2025 May
Assessing kidney and collecting system in patients with ureter stone with statistical shape analysis
Mustafa Çağatay Büyükuysal 1, Engin Denizhan Demirkıran 2, Gökhan Ocakoğlu 3
1 Department of Biostatistics, Faculty of Medicine, Bülent Ecevit University, Zonguldak, 2 Department of Urology, Faculty of Medicine, Bülent Ecevit University, Zonguldak, 3 Department of Biostatistics, Faculty of Medicine, Uludağ University, Bursa, Turkiye
DOI: 10.4328/ACAM.22002 Received: 2023-10-17 Accepted: 2024-09-02 Published Online: 2024-12-12 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):315-319
Corresponding Author: Mustafa Çağatay Büyükuysal, Department of Biostatistics, Faculty of Medicine, Bülent Ecevit University, Zonguldak, Turkiye. E-mail: cbuyukuysal@gmail.com P: +90 555 625 00 55 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9810-5633
Other Authors ORCID ID: Engin Denizhan Demirkiran, https://orcid.org/0000-0002-0021-5402 . Gökhan Ocakoğlu, https://orcid.org/ 0000-0002-1114-605
This study was approved by the Ethics Committee of Zonguldak Bulent Ecevit University (Date: 2020-07-08, No: 2020/14-11)
Aim: Despite semi-rigid ureteroscopy being the standard treatment for ureteral stones, it is hard to understand whether the treatment has reached success mainly in an early period. It This study aimed to investigate the shape differences in the CT images of kidneys and collecting systems compared between preoperative and postoperative periods.terms.
Material and Methods: Kidney and collecting system CT images for both terms were evaluated with statistical shape analysis to detect any morphological changes.
Results: High levels of kidney deformations were observed at the medial point of the superior segment and the extremitas superior. For the collecting system, a high level of deformation was is seen in the area around the hilum renal inferior. The two periods have no significant shape difference between the kidney and the collecting system.
Discussion: The most significant aspect of this study is the quantitative quantitatively demonstration, for the first time, of the shrinking observed in the kidney and collecting systems following treatment for ureteral stones. Our method gives objective and qualitative results by making appropriate landmarks landmarking on the CT image by a physician familiar with the renal anatomy. This new method can be used to follow up stone-induced obstruction due to its ease of application and objective results
Keywords: Collecting System, Kidney, Statistical Shape Analysis
Introduction
Semi-rigid ureteroscopy is the standard treatment for ureteral stones. Although it is known as the most effective treatment method for patients with ureteral stones, it is hard to understand whether the treatment has reached success, mainly in an early period. Ureteral stone patients account for about 70% of those treated for stone disease [1]. In the management process of the patients with ureteral stone, the aim is to protect the kidney from possible morbidities and make the collecting system stone-free. Hydronephrosis is seen in 92-94% of the patients with ureteral stones [2]. When the obstructing ureter stone occurs, it first causes the collecting system pressure to increase and causes dilatation of the renal pelvis and calyces and stretching of the renal capsule. Peristalsis is subsequently disrupted, and collecting system pressure increases further, resulting in renal failure. Dilatation in the collecting system and blunting of the papillary tips are present 42 hours after the onset of obstruction [3]. The kidney size expands and shows a cystic appearance compared to the normal opposite side kidney after 6 weeks of obstruction [4]. Drainage can be provided temporarily by percutaneous nephrostomy or ureteral stents that are similar in effect and complication [5]. However, the primary treatment is to eliminate the cause of obstruction. Delay of drainage can lead to fever, infection, and renal failure. Studies have shown that one-third of patients with unilateral stone-induced obstruction lasting more than 4 weeks have irreversible renal injury [6].
The severity of obstruction is a determines determinant of both kidney function loss and stone management [3, 7]. After hydronephrosis has been is eliminated, the damage progression is prevented, and the kidney starts to function again. Therefore, even if there are is no signs of pain or infection, hydronephrosis must be treated [7].
It is generally accepted that hydronephrosis regresses and kidney size decreases after ureteral stone treatment. Hydronephrosis regression and kidney shrinkage may indicate be used as an indicator of the resolution of the obstruction after adequate treatment. With the decline in hydronephrosis, it is evident can be seen that the patient is steering clear of progressive kidney damage caused by obstruction. However, this decline has been demonstrated using the grading systems described in the imaging methods. Moreover, to the best of our knowledge the results have yet to be demonstrated quantitatively. to the best of our knowledge. We believe think the decrease in hydronephrosis and kidney sizes should be demonstrated objectively and quantitatively after ureteral stone treatment.
Many studies in the field of medicine consider the geometrical properties of organs or organisms, by taking its geometrical properties into and morphometric methods are frequently preferred for examining the structures and geometrical properties of organ-related diseases [8, 9, 10, 11]. Morphometric studies have been performed on kidneys, but modeling is mainly aimed at applying segmentation to various imaging methods [12, 13, 14]. Studies have been carried out on with the morphometric character of the kidney tumor or infundibulopelvic angle calculation to decide the treatment method for the tumors or lower pole stones [15, 16]. Studies using statistical shape analysis are new to the literature, and the only study with kidney shape probabilistic occupant models belongs to Yates and colleagues [17].
Along with the advances in imaging technology and software that enables this technology to be integrated into medicine, geometric change in the shape of the organ or structure of interest can be analyzed using key points called landmark, which have anatomical significance. It is possible to work with geometric shapes by taking the coordinates of the landmarks as the variables in the figure from the measurements taken from the organisms. Statistical shape analysis is a modern geometric morphometric method that uses the shape of organs or organisms as input data [18]. Statistical shape analysis also stands out as an auxiliary tool that allows the interpretation of structural differentiation in the relevant organ, by considering the changes in shape.
We hypothesized that the collecting system and kidney sizes shrank shrink after ureteral stone treatment and that this shrinkage could be shown quantitatively with landmark-based geometric analysis. In this study, we aimed to compare similar areas in at CT images taken from the pre- and post-operated patients with ureterolithiasis and thus to show whether there is a significant decline as expected.
Material and Methods
This study used the coronal abdominal CT scans of 17 (12 male, 5 female) patients with ureteral stones with a mean age of 69.2 ± 6.9. Six of the 17 patients’ CT scans were of the right and 11 were of the left kidney. The non-contrast CT scans of patients admitted to the Zonguldak Ataturk State Hospital Urology Clinic were evaluated retrospectively between from December 2019 to and March 2020. Patients who underwent semirigid ureterorenoscopy due to proximal ureteral stones were selected. separated. Only completely stone-free patients without any ureteral catheter after semirigid URS were included in the study. Among patients whose images could be accessed, those patients with anatomic renal malformations, previous kidney surgery, and accompanying kidney stones were excluded. The same surgeon operated on all patients after they received receiving general anesthesia. Then, a 9.5Fr semi-rigid ureteroscope [Karl Storz, Tuttlingen, Germany] and a Holmium YAG laser [SphinX 30 litho, holmium-YAG laser, LISA Laser Products–GmbH, Germany] were was used in the lithotomy position. A gGrasping forceps were was used for extracting fragments. Non-contrast CT scans were obtained one month before surgery and on the 30th day postoperatively. All CT imaging examinations were performed on a 16-slice SOMATOM Sensation CT scanner [Siemens AG, Forchheim, Germany].
Ethical Approval
This study was approved by the Ethics Committee of Zonguldak Bulent Ecevit University (Date: 2020-07-08, No: 2020/14-11).
Collection of Two-Dimensional Landmarks
Data of the regions marked in the kidney and collecting system were collected from two-dimensional digital
images. In each image, markings were made in the middle section of the kidney in the coronal plane. Thirteen landmarks for the kidney and ten landmarks for the collecting system [Table 1] were considered from the image corresponding to the coronal plane and marked using TPSDIG version 2.04 software. The landmarks were chosen based on reliability and anatomical coverage to maximize the description of the kidney and collecting system. description. Mirror images of six right kidney images were taken and analyzed on the same plane.
Geometric Morphometric Analysis
Statistical Shape Analysis: Statistical shape analysis of the pre- and post-treatment kidney and collecting system images of 17 patients was performed. The Generalized Procrustes analysis was used to obtained the mean kidney and collecting system shapes in pre- and post-treatment phases and the related tangent coordinates. Procrustes analysis is the an approach that obtains the minimum sum of squared differences between the landmarks [19]. Principal coordinate analysis (PCoA), a type kind of ordination method also known as metric multidimensional scaling, was applied to tangent coordinates derived from the Procrustes analysis. The PCoA routine finds the eigenvalues and eigenvectors of a matrix containing the distances or similarities between all landmark points. Euclidean distance is used in PCoA. The Eigenvalues were computed to measure the variance accounted for by the corresponding eigenvectors (coordinates). The percentages of variance accounted for by these components were are also reported. After that, the classification and changes of patients were examined for pre-treatment and post-treatment time points using PCoA. The shape deformation of the kidney and collecting system from the pre- to post-treatment phases was evaluated using the thin plate spline (TPS) method, derived from a mathematical model used in computer graphics and applied to morphometrics by Bookstein [20]. The points exhibiting the greatest enlargements or reductions, labeled as deformations were established through the TPS analysis.
General Statistical Analysis: Data regarding sex are presented as frequency (%), and those data for age are presented as mean and standard deviation values. For statistical analysis, R 3.5.1, PAST 3.0 and SPSS 21 softwares were used.
Results
Figure 1 shows the combined Procrustes mean shapes for the kidney and collecting system.
Procrustes mean shapes (Figure 2a) were obtained as a result of landmark markings from pre- and post-treatment periods of the kidney. PCoA was applied to the tangent coordinates obtained after the Procrustes analysis. PCoA of the preop and postop terms showed a variance explanation rate for the first two coordinates (45.70% and 15.30%, respectively) considered in the study group of 61% (Figure 2b). The convex hulls on the scatterplot indicate that the patients did not significantly differ in the pre- and post-treatment periods. TPS analysis was also performed using mean shapes obtained from the Procrustes analysis. The A high level of deformations for in the kidney from pre- to post-treatment term observed in the TPS graphic (Figure 2c). When the figure is examined, it is seen that in the area including the most medial point of the superior segment (Landmark 2) and extremitas superior (Landmark 3), an expansion occurred in the post-treatment period compared to the pre-treatment period. In addition to this, while the general shape of the kidney is determined to be have shrunk compared to the preoperative period, except for the area of landmarks 2 and 3, it is seen that the region where the shrinkage is observed at the highest level occurs in the region including the middle of the 9th and 11th points (Landmark 10) and extremitas inferior (Landmark 11).
Procrustes mean shapes (Figure 3a) were obtained as a result of landmark markings from the pre-treatment and post-treatment periods of the collecting system. PCoA was applied to the tangent coordinates obtained after the Procrustes analysis. PCoA of the preop and postop terms showed a variance explanation rate for the first two coordinates (43.15% and 20.56%) considered in the study group of 63.71% (Figure 3b). The convex hulls on the scatterplot indicate that the patients did not significantly differ in the pre-treatment and post-treatment periods.
TPS analysis was also performed using mean shapes obtained from the Procrustes analysis. The A high level of deformation in for the collecting system from pre-treatment to post-treatment term was observed in the TPS graphic (Figure 3c). When the figure is examined, it is seen that in the area around the hilum renale inferior (Landmark 10), an expansion occurred in the post-treatment period compared to the pre-treatment period. In addition to this, while the general shape of the collecting system is determined to have be shrunk compared to the preoperative period, except for the area around landmark 10, it is seen that the region where the shrinkage is observed at the highest level occurs in the regions mainly including inferolateral part of the collecting system as hilum renale superior (Landmark 1) and superior fornix of superior calyx group (Landmark 2), superior fornix of middle calyx group (Landmark 5) and inferior fornix of middle calyx group (Landmark 6), infundibular junction point of middle and inferior calyx groups (Landmark 7) and superior fornix of inferior calyx group (Landmark 8), superior fornix of inferior calyx group (Landmark 8) and inferior fornix of inferior calyx group (Landmark 9).
Discussion
In this study, we have shown for the first time, that the size of the kidney and collecting system shrank quantitatively after ureteral stone treatment. In addition to the general changes, the landmark-based shape analysis approach showed us the changes on a regional basis. Although there is no statistical difference between the mean shapes before and after the treatment, kidney and collecting system shrinkage were was demonstrated in the deformation graphs. As a result of both analyses, it was found that the kidney showed the most significant change in the inferomedial part after the obstruction resolved. In addition to the general shrinkage in the figures, a slight expansion was found in the superomedial part of the kidney and the hilum renal area of the collecting system. It is noteworthy that the area in where which the enlargement is detected in the kidney is closest to the section of the collecting system that shows the most shrinkage, and the area where the enlargement in the collecting system is located is the region where the kidney shows the most shrinkage. These expansion areas may have appeared secondary to the deformation caused by the intense shrinkage regions.
The kidney is surrounded by the Gerota’s fascia like a natural anatomic barrier, which keeps the kidney immobilized and prevents the spread of perirenal fluid, hematoma, or infection. This fascia envelops the kidney from all sides except the inferior part. The two fascia leaves do not conjunct at the lower part of the kidney, which where remains are uncovered [21]. The most shrinking areas of the kidney and collecting system that shrink the most are located in the inferior part due to the anatomy of the Gerota’s fascia, which that does not cover the lower kidney.
Conclusion
As far as we know, no studies in the literature focus on kidney size after ureteroscopy. The change in collecting system dimensions after ureteroscopy has been revealed before. However, it has yet to be demonstrated using a as landmark-based or quantitative approach. quantitatively. Sarıca et al. showed that hydronephrosis levels decreased in patients operated on for ureteral stones. However, they only compared this to the degree of hydronephrosis [22]. After ureteroscopy, Chen et al. showed that hydronephrosis regressed in groups with and without DJ stent. They also classified made classification patients as having hydronephrosis and no hydronephrosis [23]. The results of both studies are presented given subjectively. Furthermore, unlike our study, Tahanaj M. et. al. studied on association of kidney shapes with via disease and anthropometric factors and found that kidney shape has a statistically significant association with chronic kidney disease, type-2 diabetes and hypertension [24]. Our method gives objective and qualitative results by making appropriate landmarks landmarking on the CT image by a physician familiar with the renal anatomy. This new method can be used to follow up on stone-induced obstruction due to its ease of application and objective results.
Limitation
Our study has some limitations. Firstly, the retrospective structure of the study and the low number of cases evaluated were significant drawbacks. Furthermore, the anatomical shape differences between the kidneys on both sides were not considered when mirroring the images. In studies to be conducted with more cases, the difference in mean shapes can be reported more significantly. This study showed shrinkage in the kidney and collecting system after ureteral stone treatment. To the best of our knowledge, this is the first study to show that pre- and post-treatment kidney and collecting system shapes of patients with ureteral stones can be compared using the landmark-based geometric morphometric method by considering the topographic distribution. We hope that the results obtained from this study will serve as a guide for to future clinical studies by demonstrating localized variations in the components of the kidney and collecting system.
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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Mustafa Çağatay Büyükuysal, Engin Denizhan Demirkıran, Gökhan Ocakoğlu.Assessing Kidney and Collecting System in Patients with Ureter Stone with Statistical Shape Analysis. Ann Clin Anal Med 2025;16(5):315-319
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An innovative approach: Prompt withdrawal of the drain allows for fistula closure in some prolonged postoperative pancreaticobiliary fistulas
İsmail Hasırcı 1, Mehmet Eşref Ulutaş 2, Gürcan Şimşek 1, Ogün Erşen 3, Adil Kartal 1, Müslim Yurtçu 4, Selman Alkan 5, Kemal Arslan 1
1 Department of General Surgery, University of Health Sciences, Konya City Hospital, Konya, 2 Department of General Surgery, University of Health Sciences, Gaziantep City Hospital, Gaziantep, 3 Department of General Surgery, Ekol Hospital, İzmir, 4 Department of Pediatric Surgery, Meram Selcuk University, Konya, 5 Department of General Surgery, Meram Selcuk University, Konya, Turkey
DOI: 10.4328/ACAM.22185 Received: 2024-03-20 Accepted: 2024-10-03 Published Online: 2024-12-02 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):320-324
Corresponding Author: İsmail Hasırcı, Department of General Surgery, University of Health Sciences, Konya City Hospital, Konya, Turkey. E-mail: drihasirci@hotmail.com P: +90 332 221 00 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8400-3361
Other Authors ORCID ID: Mehmet Eşref Ulutaş, https://orcid.org/0000-0002-9206-4348 . Gürcan Şimşek, https://orcid.org/0000-0003-4087-9331 . Ogün Erşen, https://orcid.org/0000-0001-7213-9122 . Adil Kartal, https://orcid.org/0000-0002-5045-3273 . Müslim Yurtçu, https://orcid.org/0000-0002-7250-6719 . Selman Alkan, https://orcid.org/ 0000-0003-2974-7610 . Kemal Arslan, https://orcid.org/0000-0002-3880-8318
This study was approved by the Ethics Committee of University of Health Sciences, Hamidiye Scientific Research (Date: 2021-11-26, No: 21-695)
Aim: In the literature, there are different approaches to the treatment of postoperative pancreaticobiliary fistulas. In this study, we present our clinical experience, emphasizing that drains can prevent the closure of some fistulas.
Material and Methods: In patients with fistulas, drain flow was monitored until the fistula tract developed. In general, we waited until the 15th day to ensure that the fistula tract fully matured. Then, we promptly removed the drain without replacing or shortening it. The patients were followed up with clinical and imaging methods.
Results: We had a total of 20 patients with pancreaticobiliary fistulas. The mean age of the patients was 44.6 (10-81) years. Fifteen (75%) patients were male, and five (25%) were female. Twelve patients had pancreatic fistulas, and eight had biliary fistulas. Especially in patients with biliary fistulas, we removed the drains according to the criteria we determined. After the drain was removed, no clinically or radiologically negative finding was detected in any of the patients.
Discussion: We consider that our experience based on a limited number of patients will contribute to the literature by presenting the thesis that the drain itself prevents fistula closure in some patients.
Keywords: Biliary Fistula, Drain, Innovative Approach, Pancreatic Fistula, Postoperative Period
Introduction
In general surgery, a fistula is a tract with two mouths that connects two epithelial surfaces and is covered with granulation tissue. There are important issues in the management of patients with fistulas, including the content, duration, and length of fistulas, the surfaces between which the fistula develops, continuous or intermittent functioning of the fistula, flow rate, and whether it develops after surgery. The fistula may contain bile, intestinal content, pus, blood, pancreatic fluid, and lymph fluid. Sometimes only one type of content may come from the fistula, whereas two (bile and pancreatic fluid), three or mixed contents may also come from it [1-3]. Perianal fistulas are beyond the scope of the current study.
Fistulas are surgeons’ nightmare. The conservative closure of fistulas is a time-consuming process. It can be worrying for both the patient and the physician. In general, fistulas first have a period of leakage, followed by a period of fistula formation. Especially in postoperative fistulas, there is usually a drain at the surgical site. In these cases, the emergence, displacement, or obstruction of the drain may lead to a fluid accumulation, requiring drainage and a clinical picture that may lead to sepsis.
Our experience has shown that in some patients, a prolonged drain stay causes the fistula to persist. We have observed that in these cases, fistulas close abruptly in the event of the rapid or accidental removal of the drain. However, we cannot attribute the cause of every prolonged fistula to the presence of a drain. For example, in Strasberg type E bile duct injuries, the drain cannot be considered a cause of fistulas. We have experienced that the rapid withdrawal of the drain provides the closure of biliary fistulas (BFs) in some cases with minimal bile duct damage, some pancreatic fistulas (PFs), patients with bile leakage after hepatectomies, and in selected patients that meet certain criteria after the fistula tract is fully formed.
In this paper, we present a novel approach to the management of pancreaticobiliary fistulas (PBFs) that developed after abdominal surgery. We attempted to close the fistulas by withdrawing the drains promptly. Since this method has not been previously reported in the literature, our study is the first of its kind.
Material and Methods
Trial Design
This retrospective study was carried out at the General Surgery Department of the University of Health Sciences Konya City Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Participants and Eligibility Criteria
Patients who underwent hepatobiliary and pancreatic surgery in our clinic between January 1, 2016, and January 1, 2021 were screened from patient files, and those who developed postoperative PBFs were identified. Patients with other fistulas were excluded from the study. Among the patients with PBFs, only those who were followed up and treated with the method we described were included in the sample.
We used the following criteria for the decision to promptly withdraw the drains in patients with BFs:
1) Normal liver function test values.
2) Absence of septic findings.
3) Presence of defecation.
4) Fistula flow rate not exceeding 250-400 cc/day.
5) No signal loss, such as full-thickness incision on MRCP
6) Absence of suspicious findings, such as aberrant canal injury on MRCP.
7) No type E damage according to the Strasberg classification (only minor injuries were included).
8) Persistence of the fistula despite ERCP (papillotomy + stenting).
9) Maturity of the fistula tract (at least two weeks after the fistula begins to develop).
Outcomes
From the patient files, demographic information, clinical data, and laboratory and radiological records were obtained and analyzed.
Statistical analysis
Descriptive statistics, including mean, standard deviation, median, minimum, maximum, frequency, and percentage values were obtained. For statistical analyses, the Statistical Package for the Social Sciences (SPSS), version 22.0 (SPSS Inc., Chicago, IL, USA) was used.
Ethical Approval
The ethics committee of the University of Health Sciences, Hamidiye Scientific Research Ethics Committee approved the study (Date: 2021-11-26, No: 21-695).
Results
From January 1, 2016, through January 1, 2022, 3,856 laparoscopic cholecystectomy (LC), 97 pancreaticoduodenectomy (PD), 21 distal pancreatectomy (DP), and 18 hepatectomy procedures were performed in our clinic. Postoperative PBFs developed in 43 of these patients. After excluding the 23 cases in which other follow-up and treatment methods were used, 20 patients were included in the study. Twelve patients developed PFs and eight developed BFs. The flow diagram of the study is shown in Figure 1. The mean age of the patients was 44.6 years. Fifteen (75%) of the 20 patients were male, and five (25%) were female. The demographic characteristics of the patients are given in Table 1, and their diagnoses and the surgical procedures performed are summarized in Table 2. Additional interventional procedures were required in only five patients (5/20, 25%), of whom two underwent endoscopic retrograde cholangiopancreatography (ERCP) (2/20, 10%) and three underwent percutaneous drainage (3/20, 15%). Figure 2 presents the fistulography image of a case in which stenting was performed with ERCP for bile leakage. No additional intervention was undertaken in any of the remaining patients. Eight patients had prolonged BFs. Five of these patients underwent LC for symptomatic cholelithiasis, two had hepatectomies with the diagnosis of intrahepatic cholangiocarcinoma, and one underwent packing and segmentectomy due to traumatic liver injury. All of these patients had BFs persisting for weeks at different flow rates. In these cases with persistent fistulas, we attempted to promptly withdraw the drains and observed that all the fistulas were closed. There was no biloma or sepsis during hospital stay and outpatient follow-up after discharge.
Eight patients with periampullary tumors and two with pancreatic neuroendocrine tumors developed PFs after PD, and two patients developed PFs after DP. Amylase was studied in the fluid taken from the drain in all patients with PFs, and it was found to be above the serum reference level.
Fistula duration was longer than 10 days in all patients. Although the flow rate of PFs decreased, it continued to drain between 100-150 cc/day. Similar to the BFs, the PFs closed on the next day after drain removal without any leakage from the drainage area. Figure 3 shows the CT image taken one month after drain removal in a patient who developed PF after PD.
No problems related to fistula were observed in any of the patients during the first-week, monthly, or yearly follow-up.
Discussion
A postoperative PF is the most important clinical complication after PD, with an incidence ranging from 9.9% to 28.5%. This complication causes a prolonged hospital stay and increased morbidity and mortality [4-8].
In our cases with PFs, we continued to keep the drain in place postoperatively. If the drain placed during the operation did not function properly in patients with leakage, we used interventional radiological methods to place another catheter in the area. We did not consider the drain-tract-targeted approach in type B and C fistulas (as in our two patients) in the very early period, since this approach requires technical skills, and the rate of clinical response is around 60%, even in skilled hands [5-9-11].
While holding the drain in place in PFs, we waited for the fistula tract to mature and performed fistulographies (Figure 1). After the tract fully matured, we promptly removed the drain without shortening it. We believe that once the tract has matured, the drain itself prevents the fistula from closing.
The most common type of fistula was a PF, which developed after PH in 12 patients. In the follow-up of these patients, the drain was removed between the 20th and 30th postoperative days, and no problems were encountered in the following days.
BFs develop usually secondary to surgery. Endoscopic modalities, such as endoscopic sphincterotomy, stenting, and the insertion of nasobiliary drains have replaced surgery as the first-line approach in the management of minor bile duct injuries. Surgical reconstruction is recommended for major injuries [12-14].
BFs were seen in 10 patients in our series. These patients had undergone surgery for various reasons and developed BFs during the follow-up period. Their fistulas closed after the drains were promptly removed on different days.
Concerning why the drain may prevent the fistula from closing, the inner surface of the fistula is covered with granulation tissue that the drain prevents from filling the lumen completely. Shortening or replacing the drain with a thin one does not allow for the fistula to close. When the drain is promptly removed, the wall covered with granulation collapses, and the passage is closed. If the drain is removed as described, there will be no stasis remaining, and neither sepsis nor leakage will occur because the tract is completely closed.
Our study is the first in the literature to advocate that prolonged fistulas can be caused by drains, and that they can be closed with the prompt removal of the drains.
In the literature, some studies have indicated that in patients with biochemical leakage according to the last classification of the International Study Group of Pancreatic Fistula (grade A PF in the old classification), the drain can be removed early without causing any problems [10-12].
In a study from Japan, Ito et al. reported that they were able to keep the drains in BFs for months after complex liver interventions, and injected ethanol into the tract to close the fistulas [15]. However, in the current study, we showed that the same successful results can be achieved with the direct removal of the drain without the need for other methods, such as ethanol injection into the tract.
Limitation
Our study has certain limitations. We only had 20 patients, and all had PBFs. We are aware that there is no approach that can be applied to all fistulas; therefore, it is difficult to generalize our results. In addition, it should be kept in mind that our approach is appropriate in selected patients with persistent fistulas who do not have clear indications for surgical treatment.
As we showed in our limited number of patients, drains can be promptly removed in cases where there is no possibility of a problem when the fistula tract is closed.
Conclusion
Based on our knowledge and experience with a small number of patients over a long period, drains can prevent the closure of fistulas in some patients with PBFs, and the prompt removal of the drain in these cases can result in the closure of the fistula.
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. Schecter WP. Management of enterocutaneous fistulas. Surg Clin North Am. 2011;91(3):481-491.
3. Berry SM, Fischer JE. Classification and pathophysiology of enterocutaneous fistulas. Surg Clin North Am. 1996;76(5):1009-1018.
4. Søreide K, Labori KJ. Risk factors and preventive strategies for post-operative pancreatic fistula after pancreatic surgery: A comprehensive review. Scand J Gastroenterol. 2016; 51(10):1147-54.
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7. Roberts KJ, Hodson J, Mehrzad H, Marudanayagam R, Sutcliffe RP, Muiesan P, et al. A preoperative predictive score of pancreatic fistula following pancreatoduodenectomy. HPB (Oxford). 2014;16(7):620-628.
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11. Pedrazzoli S and Brazzale AR. Systematic review and meta-analysis of surgical drain management after the diagnosis of postoperative pancreatic fistula after pancreaticoduodenectomy: Draining-tract-targeted works better than standard management. Langenbecks Arch Surg. 2020;405(8):1219-1231.
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15. Ito A, Ebata T, Yokoyama Y, Igami T, Mizuno T, Yamaguchi J, et al. Ethanol ablation for refractory bile leakage after complex hepatectomy. Br J Surg. 2018;105(8):1036–43.
Download attachments: 10.4328.ACAM.22185
İsmail Hasırcı, Mehmet Eşref Ulutaş, Gürcan Şimşek, Ogün Erşen, Adil Kartal, Müslim Yurtçu, Selman Alkan, Kemal Arslan. An innovative approach: Prompt withdrawal of the drain allows for fistula closure in some prolonged postoperative pancreaticobiliary fistulas. Ann Clin Anal Med 2025;16(5):320-324
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Red cell distribution width to albumin ratio and neutrophil to lymphocyte ratio as prognostic markers in elderly emergency department patients
Dilber Üçöz Kocaşaban, Sertaç Güler, Esma Büşra Güzeş, Fatma Ceylan Çeçe, Erdal Demirtaş
Department of Emergency Medicine, Health Sciences University, Ankara Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.22283 Received: 2024-05-25 Accepted: 2024-09-24 Published Online: 2024-12-09 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):325-330
Corresponding Author: Dilber Üçöz Kocaşaban, Department of Emergency Medicine, Health Sciences University Ankara Training and Research Hospital, Ankara, Turkiye. E-mail: dilberucoz@hotmail.com P: +90 505 944 62 90 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7473-1434
Other Authors ORCID ID: Sertaç Güler, https://orcid.org/0000-0002-6266-615 . Esma Büşra Güzeş, https://orcid.org/0000-0002-7475-3406 . Fatma Ceylan Çeçe, https://orcid.org/0009-0009-6573-6987 . Erdal Demirtaş, https://orcid.org/0000-0001-8693-2711
This study was approved by the Ethics Committee of Ankara Training and Research Hospital (Date: 2023-04-26, No: E.23/1263)
Aim: The aim of this study was to evaluate Red Cell Distribution Width/Albumin (RAR) and Neutrophil/Lymphocyte Ratio (NLR) in the follow-up and treatment processes of geriatric emergency department patients.
Material and Methods: We retrospectively collected demographic, complaint, comorbidity, vital signs, and laboratory test data of elderly patients who presented to our emergency department over a 6-month period. Next, we investigated the relationship of RAR and NLR with hospitalization, discharge, and mortality.
Results: This study included 1625 patients 606 (37.3%) were hospitalized, whereas 35 (2.2%) died. RAR was significantly different among the discharged, hospitalized, and dead patients (all p < 0.001). NLR was a significant predictor of discharge (p < 0.001) but not of hospitalization or mortality (p > 0.05). In hospitalized patients, the areas under the receiver operating curves for RAR and NLR were 0.662 and 0.655, respectively, with the optimal cutoffs at 3.64 and 3.75, respectively (both p < 0.001). Our univariate logistic regression analysis results indicated that RAR and NLR are effective predictors of both hospitalization and mortality (both p < 0.001).
Discussion: RAR strongly predicts hospitalization, discharge, and mortality in elderly emergency department patients, whereas NLR appears to predict discharge alone.
Keywords: Albumin, Geriatrics, Neutrophil-To-Lymphocyte Ratio, Red Cell Distribution Width (Mesh Database)
Introduction
Population aging—an issue in both developed and developing countries—has led to an increase in the prevalence of chronic health issues [1]. Consequently, the need for and frequency of use of emergency services are increasing among elderly individuals. This situation is predicted to considerably affect emergency departments (EDs) over the next three decades. In Turkey, life expectancy is increasing every year; according to 2020 Turkish Statistical Institute data, the average life expectancy in Turkey was 78.6 years in 2017—comparable to the average life expectancy in 28 European countries (including Turkey; 80.9 years) (This information is available at: http: www.data.tuik.gov.tr). Moreover, the proportion of the population aged ≥65 years in Turkey is expected to increase from 8.5% in 2017 to 11% in 2025 (This information is available at: http: www.data.tuik.gov.tr). Similarly, in the United States, one in five individuals is expected to be aged >65 years by 2030 considerably (This information is available at: https://www.census.gov/content/dam/Census/library/publications/2015/demo/p25-1143.pdf). Currently, 10%–15% of the ED population is composed of elderly individuals, who use EDs more than younger adults. Therefore, as the aging population increases, the number of ED visits is expected to increase considerably (This information is available at: https://www.census.gov/content/dam/Census/library/publications/2015/demo/p25-1143.pdf).
Red cell distribution width (RDW) is a quantitative expression of anisocytosis, which is calculated as the standard deviation of red blood cell volume divided by mean red blood cell volume (MCV). RDW, a common hematologic parameter, is part of the standard complete blood count in hospitalized patients. Recent studies have demonstrated that, in patients with varied clinical conditions (e.g., cardiovascular disease, stroke, septic shock, and community-acquired pneumonia), a high RDW is associated with an increased mortality risk [2- 4]. RDW is a strong predictor of mortality in middle-aged and older adults; it is also recognized as an age-related prognostic biomarker in adults aged ≥45 years [5].
Serum albumin is an acute-phase protein that is used as a nutritional marker. Because its levels decrease in an inflammatory state, serum albumin is considered a negative acute-phase protein. As such, in hospitalized elderly patients, serum albumin levels are inversely correlated with morbidity and mortality [6]. Moreover, high albumin levels have been correlated with a short-term improvement in the functional status of hospitalized patients [7].
The RDW-to-albumin ratio (RAR) is a newer biomarker that has been used to evaluate the prognoses of patients with stroke [8], heart failure [9], and acute myocardial infarction (MI) [10]. In this study, we evaluated the role of RAR and the neutrophil-to-lymphocyte ratio (NLR) in assessing the outcome of elderly patients in the ED in terms of hospitalization, discharge, and mortality.
Material and Methods
Study Population
This was a single-center, retrospective, observational study. We included patients aged ≥65 years who presented to the ED of a tertiary education and research hospital over 6 months (July 1 to December 31, 2022). We included only patients with a complete blood count (CBC) and serum albumin data. However, we excluded patients who left the ED voluntarily, had no patient admission information, had hematologic malignancy, and presented with trauma.
Study Protocol
Patient age, sex, comorbidity, systolic and diastolic blood pressure, temperature, pulse rate, and fingertip oxygen saturation data were collected from the included patients’ medical records. We specifically included neutrophil and lymphocyte counts, RDW, and serum albumin data from their first ED laboratory test, before treatment was initiated. The patients were classified according to their ED outcomes: discharge, hospitalization, or mortality. ED results, mortality in the ED at follow-up, hospitalization, and discharge were recorded. We calculated NLR by dividing neutrophil count (×103 μL) by the lymphocyte count (×103 μL) and RAR by dividing RDW (%) by serum albumin level (g/dL). Sensitivity and specificity for hospitalized, discharged, and dead patients were calculated according to their cutoff RARs and NLRs. Demographic, complaint, comorbidity, vital signs, laboratory tests, and NLR and RAR data of the patients were statistically analyzed according to ED outcome groups.
Statistical Analysis
Here, continuous data are presented as means and standard deviations or medians and interquartile ranges (IQRs), whereas categorical data are presented as numbers and percentages. We used the Kolmogorov–Smirnov test to examine the conformity of the data to normal distribution. We applied Kruskal–Wallis analysis of variance to compare continuous data between discharged, hospitalized, and deceased ED patients, followed by the Kruskal–Wallis multiple comparison test to analyze the origin of between-group differences. The chi-square and Fisher exact tests were used for group comparisons of nominal variables through cross-tabulation. The diagnostic performance of RAR and NLR was evaluated based on the areas under the receiver operating characteristic (ROC) curves (AUCs), with the Youden index used to estimate the optimal cutoff points. The diagnostic accuracy of RAR and NLR values was evaluated using the following accuracy measures: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Risk factors for hospitalization and mortality were analyzed by univariate and multivariate logistic regression analyses. In the multivariate logistic regression analysis, variables considered risk factors were first included in the univariate logistic regression, and significant variables were then included in the multivariate analysis. The goodness of fit of the model was assessed using the Hosmer-Lemeshow goodness of fit. We used SPSS for Windows 20.0 (SPSS, Chicago, IL, USA) for all statistical analyses and considered p < 0.05 to indicate statistical significance.
Ethical Approval
The present study was conducted in accordance with the principles of the Declaration of Helsinki. The Ethics Committee of Ankara Training and Research Hospital approved the study (Date: 2023-04-26, No: E.23/1263).
Results
Over our 6-month study period, 1956 patients aged ≥65 years presented to the ED; all of them underwent testing for CBC and serum albumin. However, we excluded 299 patients because they had missing data and 32 patients because they had hematologic diseases or were receiving active chemotherapy treatment. Finally, 1625 patients were included in the final analysis; their mean age was 77.04 ± 7.90 years, and 54.9% of them were female. Hypertension (70.33%) was the most common comorbidity; furthermore, of all patients, 60.6% were discharged, 37.3% were hospitalized, and 2.2% died. The patients’ characteristics are presented in Table 1.
The median (IQR) RAR was 3.67 (0.14–33.26); it demonstrated significant differences between discharged, hospitalized, and dead patients (all p < 0.001). In particular, RAR was higher than in discharged patients than in both hospitalized and deceased patients; additionally, it was higher in hospitalized patients than in dead patients. The median (IQR) NLR was 4 (0.1–176.0); moreover, it was lower in discharged patients [3.3 (2.1–6.07)] than in both hospitalized [5.6 (3.0–11.4)] and deceased [6.0 (1.8–11.2)] patients. The NLRs of hospitalized and dead patients demonstrated no significant differences (p > 0.05; Table 2).
For RAR, the AUC was 0.662 in hospitalized patients (p < 0.001); furthermore, at a cutoff of 3.64, the PPV, NPV, sensitivity, and specificity were 49.2%, 73.1%, 64.8%, and 58.8%, respectively. It was 0.825 in deceased patients (p < 0.001); additionally, at a cutoff of 4.01, the PPV, NPV, sensitivity, and specificity were 9.1%, 98.9%, 77.1%, and 72.6%, respectively (Fig. 1). For NLR, the AUC was 0.655 in hospitalized patients (p < 0.001); moreover, at a cutoff of 3.75, the PPV, NPV, sensitivity, and specificity were 49.3%, 74.1%, 67.7%, and 57.1%, respectively. It was 0.614 in deceased patients (p < 0.05); at a cutoff of 5.05, the PPV, NPV, sensitivity, and specificity were 6.7%, 98.1%, 62.8%, and 68.7%, respectively (Fig. 1).
Our univariate logistic regression analysis demonstrated that the hospitalization risk was elevated in ED patients with high serum albumin and lactate levels, RDW, RAR (>3.64), and NLR (>3.75; p < 0.001). When the significant parameters in this univariate analysis were included in our multivariate analysis, an increase in lactate levels by 1 mmol/L led to an increase in hospitalization by 1.229 fold, whereas an NLR of >3.75 led to an increase in hospitalization by 1.782 fold (Table 3). Moreover, another univariate logistic regression analysis indicated that serum lactate and albumin levels, RAR, and NLR were associated with an increased mortality risk (all p < 0.001). When the significant parameters in this univariate analysis were included in our multivariate analysis, an increase in lactate levels by 1 mmol/L led to an increase in mortality by 1.445-fold (Table 3).
Discussion
In this study, RAR and NLR were both associated with increased all-cause hospitalization and death in elderly ED patients; in particular, RAR predicted mortality more effectively than NLR.
In a study by Ayrancı et al. that included 784 elderly patients, the median patient age was 75 years, and the most common comorbidity was hypertension (54.5%); furthermore, the ED mortality and hospitalization rates were 0.8% and 49.8%, respectively [11]. Our mortality (2.2%) and hospitalization (37.3%) rates were higher than those reported by Ayrancı et al. This may be due to the differences in the locations of the study hospitals and our patients’ inability to receive adequate care services due to difficulties in accessing social support.
Studies have demonstrated that a high RDW is associated with increased mortality in many clinical conditions. A high RDW may result from malnutrition and erythrocyte fragmentation [12]. Specifically, a high RDW and impaired intravascular hemodynamics are associated with vascular pathologies [12]. A recent study included a large group of elderly patients admitted to a hospital for identical reasons; the authors reported that patients with a high RDW at admission stay in the hospital 1.5–2 times longer than patients with a low RDW at admission [13]. Alakare et al. also demonstrated that an increased RDW is associated with increased mortality in elderly patients [14]. Similarly, our results indicated that patients with a high RDW have high hospitalization and mortality risks and that a high RDW predicts hospitalization.
A study on patients aged ≥72 years reported that serum albumin levels decrease with aging [15]. In hospitalized elderly patients, serum albumin levels are inversely correlated with morbidity and mortality [16]. Similarly, higher serum albumin levels were associated with a shorter recovery in functional status in hospitalized patients [7]. These results are corroborated by our current findings: in discharged patients, serum albumin levels were higher than those in hospitalized and deceased patients.
Several studies have demonstrated that NLR is a prognostic marker of acute coronary syndromes, cerebrovascular events, cancer, and acute infections [17- 20]. In the current study, NLR was significantly lower in the hospitalized and deceased patients than in the discharged patients, regardless of their diagnosis. In a study by Song et al. that included 2777 elderly patients, the AUC for NLR was 0.714 in dead patients [21].
RAR is a novel biomarker previously used to diagnose acute MI, aortic aneurysm, pneumonia, diabetes, and cancer; it is also considered a prognostic indicator [8- 10]. To our knowledge, this is the first study evaluating the use of RAR to predict hospitalization, discharge, and mortality in elderly ED patients. We found that RAR differed between discharged, hospitalized, and deceased ED patients. Moreover, the RARs of the discharged patients were lower than those of both the hospitalized and deceased patients, whereas the RARs of the hospitalized patients were lower than those of the dead patients. Hong Wu et al. reported that in patients with acute MI, 90-day mortality was lower when the RAR was <4.32 (p < 0.001) [10]. Another study reported that the RAR was associated with significant 28-day mortality in 234 patients with pneumonia in another univariate [odds ratio (OR) = 1.545, 95% confidence interval (CI) = 1.282–1.862, p < 0.001] and multivariate (OR = 1.379, 95% CI = 1.103–1.723, p < 0.005) logistic regression analyses [22]. In a study on the role of RAR in predicting mortality in 1480 patients with stroke, a high RAR was significant (all p < 0.001) in 30-day, 90-day, and 1-year mortality [8]. Similarly, a population-based, prospective, cohort study investigating the prognostic role of RAR found that higher RAR was associated with an increased risk of death from any disease according to multivariate analysis [23]. Among a total of 50,622 patients from the United States (aged ≥18 years) and 418,950 patients from the United Kingdom (aged ≥37 years), the mean RAR for the first group was 3.15 and for the second group was 2.99 [23]. The reason the mean RAR in that study were lower than in ours may be due to our patient group including an older population. The authors reported that the RAR was statistically significantly higher in predicting mortality for all causes of a total of 7,590 deaths in the first group and 36,973 deaths in the second group, regardless of age. The causes of mortality that RAR predicted with statistical significance were cancer, heart disease, cerebrovascular disease, respiratory disease, diabetes, and other causes [23].
In the current study, NLR and RAR were better at predicting hospitalization and mortality, respectively. This may have been due to the inclusion of all hospitalized patients in one group, without stratifying hospitalized patients based on which department they were admitted (inpatient care or intensive care unit); additionally, the mortality rate among our patients was low.
RAR is thus an accessible biomarker predicting hospitalization in elderly ED patients. However, this finding warrants a larger-scale prospective study.
Limitation
The main limitation of this study is its retrospective, single-center design. Studies predicting mortality after discharge and mortality during hospitalization in elderly patients are warranted.
Conclusion
The current results revealed that high RAR levels predict hospitalization and mortality in elderly ED patients. Therefore, RAR is a simple, accessible prognostic biomarker that could improve the management of elderly ED patients in the future.
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.22283
Dilber Üçöz Kocaşaban, Sertaç Güler, Esma Büşra Güzeş, Fatma Ceylan Çeçe, Erdal Demirtaş. Red cell distribution width to albumin ratio and neutrophil to lymphocyte ratio as prognostic markers in elderly emergency department patients. Ann Clin Anal Med 2025;16(5):325-330
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The role of amantadine in the anesthesia intensive care unit
Ezgi Balıkoğlu 1, Murat Aksun 2, Mehmet Ali Coşar 2, Senem Girgin 2, Mensure Çakırgöz 3, Atilla Şencan 2, Nagihan Karahan 2
1 Department of Anesthesiology and Reanimation, Health Science University, Doctor Suat Seren Chest Disease Hospital, 2 Department of Anesthesiology and Reanimation, Izmir Katip Celebi University, Ataturk Training and Research Hospital, 3 Department of Anesthesiology and Reanimation, Health Science University, Izmir Tepecik Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.22364 Received: 2024-08-08 Accepted: 2024-10-21 Published Online: 2024-12-14 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):331-335
Corresponding Author: Ezgi Balıkoğlu, Department of Anesthesiology and Reanimation, Health Science University, Doctor Suat Seren Chest Disease Hospital, Izmir, Turkey. E-mail: tekerekoglue@gmail.com P: +90 530 292 98 67 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4373-0022
Other Authors ORCID ID: Murat Aksun, https://orcid.org/0000-0002-8308-3045 . Mehmet Ali Coşar, https://orcid.org/0000-0002-2327-5192 . Senem Girgin, https://orcid.org/0000-0003-0715-7695 . Mensure Cakırgöz, https://orcid.org/0000-0001-7687-0924 . Atilla Şencan, https://orcid.org/0000-0002-3765-9891 . Nagihan Karahan, https://orcid.org/0000-0002-8042-0501
This study was approved by the Ethics Committee of Izmir Katip Celebi University, Ataturk Training and Research Hospital (Date: 2020-01-09 , No: 06)
Aim: The aim of this study is to provide information on patient-specific and clinical data relating to patients treated with amantadine in the intensive care unit, including changes in the Glasgow Coma Scale (GCS) score, patient demographics, length of stay in the Intensive Care Unit (ICU), duration of mechanical ventilation, drug dosage and route of administration.
Material and Methods: Patients over 18 who received amantadine treatment from January 2014 to December 2019 were included in the study. Patients’ age, gender, diagnosis at hospitalization, comorbidities, history of cardiopulmonary resuscitation(CPR), history of head trauma, duration of mechanical ventilation, overall condition at the end of the treatment in the ICU, GCS score at admission and discharge, route of drug administration, and total drug dose were recorded retrospectively.
Results: Of the 91 patients included in the study, 39 had a history of head trauma, and 25 had a history of cardiopulmonary resuscitation. 46 patients died. 43 were relocated to a level 2 ICU or award. The chosen route of administration was intravenous (I.V.) in 60.4% of the patients. The average difference between the GCS scores at admission and discharge in all patients showed an increase, but it was not statistically significant. The GCS score seemed to show a statistically significant increase in the head trauma subgroup.
Discussion: We believe that amantadine can accelerate neurological recovery in unconscious intensive care patients, especially those with traumatic brain injury.
Keywords: Amantadine, Glasgow Coma Scale, Intensive Care Unit, Traumatic Brain Injury
Introduction
Amantadine, an N-methyl D-aspartate (NMDA) receptor antagonist, is an antiviral agent with dopaminergic effects. Another area of use for amantadine is related to improving neurological recovery in patients with traumatic brain injury [1]. It is believed that amantadine stimulates and contributes to the recovery of the nervous system with its dopaminergic effect and prevents apoptosis by inhibiting the passage of calcium into the cell with its NMDA receptor antagonist effect [2].
Cell culture studies have shown that amantadine increases the production of glial cell-derived neurotrophic factors (GDNF), thereby inhibiting neuroinflammation. Since reducing neuroinflammation can correct cognitive functions, researchers believe that amantadine can be used in postoperative cognitive dysfunction (POCD) [3].
Some publications found in the literature review report that the use of amantadine in various disorders of consciousness accelerates and contributes to neurological recovery [4].
This study examined patients treated with amantadine due to impaired consciousness in our anesthesia Intensive Care Unit (ICU). It aimed to reveal the effect of the drug on the prognosis, most effective duration, dosage, and route of administration in achieving the optimal effect.
Material and Methods
Amantadine-treated patients hospitalized in the Anesthesia ICU of Izmir Katip Çelebi University Ataturk Training and Research Hospital between January 1, 2014, and December 1, 2019, were retrospectively screened. Ninety-one patients over 18 years of age were recruited for the thesis study.
The study was designed as a retrospective, comparative, and descriptive case series.
The gender, age, and comorbidities of the patients were noted. Diagnoses at admission into the ICU were recorded. Regardless of patients’ diagnoses at admission, their history of cardiopulmonary resuscitation (CPR) before admission to the ICU and history of head trauma were checked, resulting in subgroups. All patients’ Glasgow Coma Scale (GCS) score at the time of admission (GCS on arrival), GCS score at the end of the ICU treatment (GCS on exit), condition at the end of the ICU treatment (dead, transferred to a ward or a level 2 ICU, discharged) were analyzed. Various parameters were investigated, including the total length of stay in intensive care (days), duration of mechanical ventilation during intensive care monitoring (days), route of administration of amantadine (I.V., tablet, I.V.+tablet), the day the drug was started after admission (start time), total dose, and duration of administration (days).
GCS difference (= GCS on arrival – GKS on exit) was calculated collectively for all patients before subgrouping and then separately for the two subgroups to reveal any significant change in GCS scores for all patients. All variables were evaluated with descriptive statistics. GCS changes were compared.
All subjects were grouped as ‘increased GCS’, ‘decreased GCS’, and ‘unchanged GCS’ according to the changes in their GCS scores. The groups were compared in terms of length of mechanical ventilation and length of stay in intensive care.
Descriptive statistics and frequency analyses (n, %) were performed for average ± standard deviation or median (range) values for all variables. The assumption of normality and homogeneity for the Glasgow Coma Scale scores on arrival and on exit was evaluated. Variables that were not distributed according to this assumption were subjected to the Wilcoxon signed-rank test separately in all patient groups, the head trauma subgroup and the CPR subgroup. The subjects were examined in three groups: increased, decreased, and unchanged GCS group according to changes in the GCS score. The Kruskall-Wallis test was applied for these non-normally and non-homogeneously distributed groups. Post hoc analysis was performed with the Tamhane test. Statistical significance was set at p<0.05. Statistical analysis was performed with SPSS 22.0 Edition software (Chicago, Ill).
Ethical Approval
This study was approved by the institutional review board of Izmir Katip Celebi University, Ataturk Training and Research Hospital (Date: 2020-01-09 , No: 06). The need for informed consent was waived because anonymized data were used. The authors declare that this report does not contain any personal information that could lead to the identification of the patients.
Results
Descriptive statistical analysis was performed for all subjects. The mean age of the patients was 55±21. 29 (31.9%) were female and 62 (68.1%) were male.
Twenty-four patients had been hospitalized for motor vehicle accidents, and 15 patients had a diagnosis of fall. 6 patients had been followed up for myocardial infarction, and 8 patients had been followed up for a history of non-traumatic cerebrovascular accidents (CVA). 10 patients had been hospitalized for postoperative impaired consciousness. There were 4 patients diagnosed with pneumonia and generalized disorder. There were 2 patients for each aspiration, delirium tremens, and pulmonary edema. Three patients had been followed up for sepsis and acute renal failure. There was 1 patient follow-up for each of the following diagnoses: larynx cancer, anaphylaxis, eclampsia, electrolyte disorder, respiratory failure, disseminated intravascular coagulation, neuroleptic malignancy syndrome, and decompensated heart failure.
46 (50.5%) patients had at least one comorbidity, with hypertension (35%) and diabetes mellitus (23%) being the most common.
39 (42.9%) of the patients hospitalized in the ICU who were given amantadine had a history of head trauma.
25 (27.5%) of the amantadine-treated patients had received cardiopulmonary resuscitation before admission to the ICU.
41 (45.1%) of the patients treated with amantadine had an increase in their GCS score, while 34 (37.4%) had a decrease, and 16 (17.5%) patients did not have any change in their GCS score.
The mean GCS for all patients at admission to the ICU was 6.94±3.58, the mean GCS at the end of the ICU treatment was 7.89±5.09, and the mean GCS change was 0.94±5.41.
The median length of stay in the anesthesiology ICU was 36 (range 4-689) days. The median duration of mechanical ventilation for the patients when in the ICU was 29 (range 0-601) days.
2 (2.2%) of the treated patients were discharged home, 43 (47.3%) were transferred to a level 2 ICU or award, and 46 (50.5%) died.
The mean duration of amantadine treatment in all cases was 8.6±7.8 days. The median day when the drug had been started was day 8 (range 1-192).
The preferred route of administration was I.V. in 55 (60.4%), tablet form in 5 (5.5%), and combined (tablet+I.V.) in 31 (34.1%).
The average total dose of the administered amantadine was 2850±2254 milligrams. Descriptive data are summarized in Table 1 (Table 1).
The patients were divided into three groups according to the change in their GCS scores: the GCS score increased in 41 patients, decreased in 34 patients, and remained the same in 16 patients. The average duration of mechanical ventilation was 44.5±71, 96.7±120, and 29.5±38 days, respectively, and the mean length of stay in the ICU was 76.9±99, 101.7±132, 32.2±39 days, respectively. There was a statistical difference among these three groups in terms of duration of mechanical ventilation and length of stay in the ICU (p=0.001, p=0.001, respectively). Post-hoc analyses showed no statistically significant difference between the group with increased GCS score and the one with decreased GCS score in terms of duration of mechanical ventilation and length of stay in the ICU (p=0.089, p=0.752, respectively). The length of stay in the ICU was significantly lower in the group with unchanged GCS scores as compared to the groups with increased or decreased GCS scores. The duration of mechanical ventilation was significantly lower in the group with unchanged GCS scores as compared to the group with decreased GCS scores. Post-hoc analyses are detailed in Table 2 (Table 2).
There were 39 patients in the head trauma subgroup. Their mean age was 63±17; 10 (31.9%) of them were female and 29 (68.1%) were male. 8 (20.5%) of the patients in this group had at least one comorbidity.
For this subgroup, the average GCS score at admission to the ICU, GCS on exit, and GCS variation were 6.46±3.14, 9.97±4.72, and 3.51±5.43, respectively.
The patients’ median length of stay in the anesthesia ICU and duration of mechanical ventilation were 28 days (range 5-378) and 18 days (range 0-278), respectively.
The route of administration of amantadine was I.V., tablet, and combined (I.V.+tablet) form in 23 (29%), 2 (5.1%), and 14 (35.9%) patients, respectively.
In the head trauma group, the average duration of use and the total dose of amantadine were 10±9 days and 3333±2544 mg, respectively. The median day when the drug had been started was day 6 (range 1-40).
Of these cases, 1 (2.6%) was discharged home, 27 (69.2%) were transferred to a level 2 ICU or a ward, while 11 (28.2%) died. Descriptive data are summarized in Table 3 (Table 3).
In the subgroup of patients followed after CPR, the mean age was 55±18; 8 (32%) of the subjects were female, and 17 (68%) were male. There was at least one comorbidity in 13 (52%) patients.
For this subgroup, the average GCS at admission to the ICU, GCS on exit, and GCS variation were 5.88±3.59, 6.84±4.70, and 0.96±4.91, respectively.
The patients’ median length of stay in the anesthesia ICU and duration of mechanical ventilation were 78 days (8-689) and 63 days (4-601), respectively.
The route of administration of amantadine was I.V. in 12 (48%) patients and combined (I.V.+tablet) form in 13 (52%) patients.
In the post-CPR group, the average duration of use and the total dose of amantadine were 10±8 days and 3096±2495 mg, respectively. The median day when the drug had been started was day 12 (range 2-91).
Of these cases, 1 (4%) was discharged home, 10 (40%) were transferred to a level 2 ICU or a ward, while 14 (56%) died.
Taken together, there was no statistically significant increase in GCS scores in patients treated with amantadine (without subgrouping) (p=0.089).
The subgroup analysis examining the difference between the GCS on arrival and GCS on exit in patients admitted to the anesthesia ICU for head trauma showed a statistically significant increase in the GCS score (p=0.001).
The subgroup analysis examining the difference between the GCS on arrival and GCS on exit in patients admitted to the anesthesiology ICU post-CPR found no statistically significant increase in the GCS score (p=0.275).
Discussion
When all study patients were considered together, amantadine treatment was seen to cause an increase in the GCS score, but this was not statistically significant. In the subgroup of patients with impaired consciousness caused by head trauma, amantadine treatment was found to result in a statistically significant improvement in the GCS score. Neurological recovery in head trauma patients was consistent with prior studies [1, 5–8].
One study by Ghate et al. examined 50 patients with traumatic brain injury who were treated with amantadine. In this study, all patients were evaluated before and after treatment with a Full Outline of UnResponsiveness Score(FOUR), Glasgow Outcome Scale(GOS), and Disability Rating Scale(DRS). They reported an improvement in patients’ neurological evaluation scores [6]. In a study by Meythaler et al., patients with traumatic brain injury were divided into placebo and control groups and were treated with amantadine at different times. The results of their study found an improvement in DRS, GOS, and Mini-Mental State Examination (MMSE) scores at those times when patients were actively taking amantadine [7].
In a study that first reported neurostimulant use in post-CPR care, neurostimulants were used in addition to therapeutic hypothermia. Patients who received neurostimulants were compared with the therapeutic hypothermia group that did not take neurostimulants and were found to have a higher chance of discharge and tended to recover better(10). Our study detected an increase in the GCS score after treatment with amantadine, but the increase was not statistically significant.
In another study, patients with CVA were given amantadine, and after three months, the treatment group was compared with the control group by using the National Institutes of Health Stroke Scale(NIHSS), Modified Rankin Scale(MRS), and Barthel Index for Activities of Daily Living. The comparison showed better neurological recovery in the group treated with amantadine[10]. In our study, there were eight patients followed up for CVA of non-traumatic origin. Only 2 had an increase in their GCS score.
Amantadine has been shown to be useful in improving POCD in animals [3]. In a controlled study of 344 rats by Hongyin Tan et al., amantadine was shown to reduce postoperative inflammation. This study is the first to show the possible therapeutic effect of amantadine on POCD[3]. In our study, there were 11 patients who were followed up in intensive care postoperatively and who were considered good candidates for amantadine treatment. Of these 11 patients, seven died, and in the remaining four patients, the GCS score on exit increased by an average of 5 points compared to the GCS score on arrival. We are of the opinion that in this patient group, neurological recovery is promising, but the results should be further supported by studies on a larger number of patients.
To date, no effective drugs have been found for the treatment and prophylaxis in the current COVID-19 (Coronavirus Disease 2019) pandemic. However, scientists are investigating the effectiveness or preventiveness of the known drugs used to treat other diseases against COVID-19. Recently, it has been reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severely infects the brain stem in animals and humans and may cause not only respiratory but also neurological symptoms [11]. A study has been conducted based on a survey to assess whether amantadine and memantine would show protective antiviral efficacy against COVID-19 in individuals with neurological diseases. This study examined ten patients with multiple sclerosis and five patients with Parkinson’s disease using amantadine, as well as seven patients with cognitive impairment using memantine, all with COVID-19 viral infection confirmed by the polymerase chain reaction (PCR) test. Patients were followed up during and at the end of the 2-week self-isolation and were found to have no symptoms of the viral infection, with also no progression in their primary neurological diseases [12].
Each clinic has different experiences with the use and dose of amantadine. Although there is no clear data on dosage in the literature, our experience suggests that using 200 mg I.V. amantadine b.i.d. for five days, followed by 100 mg tablets b.i.d. for ten days, was the optimal time and dose for our clinic.
Limitation
Our study has some limitations in that it was retrospective and had an insufficient number of patients for forming different groups. Moreover, the GCS scores evaluated in our study were the GCS scores evaluated before admission into the ICU and before exit, regardless of the days when amantadine was started and discontinued. Studies using different scoring systems and different neurological evaluation methods could provide more detailed and effective results in the evaluation of neurological recovery and, thus, better clarify the effect of amantadine.
Conclusion
Post-CPR patients and patients with CVA, as well as intensive care patients in whom organic causes have been ruled out but who have not regained consciousness, and patients with postoperative disorders of consciousness, maybe the next group targeted by researchers for the use of amantadine. Prospective, randomized, controlled, and larger-scale studies are needed to better identify patient groups for amantadine treatment, to observe potential side effects, and to determine the optimal dose and duration of use of amantadine.
The unique aspect of our study is that it was not limited to one single group of patients with the same diagnosis, such as patients with a history of traumatic brain injury; instead, it covered patients who were followed up in the ICU with different diagnoses and who did not regain consciousness.
We believe that treatment with amantadine contributes to neurological recovery, especially in patients with traumatic brain injury. We could not find another study in the literature that collectively evaluated patients who were treated with amantadine for impaired consciousness in the ICU without distinguishing between the reasons for their hospitalization. This is what makes our study the first of its kind.
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. Zhang J, Tan H, Jiang W, Zuo Z. Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats. Anesthesiology. 2014;121(4):773-85.
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Ezgi Balıkoğlu, Murat Aksun, Mehmet Ali Coşar, Senem Girgin, Mensure Çakırgöz, Atilla Şencan, Nagihan Karahan. The role of amantadine in the anesthesia intensive care unit. Ann Clin Anal Med 2025;16(5):331-335
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Hypomagnesemia in pediatric intensive care unit: Etiology, risk factors and relationship of mortality
Hasan Avsar 1, Metin Kilic 2, Arzu Oto 3, Mehmet Bosnak 4
1 Department of Neonatology, Gaziantep LİV Hospital, Gaziantep, 2 Department of Pediatric Cardiology, Faculty of Medicine, Gaziantep University, Gaziantep, 3 Department of Pediatrics, Bursa City Hospital, Bursa, 4 Department of Pediatrics, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
DOI: 10.4328/ACAM.22398 Received: 2024-09-10 Accepted: 2024-10-21 Published Online: 2024-12-10 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):336-340
Corresponding Author: Hasan Avsar, Department of Neonatology, Gaziantep LİV Hospital, Gaziantep, Turkey. E-mail: dr.hasanavsar88@gmail.com P: +90 507 689 87 33 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0283-0457
Other Authors ORCID ID: Metin Kilic, https://orcid.org/0000-00031358-6492 . Arzu Oto, https://orcid.org/0000-0003-0229-2759 . Mehmet Bosnak, https://orcid.org/0000-0002-8390-5109
This study was approved by the Ethics Committee of Gaziantep University, Faculty of Medicine (Date: 2014-11-14, No: 2016 /301)
Aim: We aimed to identify the etiology, risk factors, frequency, and mortality associated with hypomagnesemia in hospitalized patients in the pediatric intensive care unit (PICU) and to contribute to reducing mortality by addressing hypomagnesemia in these patients.
Material and Methods: In this study, the files of patients admitted to the Şahinbey Research and Practice Hospital PICU between January 2014 and August 2016 were retrospectively reviewed. Age, gender, diagnosis, underlying diseases, postoperative status, Pediatric Mortality Index, and Pediatric Mortality Risk Scores were recorded. The definition of hypomagnesemia is defined as the serum magnesium level below 1.7 mg / dL (0.7 mmol / L).
Results: The clinical features of the patients are as follows: A total of 229 cases were included, with a mean age of 57.29 months (range: 1-191 months). Of these, 118 (51.5%) were male, and 111 (48.5%) were female. Hypomagnesemia was present in 44 cases (19.2%) at the time of admission, and it developed in 162 cases (7.7%) during hospitalization. In 65 patients (28.4%), hypomagnesemia was not observed either before or during hospitalization. The average duration of hospitalization was 17.3 ± 21.9 days in patients with hypomagnesemia and 10.7 ± 22.8 days in those without hypomagnesemia (p = 0.001). The mortality rate was 37.3% in the group with normal magnesium levels, 45.5% in patients with hypomagnesemia at admission, and 47.5% in patients who developed hypomagnesemia during hospitalization. Among the patients who developed hypomagnesemia during hospitalization, 81.5% had hypoalbuminemia, 30.9% had hypophosphatemia, and 35.5% had hypokalemia (p = 0.001).
Discussion: Hypomagnesemia is common in the PICU, and patients with hypomagnesemia tend to have a longer hospital stay, higher mortality rates, a greater need for mechanical ventilation, and are often accompanied by electrolyte disturbances. Magnesium levels should be closely monitored in the PICU. Larger prospective studies are needed to evaluate hypomagnesemia and its associated factors in pediatric intensive care units.
Keywords: Hypomagnesemia, Mortality, Pediatric Intensive Care Unit
Introduction
Magnesium (Mg) is the fourth most abundant essential element in the body and the second most abundant in the intracellular area. Magnesium, the main intracellular metal cation, plays an important role in basic cellular reactions. Magnesium acts as a cofactor for more than three hundred enzymes that contain ATP. It also plays a role in DNA transcription, neuromuscular stability, and protein synthesis [1].
Magnesium deficiency causes potassium (K+) to flow out of the cell and induce depolarization, leading to cardiac arrhythmias. In Mg disorders, sodium (Na+) can change the K+ gradient and transmembrane potentials, resulting in neuromuscular excitability or irritability. In Mg deficiency, an increase in the levels of IL-1, TNFα, IFN-γ, substance P and CGRP (Calcitonin gene-related peptide) is observed among the cytokines circulating in the plasma [2-5].
Hypomagnesemia has been reported in 2% of the general population, 10-20% of hospitalized patients, and 50-60% of intensive care patients [1, 4]. Mg levels at the time of admission to the intensive care unit (ICU) have been shown to be associated with mortality. Hypomagnesemia is often reported to be accompanied by electrolyte disturbances [6, 7]. Magnesium is used in pulmonary hypertension, neuromuscular hyperexcitability, bronchospasm, cardiac arrhythmia and neuroprotective treatment [1, 3, 6]. Despite this, there are no sufficient studies on pediatric intensive care patients.
In our study, we aimed to determine the etiology, risk factors, frequency, and morbidity and mortality relationship of hypomagnesemia in pediatric intensive care unit (PICU) patients.
Material and Methods
The study was conducted on patients hospitalized in the PICU of the Department of Child Health and Diseases of the Faculty of Medicine of Gaziantep University between January 2014 and August 2016. Data were collected by retrospective file scanning after the approval of the ethics committee. The study form recorded the gender of the patients, underlying disease, current disease, whether they were postoperative, length of stay, whether they were connected to a mechanical ventilator, whether they received inotropes, whether they received renal replacement therapy, whether they received plasmapheresis, the Mg+2 value during admission to the PICU, the etiology of hypomagnesemia if any, the Mg+2 value and etiology if hypomagnesemia developed during admission, the corrected Ca+2, phosphorus, albumin, Na+ and K+ values at the time of hypomagnesemia. Pediatric mortality index, Pediatric mortality risk scores and outcome were recorded.
Hypomagnesemia was defined as a serum magnesium level below 1.8 mg/dl (0.7 mmol/L).
The inclusion criteria for the study were being between 1 month and 18 years old, having been in intensive care between January 2014 and August 2016, and having sufficient data entered. The exclusion criteria from the study were not having sufficient data collection and not being between 1 month and 18 years old.
The patients were divided into three groups.
Group 1: Those with hypomagnesemia at the time of admission and the etiology, if any, was recorded.
Group 2: Patients without hypomagnesemia at the time of admission but with hypomagnesemia during admission were considered to have acquired hypomagnesemia and serum Mg level, etiology of hypomagnesemia and the day of admission were recorded.
Group 3: Those without hypomagnesemia at and during admission were recorded.
Statistical analysis
SPSS for Windows version 22.0 package program was used for statistical analyses and p<0.05 was considered statistically significant. Shapiro Wilk test was used to control the conformity of continuous variables to normal distribution. Mann Whitney U Test was used to compare 2 independent groups for variables that did not have normal distribution. Relationships between categorical variables were tested with Chi-square analysis.
Ethical Approval
This study was approved by the Ethics Committee of Gaziantep University, Faculty of Medicine (Date: 2014-11-14, No: 2016 /301).
Results
Demographic and clinical characteristics of the cases are shown in Table 1. The frequency distribution of the cases in terms of primary pathologies was as follows; 18 (7.8%) were related to the respiratory system, 44 (19.2%) to the cardiovascular system, 40 (17.4%) to the renal system, 6 (2.6%) to the gastrointestinal system, 36 (15.7%) to the neurological system, 11 (4.8%) to the endocrine system, 15 (6.6%) to hematology, 32 (14%) to malignancy and solid tumors, 5 (2.2%) after surgery, and 22 (9.6%) to other causes (burn, drowning, drug intoxication, insect bites).
The frequency distribution of cases in terms of hospitalization was as follows: respiratory failure in 82 patients (35.8%), heart failure in 31 patients (13.5%), renal failure in 24 patients (10.5%), CNS failure in 16 patients (7%), sepsis in 35 patients (15.3%), liver failure in 3 patients (1.3%), hematological failure in 16 patients (34 patients (6.9%), multiple organ failure in 6 patients (2.6%), and postoperative follow-up in 12 patients (5.3%).
In terms of risk factors in patients with hypomagnesemia at PICU admission, malnutrition was detected in 17 cases (38%), bowel resection – short bowel syndrome in 2 cases (4.5%), drugs such as furosemide in 3 cases (6%), amikacin in 3 cases (6%), amphotericin-B in 6 cases (12%), cyclosporine in 4 cases (9%), 6 cases (23%), renal losses; polyureic phase of acute tubular necrosis in 1 case (2%), chronic metabolic acidosis in 7 cases (15%), increased phosphate intake in 4 cases (9%), and blood transfusion in 4 cases (9%).
In terms of risk factors and risk distribution of cases that developed hypomagnesemia during hospitalization;
1. Drugs; Thiazide or loop diuretics (furosemide) were detected in 41 (25%) cases, aminoglycosides (amikacin) in 21 (13%) cases, amphotericin in 42 (25.6%) cases, cyclosporine in 11 (7%) cases, ethanol in 1 (0.6%) case, proton pump inhibitor in 3 (1.8%) cases, insulin in 5 (3%) cases.
2. Redistribution: Acute pancreatitis was detected in 1 (0.6%) case, DKA insulin treatment in 1 (0.6%) case, blood transfusion in 101 (62%) cases.
3. GIS causes; malnutrition was detected in 10 (6%) cases, intestinal resection short bowel syndrome in 5 (3%) cases, chronic diarrhea or long-term laxative use in 8 (5%) cases, long-term use of proton pump inhibitors in 8 (5%) cases, Nasogastric (NG) drainage in 29 (18%) cases
4. Endocrine and metabolic disorders; hypercalcemia was detected in 2 (1.2%) cases, and increased phosphate intake in 39 (24%) cases.
5. Increase in extracellular volume was detected in 32 (20%) cases.
6. Renal losses; increased diuresis after renal obstruction was detected in 1 (0.6%) case, polyureic phase of acute tubular necrosis in 3 (1.8%) cases, renal tubular acidosis in 1 (0.6%) case, hyperkalemia in 3 (1.8%) cases, chronic metabolic acidosis in 9 (5.6%) cases.
7. Syndromes causing congenital magnesium loss: Gittelman syndrome was detected in 2 (1.2%) cases, and nephrocalcinosis associated with Mg loss was detected in 2 (1.2%) cases.
Evaluation of cases with and without hypomagnesemia at admission in terms of risk factors is shown in Table 2.
Age, length of stay and electrolyte levels of patients who developed hypomagnesemia during their stay were compared. The length of stay in PICU was longer in patients with hypomagnesemia during their stay (17.3±21.9 days) compared to patients without hypomagnesemia (10.7±22.8 days) and this was found to be statistically significant (p=0.001). Serum albumin (2.9±0.6 gr/dl), serum phosphorus (3.9±1.3 mg/dl) and serum potassium (3.7±0.8 mEq/L) were found to be lower in patients who developed hypomagnesemia during their stay in the pediatric intensive care unit and this was found to be statistically significant (p=0.001).
Evaluation of Demographic Characteristics in Cases with and without Hypomagnesemia During Hospitalization is shown in Table 3.
In our study, there is a statistically significant relationship between hypomagnesemia and hypoalbuminemia, hypophosphatemia and hypopotassemia in terms of electrolytes in cases with and without hypomagnesemia during hospitalization (p=0.001). Of the cases that developed hypomagnesemia during hospitalization, 81.5% had hypoalbuminemia, 35.2% had hypokalemia, 30.9% had hypophosphatemia, 30.2% had hyponatremia and 6.8% had hypocalcemia.
When we compared the time of hypomagnesemia development and the duration of hospitalization in the group that developed hypomagnesemia during hospitalization, it was found to be 9.33±8.47 days in those who developed hypomagnesemia in the first 5 days of hospitalization, 25.64±27.76 days in those who developed hypomagnesemia after the 5th day. The duration of hospitalization was found to be longer in cases that developed hypomagnesemia after the 5th day and was statistically significant (p=0.001).
When we examined the distribution of serum Mg values of the cases according to primary disease etiologies, low Mg was found to be higher in renal and malignancy/solid tumor patients compared to the normal Mg group.
The duration of hospitalization in the PICU was 14.1±20.2 days in those with hypomagnesemia at admission, 17.3±21.9 days in those who developed hypomagnesemia during admission, and 10.7±22.8 days in the group with normal Mg. The duration of hospitalization was found to be shorter in the group with normal Mg compared to the other two groups.
Discussion
In our study, the serum Mg concentration we measured to evaluate Mg status represents only 0.3% of the total body Mg content. Standard serum total Mg concentration measurements are between 1.7-2.3 mg/dl and these values include ionized, protein-bound and complex forms. In our study, similar to other studies, hypomagnesemia was detected as 70.7%. In studies conducted on critically ill patients, the prevalence of hypomagnesemia was found to be between 14-70%, and total serum Mg measurements were mostly performed in patients [7, 8].
Many studies have shown that hypomagnesemia occurring in patients under PICU care prolongs the length of stay in hospital and intensive care, makes weaning from mechanical ventilation (MV) difficult, and increases mortality and morbidity [8-13]. Therefore, hypomagnesemia and associated risk factors should be carefully monitored in intensive care patients, and Mg replacement therapy should be started immediately in patients who develop hypomagnesemia.
In a retrospective study conducted by Saleem et al on 179 cases in the PICU, the frequency of hypomagnesemia was found to be 44.1%, 8.9% in the first 5 days and 34% in cases after the 5th day [14]. Limaya et al found hypomagnesemia in 52% of patients in a prospective study of 100 critical cases [15]. Hypomagnesemia was detected in 61% of critically ill patients by Passakiotou et al., and hypomagnesemia was detected in 44-66% by Ribeiro et al., who measured total and erythrocyte Mg levels in 7000 critically ill patients [16, 17]. In our study, similar to other studies, hypomagnesemia was detected in 70.7%.
In our study, MV connection was found to be 71.6% (116/162) in hypomagnesemia patients and 61.2% (41/67) in normomagnesemia patients. Although it was found to be high, it was not found to be statistically significant (p>0.05). In the study by Limaye et al., MV support was provided to 73% (38/52) of patients who developed hypomagnesemia, while ventilation support was provided to only 53% (22/41) of the normomagnesemia group, and MV support was found to be statistically significant with low Mg (p<0.05). The mean duration of MV in patients with low serum Mg was 8 ± 7.92 days, while in patients with normal serum Mg it was 6.17±3.84 days, the difference was not found to be statistically significant (p>0.05) [15]. In the study conducted by Laddhad et al. in 100 patients, it was found that hypomagnesemia was significantly correlated with increased ICU stay and mortality, but it did not affect the duration of mechanical ventilation [18]. Hypomagnesemia causes muscle weakness and respiratory failure, which makes it difficult to separate the patient from MV. In other studies, and in our study, it has been observed that hypomagnesemia patients require more frequent and longer-term ventilation support.
In our study, mortality rates were found to be 45.5% (20/44) in those with hypomagnesemia at admission, 47.5% (77/162) in those who developed hypomagnesemia during admission, and 37.5% (25/67) in the normomagnesemia group, but this was not statistically significant (p>0.05). In a study of Malinowska et al, it was found that 1505 patients with hypomagnesemia had a higher mortality rate compared to those with normal magnesium levels (normomagnesemia). The study highlighted a significant association between low magnesium levels and increased mortality in critically ill patients [19]. In a study of Makwana et al, a total of 323 patients were analyzed. It was found that the mortality rate was significantly higher in hypomagnesemic patients compared to normomagnesemic patients [20]. In our study and other studies, the mortality rates of hypomagnesemia patients were found to be significantly higher. The higher mortality rates in hypomagnesemia patients may be explained by the higher frequency of sepsis, septic shock, and electrolyte abnormalities, especially hypokalemia and cardiac arrhythmias, which are common causes of death in the ICU, and their relationship with hypomagnesemia.
In our study, the length of stay in the hypomagnesemia group was 17.3±21.9 days, and in the normomagnesemia group, it was 10.7±22.8 days. The length of stay in the hypomagnesemia group was significantly longer and statistically significant (p=0.001). In a study by Maqbali et al, a total of 410 patients were analyzed. It was found that hypomagnesemia patients had a significantly longer ICU length of stay compared to normomagnesemia patients, highlighting the potential impact of low magnesium levels on prolonged recovery in critically ill individuals [21]. In their study on 100 patients, Laddhad et al. found that hypomagnesemic patients had a significantly longer ICU length of stay compared to normomagnesemic patients [18].
It is stated that there is a strong relationship between hypomagnesemia and insulin resistance and that Mg supplementation reduces insulin requirements [22, 23]. In addition, use of both loop diuretics and thiazides can inhibit net Mg reabsorption and induce hypomagnesemia, which may trigger insulin resistance [24]. Studies have also reported a significant relationship between antibiotic use and the development of hypomagnesemia [24, 25]. In our study, the highest risk factors determined as 62% of patients developing hypomagnesemia were blood transfusion, 25% thiazide or loop diuretics (furosemide), 13% aminoglycosides (amikacin), 25.6% amphotericin-B, 24% increased phosphate intake, and 18% NG drainage.
Conclusion
In conclusion, in our study, the rate of mechanical ventilation (MV) connection was 71.6% (116/162) in hypomagnesemic patients and 61.2% (41/67) in normomagnesemic patients. Although the rate was higher in hypomagnesemic patients, it was not statistically significant (p>0.05). While the length of stay in hypomagnesemic patients (8 ± 7.92 days) was longer compared to normomagnesemic patients (6.17 ± 3.84 days), this difference was also not statistically significant. The frequency of low serum magnesium levels was found to be significantly higher in children hospitalized in the PICU. Hypomagnesemic children had longer hospital stays, higher mortality rates, and more frequent electrolyte disturbances. Magnesium levels should be monitored closely in the PICU. Prospective and larger studies are needed to further evaluate hypomagnesemia and its associated factors in the PICU.
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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4. Rigo J, Pieltain C, Christmann V, Bonsante F, Moltu SJ, Iacobelli S, et al. Serum magnesium levels in preterm infants are higher than adult levels: A systematic literature review and meta-analysis. Nutrients. 2017;9(10):1-10.
5. Dokuyucu R, Gogebakan B, Yumrutas O, Bozgeyik I, Gokce H, Demir T. Expressions of TRPM6 and TRPM7 and histopathological evaluation of tissues in ischemia reperfusion performed rats. Ren Fail. 2014;36(6):932-6.
6. Al Alawi AM, Majoni SW, Falhammar H. Magnesium and human health: perspectives and research directions. Int J Endocrinol. 2018;4(4):1-17.
7. Jiang P, Lv Q, Lai T, Xu F. Does Hypomagnesemia impact on the outcome of patients admitted to the intensive care unit? A systematic review and meta-analysis. Shock. 2017;47(3):288-95.
8. Solanki J, Runwal K, Beke N, Bahulikar A, Phalgune D. Serum magnesium levels in critically ill patients on admission in ICU and its correlation with outcome. J Assoc Physicians India. 2022;70(5):11-2.
9. Kim JY, Lee HJ, Lee HY, Lee SM, Lee J, Park TY. The effects of hypomagnesemia on delirium in middle-aged and older adult patients admitted to medical intensive care units. Acute Crit Care. 2022;37(3):407-14.
10. Dabla PK, Sharma S, Dabas A, Tyagi V, Agrawal S, Jhamb U, et al. Ionized Blood magnesium in sick children: An Overlooked electrolyte. J Trop Pediatr. 2022;68(2):1-8.
11. Doyle KG, Blackstone MM, Barrett BC. Subacute gummy vitamin overdose as a rare manifestation of child neglect. pediatr emerg care. 2021;37(8):479-82.
12. Peres IT, Hamacher S, Oliveira FLC, Thome AMT, Bozza FA. What factors predict length of stay in the intensive care unit? Systematic review and meta-analysis. J Crit Care. 2020;60(12):183-94.
13. Radu CP, Daniealopol V, Santini A, Darie R, Sala DT. Fatal hypocalcaemia due to hungry bone syndrome with secondary refractory hyperparathyroidism after parathyroidectomy: A case report. J Crit Care Med (Targu Mures). 2019;5(4):140-4.
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15. Limaye CS, Londhey VA, Nadkart MY, Borges NE. Hypomagnesemia in critically ill medical patients. J Assoc Physicians India. 2011;59(1):19-22.
16. Passakiotou M, Lampiri C, Kopatzidis E, Sounidakis N, Asimaki M, Gritsi-Gerogianni N. Magnesium at admission: Is it an outcome marker in the critically ill patient?. Critical Care. 2005;9(1):416-23.
17. Ribeiro HS, Burdmann EA, Vieira EA, Ferreira ML, Ferreira AP, Inda-Filho AJ. Association of magnesium abnormalities at intensive care unit admission with kidney outcomes and mortality: A prospective cohort study. Clin Exp Nephrol. 2022;26(10):997-1004.
18. Laddhad DS, Hingane V, Patil TR, Laddhad DD, Laddhad AD, Laddhad SD. An assessment of serum magnesium levels in critically ill patients: A prospective observational study. Int J Crit Illn Inj Sci. 2023;13(3):111-7.
19. Malinowska J, Małecka M, Ciepiela O. Variations in magnesium concentration are associated with increased mortality: Study in an unselected population of hospitalized patients. Nutrients. 2020;12(6):1836-43.
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Hasan Avsar, Metin Kilic, Arzu Oto, Mehmet Bosnak. Hypomagnesemia in pediatric intensive care unit: Etiology, risk factors and relationship of mortality. Ann Clin Anal Med 2025;16(5):336-340
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The role of general surgery in pediatric cases: Need for general surgery in patients under 18 and our clinical experiences
Arslan Hasan Kocamaz 1, Ömer Kişi 2, Alper Varman 2
1 Department of General Surgery, Kayseri State Hospital, Kayseri, 2 Department of General Surgery, School of Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.22403 Received: 2024-09-13 Accepted: 2024-10-21 Published Online: 2024-12-09 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):341-344
Corresponding Author: Arslan Hasan Kocamaz, Department of General Surgery, Kayseri State Hospital, Kayseri, Turkey. E-mail: md.ahkocamaz@gmail.com P: +90 530 967 64 11 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5257-9611
Other Authors ORCID ID: Ömer Kişi, https://orcid.org/0000-0001-8606-2453 . Alper Varman, https://orcid.org/0000-0002-1918-5143
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2023-09-15, No: 2023/4524)
Aim: Pediatric surgery encompasses surgical procedures for patients under 18 years of age, but there are still patients under 18 who are followed and operated on by general surgery. The aim of this study is to provide a clear definition of when general surgery should be involved in pediatric cases and to address the limitations of current practices.
Material and Methods: Data on demographic characteristics, admission indications, treatments, treatment outcomes, and complications for patients under 18 years of age who were admitted and treated in the general surgery clinic between January 2018 and January 2023 were retrospectively reviewed.
Results: Out of 41 cases treated in the general surgery clinic, 10 received medical treatment. Among the 31 patients who underwent surgery, 7 had head and neck surgery, 4 had laparoscopic cholecystectomy, and 2 had laparoscopic appendectomy. Additionally, seven patients had thoracic procedures, and 11 had colorectal procedures.
Discussion: Our study suggests that in the treatment of patients under 18 years of age, good physical development and the need for head and neck surgery or laparoscopy may necessitate the involvement of a general surgery clinic.
Keywords: General Surgery, Pediatric Surgery, Pediatric Surgical Care
Introduction
The Department of General Surgery is a specialty that treats surgical conditions requiring intervention through various surgical procedures for adult patients both nationally and internationally. In the past, many surgical specialties were considered subspecialties of general surgery, but over time, they have evolved into distinct departments. Pediatric surgery, previously a subspecialty of general surgery, became an independent department in 1982 [1]. Many diseases present different clinical and laboratory features in children compared to adults. For example, the risk of perforation in acute appendicitis increases with age in adults, while in children, the risk of perforation increases as age decreases [2]. Consequently, the field of pediatric surgery has grown in importance both globally and nationally. In the early years of the Republic, many surgical procedures fell under the domain of general surgery. However, with the rise of specialization and the establishment of many surgical subspecialties as independent fields, general surgery now primarily covers procedures related to the digestive system, endocrine system, breast surgery, endoscopic interventions, laparoscopic and robotic surgery, and minor surgical interventions. Surgical procedures involving patients under 18 years of age that fall within the domains of general surgery and urology are performed by pediatric surgery. However, the legislation does not clearly define which clinical discipline should manage patients of specific age groups. Additionally, due to various reasons, the physical development of patients does not always align with chronological age standards, leading to occasional assessments where patients under 18 may be considered adults in terms of phenotypic characteristics, medication dosages, and surgical procedures.
Our hospital established the Department of Pediatric Surgery in 1990 [3]. It continues to provide inpatient services, operate a surgical ward, and offer intensive care, along with training for medical residents. Pediatric surgery is recognized as a distinct specialty to address the unique needs of pediatric patients. Although pediatric surgery has become a specialized field, there are still situations where general surgery plays a critical role in managing pediatric patients due to certain procedural or logistical reasons [4]. Transitioning from pediatric to adult care often involves complex assessments, including physical development that may affect surgical decisions. These developmental differences can influence surgical choices. Especially in adolescents, surgical procedures may exhibit similar characteristics to those in adults [5]. Occasionally, patients may be directly referred to the general surgery clinic due to factors such as a shortage of available pediatric surgical faculty, the patient’s adult-like physical phenotype despite being under 18, rare diseases in childhood, or the need for specialized surgical interventions. In such cases, patients under 18 may be admitted and treated by the general surgery clinic.
Our study aims to review the demographic data, admission indications, and treatment outcomes of patients under 18 years of age who were admitted and treated in the general surgery clinic over a 5-year period, and to compare these findings with current literature.
Material and Methods
Demographic data, admission indications, treatments, treatment outcomes, and complications for patients under 18 years of age who were admitted and treated in the general surgery clinic from January 2018 to January 2023 were retrospectively reviewed using hospital database records.
Ethical Approval
Before starting the study, approval was obtained from the Necmettin Erbakan University Ethics Committee for Non-Interventional Research on Drugs and Medical Devices (Date: 2023-09-15, No: 2023/4524).
Results
A total of 41 cases were treated in the General Surgery Clinic. The average age of the cases was 15.8 years (ranging from 9 to 17 years), with the average age for females being 17 years (ranging from 16 to 17 years) and for males being 15 years (ranging from 9 to 17 years). The gender distribution was 56% (23) male and 44% (18) female (Table 1). Of the 41 cases, 31 received surgical treatment while 10 received medical treatment (Table 2). Among the medical cases, 1 case was admitted for type 3 hepatic hydatid cyst and underwent PAIR (Puncture, Aspiration, Injection, and Reaspiration). Four cases with abdominal pain were managed non-operatively, and 1 case was admitted for abdominal pain 8 days after a laparoscopic appendectomy but was found not to require surgical intervention (Table 3). Of the 31 cases that underwent surgical treatment, 1 case had total thyroidectomy, 1 case had left hemithyroidectomy, and 2 cases had right hemithyroidectomy due to pressure-related issues in the head and neck surgery domain. Thyroid malignancies are also common in the pediatric age group, and there are studies where pediatric patients are operated on by general surgeons [6]. In our clinic, a 16-year-old female patient with papillary thyroid carcinoma underwent right hemithyroidectomy and right central neck dissection. Parathyroid adenomas causing primary hyperparathyroidism have also been described in the pediatric age group, with surgery being the only treatment [7]. In our clinic, parathyroid adenoma excision was performed on one female and one male patient, both in their late teens. Since thyroid surgery is not performed in the pediatric surgery clinic, these cases were operated on by general surgery.
Genetic predisposition, age, infections, medications, parenteral nutrition, and comorbid conditions have been shown to influence the formation of gallstones in patients under 18 years of age [8]. The use of laparoscopic surgery in the pediatric population has grown in recent years, particularly in acute care surgery. These patients often present to hospitals without specialty-trained pediatric surgeons, and general surgeons may need to be prepared to handle these types of cases [9]. In our clinic, laparoscopic cholecystectomy was performed on 4 patients (3 females and 1 male) aged 14-17 due to cholelithiasis. Since laparoscopic hepatobiliary surgeries are not performed in the pediatric surgery clinic, these cases were operated on by general surgery. Two male patients aged 9 and 17 underwent laparoscopic appendectomy for acute appendicitis. The 9-year-old patient was referred to general surgery due to the absence of a pediatric surgical specialist, while the 17-year-old patient, who had an adult-like physical phenotype, was also managed by general surgery on the recommendation of pediatric surgery. The 17-year-old patient was readmitted on the 8th postoperative day due to abdominal pain, but after 1 day of monitoring, the patient was discharged following resolution of symptoms. A 17-year-old female patient underwent drainage for perforated appendicitis.
In the thoracic surgery domain, 5 female patients aged 16-17 underwent fibroadenoma excision from the breast. These patients presented with palpable breast masses to the general surgery clinic and were operated on by general surgery. A 15-year-old male patient underwent axillary lymph node excision. All histopathological results of these operations were benign. A 17-year-old male patient underwent lipoma excision from the scapula.
Rectal prolapse, which involves protrusion of part or all of the rectal mucosa through the anal sphincter, may require surgical treatment [10]. In our clinic, two male patients aged 16 and 17 underwent the Altemeier procedure for rectal prolapse. Both patients were directly referred to the general surgery clinic with complaints of rectal prolapse and were discharged on the 3rd and 4th postoperative days without complications. Three male patients aged 16 and 17 underwent excision and Limberg flap procedure for pilonidal sinus. Two patients were discharged on the 1st postoperative day, and one on the 2nd postoperative day without complications. Two male and one female patient aged 17 underwent drainage for perianal abscess, with all patients being discharged on the same day. Pilonidal sinus cases were referred from the clinic, while perianal abscess cases were admitted through the emergency department. A 16-year-old female patient underwent total proctocolectomy with ileal J-pouch anal anastomosis and protective ileostomy due to familial adenomatous polyposis. The patient experienced no early surgical complications and was discharged on the 4th postoperative day in good health. The ileostomy was closed approximately 3 months after the initial surgery.
Discussion
In the 2024 study by Brown and Lee, the role of general surgery in pediatric diseases and the challenges encountered in managing these conditions are addressed. The study explains not only the various responsibilities undertaken by general surgeons in pediatric cases but also their strategic thinking abilities and the responsibilities they assume in managing these cases [11].
The 2023 study by Zhou and Xu highlights that the role of general surgeons in pediatric surgery is increasingly expanding, with general surgeons taking on a critical role in some complex cases typically managed by pediatric surgeons[12]. This finding supports what we have noted in our study, emphasizing that general surgery plays a significant role in the treatment of pediatric diseases and provides a comprehensive approach in various medical and surgical situations.
Pediatric thyroid surgery includes procedures such as total and partial thyroidectomy, and these surgeries are managed by general surgeons, with an observed increase in prevalence [13]. In our study, 7 out of 31 patients underwent head and neck surgery.
Laparoscopic cholecystectomy has become a standard procedure for treating cholelithiasis in children, though its implementation can vary across centers [14]. Our study found that one of the main reasons for requiring general surgery in the pediatric age group was the need for laparoscopy. Management of rectal prolapse and pilonidal disease in pediatric patients often involves surgical intervention, and when pediatric surgical resources are limited, general surgeons may perform these procedures [15]. In our study, a significant portion of the general surgery need was in these areas.
Limitation
The retrospective nature of the study may introduce biases related to incomplete or inconsistent data recording. Future prospective studies could provide a more comprehensive view of the role of general surgery in pediatric cases. Over a span of 5 years, the sample size of 41 cases is relatively small, which may limit the generalizability of the findings to all general surgery practices. Larger and multicenter studies could enhance the generalizability of the results. Factors such as surgical techniques, surgeon experience, and institutional protocols can affect treatment outcomes. These confounding factors were not controlled for in this study, which may impact the interpretation of the results.
Conclusion
The integration of pediatric surgery and general surgery has become increasingly important and highlights the role of general surgeons in managing complex cases that often fall outside the scope of pediatric surgery. Although general surgery is traditionally focused on adult surgical patients, various factors may necessitate the treatment of pediatric patients by general surgery. Future research should focus on defining clear guidelines for when general surgery should be involved in pediatric cases and addressing limitations in current practices. The primary goal of our study was to determine that in the treatment of patients under 18 years of age, good physical development, the need for head and neck surgery, laparoscopy, and colorectal disease may require the involvement of the general surgery clinic.
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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6. Su Y, Cheng S, Diao C, Ma Y, Qian J, Cheng R. Surgical treatment of pediatric and adolescent papillary thyroid cancer: a retrospective study of 54 patients in a single center. J Pediatr (Rio J). 2022;98(4):425-30.
7. Oh A, Lee Y, Yoo HW, Choi JH. Three pediatric patients with primary hyperparathyroidism caused by parathyroid adenoma. Ann Pediatr Endocrinol Metab. 2022;27(2):142-47.
8. Zdanowicz K, Daniluk J, Lebensztejn DM, Daniluk U. The etiology of cholelithiasis in children and adolescents: a literature review. Int J Mol Sci. 2022;23(21):13376.
9. Laverty RB, Gallagher ME. Role of emergency laparoscopy in pediatric patients. In: Coccolini F, Podda M, Lim RB, Chiarugi M, editors. Mini-invasive approach in acute care surgery. Hot topics in acute care surgery and trauma. Cham: Springer; 2023. p.
10. Rentea RM, St Peter SD. Pediatric rectal prolapse. Clin Colon Rectal Surg. 2018;31(2):108-16.
11. Brown S, Lee K. General surgical approaches to pediatric diseases: a review. Pediatr Surg Clin North Am. 2024;41(2):203-13.
12. Zhou L, Xu Y. The role of general surgeons in pediatric surgical care: A review of current practices and future directions. Pediatr Surg Int. 2023;39(5):625-34.
13. Rosenberg J. Pediatric thyroid surgery: current trends and outcomes. Thyroid. 2021;31(2):223-31.
14. Smith A. Laparoscopic cholecystectomy in pediatric patients: a review. J Laparoendosc Adv Surg Tech A. 2020;30(5):525-33.
15. Johnson C. Management of rectal prolapse and pilonidal disease in children. Pediatr Surg Int. 2023;39(1):67-76.
Download attachments: 10.4328.ACAM.22403
Arslan Hasan Kocamaz, Ömer Kişi, Alper Varman. The role of general surgery in pediatric cases: Need for general surgery in patients under 18 and our clinical experiences. Ann Clin Anal Med 2025;16(5):341-344
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Are diabetes regulation and Vitamin B12 levels associated with the frequency and level of anxiety in diabetic patients?
Sertas Erarslan, Mehmet Aybars Aydin, Turkan P. Kilit
Department of Internal Medicine, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey
DOI: 10.4328/ACAM.22415 Received: 2024-09-22 Accepted: 2024-11-18 Published Online: 2024-12-09 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):345-349
Corresponding Author: Sertas Erarslan, Department of Internal Medicine, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey. E-mail: sertac_erarslan@hotmail.com P: +90 274 229 14 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6816-4154
Other Authors ORCID ID: Mehmet Aybars Aydın, https://orcid.org/0000-0003-1703-6715 . Türkan P. Kilit, https://orcid.org/0000-0003-1126-7336
This study was approved by the Ethics Committee of Kütahya Health Sciences University, Faculty of Medicine (Date: 2020-11-05, No: 2020/80-20)
Aim: In our study, we aimed to evaluate the frequency of anxiety in patients with type 2 diabetes and the effect of blood glucose regulation and vitamin B12 levels on anxiety.
Material and Methods: The study comprised 174 patients with Type 2 DM aged 18-65 years and 62 healthy controls. The study used a questionnaire form consisting of the Sociodemographic Characteristics Form, Clinical Data Form, and Beck Anxiety Scale as a data collection tool. Mann Whitney U test, t-test for independent variables, chi-square test, and Spearman correlation test were used to analyze the data. p<0.05 was accepted as a statistical significance value.
Results: Two hundred thirty-six people participated in our study, 174 in the case group and 62 in the control group. The mean age of the patient group was 53.7±9.0 years, and 51.1% were male. The study showed that HbA1c levels were regulated in 50.6% of diabetic patients, and vitB12 levels were adequate in 59.2%. There was no statistically significant difference between the anxiety levels and scores of Type 2 diabetic patients according to the regulation of HbA1c levels and vitB12 levels (p>0.05). The anxiety level and scores of diabetes patients were significantly higher than the control group (p<0.005).
Discussion: Anxiety is more common in patients with diabetes. Diabetes patients should be evaluated in terms of anxiety disorders that may accompany them. In addition, studies aimed at understanding the causes of anxiety in diabetic patients can determine the areas of intervention in this regard.
Keywords: Anxiety, Vitamin B12, Type 2 Diabetes Mellitus
Introduction
Diabetes mellitus (DM) is an important public health problem with rapidly increasing prevalence worldwide. According to 2011 estimates by the International Diabetes Federation (IDF), the number of individuals with diabetes is expected to increase from 366 million to 552 million by 2030 [Available: https://www.diabetesatlas.org]. Diabetes is a chronic metabolic disease characterized by impaired carbohydrate, fat, and protein metabolism due to insulin deficiency or impaired effects of insulin [1]. The goal in diabetic patients should be not only to control blood glucose levels but also to evaluate and prevent other system effects with a multidisciplinary approach to the management of the disease.
Recent studies have shown that the prevalence of psychiatric disorders is higher in patients with diabetes compared to the general population. Especially depression and anxiety are among the common comorbidities among patients with diabetes [2]. There is a complex two-way interaction process between diabetes and psychiatric disorders. Hyperglycemia or hypoglycemia may contribute to the development of depression and anxiety by affecting the central nervous system, while existing psychiatric conditions may adversely affect diabetes management by complicating glycemic control [3]. Again, physical complications caused by diabetes reduce the quality of life of patients, and this situation predisposes to the development of mental disorders such as depression and anxiety [4].
It is known that hematological problems such as megaloblastic anemia commonly develop in vitamin B12 deficiency [5]. In addition, plasma homocysteine levels increase in vitamin B12 deficiency due to deficiency of cobalamin, which is the active form (6), and various studies have reported that anxiety and depression develop by various mechanisms (oxidative stress, mitochondrial dysfunction, and especially dopaminergic neuron apoptosis) [7]. It is known that the frequency of vitamin B12 deficiency increases in patients with DM. Studies are showing that metformin, which is widely used especially in the treatment of diabetes, causes vitamin B12 deficiency by various mechanisms [8].
In this context, it is of great importance to understand the frequency of psychiatric disorders in patients with diabetes and the causes of these disorders. This study aimed to examine the frequency of anxiety, diabetes regulation status (HbA1c level), and the relationship between vitamin B12 levels and anxiety in individuals with diabetes.
Material and Methods
The study is a prospective case-control study conducted in Kütahya Health Sciences University Evliya Çelebi Training and Research Hospital Internal Medicine Outpatient Clinics between 01.06.2020-31.10.2020.
Inclusion criteria
Patients aged between 18-65 years and diagnosed with Type 2 DM
Exclusion criteria
Major surgery within the last one year,
Those with a history of intensive care unit hospitalization,
Acute cardiac event, Stage 3-4 heart failure,
Presence of chronic inflammatory disease,
Being on antidepressant treatment,
Those who do not use metformin and have not had a vitamin B12 test in the last year,
Patients diagnosed with COVID-19 or with a history of moderate to severe COVID-19.
Control group
Patients between the ages of 18-65 years and without a diagnosis of type 2 DM who applied to the outpatient clinic.
Research protocol
Fasting plasma glucose, HbA1c, and Vitamin B12 values, which were requested for routine control in Type 2 diabetes patients who applied to the outpatient clinic, were recorded. No non-routine investigations were ordered. Metformin is the first choice drug used in Type 2 diabetes and is used by the majority of patients with Type 2 diabetes. It is recommended in the Guideline of the Turkish Society of Endocrinology and Metabolism to check vitamin B12 in patients using metformin routinely. Patients were excluded from the study if they were not using metformin and did not have a vitamin B12 test performed in the last year.
The patient group was divided into two groups according to HbA1c level [group1: regulated (<7%), group2: non-regulated (>7%)], and the groups were compared statistically.
Vitamin B12 level below 200 pg/ml was recorded as low and above normal. The patient group was divided into two groups (group 1: sufficient, group 2: insufficient) according to VitB12 level, and the groups were compared statistically.
The independent variables of the study were vitamin B12 level and HbA1c level. The dependent variable was the anxiety level determined by the Beck anxiety scale.
The study used a questionnaire form consisting of a Sociodemographic Characteristics Form, Clinical Data Form, and Beck Anxiety Scale as a data collection tool. Beck Anxiety Scale (BAS): It is a self-assessment scale developed by Beck et al. (1988) and used to determine the frequency of anxiety symptoms experienced by individuals. It is a 21-item Likert-type scale. Its validity and reliability in Turkey were performed by Ulusoy, Şahin, and Erkmen (1998) (9). 0-7 points were evaluated as minimal anxiety, 8-15 points as mild anxiety, 16-25 points as moderate anxiety, and 26-63 points as severe anxiety.
Statistical methods
The data were recorded and analyzed using SPSS v24 software. Descriptive data of the study were expressed as percentage, mean, median, minimum, and maximum value 28. The suitability of the variables for normal distribution was evaluated by Kolmogorov-Smirnov test. The analyses used the Mann-Whitney U test, t-test for independent variables, chi-square test, and Spearman correlation test.
Ethical Approval
This study was approved by the Ethics Committee of Kütahya Health Sciences University, Faculty of Medicine (Date: 2020-11-05, No: 2020/80-20).
Results
The general characteristics of the patient and control groups in the study are given in Table 1. A total of 236 people, 174 of whom were diagnosed with type 2 diabetes mellitus in the case group and 62 in the control group, were included in the study. In the study, 51.1% (n=89) of the patient group and 54.8% of the control group were male. No significant difference was found between the groups according to gender distribution (p=0.618).
At least one additional chronic disease was present in 72.4% of the case group and 45.2% of the control group. The rate of additional chronic diseases was significantly higher in patients with diabetes compared to the control group (p<0.001). VitB12 level was found to be sufficient in 59.2% (n:103) of the case group and 33.9% (n:21) of the control group. VitB12 level was significantly higher in the case group (p₌ 0.001).
The participants’ mean age was statistically significantly higher in the case group (p<0.001). VitB12 level was statistically significantly higher in the control group (p=0.006). The mean LDL cholesterol values of the diabetic patients were 122.6±36.7 and 124.0±25.8 in the control group. There was no statistically significant difference between the mean LDL cholesterol values of the groups (p=0.821). Triglyceride levels in the case group were significantly higher than in the control group (p=0.040).
According to Beck Anxiety Scale scores, 23.0% (n=40) had minimal anxiety, 35.6% (n=62) had mild anxiety, 25.3% (n=44) had moderate anxiety, and 16.1% (n=28) had severe anxiety. In the control group, 74.2% (n=46) had minimal, 19.4% (n=12) mild, 4.8% (n=3) moderate, and 1.6% (n=1) severe anxiety. According to Beck Anxiety Scale scores, anxiety levels were found to be statistically significantly higher in the case group than in the control group (p<0.001)
The mean Beck anxiety score was 14 in the case group and 3 in the control group. Statistically, the anxiety score was significantly higher in the patient group with type 2 DM compared to the control group (p<0.001).
Table 2 shows the relationship between diabetes regulation and the Beck anxiety scale score. In the study, no statistical difference was found in terms of anxiety score in the groups separated according to HbA1c value and regulation status (p=0.908).
Table 3 shows the relationship between diabetes regulation and anxiety levels determined according to the Beck anxiety scale.
Table 3: The relationship between HbA1c and vitB12 levels and Beck Anxiety Scale levels in patients with type 2 DM.
The study found no statistical difference in the anxiety level in the groups separated according to HbA1c value and regulation status (p=0.416).
There was no significant difference between Beck Anxiety Scale scores (p=0.657) and anxiety levels (p=0.926) according to whether the vitamin B12 levels were sufficient or insufficient. Beck Anxiety Scale scores according to vitamin B12 levels of the patients are shown in Table 7, and Beck Anxiety Scale levels are shown in Table 8.
Discussion
In our study, the frequency of anxiety in diabetic patients and the relationship between anxiety and diabetes regulation and vitamin B12 level were investigated, and a higher frequency of anxiety was found in diabetic patients compared to a healthy control group. However, no significant relationship was found between anxiety, diabetes regulation, and vitamin B12 levels.
It is known that psychiatric disorders are more common in patients with diabetes than in the general population. There is data that changes in metabolic control hurt the mental health of diabetic patients. The most common psychiatric disorders associated with DM are anxiety and depression [10]. In DM, the treatment of which requires continuity as in all chronic diseases, the individual’s lifestyle and compliance with treatment are of great importance in the control of the disease. Many factors specific to the disease, treatment, and individual are effective in adaptation to diabetes. In addition, the mental state and social life of the individual are also negatively affected due to the physiopathological changes that occur due to diabetes. In addition to all these, the anxiety level of the individual with diabetes increases due to reasons such as negative effects on sexual life, failure to control blood glucose, the occurrence of complications with the disease, and stress in work life, making it difficult to control the disease [11]. In a large-scale study, it was found that patients with DM experienced significant levels of depression, anxiety, and stress, respectively, compared to healthy controls, and anxiety was more common than depression and stress [12]. In a study conducted with 400 Type 2 diabetes patients in Turkey, anxiety symptoms were found in 21.8% and depression symptoms in 42% of the patients [13]. In another study conducted in Turkey on the frequency of anxiety in patients with DM, the frequency of anxiety was found to be 38.2% in the study by Kayabaşı et al. [14]. In our study, it was found that 25.3% of diabetic patients had moderate anxiety and 16.1% had severe anxiety. Anxiety levels of diabetic patients were found to be significantly higher than the control group without diabetes. The findings of our study reveal that the frequency and level of anxiety in diabetic patients are higher, similar to the literature. It was thought that the rate differences between the studies may be due to the use of different methods and scales to determine and evaluate anxiety status.
Epinephrine secretion is stimulated during anxiety, which is defined as tension in which the self is felt to be under threat, and epinephrine is known to decrease the metabolic effect of insulin. In stressful situations, free fatty acids, cortisol, and blood glucose levels increase, and stress and anxiety are seen to be important factors in patients in whom plasma glucose levels cannot be regulated despite medical treatment. Therefore, anxiety is associated with inadequate glycemic control and increased medical complications in patients with diabetes [15, 16]. This risk has been reported to be higher in patients with younger age at diabetes onset [17]. The mechanisms between stress and HbA1c include physiological, psychological, behavioral, and environmental influences. Anxiety and stress may affect the treatment and follow-up processes in many different ways other than their physiological effects on glucose regulation. Anxiety disorders, especially avoidance of insulin and blood glucose monitoring due to phobia, keeping blood glucose at a low level due to anxiety related to diabetes complications and the risk of hypoglycaemic attacks, and excessive control of blood glucose in obsessive-compulsive disorder may adversely affect patients’ self-management [15, 18].
In a study, anxiety level was found to be high in diabetic patients, and it was reported that anxiety was related to HbA1c level [19]. In our study, no significant difference was found between HbA1c values and anxiety levels in the groups according to the state of being regulated. It was thought that this may have resulted from other factors affecting the anxiety and glucose regulation of the patients.
Vitamin B12 is an essential micronutrient required for optimal hematopoiesis in the bone marrow, neurological, and cognitive functions. Various clinical findings and diseases, including memory impairment, dementia, delirium, peripheral neuropathy, subacute combined degeneration of the spinal cord, megaloblastic anemia, and pancytopenia in deeper deficiencies may develop in its deficiency [20]. Studies have shown that the prevalence of vitamin B12 deficiency varies between 5.8% and 33% in patients with type 2 DM [21, 22]. In our study, when vitamin B12 levels of diabetic patients were evaluated, it was found to be insufficient in 40.8%. This wide variation in the prevalence of vitamin B12 deficiency in the studies in the literature and our study can probably be explained by differences in the definitions of vitamin B12 deficiency and the accepted limit values. In studies, it has been found that B12 levels of diabetic patients were lower compared to control groups [23]. This is generally explained by the fact that metformin, an agent used in the treatment of diabetes, inhibits vitamin B12 absorption in diabetic patients. Raizada et al. showed that metformin use was associated with low vitamin B12 levels [24]. In our study, when vitamin B12 values of Type 2 diabetes patients and the control group were compared, it was found that vitamin B12 values of diabetes patients were statistically significantly higher. This was thought to be due to the differences in the agents used in the treatment and the duration of diabetes. In addition, since our study was conducted with patients who were being followed up in a tertiary health center, it is expected that vitamin B12 level follow-up and support are provided. It is known that 35% of patients with vitamin B12 deficiency have neuropsychiatric symptoms, and vitamin B12 deficiency causes organic psychosis with impaired brain function. The study by Baldewicz et al. showed a relationship between low vitamin B12 levels and anxiety [25]. However, Saraswathy et al. reported in their study that vitamin B12 levels were not directly related to anxiety disorder, but homocysteine elevation due to vitamin B12 deficiency constituted a significantly increased risk for depression and generalized anxiety disorder [7]. In our study, similar to the literature, no significant difference was found between Beck Anxiety Scale scores and anxiety levels of diabetic patients according to whether their vitamin B12 levels were sufficient or insufficient.
Conclusion
Anxiety is more common in diabetic patients. The cause of anxiety may be multifactorial and should be evaluated in this respect during follow-up, and necessary support should be given. In our study, the relationship between diabetes regulation status, vitamin B12 level, and anxiety could not be determined. Our study has some weak points. These can be said to be the low number of patients and control groups, the lack of evaluation of other metabolic parameters, and the effect of insulin use. There is a need for more comprehensive studies on this subject. In this way, the cause of anxiety can be clarified, and more effective follow-up and treatment can be applied.
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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Comparison of plasma homocysteine, hs-crp, fibrinogen, vitamin B12, and folic acid levels in cases with pseudoexfoliative glaucoma and primary open-angle glaucoma
Cigdem Coskun 1, Ulviye Yiğit 2
1 Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, 2 Department of Ophthalmology, Faculty of Medicine, Haliç University, Istanbul, Turkey
DOI: 10.4328/ACAM.22421 Received: 2024-09-27 Accepted: 2024-11-11 Published Online: 2024-12-09 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):350-354
Corresponding Author: Cigdem Coskun, Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey. E-mail: drcigdem@hotmail.com P: +90 312 552 60 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2215-306X
Other Authors ORCID ID: Ulviye Yiğit, https://orcid.org/0000-0003-0176-1509
This study was approved by the Ethics Committee of Bakırköy Dr. Sadi Konuk Research and Education Hospital (Date: 2009-03-12, No: 23)
Aim: This study aims to compare plasma levels of homocysteine,hsCRP, fibrinogen, vitamin B12, and folic acid in cases diagnosed with Pseudoexfoliative Glaucoma (PEXG) and Primary Open-Angle Glaucoma (POAG).
Material and Methods: The study included 47 patients with PEXG and 42 patients with POAG. All participants underwent visual acuity measurement using the Snellen chart, intraocular pressure measurement using Goldmann applanation tonometry, examination of the anterior and posterior segments of the eye, and visual field assessment using the Humphrey Field Analyzer with the 30-2 protocol. To evaluate the biochemical parameters, blood samples were collected from the patients at 09:00 in the morning, following a 12-hour overnight fasting period, considering dietary restrictions and medication use.
Results: The homocysteine levels (14.28±6.93) and hs-CRP levels (6.86±10.29) of the PEXG group were found to be significantly higher compared to the POAG group (9.98±6.21,2.95±3.15, respectively) (p<0.01). There were no statistically significant differences between the PEXG and POAG groups in terms of fibrinogen, folic acid, and vitamin B12 levels (p>0.05). A significant negative correlation was observed between homocysteine and vitamin B12 in PEXG and POAG groups (p<0.01).In the POAG group, a significant negative correlation was found between homocysteine and folic acid (p<0.01).
Discussion: Glaucoma remains a significant cause of irreversible and preventable blindness worldwide. Vascular diseases are known to play a role in the pathogenesis of glaucoma. Homocysteine, by affecting platelet and coagulation parameters and inducing endothelial dysfunction, can contribute to vascular damage.CRP activates inflammatory processes associated with atherosclerosis in endothelial cells. We believe that homocysteine and CRP could be potential risk factors in the development of glaucoma in PEXG and POAG patients.
Keywords: Glaucoma, Homocysteine, Hs-CRP, Fibrinogen, Vitamin B12, Folic Acid
Introduction
Primary open-angle glaucoma (POAG) is a chronic, bilateral, and often asymmetrical optic neuropathy observed in adults, characterized by an open anterior chamber angle, intraocular pressure (IOP) above 21 mmHg, and acquired loss in optic nerve fibers and visual fields. Pseudoexfoliation syndrome is a pathology marked by the chronic accumulation of a gray-white fibro granular material, known as pseudoexfoliation material (PEX), on the anterior lens capsule and/or the pupillary margin [1]. Cases in which exfoliation material accumulates in the eye are defined as pseudoexfoliation syndrome (PES), while those where this accumulation leads to increased intraocular pressure are classified as pseudoexfoliation glaucoma (PEXG) [2].
The etiopathogenesis of both POAG and PEXG has not yet been fully elucidated, and research on the subject is ongoing. It is believed that the pathogenesis of optic nerve damage in POAG is complex and involves multiple factors, such as increased intraocular pressure, neurotoxicity, apoptosis, extracellular matrix changes, and hypoxia secondary to ocular and systemic vascular alterations [3]. Anterior segment ischemia, which develops in association with increased extracellular matrix modulators and oxidative stress factors in the aqueous humor, is thought to play a significant role in the pathogenesis of PEXG [4].
The vascular dysfunction implicated in the etiopathogenesis of glaucoma may develop as a result of vascular endotheliopathy. Systemic inflammation is one of the key causes of vascular endotheliopathy. C-reactive protein (CRP) and fibrinogen are markers of inflammation, and studies have reported elevated levels of these markers in glaucoma. Similarly, increased plasma homocysteine levels have been reported in glaucoma, which is associated with a higher risk of atherosclerosis and contributes to endothelial damage and dysfunction, thereby playing a role in the disease’s etiopathogenesis. Folic acid, vitamin B6, and vitamin B12 act as cofactors in homocysteine metabolism, and deficiencies in these factors lead to elevated plasma homocysteine levels [5]. In the literature, elevated serum homocysteine levels and decreased folic acid levels have been detected in PEXG, and it has been suggested that folic acid supplementation may be beneficial in these cases [6]. In our study, plasma homocysteine, hs-CRP, fibrinogen, vitamin B12, and folic acid levels were measured and statistically analyzed in cases of POAG and PEXG.
Material and Methods
Our study included 89 cases diagnosed with PEXG and POAG, followed between February 2008 and March 2009 at the Ophthalmology Clinic of Bakırköy Dr. Sadi Konuk Training and Research Hospital. All patients underwent a comprehensive ophthalmologic examination. Uncorrected and corrected visual acuity was measured using the Snellen chart. Intraocular pressure was measured using a Goldmann application tonometer. Anterior segment examination was performed using a biomicroscope. The iridocorneal angle was evaluated with a Goldmann three-mirror goniolens. After pupil dilation, the optic disc was assessed. For the evaluation of the visual field, the central 30-2 standard threshold test was performed using a Humphrey Field Analyzer.
The inclusion criteria for the study were as follows: for POAG cases, intraocular pressure of 21 mmHg or higher, or within normal limits through medical or surgical treatment; optic disc cupping upon examination; absence of other pathologies that could cause elevated intraocular pressure; typical glaucomatous visual field loss during visual field testing; and an open iridocorneal angle. For PEXG cases, in addition to the aforementioned criteria, the presence of pseudoexfoliation material in one or both eyes was required.
Patients with conditions related to hyperhomocysteinemia (such as coronary artery disease, myocardial infarction, peripheral artery disease, chronic kidney failure, uncontrolled arterial hypertension, diabetes mellitus, cerebrovascular disease, chronic alcohol use, a diet rich in B vitamins, or those taking B vitamin supplements, as well as those with ocular vascular diseases [such as retinal vein occlusion, retinal artery occlusion, or ischemic optic neuropathy]), and patients taking vitamins or medications that could affect homocysteine metabolism were excluded from the study.
To assess biochemical parameters, blood samples were collected from patients at 09:00 AM after 12 hours of overnight fasting. Blood samples for homocysteine and hs-CRP were collected into vacutainer gel tubes and for fibrinogen into 3.2% sodium citrate anticoagulant tubes. After appropriate centrifugation, the serum designated for homocysteine analysis was stored at -20°C for later testing. Fibrinogen was measured on the same day from the obtained plasma using a Dade Behring kit on a Cysmex-CA 1500 coagulation analyzer. The hs-CRP test was performed on the same day using a Radim kit on a Delta Seac nephelometer. Once all samples were collected, those for homocysteine testing were thawed and analyzed using an Immulite analyzer with the original kit by chemiluminescence method. Serum vitamin B12 and folic acid levels were also measured using the chemiluminescence method.
Statistical Analysis
The findings obtained in the study were analyzed using NCSS 2007 & PAS 2008 Statistical Software (Utah, USA). In addition to descriptive statistical methods (mean, standard deviation), the Student’s t-test was used to compare quantitative data between two groups for parameters with normal distribution, while the Mann-Whitney U test was used for comparisons between two groups for parameters without normal distribution. Pearson correlation analysis was applied to examine relationships between parameters with normal distribution, and Spearman’s rho correlation analysis was used for parameters without normal distribution. The Chi-square test was used for comparisons of qualitative data. Results were evaluated within a 95% confidence interval, with statistical significance set at p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Bakırköy Dr. Sadi Konuk Research and Education Hospital (Date: 2009-03-12, No: 23).
Results
Of the patients included in the study, 51 (57.3%) were female, and 38 (42.7%) were male. The mean age was 65.77±12.98 years. The mean age of the PEXG group was 73.48±9.69, while the mean age of the POAG group was 57.14±10.58, with a statistically significant difference in mean age between the groups (p<0.001).
The homocysteine level (14.28±6.93) and hs-CRP level (6.86±10.29) in the PEXG group were found to be significantly higher than those in the POAG group (9.98±6.21 and 2.95±3.15, respectively) (p<0.01). No statistically significant differences were found between the PEXG and POAG groups regarding fibrinogen, folic acid, and vitamin B12 levels (p>0.05) (Table 1).
The correlation between homocysteine vitamin B12 and folic acid was evaluated in both the PEXG and POAG groups. A significant negative correlation was found between homocysteine and vitamin B12 in both the PEXG and POAG groups (correlation coefficients of 41.1% and 32.4%, respectively) (p<0.01) (Table 2). In the POAG group, a significant negative correlation of 44.8% was found between homocysteine and folic acid (p<0.01). No statistically significant correlation was observed between homocysteine and folic acid in the PEXG group (p>0.05) (Table 4).
Discussion
The pathogenesis of optic nerve damage due to glaucoma is still not fully understood. Although intraocular pressure (IOP) is known as the most important risk factor, vascular risk factors also play a significant role in the pathogenesis of optic nerve damage. Atherosclerosis, vascular dysregulation, and similar conditions lead to the disruption of anatomical and functional structures. These factors cause various problems in blood circulation at the optic nerve head due to abnormal microcirculation and perfusion [7]. Elevated homocysteine levels are thought to induce smooth muscle cell proliferation through endothelial cell damage and atherosclerosis through platelet activation thrombogenesis. It is suggested that the vascular effects of homocysteine may contribute to the disruption of microcirculation at the optic nerve head in glaucoma.
Epidemiological studies have shown elevated total plasma homocysteine levels in various cardiovascular diseases. Hyperhomocysteinemia has been identified as a risk factor for the development of atherosclerosis, as well as in patients with peripheral vascular, cerebrovascular, and coronary heart diseases [8].
The incidence of systemic vascular disease is higher in cases with pseudoexfoliation [9]. Hyperhomocysteinemia has also been identified as a risk factor for non-arteritic ischemic optic neuropathy and central retinal artery occlusion [10]. Similarly, a relationship has been observed between pseudoexfoliation syndrome (PES) and central retinal vein occlusion, as well as branch retinal vein occlusion [11]. In studies conducted by Vessani et al. and Leibovitch et al., plasma homocysteine levels were found to be higher in patients with PEXG compared to the control group [12, 13].
In the study conducted by Altıntaş et al., which evaluated plasma homocysteine and nitric oxide levels, it was found that plasma homocysteine levels were higher in patients with PES and PEXG compared to the POAG and control groups. However, no statistically significant difference was observed between the groups regarding plasma nitric oxide levels [14]. Similarly, in our study, homocysteine levels were found to be statistically significantly higher in the PEXG group compared to the POAG group. In contrast, in the study conducted by Turaçlı et al., plasma homocysteine levels in patients with PES and PEXG were found to be similar to those in the control group [15].
In the study by Puustjarvi et al., which examined homocysteine levels in plasma and aqueous humor, it was found that plasma homocysteine levels were higher in the PEXG group compared to the control group, while the homocysteine level in the aqueous humor was found to be similar to that of the control group [16]. In the study conducted by Bleich et al., plasma and aqueous humor homocysteine levels in patients with PEXG were found to be higher compared to the control group. Additionally, a statistically significant positive correlation was identified between serum and aqueous humor homocysteine levels in this study. This finding suggests an important relationship between homocysteine levels in plasma and aqueous humor, which may indicate the disruption of the blood-aqueous barrier [17].
In the study by Roedl et al., homocysteine levels in tears and blood samples were investigated in patients with PEXG and the control group. They found that plasma and tear homocysteine levels were higher in patients with PEXG compared to the control group. Furthermore, they demonstrated a statistically significant relationship between the homocysteine level in tears and the homocysteine level in plasma within the PEXG group [4]. However, in the study by Bleich et al., no statistically significant difference was found in aqueous humor homocysteine levels between POAG and PEXG patients [17].
In our study, we found a statistically significant negative correlation between homocysteine and vitamin B12 levels in the PEXG group. Roedl et al. also reported an increase in homocysteine levels and a decrease in vitamin B12 and folic acid levels in the PEXG group [6]. Jacques et al. demonstrated a significant negative correlation between homocysteine levels in tears and plasma and serum vitamin B12 levels in patients with PEXG [18]. Since it has been shown that administering vitamin B12, folic acid, and vitamin B6 can reduce homocysteine levels in individuals with hyperhomocysteinemia, it is recommended that these parameters be investigated and treatment initiated in those with low levels [19]. Similarly, it has been suggested that B vitamin therapy may mitigate the adverse effects of vitamin B deficiency and reduce elevated homocysteine levels in patients with PEXG [6].
In the study by Puustjarvi et al., no statistically significant difference was found between the PEXG group and the control group regarding plasma folic acid, serum vitamin B6, and vitamin B12 levels [16]. Cumurcu et al. reported lower folic acid levels and higher homocysteine levels in the PEXG group compared to other groups in their study involving POAG, PEXG, NTG, and the control group. However, they did not find statistically significant differences in plasma homocysteine, folic acid, and vitamin B12 levels among the POAG, NTG, and control groups [20].
C-reactive protein (CRP) levels increase in inflammatory reactions occurring in vascular endothelium and smooth muscle, and elevated plasma CRP levels have been associated with vascular endothelial dysfunction and plaque formation. It has been reported that CRP exerts prothrombotic and pro-inflammatory effects on endothelial cells and that CRP has prothrombotic and pro-inflammatory effects on endothelial cells. Recently, increased levels of this protein have been demonstrated in vascular atherosclerotic events such as coronary syndromes, ischemic stroke, and peripheral vascular diseases [21]. Although many studies have reported impaired vascular endothelial function in glaucoma patients with NTG, a direct relationship between vascular inflammation and glaucoma has not been established [22].
In the study conducted by Leibovitch et al., hs-CRP levels were found to be higher in patients with normal-tension glaucoma (NTG) compared to the control group; however, they included cases with hypertension, diabetes mellitus, and ischemic heart disease in their study. In contrast, Su et al. reported no significant difference in hs-CRP levels between NTG and POAG cases in their study, where they did not include patients with atherosclerotic diseases. They concluded that excluding patients with systemic diseases would allow for a better determination of the relationship between glaucoma and CRP [22]. In our study, which did not include patients with atherosclerotic diseases, we found hsCRP levels in the PEXG group to be statistically significantly higher than those in the POAG group.
Epidemiological studies have demonstrated that plasma fibrinogen levels are a significant risk factor for coronary heart disease. In their study evaluating the coagulation and fibrinolytic systems, Matsumoto et al. found a significant increase in platelet aggregation in patients with NTG compared to those with POAG; however, they did not find a significant difference between the two groups regarding prothrombin time (PT), activated partial thromboplastin time (APTT), or fibrinogen levels [23]. Matsumoto et al. reported imbalances in coagulation and biochemical measurements in a large group of glaucoma patients [24]. In our study, we did not find a statistically significant difference in fibrinogen levels between the PEXG and POAG groups.
Conclusion
Plasma homocysteine levels were found to be higher in PEXG compared to POAG. It was observed that while plasma homocysteine levels increased in both PEXG and POAG cases, there was a decrease in vitamin B12 levels. To prevent ocular and systemic ischemic changes, as well as neurodegeneration in glaucoma, we believe that broader studies are necessary to investigate the effects of factors such as homocysteine, hs-CRP, fibrinogen, vitamin B12, and folic acid in the etiopathogenesis. Furthermore, the efficacy of vitamin B and folic acid supplementation in cases where these parameters are found to be low should also be examined.
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. Roedl JB, Bleich S, Reulbach U, Rejdak R, Kornhuber J, Kruse FE, et al. Homocysteine in tear fluid of patients with pseudoexfoliation glaucoma. J Glaucoma. 2007;16(2):234-9.
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6. Roedl JB, Bleich S, Reulbach U, Rejdak R, Naumann GO, Kruse FE, et al. Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma. J Neural Transm. 2007;114(5):571-5.
7. Flammer J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21:359-93.
8. Hermann A, Sitdikova G. Homocysteine: biochemistry, molecular biology and role in disease. Biomol Ther. 2021;11(5):737.
9. Scharfenberg E, Rauscher FG. Meier P, Hasenclever D. Pseudoexfoliation syndrome: analysis of systemic comorbidities of 325 PEX-positive patients compared with 911 PEX-negative patients. Graefes Arch Clin Exp Ophthalmol. 2019;257:2471–80.
10. Pianka P, Almog Y, Man O, Goldstein M, Sela BA, Loewenstein A. Hyperhomocysteinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology. 2000;107:1588-92.
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12. Vessani RM, Ritch R, Liebmann JM, Jofe M. Plasma homocysteine is elevated in patients exfoliation syndrome. Am J Ophthalmol. 2003;136:41-6.
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14. Altintaş O, Maral H, Yüksel N, Karabaş VL, Dillioğlugil MO, Cağlar Y. Homocysteine and nitric oxide levels in plasma of patients with pseudoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 2005;243:320-7.
15. Turaçlı E, Tekeli O, Özdemir F, Akar N. Methylenetetrahydrofolate reductase 677 C-T and homocysteine levels in Turkish patients with pseudoexfoliation. Clin Exp Ophthalmol. 2005;33(5):505-8.
16. Puustjärvi T, Blomster H, Kontkanen M, Punnonen K, Teräsvirta M. Plasma and aqueous humour levels of homocysteine in exfoliation syndrome. Graefes Arch Clin Exp Ophthalmol. 2004;242:749-54.
17. Bleich S, Roedl J, Von Ahsen N, Schlötzer-Schrehardt U, Reulbach U, Beck G, et al. Elevated homocysteine levels in aqueous humor of patient with pseudoexfoliation glaucoma. Am J Ophthalmol. 2004;138:162-4.
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Cigdem Coskun, Ulviye Yiğit. Comparison of plasma homocysteine, hs-crp, fibrinogen, vitamin B12, and folic acid levels in cases with pseudoexfoliative glaucoma and primary open-angle glaucoma. Ann Clin Anal Med 2025;16(5):350-354
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Evaluation of patients with vertebral osteomyelitis diagnosis: Ten years of experience
Nurbanu Sezak 1, Burcu Açıkalın Arıkan 2, Gülçin Oltulu 2, Özge Eren Korkmaz 3
1 Department of Infectious Diseases and Clinical Microbiology, Demokrasi University, Buca Seyfi Demirsoy Training and Research Hospital, 2 Department of Infectious Diseases and Clinical Microbiology, Buca Seyfi Demirsoy Training and Research Hospital, 3 Department of Epidemiology, Dokuz Eylül University, İzmir, Türkiye
DOI: 10.4328/ACAM.22458 Received: 2024-10-16 Accepted: 2024-11-25 Published Online: 2024-12-24 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):355-359
Corresponding Author: Nurbanu Sezak, Department of Infectious Diseases and Clinical Microbiology, Demokrasi University, Buca Seyfi Demirsoy Training and Research Hospital, İzmir, Türkiye. E-mail: sezaknurbanu1@gmail.com P: +90 505 805 75 72 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9472-1340
Other Authors ORCID ID: Burcu Açikalin Arikan, https://orcid.org/0000-0002-4955-0789 . Gülçin Oltulu, https://orcid.org/0009-0008-8790-5713 . Özge Eren Korkmaz, https://orcid.org/0000-0002-9476-4938
This study was approved by the Ethics Committee of Non-Interventional Clinical Research İzmir Buca Seyfi Demirsoy Training and Research Hospital (Date: 2024-04-24, No: 2024/270)
Aim: An infection of the vertebrae and intervertebral disc is known as vertebral osteomyelitis (VO). Examining the demographics, comorbidity variables, etiologies, significant laboratory results, and diagnostic and therapeutic techniques of VO cases that were monitored and treated over a ten-year period was the goal of this study.
Material and Methods: Demographic information, clinical symptoms, chronic illnesses, history of vertebral operations, involved vertebral levels, diagnostic methods, leukocyte count (WBC), erythrocyte sedimentation rate (ESR), serum C-reactive protein level (CRP), amount of hematocrit (HTC), results of microbiological cultures, and agent-specific serology results of the cases followed up with VO diagnosis between January 1, 2014 and January 1, 2024 were collected and analyzed from patient files.
Results: The mean age of the 125 cases included in the study was 57.5±13.8 years, and the M/F ratio was 1/1.7. The presenting complaints were pain (100%), neurological symptoms (60%), fever (15.2%), fatigue (12%), night sweats (4.8%), and weight loss (0.8%). The cases were diagnosed by imaging methods (92%) or microbiological methods (8%). Comorbidities observed included diabetes (20.8%), renal disease (10.4%), rheumatological disease (3.2%), malignancy (1.6%), history of spinal surgery (31.2%), trauma (13.6%), urinary tract infection (7.2%), nonspecific infection (6.4%), and a history of cerebrovascular events (0.8%). The average response time for ESR and CRP related to pain was found to be around the third week.
Discussion: Evaluating pain symptoms, planning imaging methods, confirming diagnosis through biopsy, and initiating pathogen-targeted treatment will be significant steps in enhancing the success of VO treatment. ESR and CRP serve as early indicators for follow-up.
Keywords: Vertebra, Osteomyelitis, Brucellosis, Treatment
Introduction
Vertebral osteomyelitis (VO) is a pyogenic, granulomatous or parasitic infection of the vertebrae and intervertebral disc. Although it usually develops via hematogenous route, it may also occur via neighborhood or direct inoculation [1]. In the literature, risk factors for the development of VO include diabetes mellitus (DM), immunosuppression, chronic heart disease, liver cirrhosis, intravenous drug use, Human Immunodeficiency Virus (HIV) infection, history of spinal surgery, presence of a foreign body in the vertebra, chronic kidney disease, presence of intravenous catheter, and history of bacteremia [2]. There has been an increase in the incidence of VO over the years due to the prolongation of life expectancy in society, the increase in the incidence of chronic diseases with advancing age, and the widespread use of spinal surgical interventions and other invasive interventions that may trigger bacteremia. This increase is especially evident in the elderly age group who need healthcare services more frequently and more frequently [3, 4].
Pain is the most common complaint that brings patients to the physician. Fever is a relatively less common symptom. Diagnosis is usually made by blood cultures, biopsy cultures and imaging methods in the presence of clinical findings, especially pain [5, 6]. In our country, brucellosis-related VO is still common in patients with a history of unpasteurized milk and dairy product consumption and animal husbandry. In these patients, the diagnosis is made with the help of detailed anamnesis and serologic tests [7]. In addition to all risk factors, an increase in the risk of VO is observed especially in the elderly population [8]. With the increase in the elderly population, easier access to healthcare services and widespread use of invasive medical interventions, VO has become an important infectious disease that infectious diseases specialists follow up with long-term antibiotic treatment. The aim of this study was to evaluate the demographic characteristics, comorbidity factors, etiologies, important laboratory findings, and diagnostic and therapeutic modalities of VO cases followed and treated in the infectious diseases unit of our hospital.
Material and Methods
The study was designed as retrospective and observational. The data of all cases followed up with the diagnosis of VO in the infectious diseases clinic and outpatient clinic of our hospital in the ten-year period between January 1, 2014 and January 1, 2024 were obtained through the hospital information system. Patients who were diagnosed with VO both clinically and by imaging methods (magnetic resonance imaging (MRI) or computed tomography (CT) and treated were included in the study. Patients with missing data were excluded. Demographic data, clinical symptoms, chronic diseases, vertebral operation history, diagnostic methods, leukocyte count (WBC), erythrocyte sedimentation rate (ESR), serum C-reactive protein level (CRP), hematocrit (HTC), microbiological culture results and agent-specific serology results were recorded. Data on the treatments administered to the patients, treatment durations and clinical response status of the patients were obtained from the patient files.
Descriptive statistics of the study were performed using the R program (Version 2024.04.1+748, Copyright (C) 2024 by Posit Software, PBC). The conformity of continuous variables to normal distribution was evaluated by Shapiro-Wilk test. Data conforming to normal distribution were expressed as mean and standard deviation, and data not conforming to normal distribution were expressed as median, Q1 and Q3. Descriptive statistics were performed using “dplyr” and “psych” packages in R.
Ethical Approval
This study was approved by the Non-Interventional Clinical Research Ethics Committee of İzmir Buca Seyfi Demirsoy Training and Research Hospital (Date: 2024-04-24, No: 2024/270).
Results
A total of 125 patients were included in the study. The mean age was 57.5± 13.8 years, 36.8% (n=46) were male and 63.2% (n=79) were female. When the presenting complaints were evaluated, pain symptoms were observed in all cases. Neurologic symptoms were present in 60%, fever in 15.2%, fatigue in 12%, night sweats in 4.8%, and weight loss in 0.8%. Imaging methods were used in 92% of the cases and microbiologic methods in 8%. The most common finding on imaging methods was an abscess (19.2% of cases) and the most common location was the paravertebral region (54%, n=13/24). Mortality was not observed in any of the cases. Demographic and clinical characteristics of the cases are shown in Table 1.
When the causes were evaluated, it was seen that brucellosis infection was the cause of VO in 10 cases (8%). In only 8 cases (6.4%), culture samples were taken from the site of involvement for diagnostic purposes. No growth was detected in 6 of these cases, 1 had methicillin-sensitive Staphylococcus aureus (MSSA) and 1 had extended spectrum betalactamase (ESBL) positive Klebsiella pneumoniae.
The cases were analyzed in terms of risk factors for the development of VO. Diabetes was present in 20.8%, renal disease in 10.4%, rheumatologic disease in 3.2%, and malignancy in 1.6%. In addition, 31.2% had a history of spinal surgery, 13.6% trauma, 7.2% urinary tract infection (UTI), 6.4% nonspecific infection, and 0.8% cerebrovascular accident (CVA) (Table 2).
When the laboratory results of the patients were analyzed, the median leukocyte count was 7800 103/uL, the median CRP was 21 mg/L, the median ESR was 51 mm/h and the median HTC was 35.5% (Table 3).
The mean duration of initial parenteral treatment was 3 weeks, the mean duration of oral maintenance treatment was 6 weeks, and the mean duration of improvement of laboratory results was 3 weeks. The mean duration of pain response with treatment was found to be 21 days.
Discussion
Vertebral osteomyelitis is a disease with an increasing incidence, affecting especially the population over the age of 50, requiring a multidisciplinary approach to diagnosis and treatment [9,10]. In our study, it was observed that the majority of the patients diagnosed with VO were females and all of them had complaints of low back pain. Low back pain is reported to be the most common symptom in the literature [5,6]. In our study, the second most common symptom was neurologic disorder, the majority of which was difficulty in walking. Fever, which may be more indicative of the diagnosis of infection, was found in 15% of the patients. In a study conducted in Turkey between 2000 and 2007 by Mete B. et al. in which 100 cases were included, it was reported that fever was found in 50% of the cases [5]. In our study, 10 of 125 cases were diagnosed with brucellosis, whereas in the study by Mete B. et al. 24 of 100 cases were diagnosed with brucellosis and 32 with tuberculosis [5]. Although we are in a country where brucellosis and tuberculosis diseases are endemic, there were no patients diagnosed with tuberculosis in our cases and our brucellosis diagnosis was low. In the study conducted by Elbahr et al. between 2009 and 2019, in which 100 cases were included, 26 of the VO cases were diagnosed with tuberculosis and 15 with brucellosis. It was found that fever symptoms were most common in VO cases diagnosed with brucellosis, with a total rate of 33% [11]. In another study conducted in Turkey, it was reported that the presence of fever was statistically significant in VO cases diagnosed with brucellosis [12].
When the studies in the literature are evaluated, it is noteworthy that Staphylococcus aureus and Mycobacterium tuberculosis are the most frequently detected agents in cases of VO [11, 13]. The reason for the low number of patients from whom the causative agent could be isolated in our study was the low rate of vertebral biopsy.
When the cases were analyzed in terms of comorbid conditions, spinal surgery, trauma, DM, renal disease, urinary tract infection, nonspecific infection and rheumatologic disease were found most frequently in our study. There were no patients with a history of intravenous drug use or living with HIV. Similarly, the most common predisposing conditions observed in studies conducted in Turkey were reported to be spinal surgery intervention and DM [11]. In a study conducted in the United States of America, the most common comorbid conditions were hypertension and DM, and the rates of HIV infection and substance abuse were higher [14].
Guidelines recommend imaging-guided biopsy cultures for the diagnosis of VO [15]. However, this is not possible in practice. Magnetic resonance imaging has been reported to have high sensitivity and specificity in many studies and has been accepted as the gold standard imaging for diagnosis [16, 17]. MRI results of all patients diagnosed with VO included in our study were compatible with VO.
When we examined the laboratory tests that may help the diagnosis in our study, we observed that the median leukocyte value was normal. CRP median value was 21 mg/L, ESR median value was 51 mm/h and HTC median value was 35.5%. It was observed that leukocyte and HTC values would not help the diagnosis. In previous studies, it has been reported that CRP and ESR values are high during diagnosis and prevent delay in diagnosis [11, 18, 19]. In the guidelines, it is stated that these parameters can be used for monitoring the response to treatment and that it would be appropriate to check the values at four-week intervals [15]. Yoon SH et al. reported that elevated CRP and ESR values in the fourth week of VO follow-up were associated with treatment failure [20]. In our study, it was observed that treatment response was detectable at the end of 3 weeks based on a decrease of more than 25% in ESR and CRP values. Based on this result, we think that CRP and ESR can be checked earlier in follow-up. Thus, when treatment failure is suspected, earlier follow-up imaging or treatment change may be considered.
Monitoring of pain is also very important in the follow-up of treatment response in patients. There is no single clear criterion for the follow-up of treatment failure in the guidelines. For this reason, clinicians follow up with clinical, laboratory and imaging methods [15]. In our study, it was observed that the average duration of pain relief was 21 days. It was observed that the laboratory response characterized by regression in CRP and ESR values and the pain response occurred on similar days. In a meta-analysis, it was reported that treatment failure may occur when pain response is not obtained in the fourth week [21].
There is no clear duration for the duration of treatment of pyogenic VO. The Infectious Diseases Society of America (IDSA) guideline suggests that 6 weeks of treatment is sufficient [15]. Recommendations for the duration of treatment vary from 6 weeks to 3 months, and there is no clear recommendation in the guidelines for the duration of intravenous treatment [15, 22, 23]. In our study, it was observed that the mean duration of parenteral treatment was 3 weeks and the mean duration of oral maintenance treatment was 6 weeks.
Limitation
There were some limitations of our study, which we think were mainly due to its retrospective nature. There may have been missed cases and we were not able to obtain information on whether there was a recurrence in the cases included in the study. Our most important limitation was the lack of biopsy culture results in most patients since imaging-guided biopsy was not performed in our hospital.
Conclusion
In conclusion, our study provides updated data that can contribute to the literature on VO cases in the last decade. In particular, confirmation of the diagnosis with biopsy and initiation of agent-specific treatment will be an important step in increasing treatment success. In regions where brucellosis is endemic, imaging methods such as MRI and CT should be used early to detect vertebral osteomyelitis in the early period. In our study, we found that CRP and ESR values decreased significantly at the 3rd week on average and we think that they can be used for follow-up. It is one of the important conclusions of our study that the decrease in pain in the 3rd week at clinical follow-up can be used together with CRP and ESR values. Our results are also instructive for clinical applications that question the necessity of long-term antibiotic treatment.
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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Ventilator associated tracheobronchitis; prospective investigation of etiology, laboratory, treatment and prognosis
Hasan Naz 1, Duru Mıstanoğlu Ozatag 2, Esra Arslanalp 3, Pınar Korkmaz 2, Hande Gürbüz 4
1 Department of Infectious Diseases and Clinical Microbiology, Faculty of Health Sciences, Derince Training and Research Hospital, Kocaeli, 2 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, 3 Department of Infectious Diseases and Clinical Microbiology, Kocaeli City Hospital, Kocaeli, 4 Department of Anesthesiology and Reanimation, Faculty of Health Sciences, Derince Training and Research Hospital, Kocaeli, Turkiye
DOI: 10.4328/ACAM.22459 Received: 2024-10-16 Accepted: 2024-11-25 Published Online: 2024-12-02 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):360-363
Corresponding Author: Pınar Korkmaz, Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, Turkiye. E-mail: drpinarkor@gmail.com P: +90 533 019 94 40 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5035-5895
Other Authors ORCID ID: Hasan Naz, https://orcid.org/0000-0001-8523-4735 . Duru Mıstanoğlu Ozatağ, https://orcid.org/0000-0002-0005-192X . Esra Arslanalp, https://orcid.org/0000-0001-8131-9037 . Hande Gürbüz, https://orcid.org/0000-0002-3562-9517
This study was approved by the Ethics Committee of Kocaeli University (Date: 2018-03-01, No: GÜ GOKAEK 2018/99)
Aim: Ventilator-associated tracheobronchitis (VAT) is an intermediate process between lower respiratory tract colonization and ventilator-associated pneumonia (VAP). This study aimed to provide data on etiologic, laboratory, treatment, and prognostic factors to prevent VAT.
Material and Methods: The study was conducted in tertiary general intensive care units (ICUs) in two different hospitals. The data were prospectively recorded on the forms prepared by visiting the ICUs daily.
Results: Three hundred and seventeen patients were included in the study. VAT developed in 54 (14.1%) patients, and VAP developed in 108 (28.3%) patients. VAT developed in an average of 10±7 days (3-35 days) during mechanical ventilatory support. Twenty-eight (51.9%) of the patients developed VAP during VAT. Inappropriate antibiotic use and prolonged stay in the ICU (>21 days) were the independent risk factors for the development of VAP following VAT. The most common microorganisms in patients who developed VAT were A.baumannii (38.9%) and K.pneumoniae (29.6%). Multidrug resistance was detected in 76% of the microorganisms. When the risk factors for the development of VAT were evaluated, prolonged stay in the ICU (>14 days), diabetes mellitus, and application of a nasogastric tube were independent risk factors. Mortality developed in 11 (20.4%) in patients with VAT.
Discussion: Inappropriate antibiotic use and prolonged stay in the ICU were the independent risk factors for the development of VAP following VAT. Prolonged stay in the ICU, male gender, diabetes mellitus, and application of a nasogastric tube were identified as independent risk factors for the development of VAT.
Keywords: Ventilator-Associated Tracheobronchitis, Ventilator-Associated Pneumonia, Antibiotherapy
Introduction
Nosocomial lower respiratory tract infections are the most common type of nosocomial infections observed in the intensive care unit (ICU) [1]. While mechanical ventilation is a lifesaving intervention in the ICU, it may cause important risks and complications, such as ventilator-associated lower respiratory tract infections, including ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT) [2]. Invasive mechanical ventilation via an endotracheal tube is an important risk factor for nosocomial lower respiratory tract infections. The major routes for acquiring nosocomial lower respiratory tract infections are oropharyngeal colonization by the endogenous flora of the host or by pathogens acquired exogenously from the ICU environment, particularly the hands or apparel of health-care workers or contaminated respiratory equipment, hospital water, or air [3]. The stomach is a potential site of secondary colonization and also a reservoir of nosocomial Gram-negative bacilli. The occurrence of endotracheal-tube biofilm formation plays an important contributory role in sustaining tracheal colonization, and additionally, it also has an important effect in late-onset nosocomial lower respiratory tract infections caused by resistant organisms. Contaminated oropharyngeal, gastric, or tracheal secretions around the cuffed endotracheal tube cause nosocomial infections in the normally sterile lower respiratory tract [4, 5].
Although there are numerous studies related to VAP, there are a small number of studies related to nosocomial VAT. As far as the literature can be evaluated, there are only three studies evaluating risk factors in VAT. There is no study on VAT in our country. In this study, it was aimed to obtain data for the prevention of VAT by determining the risk factors, etiological agents, and therapeutic information.
Material and Methods
The study was performed prospectively in the third-level general ICUs of X Hospital (Centre A) and Y Hospital (Centre B) between 1 April 2018 and 1 April 2019. Two ICUs with ten beds each were investigated in each hospital.
Inclusion and exclusion criteria
Patients over 18 years of age who were admitted to the ICU for longer than 48 hours and received mechanical ventilator support were included in the study. VAT was defined according to the following criteria: fever (>38 °C) with no other recognizable cause, increased volume and purulence of tracheal secretions and positive culture of tracheal aspirate (≥105 cfu/mL), and the absence of new infiltration on chest radiograph [6]. All infections were accompanied by microbiological documentation. The diagnosis of VAP was made according to the Centers for Disease Control and Prevention criteria. VAP was defined by the presence of at least one of the following: new or progressive and persistent infiltrate, consolidation or cavitation on chest radiograph; at least one of the following: body temperature of more than 38.5 °C or less than 36.5 °C or leucocyte count greater than 12,000 cells per μL or less than 4 000 cells per μL or altered mental status (for adults >70-year old); and at least two of the following: new onset of purulent or changes in sputum, new onset or worsening tachypnea, rales/bronchial breath sounds, worsening gas exchange with increased vent requirements; and at least one of the following: positive blood culture not related to another infection, positive pleural fluid culture, positive quantitative culture (BAL or PSB), BAL fluid with >5% cells with intracellular bacteria on microscopy or positive histopathology [7]. The first episode of VAT was included in the study. Patients with a previous episode of VAP and immunocompromised patients were excluded from the study. The demographic characteristics, underlying diseases, possible risk factors, clinical and laboratory findings of developed nosocomial infections, treatment, treatment response, and mortality data of the patients were prospectively recorded on the forms prepared by visiting the ICU daily.
Statistical analysis
The study data were analyzed by using SPSS 17.0 (Statistical Package for Social Sciences Inc.) software. The Chi-square test was used for the evaluation of dependent variables, and logistic regression analysis was used for the evaluation of risk factors for independent variables in the statistical analysis. A p-value of <0.05 was considered to be statistically significant.
Ethical approval
The study was approved by the Kocaeli University Ethics Commitee (Date: 2018-03-01, No: GÜ GOKAEK 2018/99).
Results
Three hundred and seventeen patients (250 in Centre A, 132 in Centre B) who were admitted to the ICU, received mechanical ventilatory support, and met the eligibility criteria were included in the study. VAT developed in 54 (14.1%) patients, and VAP developed in 108 (28.3%) patients. Thirty-six (66.7%) patients were male in patients with VAT, and the mean age of the patients was 75±11 years (28-93 years). The mean ICU stay length was 45±43 days (9-265 days). VAT developed in an average of 10±7 days (3-35 days) during mechanical ventilatory support.
When the risk factors for the development of VAT were investigated in the patient group receiving mechanical ventilation support, prolonged stay in the ICU (>14 days) (p = 0.000), diabetes mellitus (p = 0.011), cerebrovascular event (p = 0.034) and application of a nasogastric tube (p = 0.000) were statistically significantly higher in patients developing VAT compared to patients not developing VAT (Table 1).
The most frequently determined microorganisms in patients developing VAT were A.baumannii 21 (38.9%), K.pneumoniae 16 (29.6%) and P.aeruginosa 12 (22.2%). Forty-one causative agents (76%) were multidrug-resistant (MDR) organisms in patients with VAT. VAP developed following VAT in 28 (51.9%) of VAT patients. When VAT and VAP developed following VAT were compared, prolonged stay in the ICU (>21 days) (p = 0.007) and inappropriate antibiotic use (p = 0.030) was higher in patients whose VAP developed following VAT. The independent risk factors for the development of VAP developed following VAT (Table 2).
When the risk factors for the development of VAT were investigated in the patient group receiving mechanical ventilation support, prolonged stay in the ICU (>14 days) (p = 0.000), malignancy (p = 0.016), diabetes mellitus (p = 0.011), cerebrovascular event (p = 0.034) and application of a nasogastric tube (p = 0.000) were statistically significantly higher in patients developing VAT compared to patients not developing VAT (Table 2). Both groups included patients who developed VAP. Prolonged stay in the ICU (>14 days) [OR=5.57 (2.46-12.61)], male gender [OR=1.77 (0.72-4.32) ], diabetes mellitus [OR=1.98 (1.02-3.81)] and application of a nasogastric tube [OR=3.75 (1.22-11.57)] were independent risk factors for the development of VAT (Table 3).
All of the patients developing VAT received antibiotic treatment. The mortality developed in 11 (20.4%) of patients developing VAT.
Discussion
VAT is a major health problem in ICU patients receiving mechanical ventilatory support worldwide, and it causes high resource consumption in all countries [8]. Pathogen microorganisms cause tracheal colonization by bypassing pulmonary host defenses in patients receiving long-term mechanical ventilation in the ICU [9]. This condition may result in VAP during VAT and afterward. VAT is an intermediate process between lower respiratory tract colonization and VAP. Post-mortem studies have demonstrated that there is a continuity between bronchitis and pneumonia in mechanically ventilated ICU patients [10, 11]. The frequency of VAT is reported estimated to be approximately 11.5% [12]. The frequency of VAT (14.1%) was determined to be higher in this study. The VAT ratio obtained in this study is the highest detected in studies to date. Additionally, the development of VAP after VAT in this study’s patients was determined to be as high as 51.9%. The development of VAP after VAT is reported to be between 9% and 34% in various studies [6, 11, 13, 14]. In a prospective observational study performed on VAT patients, Nseir et al. [15] reported an appropriate antibiotic treatment is independently associated with reduced risk for transition from VAT to VAP. In this study, prolonged stay in the ICU (>21 days) (p = 0.007) and inappropriate antibiotic use (p = 0.030) were the independent risk factors for the development of VAP following VAT. The use of antibiotics in patients with VAT is not clear as a recommendation. The potential undesirable consequences of antibiotic therapy include high costs and side effects such as rash, C.difficile colitis, and antibiotic resistance. Therefore, antibiotic treatment of patients with VAT has not been supported by existing guidelines. On the other hand, studies are showing that VAP development decreases after VAT with appropriate antibiotic use [8].
In this study, A.baumannii, K.pneumoniae, and P.aeruginosa were the most frequently determined microorganisms. In various studies investigating the causative agents in VAP and VAT, similar microbiological data were observed [19-21]. MDR organisms were determined to be present at a rate of 32% and 63% in patients developing VAT [2, 19, 21]. In this study, a high rate of MDR organisms, 76%, was determined. Appropriate antibiotic use, hand hygiene, care bundles, and training are necessary to prevent the development of MDR microorganisms in ventilator-associated lower respiratory tract infections.
Being over 60 years old, the presence of chronic obstructive pulmonary disease, and the use of antibiotics within the last two weeks have been previously determined to be risk factors in patients with VAT [6]. In another study, mechanical ventilation day, tracheostomy, and length of stay in the ICU and hospital were determined to be significantly higher in the group developing VAT compared to the control group [14]. In this study, prolonged stay in the ICU (>14 days), diabetes mellitus, male gender, and nasogastric tube application were independent risk factors for the development of VAT. Dysfunction develops in the immune system with advanced age and diabetes mellitus. Nasogastric tube application in patients may lead to the colonization of oropharyngeal and gastric microorganisms and subsequent microaspiration. Long stays in ICUs, increasingly invasive interventions, and the use of drugs lead to the colonization of microorganisms. Therefore, hospitalization indications in ICUs should be questioned regularly for each patient. Although risk factors have been investigated in many studies about VAP, risk factor data about VAT are insufficient. It is important to know the risk factors related to the development of VAT in terms of determining the precautions to be taken. Therefore, determining the risk factors for VAT development in this study will contribute to the literature.
The mortality rate has been reported to be between 29% and 42% in various studies [6, 21]. There was a mortality rate of 11 (20.4%) in patients developing VAT in this study. VAT is a common nosocomial lower respiratory tract infection in ICUs. The VAT ratio obtained in this study is the highest detected in studies to date. The development of VAP after VAT in these patients was determined to be the highest compared to previous studies. Inappropriate antibiotic use and prolonged stay in the ICU were the independent risk factors for the development of VAP following VAT. The rate of MDR among causative microorganisms in VAT in ICUs in this study is the highest detected in studies to date. Long-term hospitalization, diabetes mellitus, and application of nasogastric tubes were identified as independent risk factors for the development of VAT in this study.
Limitation
The limitation of our study is that it was performed with a limited number of patients. Studies performed in more centers and with more patients are needed.
Conclusion
Appropriate antibiotic use, hand hygiene, care bundles, and training are necessary to prevent the development of MDR microorganisms in ventilator-associated lower respiratory tract infections. The presence of foreign bodies and indications for hospitalization in ICUs should be regularly questioned for each patient, especially in patients with advanced age and diabetes mellitus.
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.22459
Hasan Naz, Duru Mıstanoğlu Ozatag, Esra Arslanalp, Pınar Korkmaz, Hande Gürbüz. Ventilator associated tracheobronchitis; prospective investigation of etiology, laboratory, treatment and prognosis. Ann Clin Anal Med 2025;16(5):360-363
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The extent of awareness and knowledge of people in the northern border region of saudi arabia about the effect of diabetes mellitus on the retina
Mohammed M. Mosaed 1, 2, Ahmed M S Hegazy 2, Maha Mahmoud Abdul-latif 3, Saad H Elshafey 2, Amgad N. Elsawy 2, Mohammed M.Ismail 2, Randa Faiz Alenzi 4, Samiah Nasser Aljohani 4
1 Departmen of Anatomy, Faculty of Medicine, Al Azhar University, Egypt, 2 Departmen of Anatomy, Faculty of Medicine, Northern Border University, KSA, 3 Department of Ophthalmology, Faculty of Medicine, Northern Border University, KSA, 4 Department of Medical, Faculty of Medicine, Northern Border University, KSA
DOI: 10.4328/ACAM.22463 Received: 2024-10-17 Accepted: 2024-11-25 Published Online: 2024-12-05 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):364-368
Corresponding Author: Ahmed MS Hegazy, Departmen of Anatomy, Faculty of Medicine, Northern Border University, KSA. E-mail: Ahmed0562301954@yahoo.com Corresponding Author ORCID ID: https://orcid.org/0000-0002-5102-9263
Other Authors ORCID ID: Mohammed M. Mosaed, https://orcid.org/0000-0002-5112-3225 . Maha Mahmoud Abdul-latif, https://orcid.org/0000-0002-3865-5817 . Saad H Elshafey, https://orcid.org/0000-0002-8506-0680 . Amgad N. Elsawy, https://orcid.org/0009-0000-4951-094X . Mohammed M.Ismail, https://orcid.org/0009-0001-1177-2976
Randa Faiz Alenzi, https://orcid.org/0009-0003-0072-5036 . Samiah Nasser Aljohani, https://orcid.org/0009-0003-3694-2737
This study was approved by the Ethics Committee of Northern Border University (Date: 2024-05-19, No: 24/54/H)
Aim: Diabetic ocular complications, especially diabetic retinopathy (DR), are a major cause that leads to irreversible blindness. Awareness of diabetes and its ocular complications may help in preventing vision loss. This study evaluates the awareness of people (diabetics and non-diabetics) about the complications of diabetes in the eye, especially the retina.
Material and Methods: This study is a questionnaire-based cross-sectional study. Data was collected through an online self-administered questionnaire. The target people from 16 years to 75years in both males and females The duration of the study from May 2024 to September 2024 The comparisons between the awareness about diabetic retinopathy and the association of awareness about diabetic retinopathy and educational level were analyzed using SPSS 24.0 version software.
Results: The study included 153 individuals. The age range of participants was 16–75, and the most dominant age group was those with an age range of 46–55 (35.7%).
The ratio of male to female was 58.8:41.2, regarding education, the most dominant group was those who had a university education, 80 (52,3%), then higher education level 46 (30.1). Most of the participants, 127 (83%) non-diabetic and 26 (17%) diagnosed with Diabetes mellitus. Of most of the participants, 141(80 males and 61 females), 92.2% of participants reported that diabetes affects the retina, and 87(45 males and 42 females) 56.9% agreed with the relation between diabetic retinopathy and blindness. 121(67 males and 54 females) 79.1% of participants reported that the control of blood glucose level can prevent diabetic retinopathy There was high awareness among the participants, diabetic and non-diabetic, regarding diabetic retinopathy (DR), but annual check-ups were done in less than half of the patients. Improvement is required for scheduling annual eye examinations for the early detection of diabetic retinopathy (DR).
Discussion: The results of this study showed a high level of self-report awareness regarding the association between DM and retinopathy. These results are in harmony with other local and international studies. All these studies found that the awareness regarding the association between DM and retinopathy is high among the people of higher education. This is due to the spread of social media, which has led to increased awareness among many people. By comparing the present study with the other studies in different regions of Saudi Arabia, we found that the awareness of participants by diabetic retinopathy was 91.5% in the Northern Border region. KSA and 42% of them got their information from the doctors. Whereas in Hail, Taif, Jeddah, and a study from King Abdul Aziz University Hospital, there were 75.62%, 64%, 82.6%, and 61%, respectively, who had awareness. In a recent study in Madinah, Saudi Arabia, among 240 patients, less than half of the patients had a fair level of knowledge (47.1%) and a good level of knowledge (42.1%) about diabetic retinopathy.
Also, the results of the studies all over the world showed the level of awareness regarding diabetic retinopathy high in India 50%, USA52%, and Oman 75%. The awareness was higher in Myanmar 86% and Nigeria 84.3% The strength of this study included patients of all ages from 16 to 75, and Most of the participants have a university education or higher.
Keywords: Awareness, Diabetes Mellitus, Diabetic Retinopathy, Eye Examination, Northern Border Region Ksa
Introduction
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high glucose levels and the body’s inability to produce or use insulin, which leads to multiple microvasculopathic abnormalities of the eye, leading to diabetic retinopathy (DR) [1].
Diabetic retinopathy (DR) is one of the major causes of visual disability, leading to irreversible blindness among adults. The pathogenesis of the disease emerges as neuroretinopathy and vascular changes in the retinal blood vessels because of a breakdown of the blood-retinal barrier and obliteration of the retinal capillaries [2]. Many systematic reviews of 59 population-based studies estimated the worldwide prevalence of diabetic retinopathy (DR) to be 35% [3].
Diabetic retinopathy (DR) is one of the common complications of Diabetes mellitus (DM). The duration of DM is a significant factor in developing DR. The longer the duration of DM, the higher the risk for DR. It affects about 1/5th of diabetic patients with a duration of disease from 10 to 15 years [4] According to studies from different areas in Saudi Arabia, the prevalence of diabetic retinopathy was found to be 28%-36% among diabetic patients [5, 6].
Studies in The Kingdom of Saudi Arabia (KSA) indicate a significant increase in the prevalence and incidence rates of type 1 diabetes mellitus, mainly among children and adolescents [7].
According to many studies estimated that diabetes mellitus is a common disease in Saudi Arabia about 23%-32% of its adult population suffers from the disease. Understanding the level of public awareness of diabetes and its affection on the retina helps the decision maker to plan a future program that increases the level of knowledge in diagnosis, complications, and management among patients. The level of awareness and knowledge about diabetes is a crucial part of the early diagnosis, management, and prevention of potential visual impairment [8].
Material and Methods
This study is a questionnaire-based, cross-sectional study of diabetic and non-diabetic individuals. Data was collected through an online self-administered questionnaire. The target people were from 16 -75 years old, both sexes (male and female). The duration of the study is from May 2024 to September 2024.
The comparisons between the awareness about diabetic retinopathy and the association of awareness about diabetic retinopathy and educational level were analyzed using SPSS 24.0 version software.
Ethical Approval
This study was approved by the Local Committee of Bioethics (HAP-09-A-043) at Northern Border University (Date: 2024-05-19, No: 24/54/H).
Results
The present study included 153 individuals. The age range of participants was 16–75, and the most dominant age group was those with an age range of 46–55 (35.7%).
The ratio of males to females was 58.8:41.2, regarding education, the most dominant group was those who had a university education, 80 (52,3%), then higher education level above university education, 46 (30.1). Most of the participants 127 (83%) non-diabetic and 26 (17%) diagnosed with DM. Of most of the participants, 141(80 male and 61female), 92.2% of participant reported that diabetes affects the retina (Figure 1)
Regarding the relation between diabetic retinopathy and blindness, 87 (45male and 42 female) 56.9% were aware of the relation between diabetic retinopathy and blindness (Figure 2)
Of the participant, 121(67 male and 54 female), 79.1%of participants reported that the control of blood glucose levels can prevent diabetic retinopathy Fig.3.
The main source of information about diabetes mellitus and diabetic retinopathy was reported to be doctors (43.1%), followed by social media (22.2%).
The participants’ responses to awareness are as follows There were 141 (92.2%) who were aware that diabetes mellitus could affect the retina, whereas 121 (79.1%) were aware that control of blood sugar reduces the risk of DR, and 79 (51,6) believed that the diabetic retinopathy can treatable disease and 87(56.9%) patients were aware that DR could lead to blindness. 79 (51.6%) reported that the examination of the eye in diabetic patients every 6 months, and the reason for not having an eye examination is a lack of knowledge about the disease in 66 (43.1%). The main source of information about diabetes mellitus and DR was reported to be by doctors (43.1%), followed by social media (22.2%).
The awareness that (diabetes mellitus can cause diabetic retinopathy, that control of diabetes mellitus reduces the risk of diabetic retinopathy, and that diabetic retinopathy can lead to blindness) was compared with different demographic variables as male and female participants and with the different levels of education by using the Chi-square test.
No significant association between the sex and the awareness that diabetes mellitus can cause diabetic retinopathy, that control of diabetes mellitus reduces the risk of diabetic retinopathy, and that diabetic retinopathy can lead to blindness (P-value 0.195,0.195 and 0.131, respectively) also No significant difference There between the university educational level and the higher education.
By the comparison between the association between the family history and the awareness that DM can cause retinopathy, that control of DM reduces the risk of DR, and that DR can lead to blindness, there was no significant association between the family history and the awareness that the DM can cause the retinopathy (p-value 0.207) and that that control of DM reduces the risk of diabetic retinopathy (P-value 0.162) while there was a significant association between the family history and the awareness that diabetes can cause the blindness (p-value is < 0.00001).
By the comparison between the association between the family history and the awareness that DM can cause retinopathy, that control of DM reduces the risk of DR, and that DR can lead to blindness, there was no significant association between the family history and the awareness that the DM can cause the retinopathy (p-value 0.207) and that that control of DM reduces the risk of diabetic retinopathy (P-value 0.162) while there was a significant association between the family history and the awareness that diabetes can cause the blindness (p-value is < 0.00001).
Discussion
The study aimed to assess the level of non-diabetic and diabetic patients’ awareness in the Northern Border Governorate, KSA. Diabetes mellitus is a common cause of Diabetic retinopathy, which is one of the causes of visual impairment and blindness, and the awareness of the population of the complications of diabetes plays an important role in the prevention of diabetic retinopathy [2].
This study found that the awareness among the diabetic and non-diabetic participants is high regarding Diabetic Retinopathy, with (91.7%) being aware that DM can affect the retina. 57% are aware that DR can lead to blindness. 88.3 of the patients were also aware that control of blood sugar may reduce the risk for DR.
The results of this study showed a high level of self-reported awareness regarding the association between DM and retinopathy, this result is in harmony with other international and local studies [9, 10, 11, 12, 13] all these studies found that the awareness regarding the association between DM and retinopathy is high between the peoples of higher education whereas one study showed the lowest awareness from the rural area in India [14]. This is due to the spread of social media, which has led to increased awareness among many people. Some studies concluded that WhatsApp was the social media most used in Saudi Arabia by the participants to communicate and obtain information about diabetes, and social media was useful in improving education, awareness, and communication among people with diabetes [15].
By comparing the present study with the other studies in different regions of Saudi Arabia, we found that in this study, the awareness of participants by diabetic retinopathy was 91.5% among the participants in the Northern Border region. KSA and 42% of them got their information from the doctors. Whereas Studies from different areas in Saudi Arabia reported different levels of knowledge about diabetic retinopathy in Hail, Taif, and Jeddah, and studies from King Abdul Aziz University Hospital, Jeddah, there were 75.62%, 64%, 82.6%, and 61%, respectively, who had awareness [10, 11, 16, 17]. In a recent study in Madinah, Saudi Arabia, among 240 patients who participated, less than half of the patients had a fair level of knowledge (47.1%) and a good level of knowledge (42.1%) about diabetic retinopathy [18].
The results of the studies all over the world showed the level of awareness of diabetic retinopathy high in India 50%, USA52%, and Oman 75% [19, 20, 12]. The awareness was higher in Myanmar, 86%, and Nigeria, 84.3% [21, 22].
The variation in the level of awareness between different studies and this study was due to the variation in the level of education of each population in our study. All participants had a high level of education, and the percentage of education among the participants was high: 17% secondary, 30% university education, 53% higher than university education. Higher awareness was significantly associated with a higher level of education [12]. In a Saudi study, such a correlation between awareness and education was reported, in this study, a significant association between educational level (in this study, 43.5% of participants have higher education level) and awareness about DM and retinopathy. This was similar to the studies from Jordan [9] and Malaysia, both of which showed that higher educational people had better awareness than those with low educational levels.
In this study, there were 79% of participants awarded the control of blood sugar-preventing retinopathy. In a similar study, (70.8%) of patients reported good levels of blood glucose control the DR. [24] Other studies concluded poor diabetic control among diabetes mellitus type 2 patients, which resulted in a high rate of complications [25].
The main source of information about DM and DR (59.4%) from their doctors, followed by social media (20.3%) and their family (11.3) and friends (9.7); this is similar to the findings from the two studies from Jordan and Malaysia [9, 23].
In our study, (54%) of patients reported a family history of diabetes; this percentage was less than that in other studies conducted in Madinah (92%). [19] And studies in Riyadh, Saudi Arabia, in which 70% and 79.8% of patients had a family history of diabetes [25].
The strength of this study included patients of all ages from 16 to 75, and Most of the participants have a university education or higher.
Limitation
The present study has some limitations. Because the study was shown only in one Saudi Arabian region, the generalization of the results is limited. Additionally, the non-probability sampling method may be subjected to selection bias. The information regarding diabetic retinopathy awareness was gathered via self-reported responses to questionnaire items rather than from medical records, so the participant may have over-reported.
Conclusion
The study found a high level of awareness of diabetic retinopathy among the participants, and there was an association between the level of education and awareness. Also, medical doctors are the main source of information.
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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5. Hajar S, Hazmi AA, Wasli M, Mousa A, Rabiu M. Prevalence and causes of blindness and diabetic retinopathy in Southern Saudi Arabia. Saudi Med J. 2015;36:449–55.
6. Ahmed RA, Khalil SN, Al-Qahtani MAA. Diabetic retinopathy and the associated risk factors in diabetes type 2 patients in Abha, Saudi Arabia. J Family Community Med. 2016;23:18–24.
7. Habeb AM, Al-Magamsi MS, Halabi S, Eid IM, Shalaby S, Bakoush O. High incidence of childhood type 1 diabetes in Al-Madinah, North West Saudi Arabia (2004-2009). Pediatr Diabetes. 2011;12(8):676-81.
8. Alqurashi KA, Aljabri KS, Bokhari SA. Prevalence of diabetes mellitus in a Saudi community. Ann Saudi Med. 2011;31:19–23.
9. Bakkar MM, Haddad MF, Gammoh YS. Awareness of diabetic retinopathy among patients with type 2 diabetes mellitus in Jordan. Diabetes. Metab Syndr Obes. 2017;10:435–41.
10. Al Zarea BK. Knowledge, attitude, and practice of diabetic retinopathy amongst the diabetic patients of AlJouf and Hail Province of Saudi Arabia. J Clin Diagn Res. 2016;10:NC05–8.
11. Alzahrani SH, Bakarman MA, Alqahtani SM, Alqahtani MS, Butt NS, Salawati EM, et al. Awareness of diabetic retinopathy among people with diabetes in Jeddah, Saudi Arabia. Ther Adv Endocrinol Metab. 2018;9:103–12.
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19. Namperumalsamy P, Kim R, Kaliaperumal K, Sekar A, Karthika A, Nirmalan PK. A pilot study on awareness of diabetic retinopathy among non-medical persons in South India. The challenge for eye care programmes in the region. Indian J Ophthalmol. 2004;52:247–51.
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Mohammed M. Mosaed, Ahmed MS Hegazy, Maha Mahmoud Abdul-latif, Saad H Elshafey, Amgad N. Elsawy, Mohammed M.Ismail, Randa Faiz Alenzi, Samiah Nasser Aljohani. The extent of awareness and knowledge of people in the northern border region of saudi arabia about the effect of diabetes mellitus on the retina. Ann Clin Anal Med 2025;16(5):364-368
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Clinicopathological features of the patients with human epidermal growth factor receptor immunohistochemistry 2+ early stage breast cancer
İsmet Seven, İrfan Karahan, Fahriye Tuğba Köş, Serhat Sekmek, Doğan Bayram, Gökhan Uçar, Doğan Uncu
Department of Medical Oncology, Ankara Bilkent City Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22464 Received: 2024-10-17 Accepted: 2024-11-25 Published Online: 2024-12-04 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):369-372
Corresponding Author: İrfan Karahan, Department of Medical Oncology, Ankara Bilkent City Hospital, Ankara, Turkiye. E-mail: irfan_karahan@yahoo.com P: +90 544 739 69 91
Corresponding Author ORCID ID: https://orcid.org/0000-0003-4669-1751
Other Authors ORCID ID: İsmet Seven, https://orcid.org/0009-0001-4706-0495 . Fahriye Tuğba Köş, https://orcid.org/0000-0002-6980-4942 . Serhat Sekmek, https://orcid.org/0000-0003-4650-248X . Doğan Bayram, https://orcid.org/0000-0002-5976-2494 . Gökhan Uçar, https://orcid.org/0000-0002-7649-1075 . Doğan Uncu, https://orcid.org/0000-0002-0929-3271
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2024-02-07, No: E2-24-6181)
Aim: Human epidermal growth factor receptor 2 (HER2) 2+ with immunohistochemistry early breast cancer was evaluated with in situ hybridization (ISH) as a further assessment. Positive and negative groups may have different characteristics. This study aimed to investigate the clinicopathological characteristics of these groups.
Material and Methods: Patients with HER2 2+ early breast cancer were evaluated. ISH-positive and negative groups were compared according to patient and disease characteristics, tumor markers, and inflammatory parameters.
Results: About a quarter of the patients were ISH-positive. Many patient and disease characteristics were similar between the two groups. CEA levels were higher in the positive group. There was a negative correlation between HER2/CEP17 ratio and PR and a positive correlation between HER2/CEP17 ratio and CEA.
Discussion: HER2 2+ early breast cancer is a very heterogeneous disease, and patients can be assessed individually. Also, larger trials are needed to determine the benefit of new treatments.
Keywords: Human Epidermal Growth Factor Receptor, Immunohistochemistry, Breast Cancer
Introduction
Breast cancer is regarded as a heterogeneous tumor group, exhibiting variability in terms of underlying biology, pathological features such as hormone status and surface receptor expression, response to treatment, and clinical outcome. [1]. Human epidermal growth factor 2 (HER2)-positive breast cancer represents between 10 and 34% of all breast carcinomas and is characterized by the amplification of the ERBB2/HER2 gene and/or overexpression of the associated kinase receptor protein. This results in more aggressive tumor behavior and a reduction in survival rates. [2, 3]. The introduction of the humanized anti-HER2 monoclonal antibody trastuzumab into clinical practice, followed by the development of several other anti-HER2 targeted agents, has resulted in enhanced outcomes in both early-stage and metastatic disease. [4, 5].
By the ASCO/CAP guidelines, a clinically diagnosed HER2(+) breast cancer is defined as a tumor exhibiting complete and intense peripheral membrane staining for HER2 protein (3+ score) by immunohistochemistry (IHC) and/or HER2 gene (ERBB2) amplification by in situ hybridization (ISH). Additionally, the HER2/CEP17 ratio must be 2.0, and the mean HER2 gene copy number must exceed 4.0 signals/cell. This definition is based on that used in HER2+ clinical trials evaluating trastuzumab and other targeted therapies. However, the clinical presentation of HER2+ disease is, in fact, a more complex and heterogeneous entity, which requires further study to facilitate the development and validation of new and more effective diagnostic and therapeutic approaches. [6–9].
There is a paucity of knowledge and a lack of consensus regarding the characteristics of IHC 2+ HER2-positive early breast cancer. The objective of the present study was to evaluate the relationship between the disease, patient features, and HER2 status.
Material and Methods
The medical records of 81 women diagnosed with HER2 IHC 2+ breast cancer and admitted to Ankara Bilkent City Hospital between 2020 and 2023 were subjected to case-control analysis.
The study population comprised patients aged 18 and over who had been diagnosed with early-stage breast cancer with an IHC score of 2 in biopsy samples. Patients with advanced breast cancer were excluded from the study.
The following variables were evaluated: age at diagnosis, Eastern Cooperative Oncology Group (ECOG) performance status, biochemical laboratory values at diagnosis, estrogen receptor status, stage at diagnosis, and tumor marker levels. The study also assessed inflammatory parameters, including the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR). The patients were divided into two groups according to the results of fluorescein in situ hybridization (FISH) testing. A comparison was made between the patient and disease characteristics and laboratory values of the two groups. The correlation between the numerical values was subjected to analysis.
Statistical Analysis
IBM SPSS version 25 was used for all statistical analyses. Shapiro-Wilk test and histograms were used to test normal distribution. Normally distributed numerical values were expressed as mean, and standard deviation, and non-normally distributed values were expressed as median (min-max). Chi-square and Fisher-exact tests were used for the comparison of categorical variables between the two groups. Mann Whitney U test was used for comparison of numerical values. Spearman test was used for correlation analysis. p<0.05 was considered significant.
Ethical Approval
Ankara Bilkent City Hospital Ethical Committee approved the study (Date: 2024-02-07, No: E2-24-6181).
Results
All 81 patients were women, and 26.7% of patients were FISH-positive. Between FISH-positive and negative groups, age, medical history, family history, performance status, T stage, N stage, and histological grades were similar. Most patients were hormone receptor-positive in both groups (Table 1).
For FISH-positive and negative groups, hormone receptor expressions, Ki67 index, and CA15-3 levels were similar. CEA levels were higher in the positive group. As inflammatory markers, NLR and PLR were not significantly different (Table 2).
HER2/CEP17 ratio had a weak significant correlation between progesterone receptor expression and CEA levels (p=0.024 r= -0.27, p=0.003 r=0.358 respectively) (Figure 1,2). There was no correlation between the HER2/CEP17 ratio and estrogen receptor or CA15-3 levels (p=0.12 and p=0.24, respectively).
Discussion
The findings of this study indicate that FISH-positive and FISH-negative diseases present with numerous similarities, with only a few notable differences, such as serum tumor marker levels. Additionally, gene amplifications were found to be associated with progesterone receptor and CEA levels.
Bahremani et al. [10] evaluated HER2 2+ breast cancer patients in the Iranian population using resection and fine needle biopsy materials. They divided the patients into two groups based on the results of chromogenic in situ hybridization (CISH) testing: CISH-positive and CISH-negative. In contrast with the findings of our study, the researchers observed that the CISH-negative group had a significantly higher prevalence of hormone receptor-positive cases. The CISH-positive group exhibited a higher Ki-67 index. These discrepancies may be attributed to differences in the characteristics of the studied populations. The median ages of the two groups were similar to those observed in our study.
The study of Zaidoon et al. [11] concluded that there was a higher prevalence of hormone receptor expression in the gene-amplified group and a negative correlation between both estrogen and progesterone receptors and HER2 amplification. Thus, a negative correlation was identified between PR and the HER2/CEP17 ratio. However, no such correlation was observed for ER. Ji et al. [12] demonstrated that the HER2 FISH-amplified group exhibited a reduced frequency of ER and PR. Additionally, a positive correlation was observed between Ki67 and gene amplification, as evidenced by several other studies [13, 14] These findings contradict our own, potentially due to limitations in our sample size and features. Conversely, Alsafi et al. [15] corroborated our findings. Their study did not identify a correlation between gene amplification and the Ki67 index.
The latest data indicates that inflammatory markers may influence the prognosis of HER2-positive disease. The HELENA study investigated the prognosis of early-stage breast cancer and demonstrated that HER2 2+ cases exhibited superior outcomes compared to HER2+ cases. Additionally, the study indicated that the neutrophil-to-lymphocyte ratio (NLR) did not exert a notable influence on prognosis. [16]. Furthermore, the evaluation of inflammatory markers, specifically NLR and PLR, did not reveal any notable differences. The results of several studies have been inconclusive about these markers. In a study of early-stage breast cancer, it was concluded that NLR and PLR were not significant markers for disease-free survival [17]. Two distinct studies have reached the same conclusion: that patients with HER2-positive metastatic breast cancer who have a high level of NLR tend to have better outcomes [18, 19]. Another study revealed that PLR was an independent risk factor for survival [20]. In their investigation of the characteristics of equivocal HER2 early breast cancer, Al-Zadjali [21] et al. found no significant differences in hormonal status or neutrophil-to-lymphocyte ratio (NLR) between groups based on FISH results.
Limitation
It should be noted that the present study is subject to several limitations. The quality of the analysis was constrained by the retrospective nature of the study and the presence of missing data. Additionally, the limited sample size and the exclusive reliance on data from a single center posed challenges for a comprehensive evaluation. Nevertheless, to the best of our knowledge, this is the inaugural investigation into the clinicopathological features of HER2 IHC2+ disease within our population.
Conclusion
HER2 IHC2+ breast cancer is a heterogeneous disease, and as such, each patient should be assessed individually. In particular, a tailored approach that incorporates targeted therapies is recommended. Further investigation of different biomarkers and predictive factors may elucidate the optimal management pathway.
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
1. Ali AM, Provenzano E, Bartlett JMS, Abraham J, Driver K, Munro AF, et al. Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub-types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial: Prognosis of Early Breast Cancer. Int J Cancer. 2013;133(6):1470–8.
2. Zhao J, Wu R, Au A, Marquez A, Yu Y, Shi Z. Determination of HER2 gene amplification by chromogenic in situ hybridization (CISH) in archival breast carcinoma. Mod Pathol. 2002;15(6):657–65.
3. López-Guerrero JA, Llombart-Cussac A, Noguera R, Navarro S, Pellin A, Almenar S, et al. HER2 amplification in recurrent breast cancer following breast-conserving therapy correlates with distant metastasis and poor survival. Int J Cancer. 2006;118(7):1743–9.
4. Shah S, Chen B. Testing for HER2 in Breast Cancer: A Continuing Evolution. Pathol Res Int. 2010;2011:903202. .
5. Murphy CG, Modi S. HER2 breast cancer therapies: A review. Biol Targets. Ther 2009;3:289–301.
6. Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. J Clin Oncol. 2007;25(1):118–45.
7. Tchrakian N, Flanagan L, Harford J, Gannon JM, Quinn CM. New ASCO/CAP guideline recommendations for HER2 testing increase the proportion of reflex in situ hybridization tests and of HER2 positive breast cancers. Virchows Arch. 2016;468(2):207–11.
8. Oh D-Y, Bang Y-J. HER2-targeted therapies – a role beyond breast cancer. Nat Rev Clin Oncol 2020;17(1):33–48.
9. Atkinson R, Mollerup J, Laenkholm A-V, Verardo M, Hawes D, Commins D, et al. Effects of the change in cutoff values for human epidermal growth factor receptor 2 status by immunohistochemistry and fluorescence in situ hybridization: a study comparing conventional brightfield microscopy, image analysis-assisted microscopy, and interobserver variation. Arch Pathol Lab Med 2011;135(8):1010–6.
10. Hashemi Bahremani M, Ebrahimi A, Fallahi M. Predicting Effects of Clinicopathological Variables on Her2 Gene Amplification by Chromogenic in situ Hybridization (CISH) in IHC Her2 (2+) Breast Cancer Patients; A Study from Iran. Iran J Pathol. 2020;15(3):217–24.
11. Musa ZA, Qasim BJ, Al Shaikhly AWA. Evaluation of immunohistochemistry-equivocal (2+) HER2 gene status in invasive breast cancer by silver DNA in situ hybridization (SISH) and its association with clinicopathological variables. Iran J Pathol 2017;12(1):9-19.
12. Ji Y, Sheng L, Du X, Qiu G, Chen B, Wang X. Clinicopathological variables predicting HER-2 gene status in immunohistochemistry-equivocal (2+) invasive breast cancer. J Thorac Dis. 2014;6(7):896-904.
13. Dieci MV, Barbieri E, Bettelli S, Piacentini F, Omarini C, Ficarra G, et al. Predictors of human epidermal growth factor receptor 2 fluorescence in-situ hybridisation amplification in immunohistochemistry score 2+ infiltrating breast cancer: a single institution analysis. J Clin Pathol. 2012;65(6):503–6.
14. Shokouh TZ, Ezatollah A, Barand P. Interrelationships between Ki67, HER2/neu, p53, ER, and PR status and their associations with tumor grade and lymph node involvement in breast carcinoma subtypes: retrospective-observational analytical study. Medicine (Baltimore). 2015;94(32):e1359.
15. Abdul Raouf ALSafi R, A Ali S, Hausin Al-Khafaj A, Adnan Habib M. Assessment Of Her-2/Neu Gene Amplification Status by Chromogenic in Situ Hybridization in Breast Cancer Patients with Equivocal 2+ Her-2/Neu Immunostaining and Its Relation to The Clinic Pathological Parameters. Karbala J Med. 2016;9(2):2483–90.
16. Cherifi F, Da Silva A, Johnson A, Blanc-Fournier C, Abramovici O, Broyelle A, et al. HELENA: HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer. BMC Cancer. 2022;22(1):1081.
17. Ulas A, Avci N, Kos T, Cubukcu E, Olmez OF, Bulut N, et al. Are neutrophil/lymphocyte ratio and platelet/lymphocyte ratio associated with prognosis in patients with HER2-positive early breast cancer receiving adjuvant trastuzumab? Lung Cancer. 2015;20(3):714-722.
18. Ding N, Pang J, Liu X, He X, Zhou W, Xie H, et al. Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: Exploratory analysis of data from the CLEOPATRA trial. Breast Cancer Res 2024;26(1):9.
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20. Song D, Li X, Zhang X. Expression and prognostic value of ratios of platelet lymphocyte, neutrophil lymphocyte and lymphocyte monocyte in breast cancer patients. Am J Transl Res. 2022;14(5):3233.
21. Yaqeen A-Z, Afrah A-R, Samya A-H, Suaad A-B, Hajer A-B, Arafa M. Clinicopathological Study of Breast Carcinoma Patients with Equivocal HER2 Immunohistochemical Status: Five-Year Experience from a Tertiary Care Center. Maedica. 2023;18(1):27.
Download attachments: 10.4328.ACAM.22464
İsmet Seven, İrfan Karahan, Fahriye Tuğba Köş, Serhat Sekmek, Doğan Bayram, Gökhan Uçar, Doğan Uncu. Clinicopathological features of the patients with human epidermal growth factor receptor immunohistochemistry 2+ early stage breast cancer. Ann Clin Anal Med 2025;16(5):369-372
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Evaluation of patients applying to the emergency department for 3 years: A city hospital example
Fatih Cemal Tekin, Ramazan Köylü, Berke Yıldırım
Department of Emergency Medicine, Konya City Hospital, Konya, Turkiye
DOI: 10.4328/ACAM.22465 Received: 2024-10-18 Accepted: 2024-12-02 Published Online: 2024-12-26 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):373-377
Corresponding Author: Fatih Cemal Tekin, Department of Emergency Medicine, Konya City Hospital, Konya, Turkiye. E-mail: fatihcemaltekin@gmail.com P: +90 532 407 77 17 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8410-5552
Other Authors ORCID ID: Ramazan Köylü, https://orcid.org/0000-0002-7685-8340 . Berke Yildirim, https://orcid.org/0009-0003-5577-3369
This study was approved by the Ethics Committee of Health Sciences University Scientific Research (Date: 2023-04-07, No: 7/28)
Aim: This study seeks to gather data that can aid in the organization of emergency departments to address overcrowding, specifically during the time of patient arrival (time and day). Additionally, it aims to contribute to the existing body of knowledge on the overall patterns of emergency department visits and demographic factors that could be useful in mitigating overcrowding in emergency department.
Material and Methods: The study was conducted as a cross-sectional retrospective study. The study examined the data of patients who were admitted to the Emergency Department within 3 years, starting from the day the hospital began its operations, using hospital automation. The study assessed variables including age, gender, day and hour of admission, type of admission, and triage codes.
Results: There were 1.251.717 patient admissions to the emergency department in the determined date range. Of the patients admitted to the emergency department, 11,8% were admitted by ambulance, and 72,9% were examined with a green area code. There was a positive and highly statistically significant correlation between the number of years of emergency department admissions (p<0,05 rs =0,994).
Discussion: Necessary arrangements should be made to increase capacity and quality during peak times of the emergency department. The resulting data reveal important results in order to identify the busier times of the emergency department.
Keywords: Emergency Departments, Demographic Factors, Health Services, Misuse
Introduction
Emergency departments (EDs) are critical hospital units that operate continuously, 24/7, and (available at: https://www.resmigazete.gov.tr/eskiler/2022/09/20220913-5.htm) handle a substantial volume of cases. Emergency departments are skilled and efficient facilities that concurrently offer inpatient services and vital patient care alongside outpatient services. The substantial volume of applications, the necessity to identify and prioritize emergency patients, the requirement for prompt service delivery, the demand for continuous operation, and the need for swift diagnosis and treatment services complicate the operation of the Emergency Department. In addition, the variable structure of the ED complicates personnel planning and needs ongoing new arrangements [1-3].
The public is aware of the congested and intricate conditions of emergency departments at numerous hospitals across our nation [4]. Numerous factors, including the quality of service rendered by emergency departments (EDs), accessibility of this service, the expedited operations of EDs relative to other units, the perception of EDs as venues for applications beyond standard working hours, and the provision of outpatient clinic services without prior appointments, significantly contribute to the elevated rate of applications to EDs. These characteristics can result in a rise in the frequency of unsuitable applications to the emergency department, a decline in service quality, a deceleration of operations, and, consequently, the emergence of a congested and disorderly atmosphere [5, 6].
Examining the factors contributing to admissions in the Emergency Department, the demographic characteristics of admitted patients, and the timing of admissions is crucial for alleviating ED congestion and for effective service and personnel planning. Furthermore, these findings may inform policies about the improper utilization of EDs. This study aims to assist in the planning of emergency department services and to enhance the existing literature.
Material and Methods
The study was designed as a retrospective cross-sectional analysis. No sample calculation was conducted for the study, and all patient records admitted to the Emergency Department between three years from August 31, 2020, the facility’s inception date, were retrieved via hospital automation. The demographic features of the patients, their method of hospital arrival, presenting problems, diagnoses, time of presentation to the emergency department, and the proportion of green field patients were collected.
The data acquired from the investigation were transferred to a computer system and evaluated. In the presentation of the data, frequency data were represented as numerical values and percentages in descriptive analyses, whilst median, first quartile, and third quartile values were utilized for ordinal variables. The correlation among years, gender, and admission frequency was assessed using Spearman’s correlation (rs) analysis.
The statistical significance level was established at p<0.05 for all tests.
Ethical Approval
This study was approved by the Ethics Committee of Health Sciences University Scientific Research Ethics Committee (Date: 2023-04-07, No: 7/28).
Results
There were 1,251,717 patient applications to the Emergency Department during the specified calendar span. In 2020, there were 133,457 applications (10.7%), in 2021, 295,169 applications (23.6%), in 2022, 591,741 applications (47.3%), and in the first three months of 2023, 231,350 applications (18.5%). A strong and statistically significant connection was identified between emergency department admissions and years (p<0.05, rs = 0.994).
49.3% (560,351) of patients aged 18 years and older were male, while 50.7% (577,081) were female (Table 1). Of the individuals admitted via ambulance, 52.2% were male. Among 114,283 patients under 18 years of age assessed for trauma, 63% (71,975) were male. The patients’ age range was identified as a minimum of 0 and a maximum of 140, with a median of 34 and first and third quartile values of 23 and 49, respectively. The 140-year-old patient was of Afghan nationality, with the next oldest age being 134. Additionally, 9.1% of the patients were under 18 years old and had experienced trauma. It was established that 400.338 patients (32%) who presented to the ED had a singular application to the ED, whereas the remainder had multiple applications. Foreign nationals constituted 6.4% of the applications, with Syria (5.3%) and Afghanistan (0.7%) being the predominant nationalities among patients. 9.6% of the patients were either outpatients or ambulance patients from outside the province. Among ambulance admissions, 9.6% were patients identified as part of the Syrian population.
Among the patients admitted to the emergency department, 11.8% arrived by ambulance, and 72.9% were assessed under a green area code. 2.4% of patients were admitted solely for dressing, whereas 4% were admitted for parenteral delivery of prescription medications. Of the case types, 3.4% were forensic cases, 1.3% were road accidents, and 0.8% were occupational accidents. The forensic case rate was 21.5% among individuals admitted via ambulance.
It was found that the three most frequently entered diagnoses were M79.9-Soft tissue disorder, unspecified with 6.30%, Z00.0-General medical examination with 5.89%, and J39.9-Upper respiratory tract disease, unspecified with 5.83% (Table 2).
The volume of applications to AS significantly increased following Saturdays, peaking on Mondays with 15% of total applications. Subsequently, the number of applications declined, reaching its nadir on Thursdays at 13.9% (Figure 1). The application hours were found to be nearly identical throughout the week, with the biggest volume of applications occurring on Monday and Friday, each accounting for 14.6%.
Upon categorizing the presentation times of the Emergency Department (ED) into the intervals 00:00-06:59, 07:00-12:59, 13:00-17:59, and 18:00-23:59 (Figure 2), it was observed that 38.22% of ED visits occurred between 18:00-23:59, 31.96% between 13:00-17:59, 19.20% between 07:00-12:59, and 10.62% between 00:00-06:59. A significantly significant association was identified between the hours of presentation and the frequency of presentation (p<0.05, rs = 0.992).
The predominant time of application was identified as 13:00-17:59, accounting for 33.4%, while the second most prevalent period was 18:00-23:59, including 32.5%.
M79.9 – Soft tissue condition, not elsewhere categorized, was the most commonly diagnosed 4-digit ICD code at 6.3%, while M79 – Other soft tissue disorders, not elsewhere defined, was the most frequently diagnosed 3-digit ICD code at 11.56%. Table 2 presents the initial ten 3-digit ICD diagnostic codes.
Discussion
The population of the province where the research was conducted in 2022 is reported to be 2,296,347 (available at: https://nvi.gov.tr/istatistikler). Since the inauguration of the City Hospital, almost fifty percent of the provincial population has utilized the Adult Emergency Department. The statistical tests indicate that this number has increased in direct proportion to the years. Numerous research in worldwide literature has documented the congestion of emergency departments and the high volume of patient presentations. Investigating the causes of excessive Emergency Department utilization is crucial, and implementing solutions is necessary to prevent the escalation of overcrowding as a cyclical issue [6-8].
Despite variations among foreign national patients across provinces, the predominance of Syrian patients, followed by Afghan patients, in our study indicates that emergency department admission rates may serve as a preliminary indicator of the foreign national demographic within the provincial population [9]. In 2023, the population of Syrian nationals in the province where the study was done was recorded as 119,108 (available at: https://www.goc.gov.tr/raporlar). The total of applicants possessing Syrian nationality is 66,455, exhibiting an application rate of 55.8%. The cumulative application rate, based on the province population (available at: https://nvi.gov.tr/istatistikler), is 54.5%. The application rates for ED among Syrian nationals are comparable to the province-wide rates for AS applications. The literature lacks comparable data on this topic, necessitating more investigation [10, 11].
This study demonstrated no impact of gender on the frequency of adult patient presentations in the emergency department. Nevertheless, despite their proximity in percentage, the female gender was shown to be more prevalent. In the literature, admission rates for males and females are typically comparable, akin to our findings. [1, 12, 13]. The proportion of male patient applications was greater among those under 18 years of age. Considering that only patients under 18 years old are admitted to the adult emergency department for trauma, the findings align with national and international literature demonstrating a higher prevalence of trauma occurrences among males in this age group [13, 14].
In this study, the total forensic case admission rate of 5.5% was found to be similar to the literature [15, 16], which is between 4.2% and 7.01%. Factors such as proximity to the courts, designation as the forensic hospital, location on an intercity thoroughfare, and traffic accident applications were considered to contribute to these disparities [17].
The predominant category of ED applications consisted of green area applications. Despite varying data on the distribution of ED area codes in the literature, admissions to green areas are typically elevated. This scenario, a rationale for implementing a triage system in the emergency department, may hinder the assessment and identification of urgent cases, impede operational efficiency, and exacerbate crowding in the emergency department, creating a vicious cycle [2, 18]. The system may require future evaluation about the implementation of green spaces and outpatient clinic services.
Understanding the peak days and hours of Emergency Departments is crucial for staff and service planning. Augmenting human resources, medical equipment, and material requirements during specific times of the day while reallocating capacity enhancements to these periods will mitigate emergency department congestion and enhance service quality. Our study detected an increase in ED admissions after working hours and during holidays, consistent with national literature. The elevated volume of ED applications, particularly throughout the evening and early night hours, indicates that augmenting personnel, medical equipment, and supplies during these times may be warranted [12]. The similarity in the number of ambulance requests across the days of the week may be attributed to an inadequate supply of ambulances relative to demand. Moreover, while it may be inferred that patients have attained a specific benchmark regarding ambulance transport to hospitals or that a particular cohort of patients derives advantages from ambulance services, additional research is necessary to assess calls to 112.
The most often diagnosed conditions in patients admitted to the emergency department are crucial for emergency department and hospital planning. This issue shall be considered in the running of the Emergency Department, including the necessity for specialized areas, service conditions, equipment, and medication planning for these patients. In the national literature, some studies highlight soft tissue diagnoses akin to our research, as well as studies that emphasize alternative diagnoses. Regional disparities and the period of study were believed to influence this condition [1-3, 19].
Conclusion
Consequently, the attributes of ED applications are crucial for effective ED planning. The study’s findings indicate a significant concentration of patients beginning Saturday, with Monday being the peak day. Most patients are categorized under the green area code, and soft tissue disorders are the predominant diagnosis. These insights will aid in identifying frequently encountered diseases and inform emergency department planning regarding human resources, medical supplies, and equipment requirements.
Limitation
Since the research was a retrospective study, it was conducted on the data in the patient files.
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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4. Acar YA, Çevik E, Uyguner C, Çınar O. Ulusal Gazetelerdeki Acil Servis Haberlerinin İçerik Analizi [Turkish Media Portrayal Analysis of Emergency Health Services]. Turk J Emerg Med. 2013;13(4):166-170.
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6. Savioli G, Ceresa IF, Gri N, Bavestrello Piccini G, Longhitano Y, Zanza C, et al. Emergency Department Overcrowding: Understanding the Factors to Find Corresponding Solutions. J Pers Med. 2022;12(2):279.
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8. Sartini M, Carbone A, Demartini A, Giribone L, Oliva M, Spagnolo AM et al. Overcrowding in Emergency Department: Causes, Consequences, and Solutions-A Narrative Review. Healthcare. 2022;10(9):2-13.
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Fatih Cemal Tekin, Ramazan Köylü, Berke Yıldırım. Evaluation of patients applying to the emergency department for 3 years: A city hospital example. Ann Clin Anal Med 2025;16(5):373-377
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The predictive role of amniotic fluid and serum tenascin X for adverse perinatal outcomes
Begum Uzsezer Guler 1, Burcu Dincgez 2, Nefise Nazlı Yenigül 2, Gulten Ozgen 2
1 Department of Obstetrics and Gynecology, VM Medical Hospital, 2 Department of Obstetrics and Gynecology, Faculty of Health Sciences, BursaYuksek Ihtisas Research and Training Hospital, Bursa, Turkiye
DOI: 10.4328/ACAM.22473 Received: 2024-10-31 Accepted: 2024-12-02 Published Online: 2024-12-10 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):378-383
Corresponding Author: Burcu Dincgez, Department of Obstetrics and Gynecology, Faculty of Health Sciences, BursaYuksek Ihtisas Research and Training Hospital, Bursa, Turkiye. E-mail: burcumavis@gmail.com P: +90 530 544 88 28 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2697-7501
Other Authors ORCID ID: Begum Uzsezer Guler, https://orcid.org/0000-0002-7923-1308 . Nefise Nazlı Yenigül, https://orcid.org/0000-0003-3365-8899 . Gulten Ozgen, https://orcid.org/0000-0002-7888-7583
This study was approved by the Ethics Committee of Health Science University Bursa Yüksek İhtisas Trining and Research Hospital (Date: 2021-04-12, No: 2011-KAEK-25)
Aim: There is limited data about the association between tenascin X deficiency and obstetric outcomes. Here, we aimed to search the predictive role of amniotic fluid and serum tenascin X for adverse pregnancy outcomes.
Material and Methods: This is a prospective study conducted at a university-affiliated hospital between May 2021 and December 2021. A total of 70 patients who underwent amniocentesis for any reason were included. Patients were divided into two groups: adverse pregnancy outcome group (n=35) and controls (n=35). Demographic, laboratory and obstetrics features were recorded. Amniotic fluid and serum tenascin X levels were measured using the ELISA method.
Results: Amniotic fluid tenascin X were 19.1(8.2–39.13)ng/ml in the adverse perinatal outcome group and 22.34(2.91–61.99)ng/ml in control group which was significantly lower in adverse outcome group (p=0.020). Similarly, serum tenascin X levels were lower in adverse perinatal outcome group compared to control group (1.97[1.07–5.85]ng/ml vs 3.03[1.31–8.15]ng/ml ,p=0.030). Amniotic fluid tenascin X<20.7ng/ml predicted adverse perinatal outcomes, with a sensitivity of 74.29% and specificity of 65.7% (p=0.016, AUC=0.662). Serum tenascin X≤1.97ng/ml predicted adverse perinatal outcomes with a sensitivity of 54.29% and specificity of 80% (p=0.024, AUC=0.651). The analysis revealed no significant difference between serum and amniotic fluid (p=0.91). Amniotic fluid tenascin X levels were significantly lower in patients who developed gestational diabetes, preterm birth, premature rupture of membranes and an Apgar score ≤7.
Discussion: Amniotic fluid and serum tenascin X could be a valuable marker for predicting adverse perinatal outcomes. Large scaled, prospective randomized studies are needed to clarify this association.
Keywords: Adverse Perinatal Outcome, Amniotic Fluid Tenascin X, Serum Tenascin X
Introduction
Tenascins are extracellular matrix glycoproteins that play role in the modulation of cell signaling, collagen deposition and resistance to proteolysis [1]. The family is composed of four members: Tenascin C, R, W and X [2]. Tenascin C expresses in embrional period, modulates wound healing and neovascularization while tenascin R expresses in central nerve system. Tenascin W expression is limited to developing skeletal tissue and neural crest cells in zebrafish [3].
Tenascin X (TNX) regulates connective tissues such as muscles, joints and skin. It provides elasticity and flexibility to connective tissues via stabilizing elastic fibers and producing some types of collagen [4, 5]. Ehler Danlos Syndrome, a heritable connective tissue disorder, has been shown to be related to TNX deficiency [6]. In a study, pregnant women with Ehler Danlos Syndrome were found to be more prone to postpartum hemorrhage, preterm birth and premature rupture of membranes [7-9]. This situation raises the suspicion that TNX deficiency may be associated with adverse pregnancy outcomes such as preterm birth and premature rupture of membranes. Unfortunately, there is limited data about the association between TNX deficiency and obstetric outcomes.
To the best of our knowledge, this is the first study searching the predictive role of TNX for adverse pregnancy outcomes. Additionally, we aimed to evaluate both second trimester amniotic fluid and serum TNX levels and to determine cut-off levels for adverse perinatal outcomes.
Material and Methods
This is a single center, prospective study performed at a university affiliated research and training hospital between May 2021 and December 2021. For power analysis, NCSS statistical package program was used and it was determined that a minimum of 66 patients should be included in the study by accepting 80% power and α=0.01. A total of 70 patients who were admitted to the University of Health Sciences, Bursa Yuksek Ihtisas Research and Training Hospital, Department of Obstetrics and Gynecology, Perinatology Outpatients Clinic and underwent amniocentesis for any reason were included in the study. Then, patients were followed for their antenatal visits and adverse pregnancy outcomes were recorded. Adverse perinatal outcomes were defined as having hypertensive disorders of pregnancy, gestational diabetes, preterm birth, preterm premature rupture of membranes, intrauterine growth restriction and Apgar score ≤7. Finally, patients were grouped as adverse pregnancy outcome group (n=35) and a control group (n=35).
Inclusion criteria of the study were having single pregnancy, being between 16-35 years old, undergoing amniocentesis between 16-20 weeks of gestation, having regular antenatal visits and birth in our clinic. Pregnant women with any inflammatory or autoimmune disease, hepatic and renal dysfunction, thyroid disorders, smoking or alcohol use, history of stroke and anti-inflammatory drug use were excluded.
Age, gravida, parity, height, weight, date of last menstrual period, gestational week confirmed by ultrasound, amniocentesis week, the time between pregnancies, adverse pregnancy outcomes, birth week, birth weight, delivery type, Apgar score, maternal hemoglobin at birth, hematocrit, white blood cell (WBC), platelet, fasting blood glucose, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein parameters were recorded.
In our clinic, amniocentesis was performed between 16-20 weeks of gestation by the transabdominal route and 22 gauge needle using the free hand technique, accompanied by ultrasonography. All procedures were performed by the same perinatologist. The first 5 cc fluids taken during amniocentesis and maternal serum samples of all patients were stored in the biochemistry laboratory at -80 degrees. Tenascin X levels were measured by ELISA method.
Statistical Analysis
Normality assumption was evaluated with Shapiro Wilk test. Variables were expressed as mean ± standard deviation or median (minimum-maximum) values as descriptive statistics. Categorical variables were presented with frequency and related percentage values. Student’s t-test was used to compare normally distributed quantitative data between two groups, and Mann Whitney-U test was used to compare non-normally distributed quantitative data between two groups. Chi-square or Fisher’s Exact test was used to compare categorical data. Receiver operating curve analysis was used to determine the predictive role of amniotic fluid and serum TNX levels for adverse perinatal outcomes. The sensitivity, specificity, Youden index and cut-off values were analyzed. Also, the predictive role of amnion fluid and serum TNX were compared with receiver operating curve analysis. The statistical analysis were performed with SPSS 21.0 program and the level of significance was accepted as α=0.05.
Ethical Approval
This study was approved by the Ethics Committee of Health Science University Bursa Yüksek İhtisas Trining and Research Hospital (Date: 2021-04-12, No: 2011-KAEK-25). The study was in accordance with the Helsinki declaration. Written informed consent was taken from all study participants for using data from medical records.
Results
A total of 70 patients who underwent amniocentesis were included and grouped as adverse outcome group (n=35) and control group (n=35). Hypertensive disorders of pregnancy were detected in 8 (11.4%) patients, gestational diabetes was detected in 7 (10%) patients, preterm birth was detected in 10 (14.3%) patients, preterm premature rupture of the membrane was detected in 9 (12.9%) patients, intrauterine growth restriction was detected in 18 (25.7%) patients and Apgar score ≤7 was detected in 10 (14.3%) patients. The sociodemographic features of adverse perinatal outcomes and control groups were demonstrated in Table 1. No significant difference was detected in terms of age, gravida, parity, abortion, BMI and interval between pregnancies.
The obstetric characteristics of adverse perinatal outcomes and control groups are shown in Table 1. There was no significant difference between two groups in terms of the week of amniocentesis while birth week and weight, Apgar scores of first and fifth minutes were lower in the adverse perinatal outcome group. The Cesarean section rate was significantly higher in the adverse perinatal outcome group.
The laboratory features of adverse perinatal outcome and control groups were presented in Table 2. There was no significant difference between the two groups regarding WBC, hemoglobin, hematocrit, platelet, fasting glucose, creatinine, AST, ALT and C reactive protein levels. Median amniotic fluid TNX levels were 19.1 (8.2- 39.13)ng/ml in adverse perinatal outcome group and 22.34 (2.91- 61.99)ng/ml in control group which was statistically significantly lower (p=0.020). Similarly, median serum TNX levels were significantly lower in adverse perinatal outcome group as compared to control group (1.97 (1.07- 5.85) ng/ml vs 3.03 (1.31- 8.15)ng/ml , p=0.030).
The ROC curve evaluating the role of amniotic fluid TNX in predicting adverse perinatal outcomes is shown in Figure 1.
According to this analysis, amniotic fluid TNX cut-off value of 20.7 was found to be statistically significant in predicting adverse perinatal outcomes with 74.29% sensitivity and 65.7% specificity (p=0.016, AUC=0.662).
The ROC curve evaluating the role of serum TNX in predicting adverse perinatal outcomes is demonstrated in Figure 2. According to this analysis, serum TNX cut-off value of 1.97 was found to be statistically significant in predicting adverse perinatal outcomes with 54.29% sensitivity and 80% specificity (p=0.024, AUC=0.651).
The ROC curve comparing the role of amniotic fluid and serum TNX in predicting adverse perinatal outcomes is presented in Figure 3. The analysis revealed no statistically significant difference between serum and amniotic fluid TNX levels (p=0.91).
Amniotic fluid and serum TNX levels for each adverse perinatal outcome are shown in Table 3. No significant difference was detected between patients with and without hypertensive disorders of pregnancy in terms of amniotic fluid and serum TNX levels. Likewise, there was no significant difference according to amniotic fluid and serum TNX levels in patients with and without intrauterine growth restriction. Serum TNX levels were similar between other subgroups like hypertensive disorders of pregnancy and intrauterine growth restriction whereas amniotic fluid TNX levels were statistically significantly lower in patients who develop gestational diabetes, preterm birth, premature rupture of membrane and Apgar score ≤7.
Discussion
Tenascin X, the largest member of the tenascin family with a weight of 450 kDa, interacts with extracellular matrix components such as fibrils, collagens type I, III, and V and proteoglycans such as decorin [10]. Extracellular matrix, composed of fibrous proteins along with various types of collagen, provides the architectural and structural framework of the fetal membranes. Disruption of the collagen-rich extracellular matrix that connects the amnion and chorion layers of the fetal membranes is one of the key events leading to membrane rupture [3, 11-13]. Recent studies have shown that Ehler Danlos syndrome is related to TNX deficiency and low TNX levels could cause an increased risk of preterm premature rupture of membranes in Ehler Danlos cases [8]. This condition was explained with the reduced binding of TNX deficient fibroblasts to fibronectin, an important adhesion molecule for fetal membranes [14]. Rood and colleagues showed that fetal membranes contained significantly higher levels of TNX compared to myometrium, cervix and placenta. Moreover, it was shown that TNX expression tended to increase in amniotic fluid and decrease in fetal membranes during intraamniotic infection, independent of preterm premature rupture of membranes [3]. All these studies has supported the role of TNX deficiency in premature rupture of membranes. Consistently, we found lower TNX levels in preterm birth and premature rupture of membrane cases.
There are limited studies in the literature about the role of TNX on other perinatal outcomes. In a study, searching the effect of TNX levels in human and mouse uterine connective tissues on obstetric complications, TNX deficiency was not found to be related to major complications except one postpartum hemorrhage case. In another study, a shorter pregnancy period was reported in TNX deficient mouses [15]. Another study found an increase in abnormal mRNA expression for the tenascin-X gene in euploid fetuses with ventricular septal defects between 19 and 24 weeks of gestation [16].
In a study by Alcaraz et al, it was shown that the TNX plays a key role in the conversion of latent TGF-β to an active molecule [17]. It is known that obesity, insulin resistance and endothelial dysfunction causing early atherosclerosis occur in women with gestational diabetes. TGF-β1 is a key cytokine in obesity and insulin resistance and also plays an important role in the development of atherosclerosis. Yener et al showed that serum TGF-β1 levels were increased in patients with gestational diabetes mellitus [18]. Morisette et al showed that TNX levels in patients with congenital adrenal hyperplasia were associated with TGF-β pathway abnormalities [19]. In our study, amniotic fluid TNX levels were lower as compared to non-diabetic patients. We suggest that this condition could be related to increased TGF-β activation due to TNX deficiency which can lead to insulin resistance. It is also known that TNX increases endothelial cell proliferation by binding to VEGF-1 [20]. There are studies in the literature showing the presence of endothelial dysfunction and decreased VEGF-1 levels in gestational diabetes [21, 22]. Based on these, another mechanism explaining the relationship between TNX and gestational diabetes may be the decreased VEGF-1 interaction due to TNX deficiency that results in endothelial dysfunction.
Although there is no study about TNX deficiency in hypertension, Liang et al demonstrated that TGF-β is critical for vascular smooth muscle cells differentiation playing a role in atherosclerosis, hypertension, and aortic aneurysm [23]. Considering the role of TNX deficiency in increased TGF-β activation, we suggest that TNX deficiency could be associated with hypertensive disorders of pregnancy. Unfortunately, no significant difference was detected between patients with and without hypertensive disorders of pregnancy in terms of amniotic fluid and serum TNX levels. This could be related to the small number of hypertensive cases.
There is no study examining TNX levels in other pregnancy outcomes where inflammation, angiogenesis and fibrogenesis play a role in the etiopathogenesis. Our study primarily showed that serum and amniotic fluid TNX levels were lower in composite adverse perinatal outcomes. Moreover, amniotic fluid TNX <20.7 predicted adverse perinatal outcomes with 74.29% sensitivity and 65.7% specificity and serum TNX <1.97 predicted adverse perinatal outcomes with 54.29% sensitivity and 80% specificity. When we searched for the other oucomes seperately, amniotic fluid and serum TNX levels were lower in intrauterine growth restriction while only amniotic fluid TNX levels were lower in patients with low Apgar scores.
Another interesting finding of our study is the comparison of the predictive roles of amniotic fluid and serum TNX levels. The analysis revealed no statistically significant difference between serum and amniotic fluid TNX levels. Although there was no difference between amniotic fluid and serum in composite adverse outcomes, amniotic fluid TNX was found to be more significant between the groups when adverse outcomes examined individually.
Limitation
This study has some limitations. The data arose from single center and it had a small sample size. The predictive role of TNX levels could not be assessed for each outcome due to the small sample size.
Conclusion
Consequently, we suggest that amniotic fluid and serum TNX could be valuable marker for predicting adverse perinatal outcomes. Large scaled, prospective randomized studies are needed to clarify this association.
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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Treatment response relationship with hematologic parameters before and after chemoradiotherapy in patients with non-small cell lung cancer
Burcu Saglam Alan 1, Burak Erdemci 2, Hilal Kiziltunc Ozmen 2
1 Department of Radiation Oncology, Antalya Training and Research Hospital, Antalya, 2 Department of Radiation Oncology, Faculty of Medicine, Ataturk University, Erzurum, Turkiye
DOI: 10.4328/ACAM.22477 Received: 2024-11-03 Accepted: 2024-12-09 Published Online: 2024-12-26 Printed: 2025-05-01 Ann Clin Anal Med 2025;16(5):384-388
Corresponding Author: Burcu Saglam Alan, Department of Radiation Oncology, Antalya Training and Research Hospital, Antalya,Turkiye. E-mail: drburcusaglam@hotmail.com P: +90 507 191 3905 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3429-0942
Other Authors ORCID ID: Burak Erdemci, https://orcid.org/0000-0001-9949-5493 . Hilal Kiziltunc Ozmen, https://orcid.org/0000-0003-0695-0931
This study was approved by the Ethics Committee of Atatürk University Faculty of Medicine (Date: 2014-12-17, No: 4/32)
Aim: This study aimed to investigate the relationship between hematological parameters and treatment response in patients with advanced non-small cell lung cancer (NSCLC) treated with curative-intent chemoradiotherapy. Specifically, we evaluated whether markers like neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW) correlate with radiologically assessed tumor size changes.
Material and Methods: We conducted a retrospective analysis of 49 NSCLC patients treated between 2008 and 2014 at Atatürk University School of Medicine. All patients received neoadjuvant chemotherapy followed by concurrent chemoradiotherapy. Hematological parameters, including NLR, PLR, and RDW, were collected before and after treatment. Tumor size was measured using PET-CT, MRI, or CT, and relationships between hematological markers and tumor size changes were analyzed using the Wilcoxon signed-rank test and Spearman’s correlation, with significance at p < 0.05.
Results: The cohort included 47 males (95.91%) and two females (4.08%), with a mean age of 62.88 ± 9.91 years. Histopathologically, 79.6% had squamous cell carcinoma, and 20.4% had adenocarcinoma. Significant changes were observed in tumor size and several hematological parameters post-treatment (p < 0.05). However, no significant correlations were found between tumor size reduction and NLR, PLR, or RDW, except for a weak correlation with PDW (r = 0.301, p = 0.036).
Discussion: While NLR, PLR, and RDW reflect systemic inflammatory responses, their predictive value for tumor size reduction in NSCLC patients treated with chemoradiotherapy appears limited. Further studies with larger sample sizes are needed to confirm these findings and improve prognostic assessment.
Keywords: Non-Small Cell Lung Cancer, Chemoradiotherapy, Radiology
Introduction
In the mid-20th century, case-control-based epidemiological research established a strong association between smoking and lung cancer, which was first conclusively published in 1962 [1]. Despite advances in prevention efforts and the identification of risk factors, lung cancer continues to be the leading cause of cancer-related deaths worldwide in both men and women [2].
According to the World Health Organization (WHO) 2004 classification, approximately 85% of all lung cancer cases are categorized as non-small cell lung cancer (NSCLC), which is further divided into histological subtypes such as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. NSCLC is often diagnosed at an advanced stage due to the lack of early symptoms, making curative surgery difficult. Consequently, treatment primarily involves chemotherapy, radiotherapy, or a combination of both (chemoradiotherapy), which offers a potentially curative option in inoperable cases.
Peripheral blood biomarkers such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have emerged as potential indicators of prognosis and treatment response in NSCLC patients [3, 4]. NLR and PLR are derived from routine blood tests, reflecting the systemic inflammatory response and the balance between pro-tumor and anti-tumor immune activities. Elevated NLR typically indicates an increased inflammatory response and poor prognosis, while lower PLR is often associated with better treatment outcomes. Several studies have demonstrated the prognostic significance of elevated platelet counts in NSCLC, suggesting that platelet levels may be predictive of poor outcomes [5]. Similarly, changes in fibrinogen levels during chemotherapy have been shown to correlate with tumor response and survival [6]. In addition to these blood-based markers, advanced imaging techniques such as perfusion CT and PET-CT have been used to monitor tumor response to treatment, offering a non-invasive method to assess tumor vascularization and metabolic activity [7].
The role of the immune system in cancer progression and treatment response has also gained considerable attention. Recent studies have examined the association between immune-related blood biomarkers, such as lymphocyte count and NLR, and the effectiveness of immunotherapy in NSCLC [8, 9]. For example, elevated NLR and PLR have been linked with shorter overall survival and increased mortality, particularly in NSCLC patients undergoing immunotherapy [10]. These findings suggest that both immune and inflammatory markers play a critical role in cancer progression and may be useful for predicting treatment outcomes.
While several studies have focused on the prognostic role of these markers, there remains a gap in the literature regarding their correlation with radiologically assessed tumor responses following chemoradiotherapy. In particular, few studies have examined the changes in NLR, PLR, and other hematological parameters both before and after treatment in relation to tumor size reduction. In this context, hematological parameters such as white blood cell (WBC) count, neutrophil and lymphocyte counts, hemoglobin (Hb), red blood cell (RBC) count, platelet count, and other derived ratios like NLR and PLR are increasingly being studied as potential predictors of treatment response and prognosis.
Our study aims to investigate the relationship between hematological parameters and treatment response in patients with advanced non-small cell lung cancer who received curative-intent chemoradiotherapy. Specifically, we examine whether hematological markers obtained before and after treatment correlate with radiologically assessed tumor responses. This study seeks to address the gap in the literature by evaluating the role of these markers in predicting tumor size changes, which could serve as a reliable indicator of treatment efficacy. By providing a clearer understanding of these correlations, we aim to contribute to the development of more personalized and cost-effective treatment strategies in NSCLC.
Understanding these relationships is crucial for the development of personalized treatment strategies in NSCLC. By identifying reliable and accessible biomarkers, we can improve patient selection for different treatment modalities, optimize therapeutic outcomes, and potentially reduce the economic burden associated with more invasive or expensive diagnostic procedures. Hematologic parameters such as NLR and PLR, along with other blood-based markers, have shown promise as potential predictors of treatment response in NSCLC, particularly in resource-limited settings where advanced imaging techniques may not always be feasible.
Our study seeks to investigate whether NLR, PLR, and other hematologic parameters obtained before and after treatment are significantly correlated with tumor size changes in NSCLC patients undergoing chemoradiotherapy. By doing so, we aim to establish these parameters as predictive markers of treatment response, which could serve as a practical tool in clinical decision-making. This study not only examines the predictive value of these hematologic markers but also explores their broader implications for personalized cancer treatment. Given the accessibility and cost-effectiveness of these biomarkers, the findings could have significant clinical importance, particularly in guiding treatment decisions and improving overall outcomes for NSCLC patients.
Material and Methods
The study was designed as a retrospective analysis of patients diagnosed with non-small cell lung cancer (NSCLC) who were treated at Atatürk University School of Medicine, Department of Radiation Oncology, between 2008 and 2014. The initial cohort consisted of 152 patients, and following the application of strict inclusion and exclusion criteria, 49 patients were selected for the final analysis. The inclusion criteria required that patients had a confirmed diagnosis of NSCLC, had not undergone surgery, received neoadjuvant chemotherapy, and were treated with simultaneous chemoradiotherapy. Additionally, these patients had available hemogram data both before and after treatment, as well as radiologic imaging results such as PET-CT, MRI, or CT scans. Patients who underwent surgical interventions or those with incomplete hemogram or radiological follow-ups were excluded from the study.
Radiotherapy (RT) was delivered to all patients using a 3D conformal radiotherapy technique. RT was administered five days a week with a daily fraction size of 1.8-2 Gy over a treatment period of 6 to 7 weeks. The total RT dose delivered to the primary tumor was 60-66 Gy, while involved lymph nodes received 44-46 Gy, with concurrent chemotherapy administered during the RT course. The energy used for the RT was 6-18 MV, delivered by a Siemens-Primus linear accelerator (Siemens-Primus 2002, Germany). Chemotherapy regimens were tailored according to each patient’s clinical status and followed standard institutional protocols for NSCLC.
All patients were staged according to the 7th edition of the TNM staging system (2010). Histopathological evaluation classified the tumors as either squamous cell carcinoma or adenocarcinoma. In total, 39 patients (79.6%) were diagnosed with squamous cell carcinoma, and ten patients (20.4%) were diagnosed with adenocarcinoma.
Blood samples were collected from all patients both before and after chemoradiotherapy. The following hematological parameters were analyzed: white blood cell count (WBC), neutrophil count, lymphocyte count, monocyte count, basophil count, eosinophil count, red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), platelet count (Plt), mean corpuscular volume (MCV), mean platelet volume (MPV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet distribution width (PDW), and plateletcrit (Pct). The neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were also calculated for each patient based on these parameters.
Tumor size was assessed using radiologic imaging, which included PET-CT, MRI, and CT scans. Radiological evaluations were performed both before and after the treatment to measure tumor response. In cases where tumor size was not reported in the radiological evaluation, axial section images from the parenchyma window were used, and the largest diameter of the tumor was manually recorded. Tumor size was expressed in square millimeters (mm²) and used for pre-and post-treatment comparisons.
Statistical Analysis
The data were statistically analyzed using SPSS v20 software. Categorical variables, such as histopathological classification and gender, were expressed as numbers and percentages. Continuous variables, including hematological parameters and tumor sizes, were expressed as means and standard deviations. The normality of the data was assessed using the Kolmogorov-Smirnov test and histogram graphing methods. For pre-and post-treatment comparisons, the Wilcoxon signed-rank test was employed due to the non-normal distribution of the data. To examine the relationships between tumor size and hematological parameters, Spearman’s rho correlation analysis was performed. A p-value of less than 0.05 was considered statistically significant for all analyses.
Ethical Approval
This study was approved by the Ethics Committee of Atatürk University Faculty of Medicine (Date: 2014-12-17, No: 4/32).
Results
Of the 49 patients included in the study, 47 were male (95.91%), and two were female (4.08%). The mean age of the patients was 62.88 ± 9.91 years. Upon statistical analysis, 39 patients (79.6%) were diagnosed with squamous cell carcinoma, while ten patients (20.4%) had adenocarcinoma (Figure 1).
Tumor sizes and hematological parameters of all cases were statistically evaluated. There was a statistically significant difference in tumor size values before and after treatment (p=0.000). Additionally, WBC, neutrophil, lymphocyte, basophil, and eosinophil counts showed statistically significant differences (p=0.000). However, no statistically significant difference was observed in monocyte counts (p=0.066). The percentages of neutrophils, lymphocytes, basophils, and eosinophils also demonstrated statistically significant changes between pre- and post-treatment values (p=0.015).
Other hematological parameters that exhibited significant differences included RBC (p=0.000), Hb (p=0.000), Hct (p=0.000), Plt (p=0.000), MCH (p=0.000), PDW (p=0.000), RDW (p=0.000), neutrophil/lymphocyte ratio (p=0.000), platelet/lymphocyte ratio (p=0.000), MCV (p=0.004), MCHC (p=0.002), and MPV (p=0.003).
The relationship between tumor size and hematological parameters was evaluated, but no significant correlations were found. However, there was a weak correlation with PDW (r=0.301, p=0.036) (Table 1).
Discussion
The findings of this study contribute to the growing body of literature that examines the role of hematological parameters as prognostic markers in non-small cell lung cancer (NSCLC). Our results align with earlier studies, suggesting that certain blood-based markers, such as the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), may provide valuable insights into treatment response and patient prognosis.
Dangfan Yu et al. identified that a high preoperative platelet count is a significant prognostic marker in NSCLC patients, with poorer survival outcomes associated with elevated platelet levels [11]. In our study, we also observed a significant reduction in platelet counts after chemoradiotherapy, indicating a potential link between platelet reduction and tumor response. This result reinforces the hypothesis that changes in platelet levels may reflect tumor burden and response to treatment, as also suggested by Zhao et al., who noted fibrinogen levels correlated with tumor response [6].
In the context of immune and inflammatory responses, Cannon et al. demonstrated that NLR and PLR are significant predictors of survival in patients treated with stereotactic radiation for early-stage NSCLC [3]. Our findings support this observation, as we found significant changes in NLR and PLR following chemoradiotherapy, indicating a strong inflammatory response that could be associated with tumor regression.
Kaya et al. reported a correlation between high NLR and reduced survival in NSCLC patients, which is consistent with our findings that NLR increased after treatment [12]. However, we did not observe a clear relationship between tumor size reduction and NLR, which could indicate that other factors, such as the immune status or tumor microenvironment, might play a role in modulating NLR’s predictive value.
The lack of correlation between tumor size and hematological parameters like PLR and NLR in our study aligns with the findings of Ünal et al., who also found no significant difference in chemoradiotherapy response based on these markers [4]. This might suggest that while NLR and PLR are useful as general prognostic markers, they may not be reliable indicators of immediate tumor size reduction, especially in the context of chemoradiotherapy. Future studies could explore this further, possibly by combining NLR and PLR with more specific immune-related biomarkers, such as C-reactive protein [9], or through the use of advanced imaging techniques like perfusion CT to monitor real-time changes in tumor vascularity [7].
One of the interesting findings of our study is the significant change in red cell distribution width (RDW) before and after treatment, which has also been highlighted by Warwick et al. as a predictor of long-term survival in NSCLC patients who underwent surgery [13]. The correlation between RDW and overall patient outcomes suggests that this hematologic marker could serve as a useful tool in assessing prognosis, even in non-surgical patients undergoing chemoradiotherapy. Furthermore, the fact that RDW changes remained significant after treatment suggests that systemic inflammation and erythropoiesis may have a prolonged impact on patient survival and treatment response [13].
The study by Ji et al. also supports the prognostic value of platelet counts, particularly in early-stage NSCLC [5]. In our cohort, we observed significant changes in platelet counts after treatment, which could reflect a treatment-induced reduction in tumor burden. However, as we did not stratify patients based on early versus advanced stages, this relationship requires further investigation. A more detailed analysis of platelet behavior, potentially combined with advanced staging techniques like TNM, could help clarify whether platelet counts are a more valuable marker in early-stage versus advanced NSCLC.
The work of Cedrés et al. is particularly relevant to our study, as they examined NLR as a marker of prognosis in stage IV NSCLC patients [14]. They found that patients with a higher NLR had significantly worse outcomes, which supports our findings that NLR increases post-treatment in response to systemic inflammation. However, our inability to correlate these changes with tumor size highlights the complexity of using NLR as a sole marker of tumor response. Instead, it may be more appropriate to use NLR in combination with other inflammatory and immune markers, such as those identified in studies of immunotherapy patients [8, 10].
Additionally, it is worth noting that lymphopenia, which can result from various cancer treatments, has been linked to poorer outcomes in NSCLC patients [15, 16]. While we did not directly assess lymphopenia in our cohort, our findings related to lymphocyte count reductions post-treatment may suggest an underlying lymphopenic response, which could influence long-term prognosis. Future research should aim to explore this link more explicitly, particularly in patients receiving chemoradiotherapy.
Limitation
A major limitation of our study is the relatively small sample size of 49 patients, which reduces the statistical power and generalizability of our findings. Additionally, the retrospective nature of the study introduces potential biases, such as selection bias and incomplete data collection, particularly in terms of radiological assessments where tumor sizes were sometimes manually measured. Advanced imaging techniques, such as perfusion CT, could provide a more objective and consistent measure of tumor response.
Conclusion
In this study, we have shown that routine hematological parameters—such as neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW)—can reflect both anti-tumor immunity and systemic inflammatory responses and may have potential predictive and prognostic value in patients with non-small cell lung cancer (NSCLC). These markers, which are inexpensive and readily available from routine blood tests, provide a practical alternative to more costly examinations. However, our findings also underscore the complexity of these relationships, as no direct correlation between tumor size reduction and these hematological parameters was observed in our cohort.
Given the potential of these biomarkers, future studies should aim to evaluate them across larger and more diverse patient populations and in various cancer types. Moreover, combining these hematological parameters with other prognostic tools, such as advanced imaging techniques and immunological markers, could further improve the precision of personalized treatment strategies. In conclusion, while routine blood tests offer promising insights, more comprehensive studies are needed to fully validate their role in predicting treatment response and guiding clinical decisions in NSCLC and beyond.
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.22477
Burcu Saglam Alan, Burak Erdemci, Hilal Kiziltunc Ozmen. Treatment response relationship with hematologic parameters before and after chemoradiotherapy in patients with non-small cell lung cancer. Ann Clin Anal Med 2025;16(5):384-388
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