary hospital to this heterogeneous group of diseases, which is challenging to manage, was reviewed to explore important features for diagnosis and treatment.
Material and Methods: Ninety-two patients evaluated for ILD at the Department of Chest Diseases, Abant Izzet Baysal University Faculty of Medicine, between January 1, 2018, and 2019, were examined in terms of demographic characteristics, clinical findings, pulmonary function tests, radiological images, diagnostic methods, and treatment modalities.
Results: A total of 92 patients, with a mean age of 62.23 ± 11.78- years (range: 32-88), including 69 males, were evaluated. The most common presenting complaints among symptomatic patients (92.4%) were dyspnea (77.6%) and cough (64.7%). Following clinical, radiological, and pathological evaluations, various ILDs were identified, predominantly idiopathic pulmonary fibrosis (25%), followed by nonspecific interstitial pneumonia (15.2%), pneumoconiosis (15.2%), sarcoidosis, hypersensitivity pneumonitis, drug-induced lung diseases, collagen vascular diseases, Langerhans cell histiocytosis, respiratory bronchiolitis-
associated ILD, lymphocytic interstitial pneumonia, and cryptogenic organizing pneumonia. Diagnosis was established by clinical and radiological methods in 72 patients (78.3%), while invasive diagnostic methods, including bronchoscopy and mediastinoscopy were performed in 20 patients. It was observed that a definitive pathological diagnosis was reached in 22% of patients.
Discussion: Diagnosis of ILD relies on the interpretation of history, clinical findings, imaging modalities, and biopsy results. Considering that the inability to perform invasive procedures in patients presenting with advanced respiratory failure complicates diagnosis, it is recommended that patients, especially those in tertiary care hospitals, be evaluated by multidisciplinary teams.
Keywords: Hypersensitivity Pneumonitis, Idiopathic Pulmonary Fibrosis, Interstitial Lung, Disease, Sarcoidosis
Introduction
Interstitial lung diseases (ILDs) constitute one of the most challenging patient groups in terms of diagnosis and treatment among those presenting to pulmonary clinics. Some of their etiologies are unknown, treatment is nonspecific, and the diseases are progressive. Development of inflammation and fibrosis is a common result in the latter stages of diseases. relies on the interpretation of history, clinical findings, imaging
modalities, and biopsy results [1]. The introduction of high-resolution computed tomography (HRCT) has allowed for better
visualization of the lungs and a better understanding of patterns related to ILDs. 3 Sometimes, despite the use of all diagnostic methods together, surgical procedures are required, and in most centers, diagnosis and treatment are planned by interpreting all results together in multidisciplinary steams. The diagnosis of interstitial lung diseases yields accurate results only in the presence of a multidisciplinary approach. We completed the diagnostic algorithms for all our patients in the study with an awareness of the importance of a multidisciplinary approach. In our study, we aimed to evaluate the demographic characteristics, clinical and radiological findings, diagnostic methods, treatment responses, and follow-ups of ILDs diagnosed at a tertiary care hospital. We anticipated that these findings could provide information about the ILD profile in our city.
Material and Methods
Patients who presented to the Department of Chest Diseases, Bolu Abant Izzet Baysal University Faculty of Medicine, between January 1, 2018, and January 1, 2019, and were evaluated as having ILD were retrospectively included in the study. Patient files were reviewed, and data including age, sex, occupation, symptoms, date of diagnosis, smoking history, comorbidities, medication history, method of diagnosis, parameters of pulmonary function tests, and findings of radiological imaging were recorded. For patients who underwent biopsy, the date of the pathology report was considered as the date of diagnosis, while for clinically and radiologically diagnosed patients, the date of the first CT scan showing findings was considered as the date of diagnosis. Spirometric tests (SFT) were performed using the MIR Spirolab 4.0 device. Patients were informed before the test, and they were tested approximately 2-4 hours after breakfast when they felt comfortable sitting in an upright position with a nose clip. Based on the measurements, a restrictive type respiratory function disorder was considered if the FEV1/FVC ratio was normal or high while the FVC was less than 80%. DLCO assessment was categorized as follows: DLCO ≥ 81% was Considered ‘normal’, DLCO between 61-80% was considered ‘mildly reduced’ DLCO between 41-60% was considered ‘moderately reduced,’ and DLCO ≤ 40% was considered ‘severely reduced’ [3] HRCT (high-resolution computed tomography) was performed to better evaluate the lung parenchyma and mediastinum and to determine the appropriate site for bronchoscopic biopsy. Radiological findings were recorded. Bronchoscopy was performed on patients with suitable clinical conditions to establish or confirm a histopathological diagnosis. Transbronchial biopsies were taken during bronchoscopy, and bronchial biopsies were performed in patients suspected of having sarcoidosis. For patients in whom results could not be obtained with these methods and tissue diagnosis was necessary, open lung biopsy was recommended. For those who agreed, lung biopsy was performed via horacotomy or video-assisted thoracoscopic surgery (VATS). During the diagnostic phase, the following criteria were considered: For patients suspected of sarcoidosis, ophthalmologic consultation was requested, and a tuberculin skin test with five units of tuberculin was performed. Induration diameter was measured at 72 hours, and values ≥ 5 mm were considered positive reactions. Diagnosis was based on clinically compatible features with multi-organ involvement, histologically demonstrated non-caseating granulomas, and exclusion of other diseases with similar clinical and histological features. When biopsy could not be obtained or was inadequate, patients were considered to have sarcoidosis if their clinical and radiological features were consistent with the diagnosis [4]. The diagnosis of idiopathic interstitial pneumonia and idiopathic interstitial fibrosis was made based on the criteria outlined in the consensus report of the American Thoracic Society (ATS) / European Respiratory Society (ERS) and taking into account the latest update recommendations. 6, 7 Patients with collagen vascular disease had previously been diagnosed or were diagnosed by our department. When their clinical and radiological features were consistent, they were considered to have lung involvement, and biopsy methods were not pursued. The diagnosis of hypersensitivity pneumonitis was based on suggestive history, exposure to a possible agent, partial clinical or functional improvement with avoidance of the responsible agent, restrictive pulmonary function tests, and the presence of ground-glass opacities and/or fibrosis on HRCT [8]. All patients included in the study were evaluated in terms of radiological examinations, all diagnostic interventions, biopsy methods, histopathological diagnosis rates, and obtained diagnoses. Subsequently, patients were grouped according to their diagnoses and examined. Group 1 (G1) consisted of ILDs associated with a known cause, Group 2 (G2) comprised granulomatous ILDs, Group 3 (G3) included idiopathic interstitial pneumonias, and Group 4 (G4) consisted of rarely seen ILDs.
Statistical Analyses
Descriptive statistics are presented as mean ± standard deviation or median (minimum – maximum) values for numerical variables, and as numbers and percentages for categorical variables. The normality assumption was assessed using graphical methods (histogram, QQ plot, etc.) and tests (Kolmogorov-Smirnov, Shapiro-Wilk, etc.). The choice of test also took into account the number of observations in each group. The Kruskal-Wallis test was used for comparisons among four groups in terms of numerical variables. For comparisons of
categorical variables among groups, chi-square tests were utilized. Post-hoc tests were employed to determine which group or groups were different. Analyses were performed using
IBM SPSS v.21. A significance level of p < 0.05 was considered statistically significant.
Ethical Approval
This study obtained approval from the Bolu Abant Izzet Baysal University Clinical Research Ethics Committee (Date: 2019-12-19, No: 2019/323).
Results
Ninety-two patients, ages 32 to 88, were included in the study. Among them, 23 (25%) were female and 69 (75%) were male, with a mean age of 62.23 ± 11.78 years. The majority of symptomatic patients (92.4%) presented with dyspnea (77.6%), cough (64.7%), and chest pain (35.3%) as the main symptoms. Upon examination of physical signs, the most common findings were fine crackles (61%), clubbing (23%), and rales (20%). Regarding occupational distribution, 29.3% were workers, 19.6% were housewives, 27.2% were farmers, and 23.9% were civil servants. The most common comorbidity was obstructive lung diseases (COPD, asthma) (48.1%), followed by hypertension, coronary artery disease, diabetes mellitus, and malignancies. The mean smoking history was found to be 35.12 ± 18.58 pack-years (ranging from 5 to 100 pack-years). Spirometric findings revealed a significant decrease in DLCO (56.563 ± 21.639), with a mean FVC of 83.760 ± 20.073 and a mean 6-minute walking distance of 373.958 ± 70.853 meters (Table 1). Upon examination of the patients' diagnoses and diagnostic methods, it was found that 23 patients had idiopathic pulmonary fibrosis (IPF) (25%), 14 patients had nonspecific interstitial pneumonia (NSIP) (15.2%), 14 patients had pneumoconiosis (15.2%), 10 patients had sarcoidosis (10.8%), 7 patients had hypersensitivity pneumonitis (HP) (7.6%), 6 patients had drug-induced lung diseases (6.5%), 6 patients had collagen vascular diseases (6.5%), 5 patients had Langerhans cell histiocytosis (LCH) (5.4%), 4 patients had respiratory bronchiolitis-associated ILD (4.3%), 2 patients had lymphocytic interstitial pneumonia (LIP) (2.1%), and 1 patient had cryptogenic organizing pneumonia (COP) (1%). According to the classification of ILDs, pneumoconiosis, drug-induced lung diseases, and collagen vascular diseases were included in Group 1 – ILDs associated with a known cause; sarcoidosis and
hypersensitivity pneumonitis were in Group 2 – the granulomatous group; IPF, NSIP, respiratory bronchiolitis-associated ILD, LIP, and COP were in Group 3 – the idiopathic group; and LCH was in Group 4 – rarely seen ILDs group. The diagnosis was established by clinical and radiological methods in 72 patients, by video-assisted thoracoscopy in 10 patients, by mediastinoscopy in 7 patients, and by bronchoscopy (transbronchial-endobronchial biopsy and EBUS) in 3 patients. The diagnostic methods for diseases according to their etiologies are presented in Table 2.
Radiologically, septal thickening, mediastinal lymphadenopathy, ground-glass opacities, traction bronchiectasis, honeycombing, emphysematous areas, and basal predominance were most commonly observed in Group 3 , while mosaic perfusion and upper lobe involvement were more common in Group 2, and pleural thickening was most frequently observed in Group 1. Significant differences were found among the groups for all radiological findings except consolidation, solitary pulmonary nodules, and bronchiectasis (Table 3). When spirometric and functional parameters were compared among the groups, the lowest values for FEV1, FVC, FEV1/FVC ratio, DLCO, 6-minute walking distance, and initial and final saturations were expectedly observed in Group 3, although this difference was not statistically significant.
Discussion
In this study, we aimed to evaluate the demographic characteristics, clinical and radiological findings, diagnostic methods, treatment responses, and follow-ups of ILD patients diagnosed at a tertiary care hospital. We emphasized the importance of a multidisciplinary approach in the management of ILDs. Although the precise epidemiology is unclear, ILD continues to be a significant cause of morbidity and mortality worldwide. In recent years, deaths due to idiopathic pulmonary
fibrosis (IPF) and hypersensitivity pneumonitis (HP) have been reported to increase in the United States [14]. Studies on incidence have reported an annual incidence of 31 per 100,000 in various populations [8]. In a study by Musellim et al. involving 2,245 patients, the annual incidence of ILD in Turkey was found to be 25.8 per 100,000. 11 The same study reported sarcoidosis as the most common diagnosis at 37.6%, followed by IPF at 19.9%, pneumoconiosis at 11.8%, and HP at 4% . Similar to our study, the R-BILD Turkey study also identified IPF as the most common ILD. In our study, IPF (25.0%) among idiopathic interstitial pneumonias, pneumoconiosis (15.2%) among known causes, and sarcoidosis (10.8%) among granulomatous diseases were the most frequently identified ILDs. These findings are consistent with other studies conducted in Turkey [10, 11].
When examining the distribution of diseases by age and gender, ILDs peak in the 5th and 6th decades of life. IPF is more common in men and is most frequently observed in individuals over 75 years of age [6, 8, 12]. Baughman et al. found that 63.6% of sarcoidosis cases were female. 13 Consistent with the literature, 70% of sarcoidosis patients in our study were female, with an average age of 37.8 ± 10.2 years. In the IPF group, 87% were male, with a male/female ratio of 6.6, and the average age was 69.97 ± 8.5 years (Table 1). Women were most commonly diagnosed with sarcoidosis and HP, while IPF was most frequent in men. The relationship between diagnostic groups and gender revealed that the percentage of males was significantly lower in Group 2 (granulomatous diseases), a statistically significant finding (p = 0.039) (Table 1).
ILDs with established associations with smoking include idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial
lung disease (RB-ILD), and histiocytosis X. [17, 18] In our study, 68.5% of patients had a history of smoking. This rate was 73% in patients with IPF and 85.7% in those with pneumoconiosis. However, among patients diagnosed with sarcoidosis, 80% were non-smokers, consistent with the literature [4, 16]. When evaluating the relationship between diagnosis groups and smoking status, it was found that the rate of smoking was significantly higher in Group 4, which comprises rare ILDs (p = 0.045). Looking at comorbidities, chronic obstructive pulmonary disease (COPD), hypertension, and ischemic heart disease were found to be the most common comorbidities in a study by Schwarzkop et al. [19] Similarly, in our study, these three diseases were observed as the most prevalent comorbidities.
Dyspnea is the most common symptom in ILD, particularly in IPF, with an incidence reported between 80-90.1% in various studies . Dyspnea is least common in sarcoidosis. [19] In our patients, the most frequently observed symptoms were dyspnea (77.6%) and dry cough (64.7%). Consistent with the literature, cough rates were 60% in sarcoidosis, 91.3% in IPF, and 71.4% in NSIP in our study. Reticular and interlobular septal thickening, ground-glass opacities, traction bronchiectasis, and honeycombing, predominantly with basal involvement, are the most common CT findings in ILD [18, 19]. In our study, septal thickening, traction bronchiectasis, honeycombing, and basal predominance were most frequently observed in Group 3, with significant differences between groups for these findings. However, there were no significant differences between groups in the frequency of consolidation, bronchiectasis, or solitary pulmonary nodules (Table 2). In the R-BILD study, the most common findings in the IPF group were interlobular septal thickening (72%), traction bronchiectasis (58.2%), honeycombing (69%), and basal predominance (57.8%), while in the sarcoidosis group, mediastinal lymphadenopathy (68.9%)
was most frequent, and in the HP group, ground-glass opacities (75.9%) were the most common [10]. Pulmonary function tests (PFTs) are essential indicators in diagnosing and monitoring ILD
and predicting mortality [20-22]. One study found that patients with a 5-10% decline in FVC had worse clinical outcomes than those with stable FVC values [20]. According to the British Thoracic Society’s recommendations, in IPF patients, a decrease of more than 10% in FVC or more than 15% in DLCO within the first 6-12 months is associated with high mortality . 22 A study from our country indicated that FVC and DLCO values were not significant predictors of mortality; instead, the 6-minute walk test (6MWT) was the only independent functional parameter affecting mortality [22]. In our study, although the DLCO value was expectedly lowest in Group 3, there was no significant relationship between diagnostic groups and other PFT parameters, including walk tests (Table 3).
Regarding diagnostic methods, 78.3% of diagnoses were made using clinical and radiological methods, 10.9% through video thoracoscopy (VATS), 7.6% through mediastinoscopy, and 3.3% through EBUS and FOB. In the study by Şengül et al., 39.13% of diagnoses were made using clinical and radiological methods, 34.78% through bronchoscopy, 10.87% through mediastinoscopy, 8.7% through open lung biopsy, 2.17% through skin biopsy, and 1.09% through lymph node biopsy, renal biopsy, and pleural fluid analysis each [11]. The application rate of invasive biopsy methods in our study, as in the national and international literature, was low [22]. Therefore, our study aligns with the literature. Additionally, ATS and ERS recommendations state that open lung biopsy is not recommended if clinical, laboratory, and radiological features are typical for IPF and the biopsy results would not change the treatment decision [1].
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Fishman AP, Elias JA, Fıshman JA. Fishman‘s Pulmonary Diseases and Disorders, 4th Edition. 2008.p.66-8.
3. Wagner J. Pulmonary Function Testing. A Practical Approach. 1st ed. USA: Williams and Wilkins. 1992.p.1-61.
4. Kaya A, Alper D. Sarcoidosis: Definition, Classification, Epidemiology, Sarcoidosis in the Light of Current Information. Scientific Medical Publishing House. 1999.p.5-11.
5. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-48.
6. Montesi SB, Fisher JH, Martinez FJ, Selman M, Pardo A, Johannson KA. Update in Interstitial Lung Disease 2019. Am J Respir Crit Care Med. 2020;202(4):500-7.
7. Selman M, Chapela R, Raghu G. Hypersensitivity pneumonitis: Clinical manifestations, pathogenesis, diagnosis and therapeutic strategies. Semin Respir Crit Care Med. 1993;14:353-64.
8. Dove EP, Olson AL, Glassberg MK. Trends in idiopathic pulmonary fibrosis-related mortality in the United States: 2000-2017. Am J RespirCritCareMed. 2019;200:929-31.
9. Musellim B, Okumus G, Uzaslan E. Turkish Interstitial Lung Diseases Group. Epidemiology and distribution of interstitial lung diseases in Turkey. Clin Respir J. 2014;8:55-62.
10. Aycicek O, Cetinkaya E, Demirci Ucsular F, Bayram N, Senyigit A, Aksel N, et al. Research Burden of Interstitial Lung Diseases in Turkey – RBILD: Interstitial Lung Diseases in Turkey. 2022;39(1):e2022006.
11. Şengül B, Uzun O, Fındık S, Atıcı G. Examination of 92 patients diagnosed with interstitial lung disease in our clinic Tuberculosis and Thorax Journal. 2009;57(3):314-26.
12. Baughman RP, Teirstein AS, Judson MA. Clinical Characteristics of Patients in a Case Control Study of Sarcoidosis. Am J Respir Crit Care Med. 2001;15:1885-89.
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14. Hidalgo A. Smoking-related interstitial lung diseases: Radiologic-pathologic correlation. European radiology. 2006;16(11):2463-70.
15. Schwarzkop L, Witt S, Waelscher J, Polke M, Kreuter M. Associations between comorbidities, their treatment and survival in patient swith interstitial lung diseases – a claims data analysis. Respir Res. 2018;19(1):73.
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17. George PM, Spagnolo P, Kreuter M, Altinisik G, Bonifazi M, Martinez FJ, et al. Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities. Lancet Respir Med. 2020;8(9):925-934.
18. Schmidt SL, Sundaram B, Flaherty KR. Diagnosing fibrotic lung disease: when is high-resolution computed tomography sufficient to make a diagnosis of idiopathic pulmonary fibrosis? Respirology. 2009;14(7):934-9.
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21. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. 2008;63(Suppl 5):S1-58.
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24. Pleasants R, Tighe RM. Management of Idiopathic Pulmonary Fibrosis. Ann Pharmacother. 2019;53(12):1238-48.
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Elif Açar, Suat Konuk, Emine Özsarı, Orhan Kayakıran. Retrospective evaluation of 92 cases on the diagnosis and treatment of interstitial lung diseases. Ann Clin Anal Med 2024;15(12):839-844
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Comparison of open and endoscopic surgical methods in tuba-ovarian abscess management
Faruk Ikizoglu, Ramazan Ozyurt, Murat Ekin
Deaprtement of Obstetrics and Gynecology Bakırköy Sadi Konuk Research and Training Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.22255 Received: 2024-05-07 Accepted: 2024-06-12 Published Online: 2024-09-13 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):845-849
Corresponding Author: Ramazan Ozyurt, Deaprtement of Obstetrics and Gynecology Bakırköy Sadi Konuk Research and Training Hospital, Istanbul, Turkey. E-mail: atasagun02@hotmail.com P: +90 212 414 71 71 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6822-2222
Other Authors ORCID ID: Faruk Ikizoglu, https://orcid.org/0000-0002-9320-3311 . Murat Ekin, https://orcid.org/0000-0002-4525-5125
This study was approved by the Ethics Committee of Bakırköy Sadi Konuk Research and Training Hospital (Date: 2023-09-16, No:2023-20-13)
Aim: The study aims to compare the effectiveness of laparoscopy and laparotomy in the management of tuba-ovarian abscess (TOA).
Material and Methods: This is a retrospective thesis study analyzing 54 patients who were operated on with the diagnosis of TOA. Medical records of patients aged 21-65 years were scanned and the data were recorded. Patients were divided into two different groups those who underwent laparoscopy (n=21) and those who underwent open surgery (n=33). Abscess size, laterality and length of hospital stay were recorded. Duration of the surgical procedure, whether transfusion was required, postoperative complications, and laboratory findings were also noted.
Results: There was no difference between the age, BMI, gravida, parity, and delivery method of the participants according to the surgery types (p>0.05). The total duration of antibiotic use and the need for changes in antibiotic therapy were longer in patients who underwent abscess drainage by laparotomy. The hysterectomy rate was higher in patients whose TOA was managed by laparotomy (p<0.01). Laparotomy resulted in longer operating times and ileus rates. There was no difference between the two groups in terms of abscess size, duration of preoperative antibiotic use, laterality, need for blood transfusion, pulse, temperature values, salpingectomy, salpingoophorectomy, intestinal or ureteral injury rates, and wound site infections (p>0.05). The type of surgery did not affect the hemoglobin, hematocrit and white blood cell values.
Discussion: Treatment of TOA with laparoscopic surgery was found to be more advantageous than open surgery in terms of hospital stay, operation time and response to antibiotic therapy.
Keywords: Tuba Ovarian Abscess, Laparoscopy, Laparotomy
Introduction
The female genital system is frequently affected by sexually transmitted infections. If the infection becomes an acute infection of the upper genital tract, which includes any or all of the uterus, fallopian tubes, and ovaries, it is referred to as pelvic inflammatory disease (PID). PID may heal spontaneously or with medical treatment, or it may progress to oophoritis, endometritis, salpingitis, hepatitis, peritonitis and/or tubo-ovarian abscess (TOA). PID may turn into a pus-filled mass that includes the ovaries and tubes and may cause agglutination of the organs in the tubo-ovarian complex. TOA is most commonly seen in patients of reproductive age and generally occurs as a complication of PID [1, 2].
TOA is a disease that requires urgent intervention and has high morbidity and mortality. Medical, surgical, or combined approaches in which both treatments are applied together may be required [3,4]. With current practice, the mortality rate for unruptured abscesses approaches zero. Mortality rates in patients with ruptured abscesses vary between 1.7-3.7 percent [5]. Surgical intervention may be required in patients with ruptured abscesses, signs of peritoneal irritation (acute abdomen), and patients who do not respond to antibiotic treatment.
While the abscess can be drained by laparoscopy or laparotomy, minimally invasive drainage methods such as colpotomy, percutaneous drainage and transvaginal drainage can also be used [6, 7]. However, surgical interventions are advantageous as they allow evaluation of intra-abdominal adhesions and adjacent organs in addition to abscess diagnosis and drainage. This study was planned to compare the effects of laparoscopic and laparotomic surgical treatments in the management of TOA on clinical results, laboratory findings and postoperative results. In addition, it is aimed to contribute ideas to the surgeon in the treatment of TOA by determining the advantages and disadvantages of two different surgical approaches.
Material and Methods
This is a retrospective thesis study analyzing 54 patients who were operated on with the diagnosis of TOA in our hospital between 2018 and 2023. Medical records of patients aged 21-65 years old who were admitted to Deaprtment of Obstetrics and Gynecology, Bakırköy Sadi Konuk Research and Training Hospital were retrospectively scanned and the data were digitally recorded in Excel and SPSS programs. Immunosuppressed patients, patients with malignancy, patients who were found to have no abscess during surgery, and patients with incomplete medical records were excluded from the study.
Patients who had the data we requested in the screening performed by entering the words TOA, abscess, pyosalpinx, abscess, tuboovarian abscess from the electronic monitoring system unit were included in the study. Demographic data of the patients such as age, parity, gravida, birth types and numbers, abortion, height, weight, and body mass index were recorded. In addition, history of intrauterine device use, PID, systemic infection, diabetes mellitus and hypertension, which are risk factors for TOA, were questioned. Abscess size and laterality were recorded. Additionally, the patient’s vital signs such as fever and pulse at the time of admission were noted. Duration of the surgical procedure, whether transfusion was required, postoperative complications, and laboratory findings were noted. Based on these findings, we divided our patients into two different groups: those who underwent laparoscopy (n=21) and those who underwent open surgery (n=33).
Statistical Analysis
SPSS 26 (Statistical Package for the Social Sciences) program was used for statistical analysis of the data. Quantitative variables were presented as mean, standard deviation, median, min and max values, and qualitative variables were presented as frequency and percentage. Whether the data showed a normal distribution or not was determined with the help of Shapiro Wilks test and Box Plot graphics. Student’s t-test was used in the analysis of normally distributed data, and repeated measures were used in intra-group evaluations. Chi-Square test, Fisher’s Exact test and Fisher Freeman Halton test were used to compare qualitative data. P<0.05 was considered statistically significant within the 95% confidence interval.
Ethical Approval
This study was approved by the Ethics Committee of Bakırköy Sadi Konuk Research and Training Hospital (Date: 2023-09-16, No:2023-20-13). Data collection started after receiving approval from the ethics committee approval.
Results
The patients’ ages ranged from 25 to 58, with an average of 41.30±7.29 years. The height of the participants ranged from a minimum of 150 cm to a maximum of 175 cm, with an average of 161.98±4.83 cm. The weight of the cases varies between 50 and 83 kg, and the average is 62.87±6.71 kg. BMI values range from 19.8 to 33.2 kg/m2, with an average of 23.99±2.71 kg/m2. When the gravidas of the cases were examined, it was seen that 5.6% did not give birth, 16.7% had 1 pregnancy, 42.6% had 2 pregnancies and 35.2% had 3 or more pregnancies. When their parities were examined, it was seen that 13.0% did not give birth, 24.1% had 1 parity, 35.2% had 2 parities, and 27.8% had 3 or more parities. It was determined that 31.5% of the cases had 1 birth, 20.4% had 2 births, 11.1% had 3 births, and 7.4% had 4 births. Of those diagnosed with TOA, 42.6% (n=23) smoked, 29.6% (n=16) used IUD, 9.3% (n=5) had DM and 9.3% (n=5) had a history of HT. According to the type of surgery, it was determined that 38.9% (n = 21) of the cases had laparotomy and 61.1% (n = 33) had laparoscopic surgery. Table 1 details the demographic data of participants in both surgery groups.
Table 2 details the changes in the parameters evaluated before and after surgical intervention. Abscess sizes varied between 2.5 and 12.2, and 77.8% (n=42) of the cases were unilateral and 22.2% (n=12) were bilateral. The average duration of the patients receiving intravenous antibiotics before surgery was 3.91±2.76 days and the average total duration of intravenous antibiotics was 11.00±5.03. Operation times of the cases participating in the study ranged between 55 and 200 minutes, and the average time was 118.52±37.25 minutes. It was determined that 7.4% of TOA patients had ileus, 5.6% had intestinal damage, 3.7% had ureter damage, and 5.6% had wound infection. When the pathology results were examined, it was seen that 1.9% had endometrioma, 1.9% had granulosa cell tumor and 96.3% had salpingoophoritis.
There was no difference between the age, BMI, gravida, parity, and delivery method of the cases according to the surgery types (p>0.05). The total duration of antibiotic use and the need for changes in antibiotic therapy were longer in patients who underwent abscess drainage by laparotomy. The hysterectomy rate was higher in patients whose TOA was managed by laparotomy (p<0.01). Laparotomy resulted in longer operating times and ileus rates. There was no difference between the two groups in terms of abscess size, duration of preoperative antibiotic use, laterality, need for blood transfusion, pulse, temperature values, salpingectomy, salpingoophorectomy, intestinal or ureteral injury rates, and wound site infections (p>0.05). The type of surgery did not affect the hemoglobin, hematocrit and white blood cell values on the 1st day after the operation, and on the 1st week after the operation (Table 3).
Discussion
Tuba ovarian abscess is a serious, life-threatening inflammatory disease affecting the female pelvic organs. In this study, we compared patients who underwent laparotomy or laparoscopy due to tuboovarian abscess in terms of antibiotic use, postoperative complications and length of hospital stay, in addition to demographic and laboratory values. Although the age scale of TOA patients is wide, it was observed predominantly in women in the reproductive period. The age range of the cases ranged between 25 and 58 and was found to be compatible with the literature [8]. The number of patients with postmenopausal TOA (7.2%) was also consistent with the literature. Although we cannot establish a clear connection between birth rates, BMI, smoking and TOA, there are studies reporting that high BMI and parity increase the risk of TOA and reduce the response to antibiotics [9]. The fact that 42.6% of TOA patients have a history of smoking suggests that smoking reduces immune resistance and increases the tendency to infection. The detection of IUD in 29.6% of the cases is consistent with the literature rates and supports that IUD poses a risk for TOA. On the other hand, IUD use and history of hypertension and DM did not affect the operation option.
Abscess sizes of the cases ranged between 2.5 and 12.2. We recommended surgery to patients with a TOA of 7 cm or more if there was no shrinkage after antibiotic treatment. However, we did not observe a relationship between abscess size and the surgical procedure to be performed. Although TOA was bilateral in 22% of the participants, laterality did not have a significant impact on the choice of surgical method. We did not observe any significant difference between open and laparoscopic methods in terms of duration of preoperative antibiotic use and vital signs such as fever and pulse. The age, BMI values, gravida, parity, type of birth, number of abortions and comorbidities of the cases did not differ between the surgical groups. The average duration of total antibiotic use was 9 days in TOA patients who underwent laparoscopic surgery and 14.14 days in open surgery. Consistent with the literature, short-term antibiotic use in the L/S group required short-term hospitalization [10]. The need for more antibiotic changes in the laparotomy group can be considered an important finding. Although there was no difference in surgical complications between laparoscopy and laparotomy, ileus was more common in those who underwent laparotomy in our study. Although the rates of other postoperative complications (intestinal damage, ureteral injury, wound infection) are consistent with previous studies, the frequent occurrence of ileus in the laparotomy group is different from the literature data [11].
Clinical studies recommend TAH+BSO as a comprehensive treatment method in TOA patients who have completed parity [3, 7]. However, this strategy increases the duration of surgery and complications. Some studies have revealed unilateral salpingo-oophorectomy as a more reasonable treatment option [12]. In our cohort, 55.6% of the patients underwent salpingo-oophorectomy, and the length of hospital stay and amount of bleeding were similar. We determined that hysterectomy increases complication rates. In patients who have completed parity or are postmenopausal, TAH+BSO is still a reasonable option. In relatively young patients, unilateral salpingo-oophorectomy can be performed by leaving the intact tube and ovary. We found the salpingectomy and salpingoophorectomy rates to be similar in both groups. The only difference in surgical procedures was in hysterectomy rates. While hysterectomy was required in 9 cases during L/S, it was required in 2 cases during open surgery. Although the literature reports that the need for blood transfusion is less in laparoscopy [6, 7], we found HB, HTC values and transfusion rates to be similar between the two groups. The decrease in WBC and CRP values measured on postoperative days 1 and 7 was similar to the two groups. However, the literature stated that the decreases in WBC and CRP on days 1 and 7 were faster in laparoscopy [8]. This may be due to differences in patient population and surgeon experience.
In the current study, we found granulosa cell tumor of the ovary in only 1 of 54 patients (1.85%). In a study conducted in Athens, concurrent gynecological malignancy was detected in 8 cases with postmenopausal TOA [13, 14]. We detected malignancy in one of 5 patients with postmenopausal TOA. In light of these data, pathology results should be followed closely, keeping in mind that there may be malignancy in postmenopausal TOA patients [13, 14].
Conclusion
The study has some limitations. Despite the limitations such as being retrospective, small number of patients and being single-centered, the abundance of demographic and laboratory data evaluated makes our study important. Treatment of TOA with endoscopic surgery was found to be more advantageous than open surgery in terms of hospital stay, operation time and response to antibiotic therapy. Abscess size appeared to be unrelated to the choice of surgery types. When performed based on the surgeon’s experience, laparoscopic management of TOA has been found to be advantageous in many respects over open surgery.
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.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Granberg S, Gjelland K, Ekerhovd E. The management of pelvic abscess. Best Pract Res Clin Obstet Gynaecol. 2009;23(5):667–78.
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8. Kuo CF, Tsai SY, Liu TC, Lin CC, Liu CP, Lee CM. Clinical characteristics and treatment outcomes of patients with tubo-ovarian abscess at a tertiary care hospital in Northern Taiwan. J Microbiol Immunol Infect. 2012;45(1):58–64.
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Download attachments: 10.4328.ACAM.22255.pdf
Faruk Ikizoglu, Ramazan Ozyurt, Murat Ekin. Comparison of open and endoscopic surgical methods in tuba-ovarian abscess management. Ann Clin Anal Med 2024;15(12):845-849
Citations in Google Scholar: Google Scholar
Ileocecal resection in Crohn’s disease: Our clinical experience
Uğur Topal 1, Mustafa Koray Demiryürek 1, Burak Yavuz 1, İshak Aydın 1, Orçun Yalav 2, İsmail Cem Eray 1
1 Department of General Surgery Faculty of Medicine, Çukurova University, 2 Department of General Surgery, Acibadem Adana Hospital, Adana, Turkey
DOI: 10.4328/ACAM.22262 Received: 2024-05-13 Accepted: 2024-07-02 Published Online: 2024-08-16 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):850-854
Corresponding Author: Uğur Topal, Department of General Surgery Faculty of Medicine, Çukurova University, Adana, Turkey. E-mail: sutopal2005@hotmail.com P: +90 322 338 60 60 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1305-2056
Other Authors ORCID ID: Mustafa Koray Demiryürek, https://orcid.org/0009-0000-3531-1843 . Burak Yavuz, https://orcid.org/0000-0002-5262-0346 . İshak Aydın, https://orcid.org/0000-0002-6366-2461 . Orçun Yalav, https://orcid.org/0000-0001-9239-4163 . İsmail Cem Eray, https://orcid.org/0000-0002-1560-7740
This study was approved by the Ethics Committee of Çukurova University, Faculty of Medicine (Date: 2023-11-03 No: 138/27)
Aim: This study aimed to evaluate the clinical and surgical outcomes of patients undergoing ileocecal resection for Crohn’s disease and analyze their postoperative course.
Material and Methods: Data from 62 patients who underwent ileocecal resection between January 2014 and February 2022 were retrospectively reviewed. Demographic characteristics, surgery duration, anastomosis configuration, stoma necessity, clinical remission, and postoperative Rutgeerts scores were evaluated.
Results: The average age was 40.4±12.8, and the average age at diagnosis was 32.0±12.8. The average BMI was 21.48±3.54. Males comprised 61.3% (n=38) and females 38.7% (n=24). The average surgery duration was 145.6±61 minutes. Anastomosis was performed on 52 patients. Steroid use (>20mg/day preoperatively) correlated with higher complication rates (50% vs 12%, p<0.05). Active smokers had higher postoperative complication rates. One patient experienced anastomotic leakage. The median Rutgeerts score was 0 (0-4). Recurrence was observed in 12 patients. No significant difference was found between clinical remission and Rutgeerts scores. Post-operative prophylaxis was required in 66.1% (n=41), with 53% starting treatment within 30 days postoperatively.
Discussion: Ileocecal resection is an effective and safe treatment for complicated Crohn’s disease. Smoking cessation and awareness of increased postoperative complications in patients on high-dose steroids are crucial. Individualized treatment approaches yield satisfactory outcomes.
Keywords: Crohn’s Disease, Postoperative Complications, Steroids, Smoking
Introduction
Lower case (Crohn’s disease) is a chronic inflammatory disease that can affect any part of the gastrointestinal tract from mouth to anus, characterized by transmural inflammation and a course of disease marked by remissions and exacerbations. It often exhibits a skipping pattern of involvement. The most commonly affected areas are the terminal ileum and colon. The involvement of different regions of the gastrointestinal system and the disorders it causes in different organ systems lead to diverse clinical presentations, necessitating the personalization of treatment [1, 2].
Despite significant advances in the medical treatment of Crohn’s disease, surgery still plays an important role in its management. Approximately 50-60% of patients with Crohn’s disease require at least one surgical resection within the first ten years of diagnosis [3]. However, surgery does not provide a definitive cure for the disease, resulting in a high rate of recurrence in many patients. Surgical indications of Crohn’s disease include both acute and chronic complications, as well as the failure of medical treatment [4].
To date, various surgical techniques for different Crohn’s disease locations and behaviors have been reported, but the surgical management of Crohn’s disease remains challenging. The main difficulties include the extent of the surgery, timing, anastomosis configurations, the condition of the mesentery, the status of preoperative immunosuppressive treatment, and postoperative follow-up [5]. Surgical approaches in Crohn’s disease bring about various postoperative complications, affecting the overall quality of life and leading to the inability to receive medical treatment. The frequency of postoperative complications following ileocecal resection varies between 20% and 47% in the literature [6].
The clinical recurrence of the disease following ileocolic resection in Crohn’s disease is a significant and challenging problem. Despite numerous studies focusing on disease-related and patient-related factors that could affect the risk of recurrence, a high rate of recurrence is still observed. Endoscopic recurrences can be found in 70-90% of patients in the first year after surgery. Although the number of patients with clinically significant recurrence is lower, approximately 40% of patients may require reoperation within 5 years, and 55% within 10 years [7, 8].
In this study, we aimed to evaluate the clinical and surgical outcomes of patients who underwent ileocecal resection for Crohn’s disease at a tertiary center and to analyze their postoperative course.
Material and Methods
Patients diagnosed histologically with Crohn’s disease and who underwent ileocecal resection were included in the study. Patients under 18 years of age and those with incomplete medical records were excluded. A dataset was created using hospital electronic medical records, gastroenterology follow-up forms, and, when necessary, telephone interviews. Our study was a single-center, retrospective study based on a database that was prospectively updated.
Patients’ demographic characteristics such as age, gender, body mass index (BMI), preoperative C-reactive protein levels, serum albumin (g/dL), and hemoglobin (g/dL) levels; surgical indications, surgery duration, anastomosis configuration, and stoma necessity including postoperative stoma necessity (in case of leakage) were evaluated. The relationship between postoperative complications, the nature of the operation, stoma status, smoking, and preoperative steroid use exceeding 20 mg/day in the last month was analyzed. Additionally, patients’ clinical remission after surgery and their Rutgeerts scores in postoperative colonoscopies were examined, and the need for prophylactic treatment was analyzed.
Early postoperative complications were defined as any surgical or other medical events occurring within 30 days post-surgery. Definitions for surgical complications were used as previously described in the literature [9].
Surgical Technique
All operations were performed under general anesthesia, either on an emergency or elective basis depending on the patient’s presentation. The choice of open or laparoscopic method was made by the surgeon. Regardless of the surgical approach, the resection was limited to the macroscopically diseased bowel segment only, with the mesentery dissected and tied close to the bowel wall. The configuration of the anastomosis was chosen based on intraoperative findings, using either double-layered side-to-side hand-sewn anastomosis or stapler anastomosis. Indications for diverting the anastomosis included chronic high-dose steroid therapy, severe intra-abdominal sepsis, and malnutrition.
Follow-Up
Routine colonoscopic examinations are performed 6-12 months after surgery at our clinic. Endoscopic data were prospectively collected. Lesions in all segments, including the anastomosis site and neo-terminal ileum, were reported. The endoscopist assessed the Rutgeerts score for each patient. The choice of medical treatment and the need for prophylactic treatment in our clinic were made according to the ECCO Guidelines [10, 11].
Statistical Analysis
Statistical analyses were conducted using SPSS version 22.0. The conformity of numerical data to normal distribution was examined using the Kruskal-Wallis test. Numerical data adhering to a normal distribution were presented as mean and standard deviation, while categorical variables were presented as frequency and percentage. The Chi-square test was used for the comparison of categorical variables. In the analyses, a p-value of <0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Çukurova University, Faculty of Medicine (Date: 2023-11-03 No: 138/27).
Results
Our study included 62 patients with an average age of 40.4 and a female gender ratio of 38%. The preoperative albumin level was 2.79 g/dL. 48% of the patients were active smokers, and 20% had used >20mg/day of steroids in the last month. The most common indications for surgery were strictures in 18 patients, enterocutaneous fistula in 14 patients, and non-responsiveness to treatment in 14 patients. Demographic and clinical data are shown in Table 1.
The average duration of surgery was 145 minutes. Elective surgery was more common (47 vs. 15), and open surgery was performed in 38 patients compared to 24 for laparoscopic surgery. Stapler anastomosis was more frequently used (47 vs. 5). The rate of stoma creation in emergency cases was significantly higher compared to elective cases (p<0.05). The most important reason for unplanned hospital readmission postoperatively was surgical site infection in 4 patients, abdominal pain in 3 patients, ileus in 1 patient, and evisceration in 1 patient. Postoperative complications were observed in 12 patients, with surgical site infection being the most common (9 patients). The rate of complications in patients who used >20mg/day steroids in the last month preoperatively was higher compared to those who did not (50% vs 12%, p<0.05). The rate of postoperative complications was higher in active smokers compared to non-smokers (36% vs 3%, p<0.05). It was determined that 66.1% of the patients (n=41) required post-operative prophylaxis, with 53% starting treatment within the first 30 days post-operatively, and 14% starting after the 30th day. This data is shown in Table 2.
Recurrence was observed in 12 patients during postoperative ileocolonoscopies. No significant difference was found between clinical remission and Rutgeerts score in terms of risk. This is shown in Table 3 and Figure 1.
Discussion
In this study, where we presented the outcomes of patients undergoing ileocecal resection due to Crohn’s disease, we found that the most common indication for surgery was strictures, the majority of operations were elective and open, and stapler anastomosis was more frequently applied. The rate of stoma creation in emergency cases was significantly higher compared to elective cases. Surgical site infection was the most common postoperative complication. We observed that patients who used >20mg/day steroids in the last month preoperatively had a higher rate of complications. Active smokers also had a higher rate of postoperative complications. We detected a recurrence rate of 20% in postoperative ileocolonoscopies. No significant difference was found between clinical remission and Rutgeerts score regarding risk.
One of the most concerning postoperative complications among colorectal IBD surgeons is intraabdominal abscess leading to intraabdominal sepsis, which is associated with anastomotic complications. Recognizing patients at higher risk for intraabdominal sepsis is crucial and affects surgical strategy, guiding surgeons towards the creation of a stoma in patients with a higher likelihood of anastomotic leakage [12]. The REMIND multicentric study investigated factors associated with early (30 days) postoperative complications following ileocecal resection. Treatment with corticosteroids in the 4 weeks before surgery was associated with an increased rate of postoperative complications (odds ratio (95% confidence interval) = 2.69 (1.15-6.29); P=0.022)9. Our series also demonstrated an increased postoperative complication rate associated with the use of >20 mg steroids.
The pathophysiological mechanism behind the link between smoking and Crohn’s disease is still not fully understood. Changes in the immune system, intestinal permeability, motility, gut microbiome, and bacterial overgrowth could be factors in this complex, multifactorial interaction. The impact of smoking on the course of Crohn’s disease has been the subject of various studies [13-15]. In the study by Kulaylat, A. N., et al., multivariate analysis showed that smoking status was associated with morbidity (OR 1.20, P = 0.003), particularly infectious (OR 1.30, P < 0.001) and pulmonary (OR 1.87, P < 0.001) complications, and readmissions (OR 1.58, P = 0.004) [14]. Furthermore, the literature has confirmed that smoking patients have a higher risk of early clinical recurrence and surgical recurrence. Also, smoking during the perioperative period is closely associated with disease recurrence within 1 year post-surgery [15]. In our series, we found evidence supporting the literature that active smokers had a higher rate of complications.
In patients with Crohn’s disease, trends related to stoma formation have been changing over time. Temporary stomas are created during surgery to reduce the risk of intra-abdominal septic complications, while permanent stomas are often associated with severe perianal Crohn’s disease. The necessity of stoma formation in Crohn’s patients has been a significant source of concern [16]. Especially in patients operated on in emergency status, we created stomas with the intention of preventing septic and anastomotic complications.
The Rutgeerts score (RS) was developed to predict postoperative recurrence in Crohn’s patients [17]. This scoring system has been found to be closely associated with postoperative endoscopic recurrence. Patients with low-grade mucosal inflammation (i0 and i1) have a symptomatic recurrence rate of 9% within 7 years, whereas those with high-grade disease (i3 and i4) have shown nearly 100% symptomatic recurrence within a 4-year interval [18]. A 2016 study in the UK found Rutgeerts i4 lesions to be a risk factor for re-operation due to anastomotic strictures [19]. In our series, no significant difference was found between clinical remission and Rutgeerts score regarding risk.
Limitation
The limitations of our study include its retrospective nature and the limited number of patients, which prevented comparative analyses.
Conclusion
In conclusion, when performing ileocecal resection for Crohn’s disease, individualized treatment approaches and measures to prevent postoperative complications must be taken on a patient-by-patient basis. It is crucial to quit smoking before surgery, and it should be kept in mind that patients receiving high doses of steroids preoperatively have a higher likelihood of developing postoperative complications. Individualized treatment approaches can lead to gratifying clinical outcomes in Crohn’s disease with ileocecal resection. Multicentric prospective studies are needed to confirm these results.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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3. Mege D, Panis Y. Unmet therapeutic needs: focus on intestinal fibrosis surgical approach: Resection, strictureplasty and others. Dig Dis. 2017;35(1-2):38-44.
4. Birnbaum DJ, Bège T, Berdah SV. Gestione chirurgica delle malattie infiammatorie croniche dell’intestino: trattamento chirurgico della malattia di Crohn. [Surgical Management of Chronic Inflammatory Bowel Diseases: Surgical Treatment of Crohn’s Disease] EMC – Tec Chir Addom. 2015;21(2):1-13.
5. Meima-van Praag EM, Buskens CJ, Hompes R, Bemelman WA. Surgical management of Crohn’s disease: A state of the art review. Int J Colorectal Dis. 2021;36(6):1133-45.
6. Bak MT, Ruiterkamp MF, van Ruler O, Campmans-Kuijpers MJ, Bongers BC, van Meeteren NL, et al. Prehabilitation prior to intestinal resection in Crohn’s disease patients: An opinion review. World J Gastroentero. 2022;28(22):2403-15.
7. Reynolds IS, Doogan KL, Ryan ÉJ, Hechtl D, Lecot FP, Arya S, et al. Surgical strategies to reduce postoperative recurrence of Crohn’s disease after ileocolic resection. Front Surg. 2021;8:804137.
8. Muñoz-Juárez M, Yamamoto T, Wolff BG, Keighley MR. Widelumen stapled anastomosis vs. conventional end-to-end anastomosis in the treatment of Crohn’s disease. Dis Colon Rectum. 2001;44(1):20-25.
9. Fumery M, Seksik P, Auzolle C, Munoz-Bongrand N, Gornet JM, Boschetti G, et al. Postoperative complications after ileocecal resection in Crohn’s disease: A prospective study from the REMIND group. Am J Gastroenterol. 2017;112(2):337-45.
10. Adamina M, Bonovas S, Raine T, Spinelli A, Warusavitarne J, Armuzzi A, et al. ECCO guidelines on therapeutics in Crohn’s disease: surgical treatment. J Crohns Colitis. 2020;14(2):155-68.
11. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14(1):4-22.
12. Gklavas A, Poulaki A, Dellaportas D, Papaconstantinou I. Risk factors for postoperative complications after elective ileocolic resection for Crohn’s disease: A retrospective study. Ann Gastroenterol. 2020;33(6):645-52.
13. Bolckmans R, Kalman T, Singh S, Ratnatunga KC, Myrelid P, Travis S, et al. Does smoking cessation reduce surgical recurrence after primary ileocolic resection for Crohn’s disease?. Dis Colon Rectum. 2020;63(2):200-6.
14. Kulaylat AN, Hollenbeak CS, Sangster W, Stewart Sr DB. Impact of smoking on the surgical outcome of Crohn’s disease: A propensity-score matched National Surgical Quality Improvement Program analysis. Colorectal Dis. 2015;17(10):891-902.
15. Guo Z, Cao L, Guo F, Gong J, Li Y, Gu L, et al. The presence of postoperative infectious complications is associated with the risk of early postoperative clinical recurrence of Crohn’s disease. World J Surg. 2017;41(9):2371-77.
16. Everhov ÅH, Kalman TD, Söderling J, Nordenvall C, Halfvarson J, Ekbom A, et al. Probability of stoma in incident patients with Crohn’s disease in Sweden 2003-2019: A population-based study. Inflamm Bowel Dis. 2022;28(8):1160-8.
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Uğur Topal, Mustafa Koray Demiryürek, Burak Yavuz, İshak Aydın, Orçun Yalav, İsmail Cem Eray. Ileocecal resection in Crohn’s disease: Our clinical experience. Ann Clin Anal Med 2024;15(12):850-854
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The level of keratoconus awareness among general population in Northern Border Region of Saudi Arabia
Maha Mahmoud Abdul-Latif 1, Mujeeb Ur Rehman Parrey 1, Saja Radhi Alanazi 2, Rouh Maskhur Alanazi 2, Ryanh Hamoud Alanazi 2, Majd Nasser Alshammari 2, Hanaa El-Sayed Bayomy 3,4
1 Department of Surgery, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia, 2 College of Medicine, Northern Border University, Arar Saudi Arabia, 3 Department of Family and Community Medicine, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia, 4 Department of Community, Faculty of Medicine, Benha University, Egypt
DOI: 10.4328/ACAM.22274 Received: 2024-05-21 Accepted: 2024-07-09 Published Online: 2024-10-25 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):855-859
Corresponding Author: Mujeeb Ur Rehman Parrey, Department of Surgery, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia. E-mail: drparrey@gmail.com P: +96 650 412 71 26 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2731-5438
Other Authors ORCID ID: Maha Mahmoud Abdul-Latif, https://orcid.org/0000-0002-3865-5817 . Saja Radhi Alanazi, https://orcid.org/0009-0001-3481-0939 . Rouh Maskhur Alanazi https://orcid.org/0009-0006-9569-1917 . Ryanh Hamoud Alanazi, https://orcid.org/0009-0006-0489-7304 . Majd Nasser Alshammari, https://orcid.org/0009-0006-3652-4107 . Hanaa El-Sayed Bayomy, https://orcid.org/0000-0001-7273-7931
This study was approved by the Ethics Committee of Northern Border University (Date: 2023-06-11, No: 45/44/H)
Aim: The study aims to evaluate the level of awareness regarding keratoconus (KCN) among residents of the Northern Border Region in Saudi Arabia.
Material and Methods: This cross-sectional study, conducted in the Northern Border Region of Saudi Arabia, utilized an electronically distributed questionnaire. Participants aged 18 to 65 provided informed consent. Data analysis was performed using STATA/SE 11.2 and MS Excel, employing descriptive statistics and the Chi-square test. Stepwise multiple logistic regression identified significant predictors of good KCN awareness (P<0.05).
Results: Among 511 participants, predominantly female (76.52%) and young adults (18-29 years) with at least a bachelor’s or diploma degree, only 19% demonstrated good awareness. Significant differences in awareness were observed by gender, education level, and family history of KCN. The internet/social media was the primary information source (53.62%). Over half recognized eye rubbing and allergies as risk factors, and most acknowledged the need for treatment. Awareness of specific treatments was low, with only 23.09% and 24.07% knowing about contact lenses and corneal collagen cross-linking, respectively. Notably, 27% incorrectly believed KCN could be treated with eye drops. Awareness of KCN complications varied, with 56.16% recognizing its impact on quality of life.
Discussion: Keratoconus awareness among participants was poor, with misconceptions about treatment modalities. Proper awareness campaigns and education programs are needed to enhance this awareness and improve the quality of life for affected individuals.
Keywords: Awareness, Cornea, Keratoconus, Northern Border Region, Saudi Arabia
Introduction
Keratoconus (KCN) is an idiopathic, chronic, non-inflammatory, ectatic eye condition in which the normally dome shaped cornea bulges outward, leading to a conical shape. This alteration results in irregular myopic astigmatism, diminishing both far and near visual acuity, and increased sensitivity to glare and light [1]. While the exact etiology remains elusive, various risk factors have been identified, including genetic predisposition, habitual eye rubbing, and certain medical conditions such as asthma, allergies, Ehlers-Danlos syndrome, and Down syndrome [2-5]. Typically, keratoconus manifests during adolescence or early adulthood, with a protracted progression over the subsequent one to two decades. As the condition advances, the cornea becomes more pronouncedly distorted, exacerbating visual impairment [6].
Timely diagnosis by an ophthalmologist is essential for initiating appropriate management strategies aimed at stabilizing corneal morphology and impeding disease progression. Treatments may encompass the use of rigid contact lenses and corneal cross-linking surgery, with the latter proving effective in retarding keratoconus progression [7]. In severe cases, where corneal integrity is compromised, a corneal transplant may be necessitated to restore visual function.
Research underscores the significant impact of keratoconus on individuals’ vision related quality of life, underscoring the importance of heightened awareness and early intervention [8-9]. Studies conducted around the world have reported prevalence and incidence rates of keratoconus based on 100,000 persons and 100,000 years, respectively [10]. Incidence of keratoconus most commonly occurs between the ages of 20 and 30 years, with progression occurring until the age of 35. Some studies report higher rates of keratoconus in men, while others report higher rates in women. Moreover, the interplay of genetic predisposition, environmental factors such as ultraviolet (UV) radiation exposure, and lifestyle variables including ethnic background and dietary habits further modulate the disease trajectory. Notably, syndromic conditions such as Down syndrome have been implicated in keratoconus pathogenesis, emphasizing the multifactorial nature of its etiology. and diabetes mellitus. Conversely diabetes may act as a preventative measure against keratoconus [11].
Contemporary therapeutic modalities encompass a spectrum of interventions, ranging from conventional approaches like contact lenses to advanced surgical techniques including intrastromal corneal ring segments and various forms of keratoplasty. Corneal cross-linking, heralded as a cornerstone in keratoconus management, offers promise in halting disease progression and preserving visual function [12-13].
Currently, ongoing research aims to improve current therapeutic methods and investigate new approaches to enhance the effectiveness and safety of treatment for keratoconus. However, prioritizing preventive measures and early detection is crucial in mitigating the harmful effects of the condition. Despite studies on keratoconus awareness in some areas, comprehensive data from regions like the Northern Border Region of Saudi Arabia are still lacking [14-15].
Against this backdrop, our study endeavors to delineate the level of keratoconus awareness among the general population in the Northern Border Region via a predesigned questionnaire. Furthermore, we sought to assess the influence of demographic variables on the dissemination of knowledge regarding this sight-threatening condition, thereby facilitating targeted educational initiatives and bolstering public health interventions.
Material and Methods
Study setting and design
A population-based cross-sectional study was conducted in Arar, Turaif, Al Uwayqilah, and Rafha, major cities in the Northern Border Region of Saudi Arabia, from June 15, 2023, to April 15, 2024.
Research tool
The level of KCN awareness was assessed using a pre-designed questionnaire validated by the Ophthalmology Department at NBU. The questionnaire was distributed electronically via a Google form through various social media platforms. The introductory part of the questionnaire outlined the study’s objectives, and respondents provided written informed consent before participating.
Inclusion and exclusion Criteria
Both genders aged 18 to 65 residing in the Northern Border Region were included. Individuals living outside the study area and those with mental challenges were excluded.
Sample size and sampling method
Random sampling was employed, with a minimum sample size of 376 calculated using the formula:
n = (Z1-α/2)^2 * P * (1-P) / d^2
Where: n = sample size Z1-α/2 = standard normal variate at 5% type 1 error (1.96) P = expected awareness (43.0%) d = absolute error (0.05)
Data analysis
Statistical analysis utilized STATA/SE version 11.2 for Windows (STATA Corporation, College Station, Texas), and MS Excel. Descriptive statistics were employed, presenting data in terms of frequency and percentage. Knowledge about keratoconus on risk factors, treatment options and complications among different study groups was compared using the Chi-square test (χ2). Each correct response in the knowledge questions was scored as one, while incorrect one was scored as zero. Scores of 11 or lower indicated ‘poor awareness,’ while scores above 11 ‘good awareness’. Stepwise multiple logistic regression analysis identified significant predictors for good awareness about keratoconus among participants, with statistical significance set at P<0.05.
Ethical approval
This study was approved by the Ethics Committee of Northern Border University (Date: 2023-06-11, No: 45/44/H).
Results
A total of 511 individuals consented to participate in the study, comprising 391 (76.52%) females. Among them, 249 fell within the age group of 16 to 29 years. More than half of the participants (50.49%) hailed from families with three or more members, while the majority (68.88%) had attained either a bachelor’s or diploma degree. The comprehensive socio-demographic profile of the study participants is detailed in Table 1. The participants’ KCN awareness is displayed in Table 2. More than half of the participants identified eye rubbing and ocular or systemic allergy (51.86% and 50.29%, respectively) as potential risk factors for KCN. Regarding the treatment, although most participants (74.17%) recognized the necessity of treatment for KCN, only a small percentage were familiar with treatment options like hard contact lenses and corneal collagen cross-linking (23.09% and 24.07%, respectively). Unfortunately, 27% of participants mistakenly believed that KC could be treated solely with eye drops. Concerning KCN-related complications, 41.1% of participants believed that KC impacts far vision exclusively, while 29.75% thought it affects both far and near vision. A significant majority (56.16%) acknowledged that KCN results in a diminished quality of life.
The overall demonstrated good awareness was demonstrated by only 97 (19%) study participants, while the majority, 414 (81%), exhibited poor awareness. Table 3 outlines the relationships between the KCN awareness level and different sociodemographic characteristics.
Significantly varied awareness levels were observed among genders, education levels, and individuals with a family history of KCN (p-values of 0.03, 0.008, and 0.001, respectively). Conversely, no significant difference was noted concerning ages and geographical locations. Multiple logistic regression of good KCN awareness conditioned on significant predictors revealed that the good awareness was mainly associated with family history of KCN, reliable source of information (seminar/ lecture/ workshop) and the participants’ level of education.
Figure 1 illustrates the frequency distribution of the sources of information about keratoconus among the study participants.
The primary source of information about KCN was the internet/social media, reported by 53.62% of participants, followed by friends/relatives, mentioned by 33.66% of the participants.
Discussion
This is the first study to evaluate the level of keratoconus (KCN) awareness among residents of the Northern Border Region in Saudi Arabia and to assess the influence of demographic variables on this awareness. Out of 511 total study participants, 391 (76.52%) were female. Among them, 249 were aged 16 to 29. Over half (50.49%) came from families with three or more members, and the majority (68.88%) had a bachelor’s or diploma degree.
The current study revealed that overall KCN awareness was very poor, with only 19% demonstrating good awareness. This aligns with findings from the Aseer region of Southern Saudi Arabia, where good awareness was reported in 18.7% of participants [14]. However, KCN awareness was higher (38.4%) in Riyadh, possibly due to more participants having personal experience with the disease, as over 50% were diagnosed with KCN [16].
Eye rubbing and ocular or systemic allergy were identified by 51.86% and 50.29% of surveyed participants respectively as risk factors for KCN. Similarly, a study in the Eastern Province of Saudi Arabia reported these factors in 45.9% and 42.3% of participants, respectively [17].
However, these findings are in contradiction to another study conducted in Medina, Saudi Arabia where only 28.9% participants believed that eye rubbing could be a KCN risk factor and 27.8% thought that there is a relation between KCN and allergy [18]. This could be because of the difference in geographical location as in their study the overall good KCN awareness was also only 5.9%.
Regarding the treatment options, only 24.07% of study participants were familiar with corneal collagen cross-linking, while 27% had misconception that KCN could be treated by eye drops. Comparable results were found in Hail, Saudi Arabia, where 26.5% knew about cross-linking and 21.8% had misconceptions about eye drops [19]. However, in Abha, Saudi Arabia this misconception was higher (32.5%), likely due to their sample being exclusively non-medical students [20].
Concerning KCN-related complications, a significant majority (56.16%) acknowledged that KCN results in a diminished quality of life. Numerous studies both within Saudi Arabia and internationally endorse that KCN adversely affects both general and vision-related quality of life [21-22].
Limitation
The current study’s dependence on self-reported data and the potential biases typical of survey-based research should be recognized as significant limitations. Additionally, future research could investigate other factors like the status of healthcare facilities affecting KCN awareness.
Conclusion
The keratoconus awareness level among study participants was very poor. Misconceptions regarding treatment modalities existed. The primary source of information was the internet and social media, likely contributing to misinformation and poor awareness. To improve general and vision-related quality of life for those affected by KCN, awareness should be enhanced through awareness campaigns and education programs involving ophthalmology professionals.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Maha Mahmoud Abdul-Latif, Mujeeb Ur Rehman Parrey, Saja Radhi Alanazi, Rouh Maskhur Alanazi, Ryanh Hamoud Alanazi, Majd Nasser Alshammari, Hanaa El-Sayed Bayomy. The level of keratoconus awareness among general population in Northern Border Region of Saudi Arabia. Ann Clin Anal Med 2024;15(12):854-858
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Assessment of cytotoxic and apoptotic properties of Thymoquinone-oxime derivative on U87 glioma cells
Esma Özdemir Anayurt 1, Muhammed Oğuz Yıldız 2, Kubra Bozali 4, 5, Macit Koldaş 2, 4, Sümeyye Koç 4, 5, Eray Metin Guler 3, 4
1 Department of Medical Biochemistry, Golbası State Hospital, Adıyaman, 2 Department of Medical Biochemistry, University of Health Sciences, Istanbul, 3 Department of Medical Biochemistry, Faculty of Medicine, University of Health Sciences, Istanbul, 4 Department of Medical Biochemistry, Faculty of Hamidiye Medicine, University of Health Sciences, İstanbul, 5 Department of Medical Biochemistry, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul, Türkiye
DOI: 10.4328/ACAM.22315 Received: 2024-06-28 Accepted: 2024-08-12 Published Online: 2024-10-21 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):860-864
Corresponding Author: Esma Özdemir Anayurt, Department of Medical Biochemistry, Golbası State Hospital, Adıyaman, Türkiye. E-mail: es216ra@gmail.com P: +90 530 182 57 13 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0761-473X
Other Authors ORCID ID: Muhammed Oğuz Yıldız, https://orcid.org/0009-0008-7087-5087 . Kubra Bozali, https://orcid.org/0000-0003-2416-0773 . Macit Koldaş, https://orcid.org/0000-0001-8967-2708 . Sümeyye Koç, https://orcid.org/0000-0002-4773-0161 . Eray Metin Guler, https://orcid.org/0000-0003-4351-1719
Aim: Glioblastoma, characterized by its invasive nature, stands as one of the prevalent primary malignant brain tumors. Thymoquinone (TQ) has demonstrated notable anticancer effects across various cancer types. Nevertheless, the comprehensive molecular underpinnings behind TQ’s anticancer efficacy remain partially elucidated. Given TQ’s capacity to traverse the blood-brain barrier and its selective cytotoxicity towards glioblastoma cells over primary astrocytes, it emerges as a highly promising chemotherapeutic agent for gliomas and glioblastomas. This study’s principal objective was to delve into the impact of Thymoquinone-Oxime (Ox) on cytotoxicity and apoptotic attributes within the U87 cell line.
Material and Methods: Various concentrations of TQ-Ox (1.56-200 μM) were applied to the U87 glioma cell line for a 24-hour incubation period. Cytotoxicity was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while apoptosis quantification utilized Annexin V and7-aminoactinomycin D (7-AAD) in conjunction with flow cytometry.
Results: Cytotoxicity assessments revealed a concentration-dependent induction by TQ-Ox across the range of 1.56 to 200 μM. Notably, TQ-Ox effectively reduced the proliferation of U87 cells, with determined IC50 doses at 193.67 μM. Furthermore, a higher rate of necrosis, constituting 73.2%, was observed at 150 μM concentration (p<0.05).
Discussion: Our observations propose that TQ-Ox elicits dose-dependent cytotoxic and apoptotic effects on glioma cells. Eventually, it may be a candidate compound for the treatment of brain cancer and additional in vitro and in vivo research on this TQ-Ox may be required.
Keywords: Apoptosis, Cytotoxicity, Glioma Cell, U87, Thymoquinone-Oxime
Introduction
Glioblastoma represents the prevailing high-grade astrocytoma, categorized as a WHO grade IV astrocytoma. This variant constitutes 45% of all primary malignant central nervous system neoplasms and is associated with the most serious clinical prognosis [1]. This clinical inadequacy can be attributed to a multitude of factors, encompassing tumor heterogeneity, susceptibility to mutational events, heightened tumor infiltration, and augmented expression of focal adhesion kinase (FAK) protein within glioblastoma. This elevated FAK protein expression is correlated with escalated rates of both migratory and invasive behaviors [2]. Under the prevailing paradigm of treatment, which involves maximal yet safe surgical resection followed by a combination of external beam radiation and concurrent chemotherapy, the median overall survival duration for individuals confronting a fresh diagnosis of glioblastoma multiforme (GBM) merely extends to a span of 12 to 15 months [3, 4].
Thymoquinone constitutes the primary bioactive constituent within the unprocessed extract of Nigella sativa Linn seeds, and scientific investigations have indicated that TQ possesses noteworthy antineoplastic attributes [5, 6]. Numerous investigations have demonstrated the inhibitory impact of thymoquinone on the proliferation of different utilicancer cell types. These encompass breast, colon, ovarian, laryngeal, and lung malignancies, as well as myeloblastic leukemia and osteosarcoma [7]. The antineoplastic efficacy of TQ has been substantiated across various in vivo and in vitro models targeting diverse tumor types. TQ has demonstrated the ability to traverse the blood-brain barrier, prompting apoptosis in glioma and glioblastoma cells. Furthermore, TQ displays antimetastatic and anti-invasive attributes [8]. TQ exhibits preferential cytotoxicity towards glioblastoma cells when contrasted with normal human astrocytes [6]. TQ-induced tumor cell apoptosis operates through a molecular framework involving the activation of caspase 8, 9, and 3, an increase in Bax expression coupled with a decrease in Bcl2 levels, as well as the impediment of PI3K/Akt and NF-κB signaling pathways [6, 9].
Oxime compounds, due to their notable roles as acetylcholinesterase reactivators, have been under investigation for decades. They have also been explored for their potential antibacterial, antifungal, anti-inflammatory, antioxidant, and anti-cancer activities against a range of diseases [10, 11].Oximes have been employed in formulating diverse kinase inhibitors, encompassing inhibitors of phosphatidylinositol 3-kinase (PI3K), phosphorylase kinase (PhK), and Jun N-terminal kinase (JNK). A number of these kinases serve as molecular targets for compounds exhibiting anticancer properties [11, 12].The derivatives were assessed against cancer cell lines originating from various tissues, including the colon, central nervous system, lung, breast, and ovary. All derivatives exhibited notable and promising anticancer characteristic [12, 13].
Material and Methods
Thymoquinone-oxime Synthesis
In the context of this investigation, we explored the therapeutic impact achieved through the incorporation of an oxime functional group into the TQ compound, which possesses potent anticancer attributes. In this study, we synthesized the oxime derivative of TQ, characterized by combined lipophilic and hydrophilic traits according to the principles reported previously [13]. Subsequently, we evaluated the cytotoxic and apoptotic characteristics of TQ-Ox within the U87 glioma cell line. TQ-Ox on U87 cells was examined by H-NMR, C-NMR, and elemental analysis [13].
Cell line treatment
The U87 cell line was cultured within an incubator containing 5% CO2 at 37°C using Eagle’s Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (P/S). All reagents were sourced from Sigma-Aldrich (Seelze, Germany).
Cytotoxicity
The evaluation of TQ-Ox cytotoxicity involved the use of a (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay procured from Sigma-Aldrich, Seelze, Germany. The U87 cell line was seeded into a 96-well plate at a density of 8 x 103 cells/mL and incubated under 5% CO2 at 37°C with saturated humidity for a 24-hour duration. Subsequently, the medium was subjected to 1.56-200 μM concentrations of TQ-Ox for an additional 24 hours. After this incubation period, 10 μL of MTT solution (5 mg/mL) was introduced to each well and allowed to incubate at 5% CO2 and 37°C for 3 hours. Following this, 100 μL of dimethyl sulfoxide (DMSO) from Sigma-Aldrich, Seelze, Germany was added to each well and incubated at 24°C for 20 minutes. The resultant purple solution was quantified spectrophotometrically at 540 nm using a BioTek Synergy™ HTX Multimode Reader based in the USA.
Apoptosis
To discern apoptotic cells, the Annexin V-Cyanine5/7-AAD Apoptosis kit (Elabscience®, E-CK-A222, USA) was employed. This approach hinges on the calcium-dependent binding of Annexin V to phosphatidylserine. Specifically, Annexin V-Cyanine5, a variant conjugated with Cyanine5, binds to phosphatidylserine on the external surface of apoptotic cell membranes, a phenomenon that can be detected through flow cytometry. In addition, the 7-aminoactinomycin D (7-AAD) dye was utilized to stain DNA within cells undergoing late apoptosis or necrosis. By simultaneously utilizing Annexin V and 7-AAD, it becomes possible to differentiate cells at various stages of apoptosis.
Cell suspensions, spanning concentrations of 25 μM, 50 μM, 100 μM, 150 μM, and 200 μM, were subjected to 7-AAD staining to facilitate the identification of apoptotic cells. The experimental protocol adhered closely to the guidelines provided by the manufacturer. Following the incubation of cell suspensions with Annexin V-Cyanine5 and 7-AAD, flow cytometry analysis (BD, FACS Canto II; Ex/Em: 488/525 nm) was employed to evaluate the apoptotic progression of glioma cells.
Statistical Analysis
The obtained data were analyzed using the SPSS version 26.0 (Chicago, IL, USA). The Independent samples Kruskal-Wallis H test was used to compare more than two independent parameters. Pairwise comparisons were performed using the Dunn-Berferonni post-hoc method. All experiments were done in quadruplicate, and data were expressed as the mean (SD) of the number of experiments. The IC50 values of TQ-Ox on cell line U87 were calculated by nonlinear regression analysis.
Ethical Approval
Ethical approval is not required for cell culture studies, however our study was conducted in accordance with ethical rules.
Results
Effect of TQ-Ox on U87 Cell Cytotoxicity by MTT
To detect the cell cytotoxicity, U87 cells were treated with increasing concentrations of TQ-Ox (1.56-200 μM) for 24 hours. The control was with no treatment.
Cytotoxicity showed that the TQ-Ox induced in a concentration-dependent manner between 1.56 to 200 μM, see Figure 1. TQ-Ox demonstrated the capacity to attenuate the proliferation of U87 cells. No statistical difference was found when all doses were compared with the control (p>0,05). The IC50 dose of TQ-Ox wasdeterminedat193.67 Μm.
The apoptotic effect of TQ-Ox on U87 cells was determined by Annexin. U87 cells were viable at 25, 50, 100, 150 and 200 μM concentrations. Figure 2 illustrates the contrasts observed in flow cytometric outcomes when juxtaposed with control concentrations. Notably, the population of live cells (a) exhibited a significant decline at concentrations of 50 μM (p<0.05), 150 μM (p<0.001) and 200 μM (p<0.01) in comparison to the control. Additionally, early apoptosis (b) demonstrated noteworthy escalation at concentrations of 100 μM (p<0.05) and 200 μM (p<0.01) relative to the control. Late apoptosis (c) similarly showcased marked amplification at concentrations of 25 μM (p<0.05), 150 μM (p<0.01), and 200 μM (p<0.001) compared to the control. Lastly, the proportion of deceased cells exhibited prominence particularly at the concentration of 150 μM (p<0.05) when contrasted with the control.The highest necrosis was observed at 150 μMwith 73.2%.
Discussion
Glioma stands as the prevailing manifestation of neoplasms within the central nervous system (CNS), originating from glial cells. Within the United States, the annual diagnosis rate for gliomas is reported at six cases per 100,000 individuals [14].Several professions, environmental carcinogens, and dietary factors (including N-nitroso compounds) have been suggested to correlate with an increased risk of glioma. Yet, among these factors, the only environmental element that has been definitively linked to an elevated risk of brain tumors, including gliomas, is therapeutic X-irradiation [15]. The usual treatment involves extensive surgery, followed by chemotherapy and radiation. Being vigilant can help diagnose it early. Because the outlook is grim, it’s crucial to discuss patients’ care preferences soon after diagnosis, even if opting for comprehensive treatment.Progress in surgical techniques, radiotherapeutic modalities, and supplementary chemotherapy regimens has demonstrated incremental enhancements in both the survival rates and quality of life for individuals afflicted with GBM. However, the overall prognosis remains disheartening [16]. Hence, there exists a necessity to formulate novel therapeutic approaches aimed at the prevention and management of this condition. In the context of this investigation, the cytotoxic and apoptotic attributes of the oxime derivative of TQ have been explored within a human glioma cell line.
TQ’s anti-inflammatory, antioxidant, and antineoplastic effects have been demonstrated in both in vitro and in vivo settings [17]. Numerous researchers have indicated that the growth-inhibitory impacts of TQ are selectively targeted towards cancerous cells [2, 6, 8, 9,13]. In a specific study, the administration of TQ led to heightened cellular levels of PTEN proteins, thereby inducing a noteworthy reduction in the phosphorylated Akt, a recognized modulator of cell survival in doxorubicin-resistant human breast cancer cells. Through flow cytometric analysis and agarose gel electrophoresis, a prominent elevation in the Sub-G1 cell populace and the emergence of distinctive DNA ladders became evident upon exposure to TQ treatment, underscoring the initiation of cellular apoptosis [18]. In an alternate study investigating the antineoplastic effects of thymoquinone on human astrocytoma cells (U87 cell line, representing a solid tumor model) and Jurkat cells (T lymphoblastic leukemia cells), TQ induced a degradation of α/β tubulin in both cancer cell varieties, a phenomenon contingent on concentration and duration. This perturbation correlated with the upregulation of the tumor suppressor p73, subsequently culminating in the induction of apoptosis [19]. Furthermore, thymoquinone prompted DNA damage, led to telomere attrition through telomerase inhibition, and elicited cellular demise within glioblastoma cells [8]. Taken together, these findings imply that concentrations of TQ which exhibit cytotoxic effects on glioblastoma cells do not impact the growth of normal human astrocytes [20]. This observation is consistent with prior studies indicating the selective nature of TQ towards cancer cells [9, 21, 22].
Over the course of numerous years, oxime compounds have been the focus of comprehensive investigations owing to their pivotal role as acetylcholinesterase reactivators and their potential utility as therapeutic agents across diverse disease contexts. The rational incorporation of an oxime moiety into an appropriate chemical structure emerges as a reasoned strategy for synthesizing cytotoxic agents. A multitude of oxime derivatives have been noted for their potential therapeutic efficacy against cancer [11]. There are studies on the treatment of glial cells with oxime compounds. In these studies, oxime-derived compounds have been shown to reduce inflammation and prevent neuronal apoptosis [23]. Due to the promising studies of oxime derivative compounds on cancer, we hypothesized that the TQ-Ox compound could affect glioma cells. Within the context of our investigation, we have indeed illustrated the cytotoxic and apoptotic impacts of TQ-Ox.
There are many studies on thymoquinone-associated cancer cells and models in the literature, but there is no relevant study investigating the efficacy of TQ-Ox to be synthesized against glioma cells to increase the efficacy of thymoquinone.In our preceding study, we assessed the effectiveness of the oxime derivative of TQ alongside established chemotherapeutic agents, Cisplatin and Taxol, against both ovarian cancer and healthy cell lines. The findings established that TQ-Ox exerts a more robust induction of cell death within the cancer cell line [13]. Furthermore, in a separate investigation, we explored the potential of TQ-Ox to hinder theproliferation of the human hepatocellular carcinoma cell line HepG2 and the healthy epithelial cell line THLE-2, employing concentrations ranging from 2.5 µM to 180 µM. Our results demonstrated a concentration-dependent pattern wherein TQ-Ox exhibited enhanced efficacy in curbing the proliferation of HepG2 cells compared to the healthy THLE-2 cells, a phenomenon that correlated with the promotion of intracellular reactive oxygen species (iROS) activity in HepG2 cells(24). Presently, our focus shifted towards investigating the impact of TQ-Ox on U87 glioma cells. The outcomes, mirroring our previous research endeavors, reveal that U87 cells treated with TQ-Ox manifest a substantial reduction in cell viability, following a concentration-dependent pattern.
Conclusion
Based on the outcomes, our findings suggest that TQ-Ox exerts dose-dependent cytotoxic and apoptotic effects on glioma cells. The potent anti-proliferative effect of TQ-Ox observed in our study highlights its potential as a promising candidate for brain cancer treatment. Consequently, further in vitro and in vivo investigations into the properties of TQ-Ox may be.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Esma Özdemir Anayurt, Muhammed Oğuz Yıldız, Kubra Bozali, Macit Koldaş, Sümeyye Koç, Eray Metin Guler. Assessment of cytotoxic and apoptotic properties of Thymoquinone-oxime derivative on U87 glioma cells. Ann Clin Anal Med 2024;15(12):860-864
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Comparison of tocilizumab and intravenous immunoglobulin treatment in intensive care unit patients with COVID-19 who developed cytokine storm: A single-center retrospective study
Serkan Kalkan 1, Selcuk Demırcan 2, Zeliha Korkmaz Dıslı 1, Deccane Duzencı 3, Funda Memısoglu 4, Murat Yalcınsoy 5, Murat Bıcakcıoglu 3, Mustafa S. Aydogan 3, Zafer Dogan 3, Aytac Yucel 6, Ayse B. Ozer 3
1 Department of Intensive Care Unit, Faculty of Medical, Inonü University, Malatya, 2 Department of Reanimation Intensive Care Unit, Malatya Training and Research Hospital, Malatya, 3 Department of Intensive Care Unit, Fethi Sekin City Hospital, Elazığ, 4 Department of Infectious Diseases, Faculty of Medical, Inonü University, Malatya, 5 Department of Chest Diseases, Faculty of Medical, Inonü University, Malatya, 6 Department of Anesthesiology, Doruk Private Nilüfer Hospital, Bursa, Turkiye
DOI: 10.4328/ACAM.22323 Received: 2024-07-03 Accepted: 2024-08-26 Published Online: 2024-10-23 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):865-870
Corresponding Author: Ayse Belin Ozer, Department of Intensive Care Unit, Doruk Private Nilüfer Hospital, Bursa, Turkiye. E-mail: belin.ozer@inonu.edu.tr P: +90 533 447 89 24 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0113-6466
Other Authors ORCID ID: Serkan Kalkan, https://orcid.org/0000-0002-6538-5322 . Selçuk Demircan, https://orcid.org/0000-0002-0202-2110 . Zeliha Korkmaz Dıslı, https://orcid.org/0000-0002-4527-2427 . Deccane Duzenci, https://orcid.org/0000-0002-7572-2759 . Funda Memişoğlu, https://orcid.org/0000-0003-3905-1182 . Murat Yalçınsoy, https://orcid.org/0000-0003-3407-7359 . Murat Bıçakçığlu, https://orcid.org/0000-0001-9101-6857 . Mustafa S. Aydoğan, https://orcid.org/0000-0002-7106-1156 . Zafer Doğan, https://orcid.org/0000-0002-6992-8945 . Aytaç Yücel, https://orcid.org/0000-0003-0270-8339
This study was approved by the Ethics Committee of Inonu University (Date: 2023-10-31, No: 2023/4941)
Aim: Coronavirus disease 2019 (COVID-19) may trigger a severe inflammatory response. In the present study, the effects of tocilizumab and intravenous immunoglobulin (IVIG) on mortality in COVID-19 patients with cytokine storms were examined and compared.
Material and Methods: This retrospective study included all COVID-19 patients who were diagnosed and followed in the intensive care unit between April 2020 and May 2022. The patients were divided into two groups depending on whether they were receiving IVIG or tocilizumab treatment. In addition to the patients’ demographic information, the 28-day mortality was recorded. Their PaO2/FiO2 ratio, CRP, procalcitonin, lymphocyte, ferritin, and D-dimer levels were also recorded before drug administration and on the first day, third day, and first week following the drug administration.
Results: Of the 73 patients included in this study, 43 (59%) received tocilizumab (Group T), while 30 (41%) received IVIG treatment (Group IVIG). No significant statistical differences were detected between the groups in terms of demographic data, pre-drug inflammatory parameters, improvement in PaO2/FiO2 ratios, and 28-day mortality. The rate of change in CRP levels was significantly higher in Group T than in Group IVIG on day 3 (p=0.010) and in the first week (p=0.001). The improvement in ferritin levels in the first week was significantly higher in Group T (p=0.018).
Discussion: No significant difference was detected between the effects of IVIG and tocilizumab on mortality in COVID-19 patients with cytokine storm. However, tocilizumab suppressed inflammation more strongly than IVIG.
Keywords: Ards, Covid-19, Cytokine Storm Syndrome, Ivig, Tocilizumab
Introduction
The coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which results in severe acute respiratory failure, became a significant public health concern in the last three years. SARS CoV-2 might cause damage and death in many organs, especially the lungs, by targeting angiotensin-converting enzyme (ACE)-2 receptors [1, 2]. The term ‘cytokine storm’ refers to a condition wherein cytokines are released in excessive amounts into the systemic circulation and are held responsible for the abovementioned damages [1, 3]. In the final stage of the disease, it was observed that systemic levels of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6 and IL-7, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1-α, C-reactive protein (CRP), ferritin, and D-dimer are significantly increased [4]. Steroids, hydroxychloroquine, IL-6 and IL-1 inhibitors, TNF-α inhibitors, and Janus kinase inhibitors have been suggested as potential treatment agents [5, 6].
Previous studies involving tocilizumab, an IL-6 receptor blocker, have produced conflicting results [7, 8]. Intravenous immunoglobulin (IVIG) is an immunomodulatory treatment utilized in various inflammatory diseases. Dynamic cytokine storms and T-cell lymphopenia have been linked to COVID-19 severity [9].
In our clinic, tocilizumab was administered to patients who developed cytokine storms because of COVID-19. However, in cases where tocilizumab was not available or where there was a suspected or confirmed bacterial infection, IVIG was used instead. No study was found in the literature comparing the effects of tocilizumab and IVIG on inflammation, particularly mortality, in COVID-19 patients requiring intensive care and experiencing cytokine storms. Therefore, this retrospective study aimed to compare the efficacy of tocilizumab and IVIG treatments in patients who were followed up in the tertiary intensive care unit and developed cytokine storms because of COVID-19.
Material and Methods
Study Design
The present study employed a single-center retrospective design and was conducted at a tertiary university hospital following approval by the Inonu University Scientific Research and Publication Ethics Board and the Health Sciences Non-invasive Clinical Research Ethics Board, with decision number 2023/4941 on 31 October 2023. Patients diagnosed with COVID-19 between April 2020 and May 2022, who were followed up and treated in the intensive care unit and developed a cytokine storm, were included in the study.
Inclusion criteria. Patients whose COVID-19 diagnosis was confirmed through clinical, laboratory, and imaging methods, who were aged 18 years and older, and who developed a cytokine storm were included in the study. The development of a cytokine storm was determined based on increasing CRP, IL-6, ferritin, and D-dimer levels and decreasing lymphocyte count compared with the patient’s baseline values (or values before the onset of the disease, if available).
Exclusion Criteria
Patients who received immunomodulatory/immunosuppressant treatments other than tocilizumab and IVIG, those who received tocilizumab and IVIG simultaneously or sequentially, who were pregnant, who died during treatment, who had solid organ transplantation and who had other underlying or concomitant inflammatory diseases were excluded from the study.
The diagnosis of COVID-19 in our hospital and clinic was made based on the SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test conducted on nasopharyngeal swab samples and thorax CT findings during the COVID-19 pandemic if there were associated symptoms. Patients with COVID-19 who developed a cytokine storm were categorized into two groups based on whether they received tocilizumab or IVIG treatment.
Group T (n=43): This group comprised individuals who received tocilizumab alongside standard treatment (1 mg/kg/day methylprednisolone, low-molecular-weight heparin, empiric antibiotic, mucolytic, and proton pump inhibitor). Tocilizumab was administered in our clinic in two consecutive doses during the pandemic, with a 12- to 24-hour interval, based on the patient’s weight (8 mg/kg/day, max 800 mg).
Group IVIG (n=30): This group consisted of individuals who received IVIG as well as standard treatment. IVIG treatment was given at a dose of 0.4 mg/kg/day (total 2 g/kg) for five consecutive days in our clinic.
In our clinic, tocilizumab treatment was not used in the presence of neutropenia (0.5×10³ cells/ul), thrombocytopenia (50×10³ cells/ul), gastrointestinal perforation, and active bacterial infection. Procalcitonin levels were utilized to assess active bacterial infections, along with clinical symptoms and demonstration of the infectious agent in gram staining or culture in microbiological samples. Tocilizumab was not administered to any patient with a procalcitonin level above 2 ng/ml. In this clinic, patients were treated with IVIG. Additionally, hepatitis markers were tested in all patients to detect latent hepatitis B infection or carrier status.
The primary outcome of the study was 28-day mortality, while the secondary outcome was the change in inflammatory parameters.
Patient data were obtained retrospectively through the electronic system and patient follow-up cards. Demographic characteristics, age, gender, comorbidities, clinical status, inflammatory parameters (CRP, ferritin, D-dimer, procalcitonin, fibrinogen, IL-6), PaO2/FiO2 ratio, need for mechanical ventilation and 28-day mortality were recorded. Disease severity was measured using the Acute Physiology and Chronic Health Evaluation II (APACHE II), while organ dysfunction was determined using the SOFA Score.
Statistical Analysis
The IBM SPSS Statistics 22 program was used for statistical analysis. Before conducting the analyses, the Shapiro–Wilk test was utilized to examine whether the data met the assumption of normality to select analyses that were appropriate for the data. In cases where the data met the normality assumption, the independent samples t-test was used for between-group comparisons, while the Mann–Whitney U test was used in cases where it was not met. The homogeneity of variances assumption for the t-test in independent groups was examined using the Levene’s test. Within-group comparisons were conducted using the Wilcoxon test. Gender, comorbidities, pulse steroid intake, oxygen delivery method, and 28-day mortality were evaluated with the chi-square test, and p<0.05 was considered significant.
Ethical Approval
This study was approved by the Ethics Committee of Inonu University (Date: 2023-10-31, No: 2023/4941).
Results
During the study period, a total of 547 patients were treated in the COVID-19 intensive care unit (Figure 1). No statistically significant differences were detected between the groups in terms of age, gender, comorbidities, APACHE and SOFA scores, time from hospital admission to medication administration, oxygen treatment methods, and 28-day mortality. However, patients in Group IVIG received more steroids (Table 1).
There were no statistically significant differences between the groups in PaO2/FiO2 ratios, D-dimer levels, and lymphocyte levels. Notably, CRP levels were significantly lower in Group T than in Group IVIG on the third day and in the first week after the administration of the drug. Procalcitonin levels were statistically and significantly higher in Group IVIG than in Group T only during the first week. Ferritin levels were significantly higher in Group T before and on the first and third days after the drug administration, with no significant difference detected between the groups during the first week. IL-6 levels were significantly higher in Group T on the third day and during the first week (Table 2).
The values before the administration of the drug were compared with the values on the first day, third day, and first week after the administration. The PaO2/FiO2 ratios were found to be significantly higher on the third day and first week in the groups (p=0.018 and p=0.009, respectively, for Group T and p=0.035 and p=.017, respectively, for Group IVIG). The CRP levels were higher in Group T on the third day and in the first week (p=0.001 and p=0.001, respectively), while Group IVIG exhibited a significant decrease in the first week (p=0.014). No significant changes were detected in procalcitonin levels in the groups. Lymphocyte levels decreased significantly on the first day in Group T (p=0.002) and on Day 3 in Group IVIG when compared to before the drug administration (p=0.008). The ferritin levels increased in Group T on the first day and decreased in the first week compared to pre-administration (p=0.031 and p=0.048, respectively). The D-dimer levels were significantly higher on the third day and in the first week in Group T than before the drug administration (p=0.002 and p=0.008, respectively). IL-6 levels increased significantly with tocilizumab in all periods when compared to before administration (day 1: p=0.037, day 3: p=0.001, and week 1: p=0.001, respectively, in Group T).
When comparing changes in inflammatory parameters relative to values before drug administration, significant differences were observed between the groups. The rate of change in CRP levels was significantly higher in Group T than in Group IVIG on Day 3 (p=0.010) and during the first week (p=0.001). Similarly, the rate of change in IL-6 levels was significantly elevated in Group T compared to Group IVIG on Day 3 (p=0.001) and during the first week (p=0.004). The improvement in ferritin levels was significantly higher in Group T during the first week (p = 0.018). However, the change rates in PaO2/FiO2, procalcitonin, and D-dimer levels did not differ significantly between the groups.
Discussion
Various treatment modalities, including corticosteroids and inhibitors targeting mediators such as IVIG, IL-1, IL-6, TNF, IFN-γ, and Janus kinase have been utilized in the suppression or treatment of the cytokine storm associated with COVID-19 [10- 14]. In the present study, patients who were followed up in the intensive care unit because of COVID-19-related cytokine storm and were treated with tocilizumab or IVIG were evaluated retrospectively. First, it was retrospectively confirmed that all patients included in the present study experienced a cytokine storm, characterized by increased CRP, ferritin, and D-dimer levels and decreased lymphocyte values. Furthermore, demographic characteristics, ARDS severity, disease severity, time from hospitalization to medication administration, and oxygen support treatments were similar in the groups. No differences were detected in terms of mortality between those treated with tocilizumab and those given IVIG.
High IL-6 levels have been shown to cause damage to pulmonary tissues and facilitate the spread of the virus [15]. Some studies have reported that they detected no significant differences in mortality rates between patients who were given tocilizumab and those who were not, and the mortality rate was reported to be between 24% and 34% [7, 12]. However, it was observed in these studies that all hospitalized COVID patients were included, critically ill patients were in the minority, and intensive care admission was associated with mortality. In another study, it was reported that mortality was high in patients with high IL-6 levels who were not treated with tocilizumab and in patients with low IL-6 levels who were treated with tocilizumab. In the same study, when only those given tocilizumab were considered, it was found that 24 out of 59 cases resulted in mortality [16]. However, the PaO2/FiO2 ratios and inflammatory markers of the patients who were included in the present study were more severe than in the abovementioned studies. In the study conducted by Saffo et al., 30-day survival was reported to be 40%; in other words, there was 60% mortality [17]. The findings of the previous study are compatible with the results of the present study.
IVIG stimulates regulatory T-cells, regulates the complement system, and clears cytokines. It was also suggested that it might inhibit cytokine production and trigger apoptosis in dendritic cells, natural killer cells, macrophage T and B lymphocytes [18]. Among previous studies that investigated the effects of IVIG on mortality in patients with a cytokine storm because of COVID-19, some reported that IVIG had no effects on mortality, while others reported that it reduced mortality [14, 19, 20]. However, studies have also emphasized that IVIG is effective if given early before the disease reaches the severe stage [21]. A recent meta-analysis reported that IVIG did not reduce mortality, but high doses had positive effects on mortality in patients with severe COVID-19 [22].
In the literature review, no study that directly investigated the effects of tocilizumab and IVIG on mortality was found. The research closest to the present study was a retrospective study conducted by Zantah et al. on 84 patients, comparing anakinra/IVIG with tocilizumab. Although no differences were detected between the groups in terms of mortality, the total mortality rate of the groups was reported to be 19% [23]. In another prospective study, all patients were given tocilizumab, but IVIG was added to the treatment modality for those whose ferritin levels continued to increase despite tocilizumab use. The mortality rate was reported to be 15.4% in the group that received only tocilizumab and 38.46% in those that received IVIG along with tocilizumab [24]. In our study, the mortality rate among patients treated with tocilizumab was approximately 70%. The higher mortality rate in the present study than in the literature was attributed to the fact that only patients who needed intensive care were included in the study. Moreover, the patients had worse PaO2/FiO2 ratios and other inflammatory parameters, leading to the later administration of immunosuppressants compared to other studies.
Corticosteroids are also employed to attenuate the inflammatory response in COVID-19 patients [25]. Notably, our study found that more pulse steroids were given to those who received IVIG, which led to the conclusion that steroids were added to more patients in the IVIG group to increase immunosuppression due to tocilizumab’s earlier and more potent immunosuppressive effect compared to IVIG.
Previous studies have demonstrated improvements in inflammatory mediators and PaO2/FiO2 ratios after tocilizumab and IVIG administration [10, 21, 22, 24, 30]. However, no significant differences were detected in inflammatory marker levels (except ferritin) before and after tocilizumab or IVIG administration. Similar increases in PaO2/FiO2 ratios were observed three days and one week after tocilizumab and IVIG administration. Notably, the decrease in CRP level was earlier and greater in patients treated with tocilizumab. Ferritin levels were higher before drug administration in the tocilizumab group on the first and third days, subsequently declining to similar levels in the two groups, albeit with a greater decrease observed in the tocilizumab group in Week 1.
Although no statistically significant differences were observed in procalcitonin levels until the first week, according to our laboratory reference ranges, values above 2 ng/ml require evaluation in favor of bacterial infection. Therefore, although the average value was below 0.5 in individuals treated with tocilizumab, it was approximately 4.5 in those treated with IVIG. This occurred because tocilizumab is contraindicated in the presence of bacterial infection, necessitating the use of IVIG as an alternative treatment agent in this patient group. The observed increase in IL-6 levels following the administration of tocilizumab was consistent with the literature data [10].
Study limitations. The present study had some limitations. It was conducted in one center retrospectively, the number of patients was low and individuals who did not take the featured medications were not included.
Conclusion
Tocilizumab and IVIG had similar effects on mortality among patients who developed cytokine storms and were followed and treated with the same approach. Both treatments improved oxygenation. However, the suppression of inflammation was noted to be earlier and more significant with tocilizumab. In conclusion, when tocilizumab is unavailable or cannot be used, IVIG should be considered as an alternative agent or treatment option. Conversely, when IVIG is not accessible or suitable, tocilizumab may be administered with comparable effectiveness.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Serkan Kalkan, Selcuk Demırcan, Zeliha Korkmaz Dıslı, Deccane Duzencı, Funda Memısoglu, Murat Yalcınsoy, Murat Bıcakcıoglu, Mustafa S. Aydogan, Zafer Dogan, Aytac Yucel, Ayse B. Ozer. Comparison of tocilizumab and intravenous immunoglobulin treatment in intensive care unit patients with COVID-19 who developed cytokine storm: A single-center retrospective study. Ann Clin Anal Med 2024;15(12):865-870
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Comparison of urine culture and complete urinalysis results in female patients with suspected urinary tract infection
Hacer Özlem Kalaycı 1, Ahmet Burak Gürpınar 2, Hüseyin Erdal 3
1 Department of Medical Microbiology, Faculty of Medicine, Ordu University, Ordu, 2 Department of Medical Biochemistry, Faculty of Medicine, Ordu University, Ordu, 3 Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray, Turkiye
DOI: 10.4328/ACAM.22349 Received: 2024-07-31 Accepted: 2024-09-02 Published Online: 2024-10-11 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):871-875
Corresponding Author: Hacer Özlem Kalaycı, Department of Medical Microbiology, Faculty of Medicine, Ordu University, Ordu, Turkiye. E-mail: ozlemtekeli55@hotmail.com P: +90 506 284 19 59 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2358-6764
Other Authors ORCID ID: Ahmet Burak Gürpınar, https://orcid.org/0000-0003-3227-4682 . Hüseyin Erdal, https://orcid.org/0000-0003-0786-5077
This study was approved by the Ethics Committee of Ordu University Non-Interventional Scientific Research (Date: 2024-05-24 , No: 45)
Aim: This study aims to assess the effectiveness of fully automated urine tests by using urine culture results from female patients with suspected urinary tract infections as the reference standard and to determine their practicality for clinicians.
Material and Methods: Chemical and microscopic analysis of urine was performed using a fully automatic urine analyzer (Roche Cobas 6500 u601-u701, Roche Diagnostics GmbH, Mannheim, Germany) in patients with a preliminary diagnosis of symptomatic urinary tract infection who were admitted to xxx University Training and Research Hospital gynecology outpatient clinic between January 2023 and January 2024. Midstream urine samples sent in sterile containers were inoculated on 5% sheep blood agar and EMB agar with a 0.001 caliber core and incubated at 37°C for 18-24 hours under aerop conditions. According to complete urinalysis, leukocyte count ≥5 and bacterial count ≥1 were considered positive, leukocyte esterase positivity and nitrite positivity were considered positive.
Results: Escherichia coli (E.coli), Streptococcus agalactiae, Klebsiella pneumoniae, Staphylococcus sapropyticus and Candida spp. were most frequently isolated from a total of 295 urine cultures. The most effective antibiotics against the isolated E.coli strains were nitrofurantoin, fosfomycin, imipenem, meropenem and amikacin. When culture results were taken as gold standard, the diagnostic sensitivity, specificity and accuracy rates of leukocyte esterase and nitrite positivity were 78.3%, 44%, 52.1%, 24.1%, 99.9%, 82.1% for leukocyte esterase and nitrite, respectively.
Discussion: We think that nitrite positivity may be a guide for unnecessary urine culture requests, but urinalysis parameters should not be used instead of culture due to their low accuracy rates.
Keywords: Urine Culture, Urinalysis, E.Coli, Sensitivity, Accuracy
Introduction
Urinary tract infections are the most common infections in the community, which can range from asymptomatic cystitis to clinics with severe symptoms and are mostly caused by bacteria [1]. Approximately 10-35% of women experience urinary tract infections at some point in their lives. Asymptomatic bacteriuria is frequently detected in 2-7% of pregnant women and it has been suggested that this condition is associated with preterm delivery and pyelonephritis [2]. Diagnosis and treatment of urinary tract infections are of great importance. In urinary tract infections, complaints such as pollacuria, sudden urinary urgency, dysuria, slowing of urinary flow, nocturia, suprapubic and/or lumbar pain may be observed [3]. Laboratory findings include pyuria, bacteriuria, leukocyte esterase positivity, nitrite positivity and the growth of pathogenic bacteria in urine culture, which is considered the gold standard [4, 5]. Urine culture results require 24-48 hours for visualization and require more workload than complete urinalysis. Therefore, antibiotic treatment is usually initiated empirically based on clinical symptoms and complete urinalysis results and then it was adjusted according to culture results. In order to initiate appropriate treatment, the accuracy and reliability of complete urinalysis should be high [6]. Such methods are frequently used in routine laboratories because they are easily applicable and inexpensive, and they accelerate the workflow [7]. Broad-spectrum antibiotics such as quinolones, TMP-SMX, cephalosporins, aminoglycosides and cephalosporins are recommended as the first choice in the treatment of urinary tract infections. Quinolones are also not preferred in pregnant women. As in the whole world, antibiotic resistance is developing at increasing rates in our country due to empirical antibiotic use [8]. Studies have reported that there may not always be a positive correlation between pyuria, nitrite and leukocyte esterase positivity detected by urinalysis and growth in culture [9, 10]. In this study, our purpose was to evaluate the performance of fully automated urine tests by accepting the urine culture results of female patients presenting with suspected urinary tract infections as a reference and to evaluate the convenience for clinicians.
Material and Methods
In this study, we retrospectively analyzed data from patients initially diagnosed with symptomatic urinary tract infections who visited the gynecology outpatient clinic at xxx University Education and Research Hospital between January 2023 and January 2024. The hospital information system was used to document complete urine tests and urine culture sensitivity reports for all patients.
Urine samples were first subjected to chemical and microscopic analysis using a fully automatic urine analyzer (Roche Cobas 6500 u601-u701, Roche Diagnostics GmbH, Mannheim, Germany). According to the fully automatic urine analyzer, values with a leukocyte count of ≥5 and a bacterial count of ≥1 were evaluated as positive, and according to chemical tests, leukocyte esterase positivity and nitrite positivity were evaluated as positive. Urine culture was also studied from urine samples simultaneously with the complete urine test. Midstream urine sent as early as possible (within two hours after collection) in a sterile container was inoculated onto 5% sheep blood agar and EMB agar with a 0.001 caliber loop and incubated for 18-24 hours at 37°C under aerobic conditions. Growth was evaluated quantitatively. For this study, urine samples with growth of ≥5×104 cfu/ml at the end of incubation were evaluated as positive cultures. The growth of 3 or more microorganisms in urine culture was evaluated as contamination. Identification and antibiotic susceptibility studies of the grown microorganisms were performed with the Phoenix 100 (Becton-Dickinson, USA) automated system and were evaluated according to the criteria of The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212 strains were used for quality control. Specifity, sensitivity, positive predictive values and negative predictive values were calculated to evaluate the diagnostic performances of chemical and microscopic analysis of complete urine examination, taking urine culture positivity as reference.
Urine sample data of 1496 patients who applied to the Gynecology and Obstetrics clinic with a preliminary diagnosis of urinary tract infection were included in the study. Data for which only urine culture or only complete urinalysis was requested were not included in the study.
Statistical Analysis
Statistical analyses were conducted using the MedCalc software (version 20.009; Ostend, Belgium). Descriptive statistics included number, frequency, percentage, arithmetic mean, standard deviation, median, and 25th and 75th percentile values. The Kolmogorov-Smirnov test was employed to assess the normality of numerical data distributions. The Mann-Whitney U test was used for pairwise group comparisons. Urine culture results served as the reference for evaluating urine strip and microscopy parameters in terms of diagnosis. Sensitivity, specificity, positive and negative predictive values, and AUC (Area Under the Curve) values were calculated. Additionally, ROC analysis was performed to determine the areas under the curve for leukocyte microscopy and bacteria values. A significance level of p<0.05 was used for interpreting the results.
Ethical Approval
This study was approved by the Ethics Committee of the Ordu University Non-Interventional Scientific Research (Date: 2024-05-24 No: 45).
Results
1496 complete urinalysis and urine cultures were studied from urine samples taken from patients who applied to the gynecology and obstetrics outpatient clinic. The causative microorganism grew in 295 of these. No growth was observed in the cultures of 961 patients. The urine of 240 patients was evaluated as contaminated. The result of 295 patients in whom growth was detected in the culture was reported as 105 cfu/ml and a single species of bacteria. The most frequently isolated agents were Escherichia coli (n: 150), Streptococcus agalactiae (n: 36), Klebsiella pneumoniae (n: 27), Staphylococcus sapropyticus (n: 7) and Candida spp. (n: 7), respectively. E.coli strains were found to be resistant to 51% (n:78) to ampicillin, 29.3% (n:44) to TMP-SXT, 29.3% (n:44) to ciprofloxacin and levofloxacin, 18% (n:27) to ceftriaxone and cefixime. Klebsiella pneumoniae strains were found to be resistant to piperacillin-tazobactam, 14.8% (n:4) to ceftriaxone, 11% (n:3) to TMP-SXT and fosfomycin. While no fosfomycin resistance was observed against E.coli, fosfomycin resistance was observed in 11.1% (n:3) against Klebsiella pneumoniae. Imipenem and meropenem resistance of E.coli strains was determined as 0.07% (n:1), 0.13% (n:2) nitrofurantoin resistance and 1.2% (n:3) amikacin resistance. Extended Spectrum Beta Lactamase (ESBL) enzyme positivity was found as 18% and 14.8% in Escherichia coli and Klebsiella pneumoniae isolates, respectively. Resistance rates are not given since the number of other isolated microorganisms is low. Sensitivity values for leukocyte esterase, nitrite, leukocyte microscopy and bacterial microscopy are 78.3%, 24.1%, 65.4%, 42.3% and specificity values are 44%, 99.9%, 61.6%, 65.7%, respectively. The positive predictive value of the nitrite test is remarkable with 98.6%. When the culture result is taken as the gold standard, the diagnostic accuracy performance of complete urinalysis results is given in Table 1.
In patients with no growth in culture (n: 961), 35.4% (n: 340) had leukocyte positivity, and in 28.3% (n: 178) of 628 urine samples with leukocyte positivity, causative microorganism growth was detected in urine culture.
In 293 (30.5%) of 961 samples with negative culture results, leukocyte esterase, nitrite, bacteria and leukocyte values, which are indicators of infection in complete urinalysis, were found to be within normal limits. When we examined the 961 samples with negative culture results, only one of the samples was found to be nitrite positive. In only 423 (44%) of the samples with negative culture results, both leukocyte esterase and leukocyte negativity were detected in microscopy.
In the ROC analysis for leukocyte microscopy, the area under the curve (AUC) was found to be 0.660, (CI 95% = 0.622 – 0.698), and for bacterial microscopy, the area under the curve (AUC) was found to be 0.539, (CI 95% = 0.500 – 0.579. The ROC analysis for leukocyte microscopy and bacterial microscopy tests is given in Table 2.
When we evaluated the culture results according to the seasons, the growth in urine (85/266, 32%) was found to be higher in winter and the growth in urine (55/303, 18%) was found to be lower in autumn.
Discussion
Urinary tract infections (UTIs) are prevalent bacterial infections in women, attributed to factors such as a short urethra, proximity to the rectum, bacterial contamination of the bladder, and inadequate personal hygiene [1]. These infections can range from asymptomatic to severe and potentially fatal cases. Additionally, UTIs contribute to extended hospital stays, significant workforce loss, and economic burdens, emphasizing the importance of timely diagnosis and treatment [11]. Clinicians should initially order a complete urinalysis for symptomatic patients, and if findings such as leukocytes and bacteria in microscopic analysis, or nitrite and leukocyte esterase in chemical analysis, are present, a urine sample should be cultured. The compatibility of urine culture, the gold standard, and complete urinalysis results is crucial for accurate diagnosis. However, studies have indicated that nitrite and leukocyte esterase positivity and leukocyte microscopy may not always align with culture results [9, 10].
Parlaktaş et al. evaluated complete urinalysis and culture results in patients with a preliminary UTI diagnosis and underscored the importance of urine culture for accurate diagnosis and treatment [12]. Our study reviewed the complete urinalysis and culture results of 1,496 patients, revealing that 64.2% of the culture results were negative. Similarly, Kayaalp et al. found that 97.7% of 32,998 samples had negative culture results [13]. Other studies by Martinez et al. and Okada et al. reported negative culture results at rates of 52% and 68.3%, respectively [14, 15]. Hence, complete urinalysis appears crucial before deciding to order a culture.
In our study, Escherichia coli was the most frequently isolated microorganism (51%) in UTIs at Ordu University Training and Research Hospital Gynecology and Obstetrics Outpatient Clinic, followed by Streptococcus agalactiae (12.2%) and Klebsiella pneumoniae (9.2%). Similar findings were reported by Çeken and Avcı (86%), Öner et al. (79.4%), and Sezgin and Nar (71.9%) [16- 17]. The most effective antibiotics against E.coli strains in our study were fosfomycin, imipenem, meropenem, nitrofurantoin, and amikacin [17]. Sezgin and Nar reported high resistance to ampicillin and trimethoprim-sulfamethoxazole in E.coli isolates, a trend also noted globally by Bryce et al., who found high resistance rates to these antibiotics and low resistance to nitrofurantoin [18].
Quinolone antibiotics are commonly used empirically for UTI treatment. Sezgin and Nar reported a 4% quinolone resistance in E.coli, while our study found a 29.3% ciprofloxacin resistance [17]. The highest resistance in E.coli strains was against ampicillin, trimethoprim-sulfamethoxazole, ciprofloxacin, and levofloxacin.
Evaluating the positive and negative predictive values of diagnostic methods aids in UTI treatment. Özer et al. reported these values as 29.9% and 95.3% for leukocyte esterase, 27.6% and 95.6% for leukocyte microscopy, and 80.7% and 93.1% for nitrite [19]. Our study found 30% and 86.9% for leukocyte esterase, 34.3% and 85.3% for leukocyte microscopy, and 98.6% and 81.1% for nitrite, highlighting nitrite’s high positive predictive value.
European urinalysis guidelines recommend analytical sensitivity and specificity ranges for leukocyte esterase (80-90%) and nitrite tests (20-80% sensitivity, >90% specificity). Sezgin and Nar reported nitrite test sensitivity and specificity as 17.1% and 99%, respectively, while Yüksel et al. found 17.7% and 90.1% [20]. Our study determined nitrite test sensitivity and specificity as 24.1% and 99.9%, suggesting it as a strong predictor of negative culture results.
Gülcan et al [21]. reported leukocyte esterase sensitivity at 89.3%, specificity at 18.2%, positive predictive value at 55.4%, and negative predictive value at 60.0%. Mokube et al [22]. found leukocyte esterase sensitivity at 20.8%, specificity at 80.8%, positive predictive value at 25%, and negative predictive value at 77%. Our study found leukocyte esterase sensitivity at 78.3%, specificity at 44%, positive predictive value at 30%, and negative predictive value at 86.9%. Sezgin and Nar reported leukocyte and nitrite presence concordance with culture at 88.4% and 69.8%, respectively [17], and Güdücüoğlu et al [22]. reported an 88.25% accuracy rate comparing leukocyte results with culture results. High false negative rates for leukocytes in culture-positive patients may result from the limitations of fully automated urine devices. In our study, leukocyte positivity was noted in 35.4% of culture-negative patients. Factors such as undetected bacteria in routine culture media, urethritis-causing agents (e.g., Chlamydia, Neisseria, Mycoplasma), and antibiotic use should be considered. Our comparison of leukocyte esterase and nitrite results with culture showed accuracy rates of 52.1% and 82.1%, respectively [23].
Yüksel et al [20]. found high sensitivities for leukocyte esterase (86.1%) and leukocyte microscopy (88.0%), and high specificities for nitrite (95.4%) and bacterial (86.6%) examinations. Kayaalp et al [13]. reported the highest sensitivity (78.8%) and specificity (97.8%) for bacterial microscopy, and 68.2% and 87.8% for leukocyte microscopy. Kaçmaz et al. found pyuria sensitivity at 76%, and Özer et al. at 67.8%. Our study found high sensitivities for leukocyte esterase (78.3%) and leukocyte microscopy (65.4%), and high specificities for nitrite (95.9%) and bacterial microscopy (65.7%). In 28.3% (178/628) of pyuria samples, culture showed growth, indicating limited usefulness of pyuria alone for UTI diagnosis.
In 30.5% of samples with negative culture results, leukocyte esterase, nitrite, bacteria, and leukocyte values in complete urinalysis were within normal limits. Among 961 negative culture samples, only one was nitrite positive, and 44% had both leukocyte esterase and leukocyte negativity in microscopy.
Yüksel et al [20]. reported an AUC of 0.852 for leukocyte microscopy in ROC analysis, Zorbozan et al [24]. found 0.923 for leukocyte microscopy, and Üzmez et al [25]. reported 0.793 and 0.861 for leukocyte and bacterial counts, respectively. Our study found AUC values of 0.660 for leukocyte microscopy and 0.539 for bacterial microscopy.
Lacking previous antibiotic resistance data for female UTI patients in our province limits our ability to report changes in resistance rates. We also acknowledge the absence of clinical evaluation data as a limitation of our study, despite the preliminary UTI diagnosis being recorded in our hospital’s information system during retrospective evaluation.
Conclusion
In conclusion, urinalysis parameters do not have the precision required to substitute culture tests. As the workload in medical laboratories increases, fully automated urinalysis devices could be beneficial for high-throughput environments. For cost efficiency, positive nitrite results may help in avoiding unnecessary urine cultures. However, negative nitrite results are insufficient to rule out urinary tract infections, making urine culture necessary. Furthermore, leukocyte esterase shows poor diagnostic performance in both identifying and excluding the presence of disease.
Inappropriate antibiotic use has led to increased resistance in many microorganisms. The sensitivity to ampicillin and trimethoprim-sulfamethoxazole is decreasing, making their empirical use risky and potentially ineffective. Conversely, no resistance to nitrofurantoin and fosfomycin was found in urinary tract infections attributed to E.coli, supporting their recommendation for empirical treatment. The growing resistance to quinolones should also be considered. To combat resistance, it is crucial to know the susceptibility rates of microorganisms causing urinary tract infections in our region and to apply our study’s findings to enhance treatment success rates.
Limitation
Our study has several limitations that should be acknowledged. First, the data on urinalysis parameters and culture results were collected from a single center, which may limit the generalizability of our findings to other settings or populations. Second, while we evaluated the performance of automated urinalysis devices, our study did not include a direct comparison with manual microscopy, which is a commonly used method in many laboratories. Third, the antibiotic resistance patterns were based on data from a specific time period, and resistance rates can change over time; therefore, ongoing surveillance is necessary. Finally, our study did not assess the clinical outcomes of patients, which would provide more comprehensive insights into the impact of our findings on patient care. Future research should address these limitations by including multicenter data, comparing different diagnostic methods, monitoring resistance trends over time, and evaluating patient outcomes.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Antifungal treatment strategies to reduce mortality in ıntensive care
Havva Kubat 1, Elif Karabacak 1, Esra Aybal 2, Bahadır Ozelbaykal 3
1 Department of Pharmacology, 2 Department of Anesthesia and Reanimation Intensive Care, 3 Department of Ophthalmology, Adana City Training and Researching Hospital, Adana, Turkiye
DOI: 10.4328/ACAM.22354 Received: 2024-08-04 Accepted: 2024-09-24 Published Online: 2024-10-22 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):876-880
Corresponding Author: Elif Karabacak, Department of Pharmacology, Adana City Training and Researching Hospital, Adana, Turkiye. E-mail: elifkarabacak2010@hotmail.com P: +90 322 455 90 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2054-4542
Other Authors ORCID ID: Havva Kubat, https://orcid.org/0000-0003-0958-9045 . Esra Aybal, https://orcid.org/0000-0002-3237-4838 . Bahadır Ozelbaykal, https://orcid.org/0000-0001-5898-9016
This study was approved by the Ethics Committee of Adana City Education and Research Hospital (Date: 2023-12-21, No: 3027)
Aim: Mortality of fungal infections is high in intensive care units. Waiting for culture results to start antifungal medication may lead to treatment delay and death. This study aimed to evaluate the mortality of adult patients who were administered antifungal medication for the treatment of culture-proven or possible invasive fungal infections in intensive care units.
Material and Methods: Data from patients who received antifungal therapy in a tertiary intensive care unit over a 24-month period were used. Fungal agents growing in the materials taken from the patients, APACHE II scores of the patients, antifungal drugs administered, and survival status were recorded.
Results: 320 patients were included in the study. Antifungal medications were started prophylactically in 42.5%, empirically in 37.2%, and targetedly in 20.3%. Of the patients who received prophylactic treatment, 50.7% died, while 70.6% of empirical, and 66.2% of targeted therapy patients died. Applying prophylactic antifungal treatment significantly reduced the mortality rate compared to empirical and targeted treatments (p=0.003 and p=0.04, respectively). The most frequently occurring fungal agent in culture samples was Candida albicans (43.5%). The most commonly used antifungal drug was fluconazole (69.7%). The mean values of the Apache II score and colonization index were statistically significantly higher in deceased patients than in survivors (p=0.023 and p=0.027, respectively).
Discussion: In this study, it was shown that applying prophylactic antifungal treatment to patient groups at risk of invasive fungal infection before colonization develops reduces mortality. Our results support the use of prophylactic antifungal drugs to reduce mortality in intensive care units.
Keywords: Antifungal Drug, Intensive Care Unit, Prophylactic Use
Introduction
Human fungal diseases are infections caused by any fungus that invades human tissues and can cause superficial, subcutaneous, or systemic disease. Infective fungi that enter human tissues and organs pose a significant threat to millions of individuals with weakened immune systems [1]. Fungal infections affect the lives of more than 6.5 million people worldwide each year, causing 3.5 million deaths [2]. Invasive fungal infections (IFI) include fungal infections in the bloodstream and/or deep tissues in a sterile area [3]. It has been reported that patients in the intensive care unit are at risk of IFI due to many reasons such as vascular catheters, broad-spectrum antimicrobial therapy, renal failure, total parenteral nutrition, and immunosuppressive agents [4]. Mortality rates in intensive care patients due to IFI can reach 30-40% [5], even 80% [6]. The role of antifungal therapy before culture diagnosis in the intensive care unit has not yet been fully defined, as there are uncertainties in identifying patients at high risk for developing IFI. The lack of well-established molecular techniques for early detection of candidemia frequently delays the recognition and treatment of this infection [7]. A delay in initiation of antifungal therapy has been reported to be associated with increased mortality [4]. Early antifungal strategies (prophylaxis, empiric, and preventive) have been developed using tools such as the Candida colonization index, clinical prediction rules, and non-culture-based fungal tests [8]. Cohort studies suggest that timely application of antifungal therapy and adequate source control are crucial [9].
This study aimed to contribute to the controversial issue of antifungal treatment strategies by examining the mortality rates of adult patients who received antifungal therapy for culture-proven or probable IFI in the tertiary intensive care units of one of the largest hospitals in the region with a high patient density in the south of Turkey.
Material and Methods
All adult patients who were hospitalized in the general intensive care and anesthesia resuscitation intensive care units of the Adana City Education and Research Hospital between January 2022 and December 2023 (2 years) and received antifungal treatment were included in the study. Patient files registered in the hospital information system with the researchers’ personal passwords were examined. Patients’ age, gender, indications for intensive care, additional diseases, Acute Physiology and Chronic Health Evaluation II (APACHE) II scores, colonization index, fungal agents grown in materials taken from patients, antifungal drugs used, indications for starting antifungal drugs, recovery, and death status were recorded. Antifungal treatments were started with the approval of an infectious diseases specialist physician. Patients were divided into 3 groups according to the status of starting antifungal treatment [10].
1. Prophylactic group: Antifungal drugs initiated for patients without IFI and at risk of IFI,
2. Empirical group: Antifungals initiated for patients with clinical signs and symptoms but no known source, suspected IFI, also considering the colonization index,
3. Targeted group: Antifungals initiated for patients with fungal growth detected as a result of cultures taken from sterile areas such as blood, pleura, peritoneum, and tissue constitute the targeted treatment group [10].
APACHE II score was calculated by recording age, fever, mean blood pressure, heart rate, respiratory rate, hematocrit, white blood cell, serum sodium, potassium, creatinine, pH value, acute renal failure, chronic disease, and postoperative status parameters electronically for each patient during the first 24 hours of admission to the intensive care unit. Blood and urine cultures were routinely obtained from all patients on their first admission to the intensive care unit. If necessary, aspirate, and sputum, among others, were added [11]. Cultures were repeated in cases such as fever and secretion increase according to the patient’s clinical condition during the intensive care unit stay. The Colonization index (CI) was calculated by the ratio of the number of culture-positive areas to the number of cultured areas. Species-level identifications in the materials taken for culture were made in the microbiology laboratory using the BD BACTECTM FX (Becton Dickinson, USA) automated blood culture system, Sabouraud dextrose agar (RTA, TR), and MALDI-TOF MS (Bruker Daltonies, USA) yeast identification system.
Statistical Analysis
The Kolmogorov-Simirnov test was performed for normality analysis. Summary statistics were calculated for the patients’ demographics, duration of stay in the intensive care unit, medical history, antifungal agents and therapy types, and microbiologic culture results. The difference between prophylactic, empiric, and therapeutic treatments on patient survival was analyzed using the Chi-square test. The Apache II scores of patients who were divided according to their survival outcome were analyzed with the Man-Whitney U test. The Apache II scores of patients who received prophylactic, empirical, and therapeutic treatments were analyzed using the Kruskal-Wallis test. Also, the colonization index of patients, grouped according to their survival outcome, was analyzed using the Mann-Whitney U test. Statistical analyses were performed by SPSS 27 software (SPSS Inc, Chicago, IL, USA). In addition, a p-value of less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Adana City Education and Research Hospital (Date: 2023-12-21, No:3027).
Results
During the 24 months, 320 of 2528 patients in intensive care receiving antifungal treatment were included in the study. 111 (34.7%) were women, and 209 (65.3%) were men. The average age of the patients is 64.5/year (18-98). The average length of stay in the intensive care unit was 35.16±26.9 days. Of the patients, 196 (61.3%) passed away, while 124 (38.7%) recovered and were transferred to the ward. The oxygen needs of the patients were provided by nasal cannula (n = 104), mask (n = 10), or mechanical ventilation (n = 206). Patients were admitted to intensive care for postoperative (n=129), lung-related diseases (n=75), general condition disorders due to underlying cancer (n=39), cardiovascular diseases (n=26), kidney-related diseases (n=30), cerebrovascular diseases (n=30), and other conditions (n=21). When examining the additional diseases of the patients, 193 (60.31%) had no comorbidities, 71 (22.19%) had one comorbidity, and 56 (17.5%) had two or more comorbidities recorded. Mortality increased significantly in those with two or more comorbidities compared to those without comorbidities (p=0.004).
The indication for starting antifungal treatment was defined as prophylactic in 42.5% (n=136), empirical in 37.2% (n=119), and targeted in 20.3% (n=65) (Table 1). The most used antifungal drug is fluconazole, 69.7% (n = 223). In second place, amphotericin B was preferred in prophylaxis, anidulafungin was preferred in empirical treatment, and micafungin was preferred in targeted therapy (Table 1). The number and percentage values of patients using prophylactic, empirical, and targeted antifungals are shown in Table 1. 50.7% of the patients in whom prophylactic antifungal treatment was initiated, 70.6% in whom empirical antifungal therapy was initiated, and 66.2% in whom targeted antifungal therapy was initiated died (Table 1). It was observed that the mortality rates of patients who started prophylactic antifungal treatment were significantly lower than those who received empirical and targeted treatment (p = 0.003 and p = 0.04, respectively). There was no significant difference between the death rates of patients receiving empirical and targeted antifungal therapy (p = 0.534).
The APACHE II score was calculated at the patient’s admission to the intensive care unit. APACHE II score mean values are close to each other in the prophylactic (31.7±11.7), empirical (32.7±10.6), and goal-directed (32±10.45) groups (p=0.989). The average Apache II score value of the deceased (33.79±10.1) was found to be significantly higher than that of the survivors (29.79±11.94) (p=0.023).
Colonization index values were found to be significantly higher in the deceased (0.16±0.16) than in the survivors (0.12±0.17) (p=0.027).
In this study, no growth was detected in the culture samples taken from the patients in 136 cases, and prophylactic antifungal treatment was started. Empiric antifungal treatment was started in 119 cases. Growth was detected in blood, pleural peritoneal fluid, and tissue biopsy materials in 68 cases, and targeted antifungal treatment was started. The most frequently isolated fungal agent was found to be Candida albicans (43.5%). Other species that follow are Candida tropicalis, Candida glabrata, Candida parapsilosis, Candida crusei, and others. The fungal species growing in culture samples, the number of patients, and their percentages are shown in Table 2.
Discussion
Fungi are responsible for approximately 20% of microbiologically documented infections in intensive care units [12]. There is no consensus on systemic antifungal treatment strategies. Patients at risk of IFI are generally at risk of rapid clinical deterioration and death. Culture is the gold standard for confirming IFI, but waiting for culture results before starting antifungal medication may compromise patient outcomes [13]. In intensive care patients, it may be too late for antifungal treatment once colonization has developed. For this reason, intensive care patients are candidates for prophylactic antifungal administration at the beginning of hospitalization [14]. In antifungal treatment, the start time of treatment is as important as the choice of appropriate drug. It has been argued that fluconazole prophylaxis reduces both colonization and invasive candidemia in high-risk premature infants and can be administered safely without the development of fungal resistance [15]. In critically ill patients, prophylactic antifungals have been found to reduce IFI by half and mortality by a quarter, and antifungal prophylaxis with fluconazole has been recommended [16]. The necessity of antifungal prophylaxis during the treatment of some cancer patients is advocated. It has been shown that antifungal prophylaxis in high-risk neutropenic patients halves the number of patients receiving antifungals without increasing mortality or IFI [17]. It has been stated that antifungal prophylaxis is effective in high-risk patients, including high-risk liver transplant recipients [18] and critical surgical patients [19]. Almost all preventive studies have demonstrated or suggested a reduction in the administration and cost of antifungals with prophylactic antifungal use. However, the clinical validity of the strategy is still pending [20]. Our results also indicate that mortality decreases with prophylactic antifungal use. Since a delay in starting antifungal treatment in the intensive care unit can result in death, prophylactic use of antifungal drugs in patients at high risk of fungal infection can reduce delays in treatment.
Of course, since not all patients in the intensive care unit are at equal risk, routine prophylaxis cannot be recommended. In our study, the ratio of the number of patients receiving antifungal prophylaxis in two years to all intensive care patients is small (5.4%), but it is an important step in terms of reducing mortality. In this study, the low mortality rate in the patient group requiring prophylactic antifungal medication indicates that the patient group at risk of IFI was correctly identified. Candida, which has been considered for years primarily as an opportunistic pathogen of immunocompromised hosts (i.e., neutropenic cancer patients and organ transplant patients), has emerged as a significant cause of morbidity and mortality in surgical and intensive care unit patients in the last two decades [21]. According to this study’s results and similar previous studies, it can be said that antifungal prophylaxis should not be limited only to neutropenic patients, but may also be beneficial for selected critically ill patients. The idea of expanding it to include the prevention of candida infections in a larger population of critically ill patients without neutropenia in the intensive care unit may be attractive.
Due to the high cost of antifungal treatment and the risk of toxicity development, it is not advisable to apply prophylaxis to every intensive care patient [14]. The effectiveness of azole prophylaxis in non-neutropenic high-risk intensive care patients is controversial. Some authors argue that increased application of azoles leads to a rise in resistant non-albicans Candida spp [10]. In order not to be late for treatment and not to cause excessive antifungal use, it is critical to accurately identify the patient group to which antifungal medication should be administered and the time of administration. Thus, treatment can be provided without increasing costs and side effects. It has been stated that the colonization index is one of several additional factors that can certainly be taken into account to increase the precision of patient selection and reduce the number of patients requiring antifungal therapy without increasing morbidity and mortality [21]. In our study, the colonization index was effective in the decision to start empirical antifungal treatment. The higher colonization index calculated in deceased patients confirms that this parameter should not be ignored. It has been shown that there is a decrease in colonization with prophylaxis in the risk group [22].
This study demonstrated that applying prophylactic antifungal treatment to patient groups at risk of IFI before colonization develops reduces mortality. It has been stated that azole-derived antifungals are safe due to their low cost and low toxicity [18]. Similar to previous research results [10], in our study, 400mg fluconazole was the most preferred antifungal for prophylaxis when used intravenously.
It is known that C. albicans is the most common species in Europe [5], and candidemia is the most common serious fungal infection developing in critically ill patients in intensive care units [23]. It has been stated that Candida spp. is the third leading cause of infections in the intensive care unit and accounts for 90% of fungal infections [6,24]. In our study, the most common fungal genus detected in intensive care patients was candida.
Previous studies have determined that APACHE II scores are independently associated with hospital mortality [25]. Similarly, in this study, mortality was found to be higher in patients with high APACHE II scores. Since the main purpose of this study was to compare mortality in prophylactic empirical target groups, the lack of difference between the APACHE II scores of these three groups demonstrated that mortality decreased with prophylactic antifungal use. Although the patients’ oxygen needs, indications for intensive care admission, and comorbid diseases were heterogeneous, the similarity of APACHE II scores among the three groups allowed us to better evaluate mortality rates. Although there was no difference in the expected mortality rates in the three groups in this study, it can be said that prophylactic antifungal use increases survival based on the result that mortality was low in the prophylactic group.
Conclusion
In this study, it was found that prophylactic antifungal administration to patients considered to be at high risk of developing IFI reduced mortality.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Evaluation of depression and sleep quality in geriatric patients with spinal cord injury
Gul Mete Civelek 1, Handan Elif Nur Bayraktar 2, Zeynep Keskin 1
1 Department of Physical Therapy and Rehabilitation, Faculty of Health Science, Ankara City Hospital, Ankara, 2 Department of Physical Therapy and Rehabilitation, Samsun Training and Research Hospital, Samsun, Turkiye
DOI: 10.4328/ACAM.22402 Received: 2024-09-15 Accepted: 2024-11-04 Published Online: 2024-11-13 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):881-887
Corresponding Author: Handan Elif Nur Bayraktar, Department of Physical Therapy and Rehabilitation, Samsun Training and Research Hospital, Samsun, Turkiye. E-mail: elifnurylmz19@gmail.com P: +90 553 189 55 90 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2462-5470
Other Authors ORCID ID: Gül Mete Civelek, https://orcid.org/0000-0002-0558-6501 . Zeynep Keskin, https://orcid.org/0000-0001-9527-5549
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2022-10-26, No: E2-22-2660)
Aim: Depression and sleep disturbances are common, challenging conditions in geriatric patients with spinal cord injury. Although both conditions are treatable, they are usually overlooked and understudied. This study aims to investigate depression, sleep disturbance, and related factors in geriatric patients with spinal cord injury.
Material and Methods: This prospective descriptive study included 69 consecutive patients with spinal cord injury who were admitted to a tertiary care center in Turkey. Demographic and clinical data were noted, including each patient’s cause of injury and impairment status. The presence of depression, presence of sleep disturbance, daytime sleepiness, presence of neuropathic pain, functional independence and comorbidities were assessed using the Geriatric Depression Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Douleur Neuropathic 4 Questions questionnaire, Barthel Index, and Charlson Comorbidity Index, respectively. Prevalence and association of depression, sleep disorders, and neuropathic pain with each other and with other demographic and clinical parameters were examined.
Results: In our study, over 90% of patients had sleep disturbance, and 20.1% had moderate or definite depression. Patients with depression had higher sleep disturbance scores, and patients with sleep disturbance had higher depression scores (p=0.001, p=0.002). Both patients with depression and patients with sleep disturbance had higher daytime sleepiness scores (p=0.005, p<0.001). Patients with sleep disturbance had a significantly higher frequency of neuropathic pain (p=0.005).
Discussion: Depression and sleep disturbance are common in geriatric patients with spinal cord injury and are associated with each other, increased daytime sleepiness and neuropathic pain. Thus, the presence of sleep disturbances and depression should be evaluated in every geriatric patient with spinal cord injury. Further, rehabilitative management of these patients should include psychiatric evaluation and interventions.
Keywords: Depression, Sleep Quality, Spinal Cord Injury
Introduction
Depression and sleep disorders, for which advanced age and poor general health are risk factors, are more frequently seen in patients with spinal cord injury (SCI) than in the general population [1- 3]. Both depression and sleep disorders interact with each other and negatively affect the quality of life of patients.
In the meta-analysis published by Williams and Mury in 2015, the mean estimated prevalence of depression diagnosis after SCI was reported as 22.2% [3]. However, there are few studies investigating depression and related factors in the elderly SCI group. In a previous study published in Sweden, which included patients 50 years of age and older with a reported SCI for at least ten years, the prevalence of depression was found to be 29%. In this study, the presence of neuropathic pain, bladder and bowel problems, not having a job, and a low ability to cope with the disease were found to be associated with depression [2]. Most of these factors are preventable or treatable. The fact that the scales used in depression screenings are different and the socio-cultural structures of the countries are variable also affects the frequency of depression and related factors.
In a relatively small number of studies investigating sleep disorders in patients with SCI, sleep disorders were found to be associated with a high level of injury, pain, disruption of circadian rhythm, fatigue, and increased daytime sleepiness [1]. Further, increased daytime sleepiness, depression, and fatigue also negatively affect the patient’s participation in the rehabilitation program during the day [4].
Our study’s objective is to examine depression, sleep disturbances, and associated factors in geriatric patients with SCI. Our literature search did not find similar studies involving this patient group. Thus, we think that the results of our study will be enlightening for physicians dealing with this fragile patient group and will contribute to future studies on these issues.
Material and Methods
Geriatric patients aged 65 and older with SCI were selected from consecutive attendees of the Physical Medicine and Rehabilitation Clinic. Information about the study was given to all participants, and they provided written informed consent before enrolling. The inclusion criteria were: 1) disabling sequelae resulting from SCI; 2) age of 65 years or older; and 3) cooperative. Patients were excluded based on the following criteria: 1) the presence of an additional neurological disease, 2) cognitive impairment, 3) an unstable condition.
Demographic and clinical characteristics of the patients, including gender, age, education status, marital status, primary caregiver, cause of injury, time since injury, impairment status (tetraplegic/ paraplegic), incompleteness/completeness of injury based on the American Spinal Injury Association (ASIA) Impairment Scale, bladder and bowel control, presence of neuropathic pain, and presence of decubitus ulcer were recorded. Patients were categorized based on the ASIA Impairment Scale (AIS), as revised in the 2011 International Standards for Neurological Classification of Spinal Cord Injury [5]. For patients with non-traumatic SCI, the onset of neurological symptoms was used to determine the time since injury.
Depression presence was determined using the Turkish version of the Geriatric Depression Scale (GDS) [6, 7]. A GDS score ranging from 0 to 10 points was considered as no depression, 11 to 13 points as moderate depression, and 14 points or more as definite depression.
Quality of sleep was evaluated using the Turkish version of the Pittsburgh Sleep Quality Index (PSQI) [8, 9]. This 19-item scale assesses seven components of sleep quality: subjective sleep quality, sleep duration, sleep latency, sleep disturbances, habitual sleep efficiency, use of sleep medication, and daytime dysfunction over the past month. Global sleep disturbance scores higher than 5 indicate clinically significant sleep disturbance. The PSQI is a valid and reliable instrument that has previously been used to assess sleep quality in geriatric patients [10].
Day-time sleepiness was evaluated using the Turkish version of the Epworth Sleepiness Scale [11, 12]. This scale consists of 8 questions relating to situations in everyday life. Participants are asked to rate the likelihood of dozing off or falling asleep in these situations. The scoring is as follows: 0 = no chance of dozing off, 1 = low chance of dozing off, 2 = medium chance of dozing off, and 3 = high chance of dozing off. The total score, ranging from 0 to 24, is obtained by summing the scores for each question. Higher scores indicate a greater degree of daytime sleepiness.
Neuropathic pain presence was evaluated using the Turkish-validated version of the Douleur Neuropathic 4 Questions (DN4) questionnaire [13]. The DN4 includes sensory descriptors and signs associated with bedside sensory examination [14]. Patients with DN4 scores equal to or higher than four were considered to have neuropathic pain.
The Turkish-validated form of the Barthel index (BI) was used to evaluate functional independence [15]. The BI is used to assess the subject’s functional ability to carry out activities of daily living (ADLs). This index includes ten items related to mobility that make up the ADLs: bathing, dressing, feeding, grooming, transfers from bed to chair and back, toilet use, bladder and bowel control, mobility, and stair climbing. Each item is assigned a score of 0, 5, 10, or 15 based on the individual’s capability to carry out the activity. The total score ranges from 0 to 100 points.
The Charlson comorbidity index was utilized to assess general comorbid conditions [16]. This index considers both the number and severity of comorbid conditions. Each of the following conditions is assigned a score of “1”: congestive heart failure, myocardial infarction, chronic pulmonary disease, peripheral vascular disease, dementia, ulcer disease, connective tissue disease, mild liver disease, and diabetes. Hemiplegia, moderate to severe renal disease, tumors, diabetes with end-stage organ damage, lymphoma, and leukemia are each given a score of “2”. Moderate to severe liver diseases are scored as “3”, and AIDS and metastatic solid tumors are each scored as “6”.
Statistical Analysis
Initially, all data were classified as continuous and categorical variables. Percentages of categorical data were determined. Distribution characteristics of continuous variables were determined [(median, standard error, mean, standard deviation, and 25%-75% interquartile range (IQR)]. The Mann-Whitney U test was used to determine whether a statistically significant difference existed for continuous variables that were not normally distributed. The χ2 test was used for categorical comparisons. The Student’s t-test was used to compare normally distributed continuous variables. P value < 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS version 25.0 software (SPSS Inc., Chicago, IL, USA).
Ethical Approval
This study was performed in accordance with the tenets of the Declaration of Helsinki, and ethical approval was obtained from the local committee.This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2022-10-26, No: E2-22-2660).
Results
A total of 69 geriatric patients with SCI were enrolled in this study. The study group comprised 28 (40.6%) women and 41 (59.4%) men with a mean age of 70±4 years. The mean time since injury was 36±54 months.
The majority of patients participating in the study were married (78.3%). Only 2 (2.9%) of the patients did not need a caregiver, and the primary caregiver for nearly half of the participants (49.3%) was their wife/husband. More than half of the patients only had primary school education (69.6%). The most common cause of SCI was falls (29%), followed by spinal stenosis and discopathies (21.7%). From the total number of patients, 72.5% had paraplegia, 27.5% had tetraplegia, 84.1% had incomplete lesions, and 15.9% had complete lesions. Further, 60.9% of patients had urinary incontinence, with 17.4% of them using intermittent urinary catheters and nearly half (44.9%) using permanent urinary catheters. Additionally, 44.9% of patients had fecal incontinence, 11.6% had a decubitus ulcer, and 79.7% had neuropathic pain. Patients’ mean Charlson comorbidity scores and Barthel index scores were 4±1 and 43±22, respectively. More than 90% of the patients experienced sleep disturbances, and 20.1% were found to have moderate or definite depression. Patients’ demographic and clinical characteristics are presented in Table 1.
There were no differences between participants with and without depression in terms of age, gender, education status, mean time since injury, impairment status, completeness of SCI, presence of urinary incontinence, presence of fecal incontinence, presence of decubitus ulcer, presence of neuropathic pain, mean Charlson comorbidity index score, and mean Barthel index score (p=0.808, p=0.597, p=0.409, p=0.534, p=0.262, p=0.614, p=0.339, p=1.000, p=1.000, p=0.230, p=0.784, p=0.849, respectively). All patients with depression were married, and 72.7% of patients without depression were married (p=0.036). Patients with depression had significantly higher PSQI scores and Epworth Sleepiness Scores (p= 0.001, p= 0.005). All patients with depression had sleep disturbances, and 90.9% of patients without depression also had sleep disturbances. However, the difference between the two groups was not statistically significant (p=0.590). Table 2 shows a comparison of patients with and without depression.
There were no differences between participants with and without sleep disturbance in terms of age, gender, marital status, impairment status, completeness of injury, presence of urinary incontinence, presence of fecal incontinence, presence of decubitus ulcer, mean Charlson comorbidity index score and mean Barthel index score (p=0.909, p=0.389, p=0.277, p=0.611, p=0.177, p=1.000, p= 0.370, p=0.471, p=0.229, p=332, respectively). Patients with sleep disturbance had significantly lower education levels and significantly higher frequency of neuropathic pain (p=0.001, p=0.005). Also, GDS scores and ESS scores were significantly higher in patients with sleep disturbance than in patients without sleep disturbance (p=0.002, p<0.001). None of the patients without sleep disturbance had depression, and 21.9% of the patients with sleep disturbance had depression. However, such a difference did not reach statistical significance (p=0.575). Table 3 shows a comparison of patients with and without sleep disturbance.
Discussion
In our study, over 90% of patients had sleep disturbance, and 21.4% had moderate or definite depression. Patients with depression had higher PSQI scores, and patients with sleep disturbance had higher GDS scores. Both patients with depression and patients with sleep disturbance had significantly higher ESS scores. Patients with sleep disturbance had a significantly higher frequency of neuropathic pain.
Many people with SCI live to an advanced age. A thorough understanding of the factors associated with healthy aging is therefore essential. As mental health is a critical component of healthy aging, the psychological challenges associated with living with SCI in the geriatric population warrant greater attention.
Depression is a prevalent psychological condition in the geriatric population, and the likelihood of developing this condition has been shown to rise following SCI [3, 7, 17]. In our study, 20.1% of geriatric patients with SCI had depression. Depressive symptoms following SCI are thought to be more closely associated with psychological factors and behaviors than with socio-demographic elements such as age and gender or with injury specifics such as the level and severity of injury [18, 19]. In line with these findings, in our study, depression was not associated with age, gender, cause of SCI, education status, time since injury, impairment status, comorbidities, and functional independence.
In contrast to previous studies, depression was more common among geriatric married patients with SCI than single ones [2, 19]. Further, in nearly 50% of the cases, the primary caregiver was the patient’s husband/wife. Patients may have more difficulties in adjusting to a life with disabilities due to the thought of being a burden for their spouse, which may, in turn, lead to depression.
In our study, we found that higher scores on the daytime sleepiness scale and higher scores in PSQI were associated with depression. Similarly, in a study investigating depressive symptoms among older adults with SCI, psychological resources, pain, and participation in physical activity were the strongest explanatory factors for depressive symptoms [2]. Depression, increased daytime sleepiness, and sleep disturbances all negatively affect quality of life and rehabilitation outcomes. Overall, all these results imply that mental health among geriatric patients with SCI should be supported through rehabilitation that strengthens their ability to manage life stressors, provides pain management, encourages participation, and promotes acceptance of the injury in social life and physical activity.
Sleep disturbance is another common but usually underdiagnosed comorbidity in SCI. In a study published in Turkey, 74.7% of the patients with SCI had subjective sleep disturbances [20]. Conti et al. reported that 43.8% of the patients with SCI had poor sleep quality [4]. Both studies used PSQI to detect sleep disturbance. In this study, we used the same scale for the detection of sleep disturbance, although in our case, only geriatric patients with SCI were included. The frequency of sleep disturbance was very high in our study. This outcome may be due to the higher incidence of sleep disturbances in older adults, as aging is linked to a rise in psychosocial factors impacting sleep, multimorbidity, polypharmacy, and specific primary sleep disorders [10, 21].
Sleep disturbance was not associated with age, gender, cause of SCI, marital status, time since injury, higher comorbidities, and functional independence in our study. Similarly, in the study by Aydın et al., sleep disturbance was not associated with age, gender, time since injury, and functional independence [20]. Indeed, in our study, the only demographic factor affecting sleep disturbance was education status. Patients with higher education status had less sleep disturbance. This may be because this group of patients can develop stronger disease coping strategies and, therefore, can also have better sleep quality.
In our study, paraplegic and tetraplegic patients had a similar frequency of sleep disturbance. Sankari et al. reported more severe sleep-disordered breathing in tetraplegic patients compared with paraplegics [1]. Tetraplegic patients, especially those with diaphragmatic dysfunction, may be at risk of nocturnal hypoxia. However, in two studies assessing general sleep quality with PSQI, sleep disturbance was more common in tetraplegics in one study and paraplegics in another study [20, 22]. Participants in our study had a very high frequency of sleep disturbance independent of impairment status. Underlying problems like comorbid diseases and physiological changes in aging, such as a decrease in total sleep time, fragmented sleep, reduction in stage 3 non-rapid eye movement phase, change in circadian phase, and increased daytime naps may have contributed to our results [23].
In our study, higher GDS and neuropathic pain scores were associated with sleep disturbance, which is in line with previous literature [24]. Also, patients with sleep disturbance had higher daytime sleepiness. In a USA-based study, late-life anxiety and depression were found to be associated with subjective sleep disturbance in older adults. The findings of this study suggest that subjective assessments of sleep quality and daytime sleepiness are more indicative of subthreshold psychiatric symptoms than objective sleep biomarkers [25]. Sufficient and refreshing sleep is important for good health, physical and cognitive. Thus, we believe that all these pathologies should be together evaluated and treated in rehabilitation settings. Sleep disturbance in geriatric patients with SCI is a multifactorial health condition, necessitating a multi-faceted treatment approach.
Strengths
To our knowledge, this is the first research that simultaneously assesses depression, sleep quality, and related factors in geriatric patients with SCI. We included geriatric patients with SCI, an under-represented group in rehabilitation research. Patients were selected carefully using strict exclusion criteria to create a homogenous study group. The study’s general findings and results may be helpful for health professionals working with geriatric patients with SCI and could provide insights for future research.
Limitation
This study has several limitations. Firstly, the study’s cross-sectional design did not permit the evaluation of the temporal relationship between variables. Secondly, subjective data may be self-reported. Finally, some limitations may have been caused by the potential for confounding factors that were not controlled.
Conclusion
Our study gives important clues for a general approach to geriatric patients with SCI. Both depression and sleep disturbances are common and treatable disorders that negatively affect the healthy aging of geriatric patients with SCI. Thus, these comorbidities should be routinely screened and treated when detected. SCI research includes mostly younger and middle-aged persons, and there is a great need for new studies investigating psychosocial problems and associated factors in geriatric patients with SCI.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Gul Mete Civelek, Handan Elif Nur Bayraktar, Zeynep Keskin. Evaluation of depression and sleep quality in geriatric patients with spinal cord injury. Ann Clin Anal Med 2024;15(12):881-887
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A bibliometric analysis of gut microbiota and thyroid cancer studies: Global trends, research gaps, and future directions
Zeliha Aydın Kasap 1, Ahmet Akbaş 2
1 Department of Biostatistics and Medical Informatics, 2 Department of General Surgery, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
DOI: 10.4328/ACAM.22448 Received: 2024-10-11 Accepted: 2024-11-11 Published Online: 2024-11-20 Printed: 2024-12-01 Ann Clin Anal Med 2024;15(12):888-892
Corresponding Author: Zeliha Aydın Kasap, Department of Biostatistics and Medical Informatics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. E-mail: zelihaaydin86@gmail.com P: +90 535 626 25 92 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5823-100X
Other Authors ORCID ID: Ahmet Akbaş, https://orcid.org/0000-0002-6333-4919
Aim: Thyroid cancer is one of the most prevalent cancers in the World. Although previous bibliometric studies have explored the role of gut microbes in various cancers, none have specifically focused on thyroid cancer. This study aimed to identify research trends and key topics in the relationship between gut microbiota and thyroid cancer.
Material and Methods: Publications published from 2007 to 2024 were retrieved from the Web of Science Core Collection database and screened based on the inclusion criteria. The VOSviewer software was used to analyze publication trends by country, institution, author, citation counts, and journal.
Results: A total of 429 studies were selected from the 417,039 studies identified between 2007 and 2024. The number of publications has increased steadily and will peak by 2023. These studies received 10,079 citations, averaging 592.88 citations per year. Frontiers in Endocrinology were the most productive journals. China had the highest citation count (831). Key research hotspots included “gut microbiota,” “thyroid cancer,” “inflammation,” and “selenium.” China and Italy were central in cooperative networks, with Tongji and Peking University being the most productive institutions. The most prolific authors are Jiang Wen, Lv Zhongwei, and Gao Dingwei.
Discussion: Research on the link between gut microbiota and thyroid cancer has grown significantly over the past two decades, with China and the USA leading. Strengthening institutional collaborations and focusing on emerging topics like “bacteria” and “Hashimoto’s thyroiditis” is recommended for future research.
Keywords: Gut Microbiota, Microbiome, Thyroid Cancer, Bibliometric Analysis
Introduction
The International Agency for Research on Cancer (IARC), affiliated with the World Health Organization, published World Cancer Statistics on February 8, 2022. According to the Globocan 2022 database, accessible through IARC, China ranks 1st (24.6%), the Republic of Korea 2nd (23.2%), and Tükiye 3rd (15.6%) in thyroid cancer worldwide (available at: https://gco.iarc.fr/en)
Our country, Türkiye, is endemic to thyroid diseases, particularly along the Black Sea coast, where genetic factors, iodine deficiency, and the Chornobyl disaster have played significant roles. Currently, thyroid nodules are found in approximately 50-60% of the population, and follow-up criteria are typically based on patient history, thyroid hormone levels, ultrasound characteristics, and biopsy results [1].
The gut microbiota composition refers to the diversity and balance of millions of microorganisms (bacteria, viruses, fungi, and other microbes) in the intestine. These microorganisms form the microbiota ecosystem in the body and play an important role in digestion-nutrient absorption, immune system regulation, protection against diseases, brain-gut axis relationship, metabolic health, inflammation, autoimmunity, and chronic disease formation [2].
The human microbiota comprises trillions of microbes, and the relationship between cancer and the microbiota is very complex [3]. Microbiota refers to collective microbial communities that live in specific environments, including bacteria, fungi, viruses, and protozoa [4]. With the evolution of technologies such as cell culture, metagenomics, and metabolomics, increasing evidence over the past two decades has shown that gut microbiota is crucial for host metabolic health and immune homeostasis [4, 5].
Evidence has shown that gut microbiota is closely associated with thyroid cancer [6]. Bibliometric analysis is a statistical method based on public literature databases (e.g., Web of Science) that is used to analyze and visualize research trends [7].
Bibliometric analysis has become one of the most widely used methods for assessing the credibility, quality, and impact of scholarly works [8, 9]. A large number of publications on microbiota and thyroid cancer have been published in recent years; however, no systematic studies have been conducted through bibliometric econometric analysis of the association between gut microbiota and thyroid cancer analysis has not been systematically studied. This bibliometric analysis can help researchers to understand the current research situation, trends, and hotspots in this field. In this study, we aimed to uncover emerging trends in articles, journals, keyword performance, and collaboration patterns between authors and institutions, and to explore hot research topics and future directions in the field of microbiota and thyroid cancer through a bibliometric analysis.
Material and Methods
Data sources
Ethical approval was not required for this study because it did not involve human or animal participants. In this study, we used the Web of Science Core Collection (WoSCC) database. This database was selected because it is the friendliest and easiest tool for bibliometric research and, contains numerous noteworthy and high-quality journals and thorough citation index records [10, 11].
Search strategy
All potentially relevant publications were collected based on title (TI) and topic (TS). The search strategy was as follows.
#1: (TI=(thyroid* OR thyroid cancer* OR thyroid nodule*) ) AND (TI=(gut microbiota* OR microbiome* OR * microbiota*)) ;
#2: (TS=(thyroid* OR thyroid cancer* OR thyroid nodule*) ) AND (TS=(gut microbiota* OR microbiome* OR * microbiota*))
Final : #1 OR #2
To capture as many data sources as possible, we use wildcards (*) that can replace any other character and allow keywords with variable endings [12, 13]. For example, “nodule*” would also return the terms of “nodule” and “nodules.” nodules. The search articles were published in all the languages between 2007 and 2024.
Study selection
The selection criteria for this study are shown with a flowchart of the WOS screening process in Figure A1 in the Appendix. Briefly, we entered search terms for an initial search, and then excluded those that did not fit according to the following inclusion criteria: (1) the types of literature included types of articles, but not letters, comments, reviews, or conference abstracts; (3) the publication was from the WoSCC databases; (4) the search period was from 2007 to 2024. (5) For the selected publication, the subjects of the publication were patients with thyroid cancer and thyroid nodules, and the studies must also assess the correlation between subjects and gut microbiota. (6) To avoid bias due to daily updates of the database, we conducted and completed the search and screening of publications on the same day.
Data collection
All included publications were reviewed, and the studies were downloaded and exported in plain text file formats in WOSCC for analysis. The following indicators were extracted from the studies: the number of publications, citation frequency, country, institution, journal, author, and keywords.
Data analysis
The data were first evaluated using the results section of the WOS database. Descriptive statistics and treemap charts of the data were obtained. The data were exported in plain text format within the scope of query operators. The obtained data were imported into the VOSviewer software.
VOSviewer (version 1.6.17) was used to create, visualize, and explore a collaborative network map of countries, journals, and authors, with each point representing a country/region, institution, or author; the number of publications determining the size of the point; and the number of collaborations determining the strength of the links between the points.
Results
Analysis of publications, citation trends, and productive journals
A total of 417,039 records from January 1, 2007, to October 7, 2024, were identified. First, 261,787 records were included because the literature included studies on thyroid cancer. After adding “gut microbiota”, the remaining 429 records were further assessed by topic reading. Finally, 429 studies that met the inclusion criteria were included in the bibliometric analysis (Figure A1). The number of annual and cumulative publications has significantly increased over the past 17 years. The number of publications peaked by 2023 (157). The distribution of publications by year is shown in Figure A2 in Appendix.
The number of citations has gradually increased from 2007 to 2024. The number of citations has increased since 2017. By 2023, it is expected to reach a high value (2,644 citations). A total of 429 articles were cited 10,079 times, and the average number of citations per year was 592,88. Of these studies, 279 (65.03%) were categorized as articles, 142 (%33.10) as review articles, and the remainder as other articles. The top ten leading journals in the field of microbiota and thyroid cancer research between 2007-2024 are shown in Table 1.
The most productive journal was Frontiers in Endocrinology (183 citations), followed by Nutrients (176), and Reviews of Endocrine and Metabolic Disorders (92). However, it ranked 10th in the number of most cited journals. These findings suggest that the relationship between microbiota and thyroid cancer has drawn increasing attention in recent years and that future research in this area may become a global hotspot.
Countries/regions analysis
63 countries/regions have published studies on the microbiota and thyroid cancer. The top 10 most productive countries are shown in Figure A3 using the treemap in Appendix. China ranked first with 168 articles, followed by the US (80), Italy (51), and Poland (17). China had the highest citation rate (831), followed by the USA (258) and Italy (219).
Among the 108 countries in the network, China and Italy are the most central and stand out as two countries with the strongest connections. Italy has established limited strong collaborations with the USA, Portugal, and Germany in this field. The results are shown in Figure 1.
Contribution of institutions and authors
This study evaluates the most productive universities and institutions. Tongji University contributed the most articles (5), followed by Sapienza University Rome (3), and other institutions. In addition, Peking University had the highest total number of citations (205), followed by Tianjin University (179) and other institutions. The institution with the highest total link strength (8) was obtained from Shandong University. The largest set of connected items consists of 11 items, and institutions are classified into three groups marked with different colors. The results are shown in Figure 2.
In the present study, we evaluated the most productive authors. Jiang.Wen and Lv. Zongwei was the most productive author, with five publications, followed by Li.dan (4) and Yu. Xiaqing (4). Pang. Yanlı, Qi. Xinyu, and Qiao. Jie had the highest total number of citations (205), whereas Jiangxi had the highest total link strength. Wen and Lv. Zhongwie (39). Co-authorship analysis was performed using the VOSviewer software. A total of 345 authors and four major collaborations were included. Jiang. Wen was the most productive author, and Lv.zhongwei, Gao.Dingwei, Luo.giong and Li.dan had strong influences. The collaboration of authors and co-cited authors is shown in Figure A4. In Figure A4, (a) represents the cooperation network among the co-cited authors, and (b) shows the VOSviewer density visualization of the co-cited authors, where dots represent authors (larger dots indicate a higher number of publications), clusters are marked with different colors, and links illustrate cooperation between authors.
Keywords visualization
Keyword co-occurrence analysis examines the co-occurrence relationships between keywords that reflect the prominent topics in a specific publication group. In this study, 429 studies that met the inclusion criteria were exported as plain text files from the WOS database, and keyword analysis was performed using VOSviewer with a threshold value of 18. A total of 346 keywords were identified after combining the duplicate and synonymous keywords. As shown in Figure 3, “gut microbiota” and “thyroid cancer” were the most prominent keywords. All keywords were divided into four main clusters: the relationship between gut microbiota and thyroid cancers, gut microbial, bacteria, and dysbiosis. These clusters reveal the most dominant research themes in this field.
Discussion
Studies have shown that gut microbiota dysfunction is closely associated with thyroid cancer, resulting in an increasing number of studies investigating the relationship between the gut microbiome and thyroid cancer over the past two decades. However, no bibliometric analysis has been conducted in this field.
This study focused on the gut microbiota and thyroid cancer findings by screening eligible studies and analyzing 429 studies published in the Web of Science database from 2007 to 2024.
This study showed that 2023 was a significant year in the field of microbiota and thyroid cancer research, with a significant increase in annual publications and total citations. The temporal trends in total citations are broadly in line with the number of annual publications, peaking in 2023 and declining over the last year because of proximity to the time of data collection.
Influential countries, governments, authors, and journals in this field were analyzed. China and the USA are the two main publishing countries in this field, accounting for 57.8% of all the research. China is the most productive country and publishes the majority of its articles. The disparity in this domain may be due to the following reasons. First, considering China’s large land area and population, there are many research institutions, resulting in a high volume of publications. Most importantly, China ranks 1st in the world in terms of the incidence of thyroid cancer [5, 14].
Thyroid cancer and, “thyroid cancer” and “intestinal microbiota” were the most prominent keywords. Additionally, “bacteria”, “inflammation”, and “Hashimoto’s thyroiditis” are the latest hotspots.
In recent years, studies have increasingly highlighted the significance of microbiota in various diseases. Numerous studies have demonstrated its association with several types of cancer, including colorectal, gastric, and pancreatic cancers, as well as conditions such as rheumatoid arthritis, malnutrition, Parkinson’s disease, and liver cirrhosis. A review of bibliometric analysis studies revealed that while there are numerous analyses exploring the relationship between microbiota and nearly all types of cancer, no bibliometric study specifically examining the link between microbiota and thyroid cancers has been identified in the literature [15-18]. One of the advantages of this study is that it fills the scientific gap.
The WoSCC database is constantly and dynamically updated and provides effective and reliable information [19-20]. In this study, a bibliometric analysis was performed to determine global trends and topics that had not yet been examined in light of data obtained from the WoSCC database, which contains high-quality literature information [21]. Publications were obtained solely by searching the WoSCC database using specific query operators, which may have resulted in an over-representation of studies from English-speaking countries. Additionally, keyword analysis depends on indexed keywords, potentially leading to inaccurate subject representations. This might also hinder the investigation of the possible links between changes in population rates and variations in thyroid cancer prevalence across different countries. This can be considered as a limitation of the present study. Despite these limitations, this study provides a comprehensive review of research on the relationship between thyroid cancer and the microbiota, while identifying key trends for future research.
This study analyzed the relationship between the microbiota and thyroid cancer; however, this relationship should be further investigated in the context of causality. Future studies should be supported by laboratory and clinical studies to elucidate the biological mechanisms underlying this relationship. Future studies can also compare the relationship between microbiota and thyroid cancer in different geographic regions and ethnic groups, which could help to understand better the regional differences in the prevalence of thyroid cancer and provide a clearer picture of global trends. Multidisciplinary studies that integrate genomic and metabolomic data can be conducted to better understand the relationship between the microbiota and cancer. In this way, how microbiota contributes to cancer development at the molecular level can be examined in more detail.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22448.pdf
Zeliha Aydın Kasap, Ahmet Akbaş. A bibliometric analysis of gut microbiota and thyroid cancer studies: Global trends, research gaps, and future directions. Ann Clin Anal Med 2024;15(12):888-892
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