June 2024
Comparison of prehospital trauma scores for prediction of mortality
Yıldız Yıldırımer Çelik 1, Gülşah Çıkrıkçı Işık 2, Eren Usul 3, Hakan Cenci 4, Ali Şahin 3
1 Department of Emergency Medicine, Ankara City Hospital, 2 Department of Emergency Medicine, Health Sciences University, Keçiören Training and Research Hospital, 3 Department of Emergency Medicine, Ankara Etlik City Hospital, 4 Department of Ambulance Service, Ankara Provincial Health Directorate, Ankara, Turkey
DOI: 10.4328/ACAM.21764 Received: 2023-05-24 Accepted: 2023-07-03 Published Online: 2024-04-04 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):373-376
Corresponding Author: Author: Yıldız Yıldırımer Çelik, Department of Emergency Medicine, Ankara City Hospital, Ankara, Turkey. E-mail: yildiz_yildirimer@hotmail.com P: +90 507 615 85 43 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6437-5870
This study was approved by the Ethics Committee of Dışkapı Yıldırım Beyazıt Training and Research Hospital (Date: 2022-09-12, No: 146/05)
Aim: Trauma with high mortality and morbidity rates, especially in young patients, is an important health problem all over the world. To make prehospital triage easier and to predict the in-hospital mortality of severe trauma patients, some triage scores and decision algorithms have been improved. There are many prehospital trauma scores that evaluate anatomic variables, physiologic variables, or a combination of both. Some of them are trige-RTS, NTS and MGAP. The aim of this study was to compare prehospital trauma scores to predict in-hospital mortality of trauma patients.
Material and Methods: This study was conducted in the capital’s training and research hospital between 01.06.2018 and 31.12.2019. Patients older than 18 years of age, admitted to the emergency department due to multiple traumas by ambulance were evaluated retrospectively. Triage revised trauma score (RTS), NTS, GCS and MGAP scores were evaluated.
Results: One hundred patients who met the criteria were included in the study. Seventy-eight of the patients were male, and mean the age was 46.52±19.36 years. Eighty-eight of the patients had blunt trauma and 31 of them died. ROC analyses were performed for prediction of mortality. The MGAP score with a cut-off value of 11 had highest sensitivity of 95.59%. NTS scores with the highest AUC value were found to be the strongest predictor of mortality.
Discussion: This study, which compared prehospital trauma scores to predict in-hospital mortality of trauma patients, has shown that with proper cut-off, all scores (GCS, RTS, NTS and MGAP) had similar predictive values. New Trauma Score might be a better option for the prediction of mortality in a pre-hospital setting. The results of this original study showed that NTS predicted in-hospital mortality better than RTS and was not inferior to MGAP. NST score had a sensitivity of less than %95 at our new cut-off point, either than choosing a lesser point for cut-off to increase sensitivity.
Keywords: Trauma, Trauma Scores, Prehospital Triage
Introduction
Trauma with high mortality and morbidity rates, especially in young patients, is an important health problem all over the world. To decrease these worse outcomes, patient transfer to a proper health center that is planned by prehospital emergency health care providers (PHCP) is essential [1]. Healthcare providers need to make an effective field triage for choosing the appropriate target health center. To make prehospital triage easier and to predict the in-hospital mortality of severe trauma patients, some triage scores and decision algorithms have been improved [2].
An ideal prehospital trauma score must prevent under-triage, that might increase the risk of mortality of incorrectly grouped patients, and over-triage, which might lead to the transfer of unnecessary patients to advanced trauma centers [3]. There are many prehospital trauma scores that evaluate anatomic variables, physiologic variables, or a combination of both [4]. The oldest and most widely used triage score was the Triage- Revised Trauma Score (triage-RTS), that evaluate the Glasgow Coma Scale (GCS), respiratory rate and systolic blood pressure of the patient. The New Trauma Score (NTS) is the revised form of RTS that evaluates the systolic blood pressure and oxygen saturation of the patient. Since NTS is a relatively new score, there is restricted number of studies about its efficacy [5]. A mechanism, GCS, Age, Arterial Pressure (MGAP) score was developed in 2010 and proved to be more successful than RTS to predict prehospital trauma severity and in-hospital mortality [6]. The aim of this study was to compare prehospital trauma scores to predict in-hospital mortality of trauma patients.
Material and Methods
Study design
This study was conducted in a training and research hospital in the capital between 01.06.2018 and 31.12.2019. Patients older than 18 years of age, admitted to the emergency department due to multiple traumas by ambulance were evaluated retrospectively. Patients’ data reached from the hospital data registration system and Prehospital Emergency Health Care’s database were evaluated. Trauma scores of the patients were calculated and in-hospital mortality was recorded.
Study population
Patients brought by prehospital emergency health care providers (112 system) to the emergency department due to multiple traumas were evaluated. The Injury severity score (ISS) of the patients was calculated to define multiple trauma patients. This was an anatomical scoring system that allocate the body to six regions as head and neck, face, chest, abdomen,
and extremity, including the pelvis and external. Each injury of that region takes points between 0 (minor) and 6 (unsurvivable).
The scores for the three most severely damaged areas of the body are squared and summed to produce the ISS score. The ISS score ranges from 0 to 75, and if any injury at any region is assigned as 6, the ISS score is automatically assigned a score of 75. Major trauma is considered when the ISS score is greater than 15 and this score linearly correlates with mortality, morbidity, hospital stay and other measures of clinical severity [7]. The study included the patients with ISS scores >15. Patients with ISS scores less than 15, patients admitted to the
emergency department on their own (without using prehospital emergency health care service), death of patients on the field, and patients transferred from different hospitals to the study center were excluded.
Evaluated scoring systems
The Triage revised trauma score (RTS), NTS, GCS and MGAP scores were evaluated. The revised trauma score evaluates the GCS, respiratory rate, and systolic blood pressure of the patients. Glasgow coma score is the most widely used scoring system in all types of medical and trauma patients that evaluates the level of consciousness according to eye-opening, verbal and motor responses and might be between 3-15 points. For the calculation of RTS, each variable is individually assessed and assigned a score ranging from 0 to 4; thus, the RTS score of the patient might be between 0–12. The RTS score of less than 11 defines 97% of lethal cases [6]. The New Trauma Score is the revised form of RTS that evaluates GCS, systolic blood pressure and oxygen saturation. For the calculation of NTS, similar to RTS, systolic blood pressure and oxygen saturation are assessed individually and assigned a score ranging from 0 to 4, but unlike RTS, GCS is directly included in the calculation [8]. Thus, this score might range from 3 to 23, and a score of 18 or higher indicates a low risk [8]. Thus, this score might change between 3 – 23 and a score of ≥18 predicts low risk [8].
The MGAP score evaluates four variables: GCS (3-15 points), blunt trauma (4 points), systolic blood pressure (>120 mm Hg: 5 points, 60-120 mm Hg: 3 points), and age <60 years (5 points) and patient with ≥23 points are at the low-risk group [9].
Statistical analyses
All data were analyzed with IBM SPSS Statistics 22.0 (IBM Corp., USA). The distribution of the variables was checked with the Kolmogorov-Smirnov test. According to normality, continuous variables were described as mean ± standard deviation or median and interquartile range (IQR 25-75%). Categorical variables were described as numbers and percentages. Chi-square tests and Fisher’s exact tests were used for categorical variables, and t-tests and Mann-Whitney U tests were used for continuous variables. The ROC curve (Receiver Operating Characteristic) method was used to determine the distinctiveness of the variables. The area under curve values of trauma scores were compared with DeLong test. Correlation coefficients and their significance were calculated using the Spearman test. P-values <0.05 were considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Dışkapı Yıldırım Beyazıt Training and Research Hospital (Date: 2022-09-12, No: 146/05).
Results
The number of patients admitted to the emergency department due to multiple traumas via the prehospital emergency health care system during the study period was 250. According to inclusion criteria, ISS scores were calculated and the number of patients with ISS ≥ 15 was 115. Of those patients, 15 were excluded due to lack of prehospital data. Thus, 100 patients meeting the inclusion criteria were evaluated. Seventy-eight of the patients were male and the mean age was 46.52±19.36 years. Eighty-eight of the patients had blunt trauma and 31 of them died. The median time of death was 12.5 hours. 78% of the patients were male and the mean age of the patients was 46.52 years (Table 1). Patients were grouped according to survival. There was no difference in gender distribution between the groups, but the mean age was significantly higher in the mortal group. Also, the trauma scores of the non-survivors were lesser than survivors. (Table 2). The correlation between trauma scores and time of death were analyzed but there was no correlation between those (p>0.05 for all trauma scores). ROC analyses were performed for predictions of mortality. Between GCS, RTS, NTS and MGAP, NTS had the highest AUC value of 0.903. Despite a numeric difference between AUC values, this difference was statistically insignificant (p>0.05 for pairwise comparisons with the Delong test). With the cut-off value of 9 for GCS, 7 for RST and 11 for NST, all scores had similar sensitivity (92.75%). MGAP score with cut-off value of 11 had the highest sensitivity of 95.59% (Table 3). As a result of the ROC analysis, NST was found to be the strongest score in predicting mortality (Figure 1).
Discussion
This study, which compared prehospital trauma scores to predict in-hospital mortality of trauma patients, has shown that with proper cut-off, all scores (GCS, RTS, NTS and MGAP) had similar prediction value. On the other hand, because of having a relative high AUC and having simple parameters to evaluate, in our opinion, New Trauma Score might be a better option for the prediction of mortality during a pre-hospital setting. Trauma is still one of the leading causes of death all over the world, and an important reason of morbidity and mortality in developed countries. It was demonstrated that effective prehospital care and rapid transfer to appropriate trauma centers might reduce morbidity and mortality [10]. For a referral to a proper trauma center, predicting in-hospital mortality is an important guide; therefore, we compared the prehospital trauma scores of the patients. We think that our result will contribute to the development of national and international field triage guidelines and simplify and improve prehospital triage. There are lots of studies comparing MGAP and RTS in the literature. Differently from our results, studies declared that MGAP should replace RTS [9, 11, 12]. One of its reasons is counting respiratory rate, a component of RTS, less than its actual number or in an inaccurate way [12]. On the other hand, it showed that the calculation of the MGAP score was easier and gave more accurate information about the patient’s general condition before hospital evaluation [11]. The New Trauma Score is a new score, designed by Jeong et al. in 2017, therefore, studies about its validity are limited [8]. The results of this original study showed that NTS predicted in-hospital mortality better than RTS and was not inferior to MGAP. In that study, patients were grouped into four categories and NTS 6-11 was grouped as high and NTS 3-5 was grouped as very high risk for death. Similarly, in our study with cut-off value of 11, NTS had %92.75 sensitivity for the prediction of mortality. American College of Surgeons Committee on Trauma (ACSCOT) has published guidelines for field triage of trauma patients since 1986 [13]. An ideal triage algorithm should limit undertriage to prevent increased risk of death for misclassified patients and also, over-triage to prevent overload in referral centers and unnecessary costs. For this reason, a good triage algorithm should have >95% sensitivity [14]. From this point of view, the only score with greater than 95% sensitivity in ou study was MGAP, but it should not be forgotten that this value was reached with a cut-off of 11, which was significantly less than 23, the original cut- off point of score. Even though, the NST score had a sensitivity of less than %95 at our new cut-off point, either than choosing a lower point for cut-off to increase sensitivity, since AUC was highest at that point and had higher specificity; we think that NST of 11, should be a good cut-off for prediction of mortality. The reason for these lower cut-off points than the original forms of scores might be the exclusion of patients who died on the field.
Limitation
First, this was a single-centered retrospective study. Since the data were based on prehospital records, it can be wondered if the calculations were accurate in the prehospital field. The study included only adult patients (pregnant ones excluded), so we could not make any comments about the pregnant patients and the pediatric population. Since patients’ deaths on field have been excluded, the advised cut-off points of scores are subject to change.
Conclusion
As a conclusion, with a proper cut-off point, RTS, NTS and MGAP had similar values for the prediction of in-hospital mortality in trauma patients. However, because of the ease of use and relatively higher AUC value than other scores, NST might be a good option for field triage in our opinion. However, multicenter
studies with greater sample sizes are needed.
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. Llompart-Pou JA, Chico-Fernández M, Sánchez-Casado M, Salaberria-Udabe R, Carbayo-Górriz C, Guerrero-López F, et al. Scoring severity in trauma: Comparison of prehospital scoring systems in trauma ICU patients. Eur J Trauma Emerg Surg. 2017;43(3):351-7.
2. Gerdin LW, Khajanchi M, Kumar V, Roy N, Saha ML, Soni KD, et al. Comparison of Emergency Department trauma triage performance of clinicians and clinical prediction models: a cohort study in India. BMJ. 2020;10(2):329.
3. Boulton AJ, Peel D, Rahman U, Cole E. Evaluation of elderly specific pre-hospital trauma triage criteria: A systematic review. Scand J Trauma Resusc Emerg Med. 2021;29:127.
4. Orhon R, Eren SH, Karadayı S, Korkmaz I, Coşkun A, Eren M, et al. Comparison of trauma scores for predicting mortality and morbidity on trauma patients. Ulus Travma Acil Cerrahi Derg/Turkish Journal of Trauma and Emergency Surgery. 2014;20(4):258-64.
5. Lecky F, Woodford M, Edwards A, Bouamra O, Coats T. Trauma scoring systems and databases. Br J Anaesth. 2014;113(2):286-94.
6. Galvagno SM Jr, Massey M, Bouzat P, Vesselinov R, Levy MJ, Millin MG, et al. Correlation Between the Revised Trauma Score and Injury Severity Score: Implications for Prehospital Trauma Triage. Prehosp Emerg Care. 2019;23(2):263-70.
7. Javali RH, Krishnamoorthy, Patil A, Srinivasarangan M, Suraj, Sriharsha. Comparison of Injury Severity Score, New Injury Severity Score, Revised Trauma Score and Trauma and Injury Severity Score for Mortality Prediction in Elderly Trauma Patients. Indian J Crit Care Med. 2019;23(2):73-7.
8. Jeong JH, Park YJ, Kim DH, Kim TY, Kang C, Lee SH, et al. The new trauma score (NTS): A modification of the revised trauma score for better trauma mortality prediction. BMC Surgery. 2017;17(1):77.
9. Mohammed Z, Saleh Y, AbdelSalam EM, Mohammed N, El-Bana E, Hirshon JM. Evaluation of the Revised Trauma Score, MGAP and GAP scoring systems in predicting mortality of adult trauma patients in a low-resource setting. BMC Emerg Med. 2022;22(1):90.
10. Morris RS, Karam BS, Murphy PB, Jenkins P, Milia DJ, Hemmila MR, et al. Field-Triage, Hospital-Triage and Triage-Assessment: A Literature Review of the Current Phases of Adult Trauma Triage. J Trauma Acute Care Surg. 2021;90(6):138-45.
11. Bouzat P, Legrand R, Gillois P, Ageron FX, Brun J, Savary D, et al. Prediction of intra-hospital mortality after severe trauma: Which pre-hospital score is the most accurate? Injury. 2016;47(1):14-8.
12. Laytin AD, Kumar V, Juillard CJ, Sarang B, Lashoher A, Roy N, et al. Choice of injury scoring system in low- and middle-income countries: Lessons from Mumbai. Injury. 2015;46(12):2491-7.
13. Sasser SM, Hunt RC, Faul M, Sugerman D, Pearson WS, Dulski T, et al. Guidelines for field triage of injured patients: recommendations of the National Expert Panel on Field Triage, 2011. MMWR Recomm Rep. 2012;61(RR-1):1–20.
14. Cassignol A, Markarian T, Cotte J, Marmin J, Nguyen C, Cardinale M, et al. Evaluation and Comparison of Different Prehospital Triage Scores of Trauma Patients on In-Hospital Mortality. Prehospital Emergency Care. 2019;23(4):543-50.
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Yıldız Yıldırımer Çelik, Gülşah Çıkrıkçı Işık, Eren Usul, Hakan Cenci, Ali Şahin. Comparison of prehospital trauma scores for prediction of mortality. Ann Clin Anal Med 2024;15(6):373-376
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Increased vitamin B12 in heart failure with reduced ejection fraction: A novel marker of disease severity and mortality
Ilke Erbay 1, Burcu Demirkan 2, Yesim Akin 1, Kevser Gulcihan Balci 2
1 Department of Cardiology, Faculty of Medicine, Karabuk University, Karabuk, 2 Department of Cardiology, University of Health Science, Ankara City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.21994 Received: 2023-09-24 Accepted: 2023-10-31 Published Online: 2023-11-06 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):377-382
Corresponding Author: Ilke Erbay, Department of Cardiology, Faculty of Medicine, Karabuk University, Karabuk, Turkey. E-mail: ilkeerbay@karabuk.edu.tr P: +90 535 385 59 91 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6817-4686
This study was approved by the Ethics Committee of Türkiye Yüksek İhtisas Training and Research Hospital (Date: 2019-02-06, No: 2019-0012)
Aim: The relationship between elevated vitamin B12 levels and liver damage is well-established, but its association with the severity of heart failure (HF) remains unclear. This study aimed to investigate the prognostic importance of vitamin B12 levels according to disease severity in HF patients with reduced left ventricular ejection fraction (HFrEF).
Material and Methods: Two hundred and three consecutive patients with HFrEF were enrolled in this study. Patients were divided into advanced and non-advanced HF groups based on specific criteria and the primary endpoint was all-cause mortality, which was prospectively assessed. Cox proportional hazards regression analyses were conducted to identify independent predictors of mortality.
Results: Of the study patients, 75 (36.9%) had advanced, while 128 (63.1%) had non-advanced HF. The advanced group had significantly higher serum vitamin B12 levels compared to the non-advanced group (p<0.001). Serum vitamin B12 level of > 707.8 pg/mL had a sensitivity of 78.3% and specificity of 76.1% in predicting all-cause mortality (area under the curve=0.863, 95% CI 0.806-0.920, p<0.001). Kaplan-Meier analysis demonstrated that patients with vitamin B12 levels > 707.8 pg/mL had significantly lower survival rates (p < 0.001). In Cox regression analysis, vitamin B12 emerged as an independent predictor of death.
Discussion: Elevated serum vitamin B12 levels in HFrEF patients are associated with advanced HF, increased ALT and GGT levels, indicating a cardiohepatic syndrome, and independently predict higher all-cause mortality risk.
Keywords: Heart Failure, Vitamin B12, Hepatic Congestion, Mortality, Biomarker
Introduction
Heart failure is a clinically significant health issue affecting approximately 1-2% of the adult population in developed countries. It is a major global health problem, causing significant mortality and hospitalization among adults [1]. Furthermore, the presence of comorbid conditions complicates the treatment process, with anemia being a significant problem that prolongs hospitalization. The incidence of anemia among individuals with HF ranges from 4% to 61%, with iron deficiency being the primary cause [2].
The prevalence of vitamin B12 deficiencies in HF patients remains uncertain, with studies reporting conflicting results [2-4]. Recent research has identified a connection between plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker for systemic congestion, and vitamin B12 levels in HF [5].
Vitamin B12 has been recognized as a potential marker for liver cell damage, as it can be released into the bloodstream from damaged liver cells [6]. Heart failure can cause disruptions in liver oxygenation due to hypotension, decreased blood oxygen levels, and hepatic congestion [7]. This hepatocyte injury can lead to the release of stored vitamin B12 into the bloodstream, resulting in increased serum levels [7-9]. While this increase has been demonstrated in acute HF [10], the difference in vitamin B12 levels according to HF stage is less clear in chronic HF.
This study aimed to investigate the association between vitamin B12 levels and HF severity and mortality in advanced and non-advanced chronic HF patients with reduced ejection fraction.
Material and Methods
Study population
The study population consisted of consecutive chronic HF patients admitted to the Department of Cardiology, between January 2017 and February 2019. The inclusion criteria were age 18 years or older, chronic stable HF with echocardiographic evidence of reduced left ventricular ejection fraction (≤40%), and experiencing symptoms corresponding to a functional class of New York Heart Association (NYHA) I-IV. Exclusion criteria included acute decompensated HF, prior myocardial infarction and myocarditis within the last six months, active infection, hypertrophic and restrictive cardiomyopathy, non-cardiac liver failure, renal failure requiring dialysis, malignancies, connective tissue-inflammatory and autoimmune diseases, pregnancy, vegan or vegetarian dietary patterns, and receiving vitamin B12 replacement therapy within the last six months.
The patients were classified into two groups based on the 2018 European Society of Cardiology Advanced HF Status Statement criteria: advanced HF group and non-advanced HF group [11]. The advanced HF group was characterized by severe and persistent HF symptoms according to the NYHA functional classification system of class III or IV and significant cardiac dysfunction with a left ventricular ejection fraction of ≤ 30% [11]. Data on demographic characteristics, physical examination findings, laboratory results, NYHA functional classes, and echocardiographic evaluations were obtained from the hospital’s electronic medical record system for all patients. The study’s primary endpoint was all-cause mortality, which was prospectively evaluated at regular intervals via outpatient visits or telephone interviews until December 2019.
Of the 245 patients screened, 26 had their vitamin B12 levels and other laboratory data measured on different days, 9 tested positive for anti-hepatitis C antibody or showed reactivity to hepatitis B surface antigen, and 7 had left ventricular assist devices, leaving a total of 203 patients available for this study (Figure 1).
Laboratory assessments
Peripheral venous blood samples were obtained from the antecubital vein and collected into standardized tubes containing EDTA for complete blood count analysis using the XE-1200 instrument (Sysmex, Kobe, Japan). Routine liver function tests that included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and gamma-glutamyl transferase (GGT) were obtained at the time of admission, as were plasma levels of vitamin B12 and NT-proBNP. Vitamin B12 and NT-proBNP levels were determined using the Beckman Coulter Access Immunoassay Systems. The manufacturer’s reference interval for vitamin B12 was 211–911 pg/mL.
Echocardiographic evaluation
Transthoracic echocardiography was performed on all patients using a commercially available device (VIVID 7, GE Medical Systems, Milwaukee, WI) using a 2.5 MHz probe. Left ventricular ejection fraction (LVEF) were measured using a modified Simpson’s method during the same visit when blood samples were collected to assess vitamin B12 levels. Tricuspid annular plane systolic excursion (TAPSE) value less than 17mm was defined as right HF accompanying left ventricular dysfunction. Echocardiography was performed to assess the diameter of the inferior vena cava (IVC), and greater than 2.1 cm was defined as IVC dilatation [12].
Approval for the study was obtained from the Bioethics Committee of Türkiye Yüksek İhtisas Training and Research Hospital (Date: Fabruary 2019 and Approval No: 2019-0012).
Statistical Analysis
All analyses were performed using the SPSS 26 software package (IBM Corp., Armonk, NY). The Kolmogorov-Smirnov test assessed the normal distribution of the variables. Variables were expressed as frequencies, percentages (%), means (±standard deviation), and medians (interquartile range), as appropriate. The Chi-square test compared categorical variables. Inter-group comparisons of continuous variables were performed using Student’s t-test (for parametric data) or the Mann–Whitney U test (for non-parametric data). A univariate linear regression model was initially constructed using all clinical, echocardiographic, and laboratory variables with significant correlations with vitamin B12 (p<0.05). Subsequently, for predicting vitamin B12 levels, all variables included in the univariate linear regression were entered into a multivariate linear regression model using the backward elimination method. Receiver operating characteristic curve (ROC) analysis was performed to assess the cut-off value of vitamin B12 for predicting all-cause mortality. Kaplan-Meier analysis was used to estimate survival over the follow-up period for categories of independent variables, and the log-rank test was used to compare survival functions calculated according to different factors. Predictive Cox regression models were created using significant variables from the log-rank test. For the model obtained, crude and multivariable-adjusted hazard ratios and 95% confidence intervals were determined for each variable. A two-sided p-value < 0.05 was considered statistically significant.
Results
The study included 203 consecutive patients with chronic stable HF, 75 (36.9%) with advanced HF, and 128 (63.1%) with non-advanced HF. Most patients (84.2%) were male, with a mean age of 52 years (range 19-70). The mean follow-up time was 20.1±8.1 months. No significant differences were found between the advanced and non-advanced groups in terms of age (p=0.309), gender (p=0.467), etiology of HF (p=0.510), hypertension (p=0.593), and diabetes mellitus (p=0.232). Characteristics of the groups are presented in Table 1.
Vitamin B12 deficiency was similar between advanced and non-advanced HF groups [8 patients (10.7%) vs. 21 patients (16.4%), respectively; p=0.390]. On the contrary, serum vitamin B12 levels were found to be significantly higher in the advanced HF group compared to the non-advanced group [829 pg/mL (137-2000) vs. 363.3 pg/mL (148.3-991), p<0.001]. The prevalence of concomitant right HF in advanced HF patients was determined to be higher compared to the non-advanced HF group [64 patients (85.3%) vs. 53 patients (41.4%), p<0.001]. Higher levels of vitamin B12 were observed in advanced HF patients with concomitant right HF compared to those without right HF [879.6 pg/mL (137.0-2000.0) vs. 803.9 pg/mL (400.0-1205.0), respectively; p=0.037]. However, a similar significant difference was not found in the non-advanced group (p=0.056).
In the univariate analysis, several variables including LVEF (r = -0.399, p<0.001), TAPSE (r = -0.423, p<0.001), NT-proBNP (R = 0.748, p<0.001), ALT (R = 0.460, p<0.001), GGT (R = 0.554, p<0.001), direct bilirubin (R = 0.504, p<0.001), and indirect bilirubin (R = 0.342, p<0.001) levels, exhibited significant correlations with vitamin B12 levels in patients with HFrEF. However, in multivariate analysis, NT-proBNP (p<0.001), ALT (p=0.002), and GGT (p<0.001) all displayed positive correlations with vitamin B12 levels, while conversely, the LVEF showed a negative association with vitamin B12 (p=0.006) (Table 2).
ROC curve analysis showed that a serum B12 level of 707.8 pg/mL had a sensitivity of 78.3% and specificity of 76.1% in predicting all-cause mortality, with an area under the curve (AUC) of 0.863 (95% CI: 0.806-0.920, p<0.001). In Kaplan-Meier analysis, the survival rate was significantly lower in patients with a serum vitamin B12 level > 707.8 pg/mL than in patients with a serum vitamin B12 level ≤ 707.8 pg/mL (62.3% vs. 93.7%, p<0.001) (Figure 2).
Mortality data were available for all patients. During the follow-up period, the overall mortality rate was 15.76% (n=32). Furthermore, the levels of vitamin B12 were higher in the deceased patients compared to the surviving patients [909.0 pg/mL (587.0-2000.0) vs. 438.5 pg/mL (148.3-2000.0), respectively; p<0.001].
Kaplan-Meier analysis was used to estimate survival during the follow-up period based on various independent variables. Variables of diabetes mellitus, advanced HF, vitamin B12, NT-proBNP, LVEF, and TAPSE that showed significant associations with mortality in the Log-Rank test, along with age and gender, were further evaluated using Cox proportional hazards regression models to determine their independent predictive value for mortality. Multivariate analysis revealed a significant association between mortality and various factors, including diabetes mellitus (adjusted hazard ratio [aHR] = 2.374, 95% confidence interval [CI] 1.033-5.454, p=0.042), advanced HF (aHR = 22.919, 95% CI 2.881-182.342; p=0.003), and serum vitamin B12 levels (aHR = 1.107, 95% CI 1.000-1.302; p=0.008) per 1 unit increase, as demonstrated in Table 3. The results of the Cox regression analysis indicated that higher levels of vitamin B12 were associated with an increased risk of mortality in patients with HFrEF.
Discussion
This study demonstrated the emergence of vitamin B12 as an independent predictor of mortality in patients with HFrEF. In fact, increased vitamin B12 levels were more prevalent in the advanced HF group, suggesting its potential relevance in disease progression.
Previous reports indicate a positive correlation between serum vitamin B12 levels and the severity of HF [13,14]. An early study by Rachmilewitz et al. [9] first investigated the use of serum cyanocobalamin to indicate hepatic injury in HF. Their study focused on 28 patients with chronic congestive HF and significant hepatomegaly. They reported a considerable decrease in serum cyanocobalamin levels in cases where compensation was achieved. However, this study did not report on changes in vitamin B12 levels after treatment and stabilization of the patients, which is important for understanding the relationship between vitamin B12 and stable chronic HF at different stages.
Numerous studies have demonstrated that advanced HF is associated with a cholestatic liver enzyme profile, characterized by elevated levels of ALT, AST, and GGT in the bloodstream, a manifestation of the cardiohepatic syndrome [15, 16]. Argan et al. [17] have reported higher levels of vitamin B12 in patients with chronic stable HFrEF compared to the general population. This elevation was associated with clinical signs of right HF and slight increases in direct bilirubin levels, suggesting the presence of cardiohepatic syndrome. Additionally, our study revealed a correlation between higher vitamin B12 levels and liver function abnormalities, such as elevated ALT and GGT levels. These findings suggest that higher vitamin B12 levels could serve as a potential marker for detecting the presence of cardiohepatic syndrome, a condition that becomes more prominent as HF progresses.
Several potential mechanisms have been proposed to explain HF’s increased serum cobalamin levels. One hypothesis is that liver dysfunction, the most extensive reservoir of vitamin B12 in the body, could disrupt cobalamin storage, releasing cobalamin from hepatocytes. Another possibility is that endothelial dysfunction resulting from hepatic congestion due to elevated venous pressure may contribute to reduced synthesis of transport proteins and diminished binding capacity of vitamin B12 [18]. Zafarullah et al. [10] conducted a study to investigate the serum levels of vitamin B12 in patients hospitalized with decompensated HF. They reported that patients with biventricular failure exhibited elevated serum vitamin B12 levels during their initial hospitalization. However, after receiving diuretic treatment and experiencing a reduction in systemic congestion, the vitamin B12 levels decreased by approximately 30% upon discharge [10]. Moreover, we found that patients in the advanced HF group had a higher rate of diuretic usage and showed dilatation of the IVC, indicating a greater degree of systemic congestion [19, 20]. These findings further strengthen the association between HF severity, the level of congestion, and elevated vitamin B12 levels.
Elevated levels of vitamin B12 in the bloodstream have been recognized as an early indication of an underlying severe condition [21]. Supporting this notion, a study conducted by Soohoo et al. [22] demonstrated a correlation between high plasma concentrations of vitamin B12 and an increased mortality risk among hemodialysis patients. Similarly, elevated vitamin B12 levels are frequently observed in hepatocellular carcinoma and hematological malignancies and are associated with mortality in these diseases [23,24]. However, the association between elevated vitamin B12 levels and mortality in HF patients has not been established.
In our study, we found that elevated levels of vitamin B12 not only provided insights into the severity of HF but also emerged as an independent predictor of mortality. These results suggest that vitamin B12 can be a potential biomarker for monitoring HF progression. Therefore, during the clinical evaluation of HF patients, clinicians should be alert to the accompanying increase in vitamin B12 levels, and closer monitoring of these patients may be warranted.
Limitation
Our study has several limitations. Firstly, the study had a retrospective design. Another limitation is the relatively smaller sample size in the advanced HF group compared to the non-advanced HF group, which could have been addressed by having an equal number of patients in both groups to strengthen our results. Furthermore, we did not assess hepatic endothelial dysfunction or monitor vitamin B12 transporters such as transcobalamin-II. Transcobalamin II is crucial in transporting vitamin B12 from the gastrointestinal system to various tissues, including the liver. At the same time, transcobalamin-I (or haptocorrin) is involved in reverse-transporting vitamin B12 from tissues back to the liver [25]. These values would have helped us determine whether transporter synthesis is affected in advanced-stage HF and the underlying reasons for the elevated serum cobalamin levels.
Conclusion
Elevated serum vitamin B12 levels in HFrEF patients are associated with advanced HF, increased ALT, and GGT levels, indicating a cardiohepatic syndrome and independently predicting higher all-cause mortality risk.
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. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz J, et al. EURObservational Research Programme: Regional differences and 1‐year follow‐up results of the Heart Failure Pilot Survey (ESC‐HF Pilot). Eur J Heart Fail. 2013;15(7):808-17.
2. Tang Y-D, Katz SD. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options. Circulation. 2006;113(20):2454-61.
3. Rizzo C, Carbonara R, Ruggieri R, Passantino A, Scrutinio D. Iron deficiency: A new target for patients with heart failure. Frontiers in Cardiovascular Medicine. 2021;8:709872.
4. Van Der Wal HH, Comin-Colet J, Klip IT, Enjuanes C, Beverborg NG, Voors AA, et al. Vitamin B12 and folate deficiency in chronic heart failure. Heart. 2015;101(4):302-10.
5. Witte KK, Desilva R, Chattopadhyay S, Ghosh J, Cleland JG, Clark AL. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J. 2004;147(5):924-30.
6. Dou J, Xu W, Ye B, Zhang Y, Mao W. Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acute‐on‐chronic liver failure. Clin Chim Acta. 2012;413(23-24):1809-12.
7. Samsky MD, Patel CB, DeWald TA, Smith AD, Felker GM, Rogers JG, et al. Cardiohepatic interactions in heart failure: an overview and clinical implications. J Am Coll Cardiol. 2013;61(24):2397-405.
8. Andrès E, Serraj K, Zhu J, Vermorken AJ. The pathophysiology of elevated vitamin B12 in clinical practice. QJM. 2013;106(6):505-15.
9. Rachmilewitz M, Stein Y, ARONOVITCH A, Grossowicz N. Serum cyanocobalamin (vitamin B12) as an index of hepatic damage in chronic congestive heart failure. Arch Intern Med. 1959;104(3):406-10.
10. Zafarullah H, Laguardia SP, Paulus BM, Battin DL, Davis RC, Weber KT, et al. Elevated serum cobalamin in patients with decompensated biventricular failure. Am J Med Sci. 2008;336(5):383-8.
11. Crespo‐Leiro MG, Metra M, Lund LH, Milicic D, Costanzo MR, Filippatos G, et al. Advanced heart failure: A position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(11):1505-35.
12. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography: Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713.
13. Herrmann M, Müller S, Kindermann I, Günther L, König J, Böhm M, et al. Plasma B vitamins and their relation to the severity of chronic heart failure. Am J Clin Nutr. 2007;85(1):117-23.
14. Herrmann M, Kindermann I, Müller S, Georg T, Kindermann M, Böhm M, et al. Relationship of plasma homocysteine with the severity of chronic heart failure. Clin Chem. 2005;51(8):1512-15.
15. Vasconcelos LA, Almeida EA, Bachur LF. Clinical evaluation and hepatic laboratory assessment in individuals with congestive heart failure. Arq Bras Cardiol. 2007;88(5):590-5.
16. Poelzl G, Eberl C, Achrainer H, Doerler J, Pachinger O, Frick M, et al. Prevalence and prognostic significance of elevated γ-Glutamyltransferase in chronic heart failure. Circ Heart Fail. 2009;2(4):294-302.
17. Argan O, Ural D, Karauzum K, Bozyel S, Aktas M, Karauzum IY, et al. Elevated levels of vitamin B12 in chronic stable heart failure: a marker for subclinical liver damage and impaired prognosis. Ther Clin Risk Manag. 2018;14:1067-73.
18. Baker H, Leevy CB, DeAngelis B, Frank O, Baker ER. Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease. J Am Coll Nutr. 1998;17(3):235-8.
19. Faselis C, Lam PH, Patel S, Arundel C, Filippatos G, Deedwania P, et al. Loop diuretic prescription and long-term outcomes in heart failure: association modification by congestion. Am J Med. 2021;134(6):797-804.
20. Lee HF, Hsu LA, Chang CJ, Chan YH, Wang CL, Ho WJ, et al. Prognostic significance of dilated inferior vena cava in advanced decompensated heart failure. Int J Cardiovasc Imaging. 2014;30(7):1289-95.
21. Flores-Guerrero JL, Minović I, Groothof D, Gruppen EG, Riphagen IJ, Kootstra-Ros J, et al. Association of plasma concentration of vitamin B12 with all-cause mortality in the general population in the Netherlands. JAMA Netw Open. 2020;3(1):e1919274.
22. Soohoo M, Ahmadi SF, Qader H, Streja E, Obi Y, Moradi H, et al. Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients. Nephrol Dial Transplant. 2017;32(6):1024-32.
23. Lin CY, Kuo CS, Lu CL, Wu MY, Huang RF. Elevated serum vitamin B12 levels in association with tumor markers as the prognostic factors predictive for poor survival in patients with hepatocellular carcinoma. Nutr Cancer. 2010;62(2):190-7.
24. Gavars D, Perminov D, Tauckels E, Lindenberga I, Auce A, Lejniece S. Association of elevated vitamin B12 with oncohematological diseases in a cohort of 79,524 patients from Latvia. Exp Oncol. 2019;41(4):354-62.
25. Ermens AA, Vlasveld LT, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in blood. Clin Biochem. 2003;36(8):585-90.
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Information received and usefulness of the sources of information to cancer patients at an oncology hospital in Turkey
Büşra İnce 1, Pınar Atak Çakır 2, Serkan Eti 3, Fatma Mutluay 4
1 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Bandirma Onyedi Eylul University, Balıkesir, 2 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Medipol University, Istanbul, 3 Department of Computer Programming, Vocational School of Health Sciences, Istanbul Medipol University, Istanbul, 4 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Medipol University, Istanbul, Turkey
DOI: 10.4328/ACAM.22018 Received: 2023-10-20 Accepted: 2024-02-29 Published Online: 2024-04-05 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):383-387
Corresponding Author: Pınar Atak Çakır, Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Medipol University, Istanbul, Turkey. E-mail: pnaratak9340@gmail.com P: +90 536 056 94 04 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5640-2998
This study was approved by the Ethics Committee of Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee (Date: 2018-08-15, No: 446)
Aim: Cancer treatment typically involves a combination of approaches like surgery, chemotherapy, and radiation therapy. Offering accurate and valuable information about cancer plays a crucial role in helping patients prepare for their treatment and improves their adherence to it. To assess the information received by cancer patients, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QL) Group has developed the EORTC INFO module. The objective of this study is to examine the reliability and validity of the Turkish version of the EORTC QLQ-INFO25 system. Specifically, it aims to evaluate how patients perceive the benefits of the information they receive and the duration for which the information remains useful to them.
Material and Methods: We administered the Turkish versions of three questionnaires to 197 patients at various stages of their illness: the EORTC QLQ-INFO25, the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30), and the EORTC Cancer In-Patient Satisfaction with Care Questionnaire (IN-PATSAT32). These stages included chemotherapy, radiotherapy, and surgery. To ensure the questionnaire’s reliability and validity, we utilized Cronbach’s alpha, inter-scale correlation, and factor analysis.
Results: The validity analysis revealed that the scale had a sufficient level of explained variance, with 66.68% accounted for by the factor analysis findings. Furthermore, the reliability analysis indicated a high level of reliability for the entire questionnaire, with a Cronbach’s alpha coefficient of 0.92. The selected questions from the EORTC IN-PATSAT32 and their correlation with the 4 identified areas and 2 items of the EORTC QLQ-INFO25 demonstrated strong convergent validity. On the other hand, there was a low correlation between the EORTC-QLQ-C30 questionnaire and the different areas of the EORTC QLQ-INFO25 questionnaire, suggesting that these two questionnaires measured distinct concepts.
Discussion: The study found that the Turkish version of the EORTC QLQ-INFO25 scale is a valid and reliable instrument for assessing the knowledge level of cancer patients. These findings suggest that the scale can be effectively utilized within the Turkish society to evaluate the information and understanding of cancer patients.
Keywords: EORTC QLQ-INFO25 Turkish, Information, Cancer, Validity, Reliability
Introduction
Cancer is a significant global and national health issue, being the second leading cause of death in Turkey [1, 2]. As cancer incidence continues to rise, there is an increasing demand for information among patients and their families regarding the disease. A study conducted by Akgül et al. revealed that patients primarily seek information from doctors and the internet, while finding the communication with assistant health personnel to be insufficient [3]. Similarly, research by Schmid Büchi et al. indicated that cancer patients often lack sufficient information and require professional support regarding disease management and treatment [4]. Compliance with treatment, communication ability, satisfaction level and quality of life of patients who reach reliable and quality information are also increasing [5].
The studies in the field of oncology are increasing day by day and the level of knowledge provided in this field is improving [6, 7]. Tools developed to evaluate the level of knowledge about cancer are very important in clinical research [8]. In our country, a limited number of measurement tools are available to measure the amount of information given to cancer patients. Most of the other scales evaluate the needs and satisfaction levels of patients [3]. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QL) has developed the EORTC Quality of Life Questionnaire-Information Module (EORC QLQ-INFO25) scale, which assesses the level of knowledge from cancer patients at different stages of care. The structure, validity, and reliability of the EORTC QLQ-INFO25 scale were tested in a large international and multi-cultural cancer population at different stages of the disease and treatment. This scale is used during routine clinical practice in the oncology department in both national and international studies. The EORTC QL working group suggests that the validity studies of their scales should be done for each country [9]. The aim of this study is to translate the EORTC QLQ-INFO25 scale into Turkish, to examine its validity and reliability and to investigate the effect of cultural differences on the patient’s level of knowledge.
Material and Methods
Participants
Our study was conducted with the approval of the Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee (dated 15.08.2018, decision 446). All individuals included in the study were given detailed information about the purpose, method, and duration of the study. In addition, patients were signed with an “Informed Consent Form”. The identities of the participants were kept strictly confidential and only aggregate data were reported.
Power analysis was applied to calculate the required sample size. As a result of the calculation made using G-power analysis, the minimum sample number required for 95% reliability and 80% power was determined as 220.
Our study is multidisciplinary care center in Turkey Istanbul Medipol University Hospital Complex of Hematology-Oncology section referencing between the years 2018-2020. The study focused on patients diagnosed with cancer based on clinical and radiographic examinations. The participation in the study was voluntary for the patients.Adult individuals over the age of 18 who received radiotherapy and/or chemotherapy treatment due to the primary tumor at different stages of the disease were included in the study. Individuals who do not have sufficient mental and speaking capacity in terms of understanding and answering the questionnaires and who have psychological morbidity were excluded from the study.
Study design
All questions in the Turkish version of the EORTC QLQ-INFO25 questionnaire were read carefully to the participants by experts in oncology and made sure that the participant understood correctly. Additional information about each patient’s disease and medical history was collected from the patient’s medical records. The first 10 patients registered were evaluated in a pilot study to confirm the questionnaire and were not included in the statistical analysis of the study.
Questionnaire
A demographic form prepared by the researchers was filled in as the first step. In this form, it included questions giving information about the age, gender, marital status, education level, systemic disease, and diagnosis of the cancerous individual. In addition, a total of three questionnaires were conducted: EORTC QLQ-INFO25, EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and inpatient satisfaction module EORTC Cancer In-Patient Satisfaction with Care Questionnaire (IN-PATSAT32) survey. In the EORTC QLQ-C30 and EORTC IN-PATSAT32 surveys both in Turkey and standardization it has been translated before they were surveyed [10, 11].
The EORTC QLQ-INFO25 questionnaire consists of 25 items that cover various aspects of information related to the disease (4 items), medical tests (3 items), treatment (6 items), other services (4 items), and 8 additional topics. In addition to these items, the questionnaire includes questions about self-help, different areas of care, the receipt of written and/or digital information, satisfaction with the information received, preferences for more or less information, and the perceived usefulness of the information received. The response format is made according to 4-point Likert scale (1-nothing, 2-some, 3-quite, 4-very much). Items 52, 53, 54 and 55, which question whether they are satisfied with the level of information they receive and whether they want more information, have a two-way answer as Yes/No. Patients who respond positively to questions about requests for more or less information are asked to provide more detailed information on the subject. The scores of these items are converted linearly to 0-100 scale according to the EORTC guide [12]. The EORTC QLQ-INFO25 questionnaire was translated from English to Turkish using the translation/reversal method and was then translated back to English by a different translator who did not see the original version of the questionnaire. In 10 consecutive interviews with oncology patients, the questionnaire was tested for understanding and clarity, and no changes were made afterwards. The Turkish version of the questionnaire was approved by the EORTC translation unit after careful evaluation of the data from the pilot test.
Statistical analysis
The data were analyzed with SPSS 25.0 version. Categorical and continuous variables were studied using frequencies and mean±standard deviations. In the study, multivariate statistics were used statistically. Kolmogorov-Smirnov and Shapiro-Wilk tests were used for normality evaluation. Factor analysis for validity, Cronbach’s Alfa, which is the internal consistency coefficient for reliability, was calculated. While making the correlation analysis between the scales, nonparametric test (Mann-Whitney test), parametric test (Student t test), and Anova tests were applied for the differences between the groups.
Ethical Approval
This study was approved by the Ethics Committee of the Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee (Date: 2018-08-15, No: 446).
Results
Pilot study
Ten women with a mean age of 54±13 were included in the study. 5 patients were breast, 1 patient bone, 1 patient pancreas, 1 patient lung, 1 patient ovary, 1 patient brain cancer. The internal validity of INFO 25 was analyzed using the Cronbach alpha coefficient (a). Internal consistency showed a reliability of 0.917.
Patient characteristics
A total of 220 patients were evaluated. 23 patients were excluded from the study because they gave inconsistent answers. Finally, 197 patients were included in the study. 31 of the participants were male (15.7%) and 166 were female (84.3%). The average age of the participants was 53±13 years. The majority of patients were married (83.8%). Considering the education level, 68.5% of the patients were below the compulsory education level (defined as school education for more than 12 years), 20.3% were at the compulsory education level and 11.1% were above the compulsory education level. The most common tumor was breast cancer (49.7%) followed by gynecological (12.7%) and gastrointestinal malignancies (11.6%). 28.8% of the patients had metastasis. The demographic and clinical features of the patients are shown in Table 1.
Debriefing Questionnaire
Most patients in the study demonstrated a clear understanding of the questions. However, there were some specific items that posed challenges for certain patients. For instance, 38 patients found the question about the ‘procedures of medical tests’ (item 36) confusing despite the researcher’s explanation. 12 patients did not answer the question about the ‘dimensions of managing the disease at home’ (item 46) due to the absence of an explanatory statement. Furthermore, it was observed that questions related to sexual activity elicited feelings of embarrassment and discomfort among the participants. This issue was not identified during the pilot study. The researcher did not have to clarify any confusion and any explanation given was easily understood.
Disclosure of information
For the analysis of the responses of the patients to the questions about the level of knowledge, the answers were compared under two headings as “none”-”a little” and “quite”-”a lot” pairs. “None”-”a little” pair was considered as “insufficient level of knowledge”, “fairly”-”very” pair “was considered sufficient level of knowledge. Analysis of the data collected; showed that patients have the highest level of knowledge about diagnosis, medical test results and whether their disease is under control. Patients had the least level of information about rehabilitation services (97.97%), extra hospital assistance (95.43%), different care places (96.95%) and the effects of treatment on sexual activity (85.79%).
According to the results of the multi-trait scale, the correlation measurements of each item with its own scale and other fields are shown in Table 2.
The correlation of each item with its own scale (Rho ≥ 0.6) represents a high convergent validity. At the same time, the correlation of each item with its hypothetical domain was greater than its relationship with other areas of the scale, reflecting the discriminant validity of the scale. The correlation between the selected questions of EORTC PATSAT32 and the 4 areas and 2 items of EORTC INFO25 were evaluated. Pearson correlation coefficients between areas with similar content showed high convergent validity.
Divergent validity was assessed by calculating the correlation between the EORTC-QLQ-C30 questionnaire and the different domains of the EORTC-INFO25 questionnaire. The findings revealed a low correlation (Spearman Rho < 0.2) between the domains of the two questionnaires, which indicates that they measure distinct concepts.
Factor analysis was used to investigate the structure of the survey. After Bartlett’s sphericity test (P < 0.000) and Kaiser-Meyer-Olkin sample adequacy criterion, 4 factors were selected after the significance was achieved in terms of sample adequacy. 1st factor, information about the disease (item 31, 32, 33, 34), 2nd factor information about medical tests (item 35, 36, 37), 3rd factor information about treatment (item 38, 39, 40, 41, 42, 43) and factor 4 included information about other services (items 44, 45, 46, 47). These four factors explained a total of 66.68% of the variance.
Cronbach’s alpha coefficients for all domains and all surveys were between 85% and 95%. In-class correlation (ICC) ranged between 0.571 and 0.861. In-class correlation (ICC) of total scales and items of the questionnaire, Cronbach’s alpha coefficient for the total scale is shown in Table 3. The items included in the questionnaire allowed the classification of information given to patients in terms of different aspects of cancer diagnosis and treatment. The level of education, economic status, and age were examined to determine the amount of information received and whether it affected satisfaction. While there was a significant difference in the level of knowledge about education level, disease, medical tests, and treatments (p<0.05), there was no difference in knowledge level for other services (p>0.05). The economic situation was found to have a significant relationship with all parameters (p<0.05). There was no significant difference in the level of knowledge among those over 50 and those under 50 (p>0.05).
Discussion
In this study, the researcher aimed to assess the quantity and quality of information provided by healthcare personnel to Turkish cancer patients. Furthermore, the study explored the overall satisfaction of Turkish patients regarding the information they received. The statistical analyses conducted indicated that the Turkish version of the EORTC QLQ-INFO25 scale is a valid and reliable tool for measuring the knowledge levels of cancer patients. The high completion rate (>90%) of the surveys suggests that the scale was well understood by the patients and was deemed clear and acceptable. The extra topics suggested by the patients proved that new items are not needed and the content validity of the scale. Group validity analyzes are generally supported by data.
Cronbach’s alpha value for each area of the survey provided the criteria (≥0.6) that the scale can be used to compare different groups. For the entire survey, Cronbach’s alpha coefficient was 0.92, which confirmed that the scale’s reliability was high. When the literature is examined, the results of other studies proved the high reliability of the questionnaire. In studies conducted in Lebanon and Iran, Cronbach’s alpha coefficient for the entire questionnaire was reported to be more than 0.7 and in Spain and Taiwan 0.7-0.9 [6, 7, 9]. The result of our study was consistent with the results of these studies investigating the reliability of the EORTC QLQ-INFO25 scale. A standard divergent validity was observed in all areas of the scale (Rho<0.5), confirming that the two questionnaires used evaluated different concepts. These findings align with previous studies conducted by EORTC. Furthermore, the convergent and divergent validity analyses conducted in this study also provided support for the expected outcomes, which is in line with the findings of other relevant studies [13, 14].
The construct validity of the questionnaire was evaluated using factor analysis. In factor analysis, load values between 0.30 and 0.59 are typically considered medium, while values above 0.60 are considered high [15]. In our study, we found that the factor load value was 0.66, indicating a medium to high level of construct validity for the questionnaire. This suggests that the items in the questionnaire are appropriately measuring the intended constructs. In Asadi-lari et al. study was found that the value is 0.79 and this result is in line with our study [9].
The limitation of our study is that the information given to the participants cannot be measured objectively. In addition, test-retest analyzes, which show that the questionnaire does not change over time, were not conducted. It is not practical to apply a standardized information program to patients, but it is not possible to collect all these data in a multinational and diverse example. However, after a more detailed analysis of intercultural differences, a common scale can be developed for each culture.
Limitation
The fact that it was a single-center study may be a limitation for generalizability. Since the study was conducted with a large group, it is recommended to conduct a further study with groups receiving the same treatment or with the same cancer types. In addition, the level of knowledge of the same age groups can be investigated.
Conclusion
According to the results obtained from our study planned and implemented in order to bring the EORTC QLQ-INFO25 scale to the Turkish culture; The validity and reliability of the scale has been determined and it can be used in Turkish society. The questionnaire is a valid scale that can be used by healthcare professionals to evaluate the knowledge level of the person specific to cancer disease in clinical trials.
Acknowledgment
We would like to thank the EORTC Organization for the translation process and all participants who participated in the research.
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. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
3. İnci FH, Baskale H, Sercekus P. Turkish adaptation, and validity-reliability study of the Cancer Information Overload Scale. Cukurova Med J. 2019;44(1):127-135.
4. Schmid-Büchi S, Halfens RJ, Dassen T. A review of psychosocial needs of breast-cancer patients and their relatives. J Clin Nurs. 2008;17(21):2895-909.
5. Koet LL, Kraima A, Derksen I, Lamme B, Belt EJ T, van Rosmalen J, et al. Effectiveness of preoperative group education for patients with colorectal cancer: Managing expectations. Supportive Care in Cancer. 2021;29(9):5263–5271.
6. Tabchi S, El Rassy E, Khazaka A. Validation of the EORTC QLQ-INFO 25 questionnaire in Lebanese cancer patients: Is ignorance a bliss? Qual. Life Res. 2016;25(6):1597-604.
7. Arraras JI, Greimel E, Sezerci O. An international validation study of the EORTC QLQ-INFO25 questionnaire: An instrument to assess the information given to cancer patients. Eur J Cancer. 2010;46(15):2726-38.
8. Bibault JE, Chaix B, Guillemassé A, Cousin S, Escande A, Perrin M et al. Chatbot versus physicians to provide information for patients with breast cancer: Blind, randomized controlled noninferiority trial. J Med Internet Res. 2019;21(11):57-87.
9. Asadi-lari M, Pishkuhi MA, Almasi-Hashiami A. Validation study of the EORTC information questionnaire (EORTC QLQ-INFO25) in Iranian cancer patients. Support Care Cancer. 2015;23(7):1875-82.
10. Güzelant A, Göksel T, Özkök S. The European Organization for Research and Treatment of Cancer QLQ-C30: An examination into the cultural validity and reliability of the Turkish version of the EORTC QLQ-C30. Eur J Cancer Care. 2004;13(2):135-44.
11. Neijenhuijs KI, Jansen F, Aaronson NK. A systematic review of the measurement properties of the European Organisation for Research and Treatment of Cancer In-patient Satisfaction with Care Questionnaire, the EORTC IN-PATSAT32. Support Care Cancer. 2018;26(8):2551-2560.
12. Arraras JI, Manterola A, Hernández B. The EORTC information questionnaire, EORTC QLQ-INFO25. Validation study for Spanish patients. Clin Transl Oncol. 2011;13(6):401-10.
13. Bjordal K, de Graeff A, Fayers PM. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. Eur J Cancer. 2000;36(14):1796–807.
14. Brédart A, Bottomley A, Blazeby JM. An international prospective study of the EORTC cancer in-patient satisfaction with care measure (EORTC IN-PATSAT32). Eur J Cancer. 2005;41(14):2120–31.
15. Laher S. Using exploratory factor analysis in personality research: Best-practice recommendations. SA J Ind Psychol. 2010;36(1):1-7.
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Büşra İnce, Pınar Atak Çakır, Serkan Eti, Fatma Mutluay. Information received and usefulness of the sources of information to cancer patients at an oncology hospital in Turkey. Ann Clin Anal Med 2024;15(6):383-387
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Antibody responses to inactivated and/or mRNA SARS-CoV-2 vaccination in patients with inborn errors of immunity
Esra Karabıber 1, Ozge Atık 2, Bilgehan Ergan 3, Fatma Merve Tepetam 2, Arzu Ilkı 3, Ahmet Ozen 4, 5, 6, Elif Karakoç Aydıner 4, 5, 6, Safa Barıs 4, 5, 6
1 Department of Chest Diseases, Division of Adult Immunology and Allergy, Faculty of Medicine, Marmara University, Pendik Training and Research Hospital, 2 Department of Chest Diseases, Division of Adult Immunology and Allergy, Süreyyapasa Training and Research Hospital, 3 Department of Medical Microbiology, Faculty of Medicine, Marmara University, 4 Department of Pediatric Disease, Division of Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, 5 Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, 6 The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
DOI: 10.4328/ACAM.22071 Received: 2023-12-13 Accepted: 2024-01-15 Published Online: 2024-04-25 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):388-393
Corresponding Author: Esra Karabiber, Department of Chest Diseases, Division of Adult Immunology and Allergy, Faculty of Medicine, Marmara University, Pendik Training and Research Hospital, Pendik, İstanbul, Turkey. E-mail: dresrabulut@hotmail.com P: +90 505 687 02 11 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8377-7637
This study was approved by the Ethics Committee of Marmara University, Faculty of Medicine (Date: 2022-09-08, No: 833)
Aim: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses significant risks for individuals with inborn errors of immunity (IEI). Limited data exists on the coadministration of diverse SARS-CoV-2 vaccine brands with distinct mechanisms of action in IEI patients.
Material and Methods: Our study, encompassing 37 IEI-diagnosed individuals, aimed to compare antibody responses following the administration of inactivated and mRNA SARS-CoV-2 vaccines, both alone and in combination.
Results: Patients with a median age of 30 years (IQR; 23-40.5) received 2 doses (43.2%), 3 doses (37.8%), or 4 doses (18.9%) of SARS-CoV-2 vaccines. The median evaluation time for anti-SARS-CoV-2 antibodies was 199 days (IQR; 90.5-298), revealing an overall seropositivity rate of 91.1% (n=34). Notably, mRNA-vaccinated patients exhibited significantly higher antibody titers than those vaccinated with inactivated vaccines (p=0.014). A positive correlation emerged between the number of vaccine doses and antibody titers (r=0.4081, p=0.009). Furthermore, correlations were observed between serum IgA, IgM, IgE levels, CD19+B cell count, and anti-SARS-CoV-2 antibody titers.
Discussion: The study affirmed the safety and efficacy of inactivated and mRNA SARS-CoV-2 vaccines, either alone or in combination, among IEI patients. With a high seropositivity rate persisting for approximately one year, the findings support the safe administration of three vaccine doses in IEI patients, ensuring prolonged protection. The study identified no severe adverse events, underscoring the vaccines’ overall tolerability in this patient population.
Keywords: COVID-19, Inactivated SARS-CoV-2 Vaccine, mRNA Vaccine, Primary Immune Deficiency, Inborn Errors of Immunity
Introduction
Coronaviruses, belonging to the RNA virus family, are known to cause mild respiratory tract infections. However, following the identification of a new coronavirus (SARS-CoV-2) in December 2019 in Wuhan, China, which led to severe acute respiratory syndromes, it rapidly spread worldwide, causing a pandemic. In Turkey, the first case was announced by the Ministry of Health in March 2020. According to the data from the Turkish Ministry of Health, 17,042,722 people have been infected with SARS-CoV-2, and the number of individuals with mortality is reported as 101,492 [avaible at: https://covid19.saglık.gov.tr/TR-66935/genel koronavirus-tablosu.html].
Inborn errors of the immunity (IEI), formerly referred to as primary immunodeficiency (PID), manifest with various clinical conditions due to approximately 485 genetic defects. While IEI patients often experience frequent and severe infections, autoimmune diseases and malignancies are also common in this patient group. Mortality is mainly associated with infections and their complications. Infections in IEI patients require more prolonged treatment durations compared to the normal population, and opportunistic infections are frequently observed.
SARS-CoV-2 infection poses a serious concern for individuals with immune system defects, as with all infections in immunocompromised patients. Although some studies report mortality rates in these patients similar to the general population [1, 2], other studies have reported up to a 20-fold increase in hospitalization and death rates [3, 7]. COVID-19 can also have a fatal course in individuals without pre-existing conditions, and certain risk factors have been identified, especially in patients, such as male gender, obesity, hypertension, diabetes mellitus, chronic lung, and heart diseases, indicating a higher severity of COVID-19 infection, increased hospitalization, and higher mortality rates. Additionally, mutations causing defects in the Type-I interferon pathway and autoantibodies against Type-I interferon have been detected in a group of previously healthy individuals before encountering SARS-CoV-2, showing an increased risk of fatal COVID-19 infection [8, 9].
Vaccines have proven efficacy in preventing infections and complications and are widely used for treatment and prevention. However, despite the development and widespread administration of vaccines against SARS-CoV-2, it is not yet clear which individuals are still at risk for infection-related mortality. In addition to vaccines, new drugs used in the treatment and the virus’s mutation leading to decreased pathogenicity may provide some relief. However, in individuals with immune system defects, the effectiveness of vaccines may be compromised or insufficient due to impaired vaccine response, necessitating comprehensive studies for a clear interpretation of vaccine efficacy.
Several studies reported the seropositivity rate after two doses of mRNA SARS-CoV-2 vaccine, mostly constituting common variable immunodeficiency (CVID), at varying rates [10-14]. Moreover, data on seropositivity after two or more doses and different vaccine combinations are limited.
During the COVID-19 pandemic in Turkey, both inactivated (Sinovac, Coronavac®, vero cell) and mRNA (BNT162b2, Comirnaty®, Pfizer-Biontech) vaccines have been administered. The first inactivated SARS-CoV-2 vaccine was initiated in February 2021 in two doses, followed by a double-dose mRNA vaccine. Initial vaccination was prioritized for healthcare workers and high-risk groups, including immunodeficiency and elderly individuals. Since efficacy studies of vaccines have been conducted on healthy individuals, studies on the efficacy of SARS-CoV-2 vaccines in patients with impaired primary and secondary immunodeficiency are limited.
This study aims to answer questions regarding i) the antibody response to different SARS-CoV-2 vaccines in IEI patients, ii) the combination of inactivated and mRNA vaccines and long-term antibody response, iii) parameters affecting the SARS-CoV-2 vaccine response, and iv) vaccine-related adverse events.
Material and Methods
The study was conducted at two tertiary centers in Istanbul, and patients diagnosed with inborn errors immunity were included if they met the following criteria: i) aged 18 years and above, ii) received a full dose of either inactivated or mRNA SARS-CoV-2 vaccine, iii) received a combination of both vaccines. Individuals who did not receive an adequate vaccine dose and those who had documented COVID-19 infection during the vaccinated or unvaccinated period were excluded from the study. The diagnosis of IEI was established according to the European Society for Immunodeficiencies criteria [15].
Anti-SARS-CoV-2 S kits (Elecsys, Anti-SARS-CoV-2 S, 2022, Germany, Roche) were used to detect anti-SARS-CoV-2 antibodies. The kits predominantly measured antibodies produced against SARS-CoV-2 IgG, along with SARS-CoV-2 IgM and IgA, and analyses were conducted according to the manufacturer’s recommendations. Blood samples were collected at the earliest 28 days after the second dose of the vaccine and at any time for those who received three or more doses. Serum samples from patients were measured after dilution at a 1/10 ratio. Anti-SARS-CoV-2 antibody results were considered seropositive if above 0.8 U/ml.
Demographic information, clinical and laboratory evaluations, IEI classification, genetic mutations, comorbidities (bronchiectasis, malignancy, hypertension, diabetes mellitus, autoimmunity, lymphoproliferation, chronic lung disease), regular receiving treatments (including immunosuppressive therapies), immunoglobulin replacement therapy (IgRT) and its administring route, whether immunosuppressive treatment was received during the vaccination period, the number of vaccine doses, vaccination dates, and vaccine brands were recorded through surveys. Immunological tests evaluated within the last year, including lymphocyte subsets, serum IgG, M, A, and E levels, were recorded. Blood sampling from patients receiving regular intravenous IgG treatment was performed before the IgRT receiving, while for those receiving subcutaneous IgG treatment, blood sampling was done independently of IgRT administration.
Statistical Analyses
Median and interquartile ranges were calculated for continuous variables, and frequency measurements were conducted for categorical values. Mann-Whitney U and Student t-tests were used for continuous and ordinal data, and Chi-square and Fisher Exact tests were employed for nominal data. Correlation tests were evaluated using Spearman correlation tests. IBM SPSS 25 (SPSS Inc, Chicago, IL) and GraphPad Prism 8 (GraphPad Software Inc., San Diego, California, USA) programs were used for statistical analyses, and a p-value of <0.05 was considered statistically significant.
Ethical Approval
The study was approved by the Ethics Committee of the Marmara University, Faculty of Medicine (Date: 2022-09-08, no: 833), and informed consent was obtained from all patients.
Results
A total of 43 patients under follow-up with a diagnosis of IEI were evaluated, and 6 unvaccinated patients were excluded from the study. Statistical assessments were performed on a total of 37 patients. The median age of patients was 30 years (IQR; 23-40.5), and 48.6% were female. Table I summarizes the demographic features of the patients in the study. Seropositivity responses were evaluated in patients who received 2 or more doses of inactivated or mRNA SARS-CoV-2 vaccines or a combination of both vaccines. Of the patients, 43.2% received 2 doses (16 patients), 37.8% (14 patients) received 3 doses, and 18.9% (7 patients) received 4 doses of the vaccine. The assessment of anti-SARS-CoV-2 antibodies in 37 patients was performed at a median of 199 days (IQR; 90.5-298). Seronegativity was detected in 3 patients, with 2 having Bruton’s disease (X-linked agammaglobulinemia, BTK mutation), and 1 patient was followed up with a diagnosis of CVID with an unknown underlying genetic mutation. The overall seropositivity rate was determined as 91.1% (n=34). Anti-SARS-CoV-2 antibody titers were significantly lower in individuals who received only inactivated vaccines than those who received mRNA vaccines (p=0.014) (Figure 1). A moderately positive correlation was found between the number of doses and anti-SARS-CoV-2 antibody titers (Figure 2, r=0.4081, p=0.009).
No significant difference was found when comparing the antibody titers of SARS-CoV-2 vaccinated and COVID-19-recovered individuals with those vaccinated and not encountered COVID-19 (p=0.25). Higher anti-SARS-CoV-2 antibody titers were found in patients not receiving IgRT than those under IgRT (p=0.007) (Figure 3). There were no serious adverse events associated with vaccination. The most common adverse events were redness at the injection site (2 patients), pain, myalgia, fever (1 patient), and maculopapular rash (1 patient after the 3rd dose of mRNA vaccine).
The 6 unvaccinated patients excluded from the study and who were receiving regular IgRT also had blood samples taken to get an idea about anti-SARS-CoV-2 antibody levels in IgG products. Interestingly, even in the unvaccinated group, lower levels of anti-SARS-CoV-2 antibodies were detected compared to the vaccinated group. Simultaneously examined IgG products also showed anti-SARS-CoV-2 antibodies at different titers, up to 2500 U/ml, and seropositivity in the unvaccinated group was thought to be associated with replacement of immunoglobulin G.
In addition, significant positive correlations were found between anti-SARS-CoV-2 antibody titers and serum IgA, M, and E levels (r=0.6677, p<0.001, r=0.5366, p=0.001, r=0.4924, p=0.003, respectively). Also, a significant positive moderate correlation was found between the number of CD19+B cells and antibody titers (p<0.001, r=0.5294).
Discussion
Evaluating vaccine responses in patients with IEI will provide insights into vaccine effectiveness and reliability in this vulnerable patient group. It is also important for vaccine strategies. In our study, responses to SARS-CoV-2 inactivated and mRNA vaccines were evaluated in 37 patients with IEI, the majority of whom had a predominantly antibody deficiency. Overall seropositivity rate was 91.1%. Two seronegative patients were, as expected, followed up with a diagnosis of Bruton’s disease. Patients who received only inactivated SARS-CoV-2 vaccine showed significantly lower anti-SARS-CoV-2 antibody titers than those who received mRNA vaccines (p=0.014) (Figure 1). Also, a moderately positive correlation was found between the number of vaccine doses and anti-SARS-CoV-2 antibody titers. Three or more vaccine doses were well tolerated with a good safety profile, and efficient antibody titers lasting 1 year were detected.
The seropositivity rate after 2 doses of SARS-CoV-2 vaccine in IEI patients varies between 20-83.3% in studies [11, 12, 16-18]. In one study, the antibody response within two months after two doses of mRNA or adenovector SARS-CoV-2 vaccine was found to be 54.8% (n=92/168). This study showed that mRNA vaccines provided more seropositivity and a higher antibody response than adenovector vaccines. Higher IgM levels and CD-19+ B cell counts were found in seropositive patients, and a positive correlation between antibody titers and IgA and M levels was reported [19]. Consistent with the literature, we also found a positive correlation between IgM, A, E, and CD19+B cell counts and SARS-CoV-2 antibody titer in our study, suggesting that these parameters could be used in predicting seropositive vaccine responses.
Another study involving 33 patients with heterogeneous IEI evaluated anti-SARS-CoV-2 IgG antibody levels after two different mRNA vaccines, and seropositivity was detected in only 16 of them. However, in the same study, the antibody response in CVID patients was found to be 80% [13]. Due to the small number of patients in our analysis, antibody responses of different IEI subtypes were not separately evaluated.
The Centers for Disease Control and Prevention (CDC) recommends a third dose of SARS-CoV-2 vaccine in moderate and severe immunodeficiencies. In a study comparing 3 doses of mRNA and inactivated SARS-CoV-2 vaccines in children and adults diagnosed with PID, 16 received mRNA, and 17 received inactivated vaccines [20]. After inadequate antibody response following two doses of vaccine in patients with humoral immunodeficiency, the study suggested that antibody responses increased after the third dose and recommended a third dose for optimal immunogenicity. Seropositivity increased from 55% to 74%. In another study, seropositivity was found to be 76% after the third dose [21]. Our study showed that, regardless of the vaccine brand, as the number of doses increased, anti-SARS-CoV-2 antibody titers also increased, and the high seropositivity rate in our patients might be due to 56.8% of them receiving 3 or more doses. Considering these data, the need for repeated SARS-CoV-2 vaccination in immunodeficiencies should be decided individually by evaluating patients’ changing clinical findings and immunological data at intervals.
In another study involving 118 IEI patients investigating the effects of different vaccine brands (adenovirus, mRNA, inactivated, and combined vaccines), seropositivity after two doses was found to be 80.6%. Antibody titers were statistically lower, especially in inactivated and adenovector SARS-CoV-2 vaccinated individuals compared to healthy controls. This study also reported higher antibody titers in mRNA vaccine recipients than in others [22]. Our study also found that antibody titers in patients with inactivated vaccines were significantly lower than those with mRNA vaccines. Interestingly, in individuals receiving combined vaccines (inactivated+mRNA), antibody titers were lower than those with only mRNA vaccines but higher than those with inactivated vaccines. This outcome may be associated with administering a third vaccine dose following two doses of an inactivated vaccine, potentially indicating a booster effect. Additionally, individuals who received a combination of vaccines exhibited lower antibody titers than those who received two doses of the mRNA vaccine; this discrepancy could be attributed to administering a single dose of the mRNA vaccine.
In another study investigating immune responses six months after mRNA vaccination and the effectiveness of the third dose, 425 IEI patients were included. The geometric mean of antibody titers after two doses of mRNA vaccine decreased similarly to healthy controls after an average of 184 days. After an average of 198 days, a third dose of mRNA vaccine was administered to 47 CVID patients, and an increase in antibody titers was observed in 17 patients with low titers after the third dose. No antibody response occurred in the other 30 patients after the second dose, and seropositivity was observed in only 2 patients after the third dose[23]. Our study evaluated antibody titers approximately after six months (median 199 days) of the last vaccination, and seropositivity was still high. In a similar study, anti-SARS-CoV-2 antibody titers and T-cell responses were evaluated approximately 173 days after SARS-CoV-2 vaccination, and in 28 patients (CVID and selective IgA deficiency), seropositivity was still present. T-cell responses also continued in 26 patients, and it was stated that vaccine responses could last up to about a year[24]. However, antibody titers were lower than healthy controls.
In the later stages of the pandemic, it was shown that IgG replacement products contained antibodies against SARS-CoV-2. Therefore, when comparing the antibody levels of those receiving IgRT and those not receiving IgRT, we found that antibody titers were higher in individuals not receiving IgRT. Although this result suggests that the amount of antibodies passed from IgG products is low, it can be considered that the humoral immune systems and antibody responses of immunodeficiency patients who do not need IgRT are functional.
In the literature, three vaccine doses are recommended and shown to increase seropositivity and antibody response. Our study, although with a small number of patients, contributes to the literature regarding patients who have received four doses of the vaccine. It also provides insight into the effectiveness of different inactivated and mRNA vaccine combinations. The combined administration of inactivated and mRNA vaccines in these patients may have provided the development of antibodies not only to the spike protein but also to the N and M proteins. The seropositivity and antibody response did not differ between those who had COVID-19 after vaccination and those who did not. When we compared the antibody titers of individuals who encountered COVID-19 before or after vaccination, we found that having the disease did not affect the titers. Our results were consistent with the literature.
Third and fourth doses of SARS-CoV-2 vaccines in patients with IEI were well tolerated without severe adverse events in our study. Although the number of patients receiving three or more doses was the majority in our analysis, four doses of vaccine did not lead to additional side effects.
Conclusion
Our study showed that inactivated and mRNA SARS-CoV-2 vaccines in IEI patients are safe and effective both alone or in combination. Additionally, a high rate of seropositivity was found in the heterogeneous IEI patient group, and this seropositivity was found to sustain for approximately up to one year. Three doses of the vaccine can be safely administered in IEI patients, and it has been concluded that it is protective for a long time.
Acknowledgment
The authors thank Dem Drug and Bussines Limited Company for their unconditional support to kit out Elecsys® Anti-SARS-CoV-2 S. We thank all patients for participating.
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. Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, et al. Coronavirus disease 2019 in patients with inborn errors of immunity: An international study. J Allergy Clin Immunol. 2021;147(2):520-531.
2. Milito C, Lougaris V, Giardino G, Punziano A, Vultaggio A, Carrabba M et al., Clinical outcome, incidence, and SARS-CoV-2 infection-fatality rates in Italian patients with inborn errors of immunity. J Allergy Clin Immunol Pract. 2021;9 (7):2904-2906.e2.
3. Shields AM, Burns SO, Savic S , Richter AG. COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience. J Allergy Clin Immunol. 2021;147(3):870-875.e1.
4. Castano-Jaramillo LM , Yamazaki-Nakashimada MA, O’Farrill-Romanillos RO, Muzquiz Zermeño D, Scheffler Mendoza SC Montoya ED. COVID-19 in the context of inborn errors of immunity: a Case series of 31 patients from Mexico. J Clin Immunol. 2021;41(7):1463-1478.
5. Ho HE, Mathew S, Peluso MJ, Cunningham-Rundles C. Clinical outcomes and features of COVID-19 in patients with primary immunodeficiencies in New York City. J Allergy Clin Immunol Pract. 2021;9(1):490-493.e2.
6. Goudouris ES , Pinto-Mariz F , Mendonça LO, Aranda CS, Guimarães RR , Kokron C , et al. Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study. J Clin Immunol. 2021;41(7):1479-1489.
7. Aydiner EK, Eltan SB, Babayeva R , Aydiner O , Kepenekli E , Kolukisa B, et al. Adverse COVID-19 outcomes in immune deficiencies: Inequality exists between subclasses. Allergy. 2022;77(1):282-295.
8. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;23(370):6515.
9. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;23(370):6515.
10. Amodio D, Ruggiero A, Sgrulletti M, Pighi C, Cotugno N, Medri C, et al. Humoral and cellular response following vaccination With the BNT162b2 mRNA COVID-19 vaccine in patients affected by primary immunodeficiencies. Front Immunol. 2021;4(12):727850.
11. Delmonte OM, Bergerson JRE, Burbelo PD, Durkee-Shock JR, Dobbs K, Bosticardo M, et al. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021;148(5):1192-1197.
12. Hagin D, Freund T, Navon M, Halperin T, Adir D, Marom R, et al. Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity. J Allergy Clin Immunol. 2021;148(3):739-749.
13. Pham MN, Murugesan K, Banaei N, Pinsky BA, Tang M, Hoyte E, et al. Immunogenicity and tolerability of COVID-19 messenger RNA vaccines in primary immunodeficiency patients with functional B-cell defects. J Allergy Clin Immunol. 2022. 149(3):907-911.e3.
14. Salinas AF, Mortari EP, Terreri S, Milito C, Zaffina S, Perno CF, et al. Impaired memory B-cell response to the Pfizer-BioNTech COVID-19 vaccine in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2022;149(1):76-77.
15. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-1770.
16. Arroyo-Sánchez D, Cabrera-Marante O, Laguna-Goya R, Almendro-Vázquez P, Carretero O, Gil-Etayo FJ, et al. Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency. J Clin Immunol. 2022;42(2):240-252.
17. Salinas AF, Mortari EP, Terreri S, Quintarelli C, Pulvirenti F, Cecca SD, et al. SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best. J Clin Immunol. 2021;41(8):1709-1722.
18. Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen, et al. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine. 2021;74:103705.
19. Shields AM, Faustini SE, Hill JH, Al-Taei S, Tanner C, Ashford F, et al. SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study. J Clin Immunol. 2022;42(5):923-934.
20. Leung D, Mu X, Rosa Duque JS, Cheng SMS, Wang M, Zhang W, et al. Safety and immunogenicity of 3 doses of BNT162b2 and CoronaVac in children and adults with inborn errors of immunity. Front Immunol. 2022;20(13):982155.
21. Shields AM, Faustini SE, Hill HJ, Al-Taei S, Tanner C, Ashford F, et al. Increased seroprevalence and improved antibody responses following third primary SARS-CoV-2 immunisation: An update from the COV-AD study. Front Immunol. 2022;2(13):912571.
22. Erra L, Uriarte I, Colado A, Paolini MV, Seminario G, Fernández JB, et al. COVID-19 vaccination responses with different vaccine platforms in patients with inborn errors of immunity. J Clin Immunol. 2023;43(2):271-285.
23. van Leeuwen LPM, Grobben M, GeurtsvanKessel CH, Ellerbroek PM, Bree JG, Potjewijd J, et al. Immune responses 6 months after mRNA-1273 COVID-19 vaccination and the effect of a third vaccination in patients with inborn errors of immunity. J Clin Immunol. 2023;43(6):1104-1117.
24. Lucane Z, Slisere B, Ozola L, Rots D, Papirte S, Vilne B, et al. Long-term immunological memory of SARS-CoV-2 is present in patients with primary antibody deficiencies for up to a year after vaccination. Vaccines (Basel). 2023;3;11(2):354.
Download attachments: 10.4328.ACAM.22071
Esra Karabıber, Ozge Atık, Bilgehan Ergan, Fatma Merve Tepetam, Arzu Ilkı, Ahmet Ozen, Elif Karakoç Aydıner, Safa Barıs. Antibody responses to inactivated and/or mRNA SARS-CoV-2 vaccination in patients with inborn errors of immunity. Ann Clin Ann Clin Anal Med 2024;15(6):388-393
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The epidemiology of pediatric trauma in the emergency department of a trauma center: An observational study
Nurgül Akça 1, Ömer Faruk Demir 2, Secdegül Coşkun Yaş 3
1 Department of Emergency Medicine, Karabuk University, Karabuk Training and Research Hospital, Karabük, 2 Department of Emergency Medicine, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, 3 Department of Emergency Medicine, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.22079 Received: 2023-12-20 Accepted: 2024-02-23 Published Online: 2024-04-05 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):394-398
Corresponding Author: Ömer Faruk Demir, Department of Emergency Medicine, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey. E-mail: demirof@yahoo.com P: +90 530 665 08 02 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2416-0274
This study was approved by the Ethics Committee of University of Health Sciences Diskapi Yildirim Beyazit Training and Research Hospital (Date: 2020-07-20, No: 92/14)
Aim: This study aimed to comprehensively analyze the epidemiology of pediatric trauma in the emergency department of a designated trauma center. The study focused on demographic factors, injury mechanisms, and outcomes, with the ultimate goal of informing preventive measures.
Material and Methods: This retrospective observational study was conducted over a one-year period. The study included pediatric trauma patients under 18 years of age admitted to the emergency department of a tertiary care hospital. Data, encompassing patient demographics, time of presentation, injury mechanisms, laboratory and radiologic examinations, consultations, procedures, and outcomes, were analyzed.
Results: Of the 434,000 patients admitted during the study year, 30,710 were pediatric trauma cases. The majority were males (64.3%) with a mean age of 10.09 years. Simple falls were the predominant mechanism (90.6%), and the 11-15 age group had the highest number of admissions. Injury patterns varied across age groups, with gender differences observed. Most admissions occurred between 16:00-00:00, and Orthopedics received the highest consultation requests. Ninety-nine percent were discharged, 0.9% were hospitalized, and one patient died. Surgical intervention was required in 97% of hospitalized cases.
Discussion: The findings of this observational study on pediatric trauma epidemiology in a trauma center’s emergency department contribute valuable insights to the existing literature. The study analyzed a significant number of patients and revealed that male children experienced trauma more frequently. The most common causes of trauma were simple falls and road traffic accidents.
Keywords: Pediatric, Emergency Medicine, Injuries, Trauma Center
Introduction
Trauma and trauma-related health problems are among the world’s leading health problems. Trauma is the leading cause of death, particularly in childhood and young adulthood [1]. The lifetime costs of trauma-related injuries are also quite high [2]. In addition to being a major cause of mortality, childhood injuries are known to result in lifelong morbidity [3]. Most importantly, these injuries have many preventable causes [4].
The management of pediatric trauma is similar to that of adult patients, but there are several anatomical, physiological, and psychological differences [3]. Therefore, different approaches are used in the evaluation of pediatric trauma patients. Data on the epidemiology and etiology of pediatric trauma patients will guide the management of this patient population. There are studies in the literature on this subject, but it is not possible to generalize the results to all countries and to all environmental conditions [5].
The aim of this study was to make a demographic analysis of pediatric patients presenting with all types of physical trauma and injury, to determine the etiology of trauma and injury, and to create a resource for the development of preventive factors.
Material and Methods
This is a retrospective observational study. It was conducted in a tertiary care hospital, defined as a trauma center.
The study included trauma patients under 18 years of age who were admitted to the Emergency Department of Diskapi Yildirim Beyazit Training and Research Hospital during a one-year period between January 2019 and January 2020. Patients who were over 18 years of age or non-trauma pediatric patients were excluded from the study. The Emergency Department where the study was conducted served both adult and pediatric trauma patients.
The study analyzed various factors including age, gender, time and date of presentation, laboratory and radiologic examinations, consultations, procedures performed in the emergency department, need for surgery, and outcomes. The mechanism of injury was analyzed in ten different subgroups (simple fall, road traffic accident, fall from height, physical assault, stab-cut injuries, gunshot injury, burns, foreign body, animal bite, and occupational accidents). The data were obtained from patient files and the electronic medical record system.
The statistical analysis was performed using SPSS version 20 (IBM Corporation, Armonk, NY). Descriptive statistics were reported as mean ± standard deviation (SD) for continuous variables, and as percentiles and rates for categorical variables. The normality of the continuous variables was evaluated using the Kolmogorov–Smirnov test. The categorical variables were compared using Pearson’s χ2 test. A p-value less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of University of Health Sciences Diskapi Yildirim Beyazit Training and Research Hospital (Date: 2020-07-20, No: 92/14).
Results
Out of the 434,000 patients admitted to the emergency department during the study year, 30,710 were pediatric trauma patients. Of these patients, 19,743 (64.3%) were male, and the mean age was 10.09 ± 5.14 years. The highest number of admissions was found in the 11-15 age group, with 9,845 (32.1%) patients, according to the analysis of patient distribution by age groups (Figure 1). The most common mechanism of injury was simple falls with 27,817 (90.6%) patients. This was followed by road traffic accidents and physical assaults, respectively (Table 1). Upon analyzing the relationship between injury mechanisms and gender, it was found that all mechanisms were significantly more common in men (p < 0.001).
Children aged 11-15 years experienced more simple falls, while children aged 6-10 years experienced more road traffic accidents than other age groups. Children aged 1-5 years had a higher incidence of admission due to falls from height, burns, and foreign bodies. Children aged 16 years and older had a higher incidence of admission due to physical assault, stab-cut injuries, gunshot injuries, animal bites, and occupational injuries. There was a significant difference in the mechanism of injury among the four age groups (p < 0.001). Table 2 provides detailed information on the age groups and mechanisms of injury.
When analyzing patient admissions by time period, 17,517 (57%) of the admissions occurred between 16:00-00:00, 11,230 (36.6%) between 08:00-16:00, and 1963 (6.4%) between 00:00-08:00.
Consultation was requested from other departments for 39.4% of the patients. The Orthopedics department had the highest number of consultations with 9576 (31.2%) patients. Some patients consulted more than one department. Table 3 shows the other departments for which consultation was requested.
Out of all the patients, 30,389 (99%) were discharged from the emergency department and 273 (0.9%) were admitted to the hospital. One patient died in the emergency department. This patient was admitted due to a road traffic accident. In the study, 97% (265) of the hospitalized patients underwent surgical treatment. The majority (73.6%) of the hospitalized patients were admitted to the orthopedic department (Table 1). Medical procedures performed in the emergency department and diagnostic tests requested were analyzed. It was found that 81.2% of children admitted to the emergency department had at least one diagnostic test requested, whereas 18.8% of children admitted to the emergency department had no diagnostic test requested. Reduction and suturation were the most common procedures performed. Direct radiography was the most frequently requested diagnostic test, accounting for 75.5% of cases (Table 3).
Discussion
In our observational study of pediatric trauma patients, injury mechanisms and demographic characteristics of 30,710 patients were analyzed. Our findings were largely consistent with existing literature.
In their study analyzing ambulance system data on pediatric traumas, Wohlgemut et al. found that the mean age was 9 years [6]. Tambay et al. found that the majority of pediatric trauma patients admitted to the emergency department were in the 7-14 age group [7]. Demir et al. conducted a study on pediatric patients admitted for forensic reasons, the majority of whom were trauma patients, and found that the mean age was 8.8 years [8]. In our study, we found that the mean age of the patients was 10 years, and the most common age group was 11-15 years.
In our study, 64.3% of the patients were male. Consistent with our results, previous studies have also reported a higher incidence of males presenting with pediatric trauma. Oliver et al reported that 68.3% of their patients were male [9]. In their study conducted in Norway, Nesje et al. found that 61% of the patients were male [10]. Although there is no definite proven reason between the frequency of trauma and gender, trauma admissions are more common in boys. Boys may engage in more risky behaviors during physical games and act more impulsively, which could be a reason for this.
Demir et al. reported that 57% of the cases occurred between 16:00-00:00 [8]. Similarly, Jalalvandi et al. found that accidents were most frequently observed during the hours of 18:00-00:00 [11]. In our study, we also found that 57% of admissions were between 16:00-00:00 when analyzed in three groups based on hours.
The study revealed that the most frequent mechanism of injury for pediatric trauma patients was simple falls, followed by road traffic accidents. This finding is consistent with a study conducted by Herbert et al in South Africa, where falls (39%) and traffic accidents (15%) were also the most common mechanisms of presentation [12]. Similarly, a study conducted in Iran found that falls accounted for 65% of trauma mechanisms, while road traffic accidents accounted for 16% [11]. A study conducted in the UK, including moderate and severe pediatric trauma, found that 40.9% of patients presented with road traffic accidents and 36.9% with falls [13]. Similarly, a study conducted in Norway that included all pediatric traumas found that the most common mechanism of trauma was road traffic accidents, accounting for 61%, followed by falls at 21% [10]. In our study, the rate of simple falls was 90.6%. This high rate may be attributed to the large number of patients and the variation in the frequency of local emergency department visits. It is known that 95% of pediatric trauma deaths occur in low- and middle-income countries [14]. The geographical and socioeconomic structure of the region is a significant factor in the epidemiology of trauma mechanisms. For instance, our population did not experience any cases of drowning within a year, despite it being a significant cause of traumatic deaths in children according to the literature [4].
When analyzing injury mechanisms by age, patients aged 16 years and older had higher rates of physical assault, stab-cut injuries, occupational accidents, and gunshot injuries. It was anticipated that these mechanisms would be more prevalent among adolescents. Additionally, foreign bodies, falls from height, and burn mechanisms were found to be more common in the 0-5 age group. Previous studies have indicated that injuries occurring at home are more frequent in this age group [11]. To prevent these types of injuries, caregivers should receive education on how to enhance safety measures in domestic environments.
In the study, the majority of pediatric trauma patients were associated with the orthopedic department. Most consultations and hospital admissions were to the orthopedic department. Jajalvaldi et al. reported that pediatric trauma patients had mostly orthopedic injuries [11]. Additionally, many studies investigating pediatric trauma have found that extremity injuries are among the most frequent [12, 15]. As our study was retrospective, we were unable to access all data, and therefore, detailed diagnoses could not be included in the study. However, the fact that the most common medical procedure performed was reduction and the most common consultation was with orthopedics shows that extremity fractures and dislocations are common in our patient population.
The study showed that the number of patients admitted in one year was considerably high. Of these, 99% were discharged, 67.7% did not require medical procedures, and 18.8% did not require diagnostic tests. These findings suggest that many admissions could be resolved with simple treatments. In addition to addressing preventable causes of pediatric trauma, it is important to discuss ways to prevent unnecessary emergency department visits.
Limitation
The study’s most significant limitation was its single-center design, as the subject of the research is highly influenced by environmental and sociocultural factors. However, the analysis of regional data also provides important contributions in this area. Since the study was planned retrospectively, it was not possible to detail the data as much as desired. Examining the patients’ diagnoses in addition to the mechanisms of injury, would have provided more valuable results. Furthermore, the unavailability of trauma scoring systems prevented the determination of the patients’ severity.
Conclusion
Our epidemiologic study, which should be evaluated in the context of its own environmental factors, provided important findings about the general reasons for the presentation and outcomes of pediatric trauma patients. The study, which included a large number of patients, found that male children were more frequently exposed to trauma and that the most common mechanisms of trauma were simple falls and road traffic accidents. Considering the diagnostic tests and consultations required for this group of patients, a significant need for resources was observed. Necessary precautions should be taken to prevent pediatric injuries with the data obtained. As a vital contribution to the field, this study provides a foundation for further research and the development of evidence-based interventions to minimize the impact of pediatric trauma on healthcare systems and, more importantly, on the well-being of the affected children.
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. Christian CW, Sege RD, The Committee on Child Abuse and Neglect, The Committee on Injury Violence and Poison Prevention, The Council on Community Pediatrics. American Academy of Pediatrics. Policy statement–child fatality review. Pediatrics. 2010;126(3):592-6.
2. Mace SE, Gerardi MJ, Dietrich AM, Knazik SR, Mulligan-Smith D, Sweeney RL, et al. Injury prevention and control in children. Ann Emerg Med. 2001;38(4):405-14.
3. Mock C, Abantanga F, Goosen J, Joshipura M, Juillard C. Strengthening care of injured children globally. Bull World Health Organ. 2009;87(5):382-9.
4. Peden M. World report on child injury prevention appeals to “Keep Kids Safe”. Inj Prev. 2008;14(6):413-4.
5. Bradshaw CJ, Bandi AS, Muktar Z, Hasan MA, Chowdhury TK, Banu T, et al. International study of the epidemiology of paediatric trauma: PAPSA Research Study. World J Surg. 2018;42(6):1885-1894.
6. Wohlgemut JM, Morrison JJ, Apodaca AN, Egan G, Sponseller PD, Driver CP, et al. Demographic and geographical characteristics of pediatric trauma in Scotland. J Pediatr Surg. 2013;48(7):1593-7.
7. Tambay G, Satar S, Kozaci N, Acikalin A, Ay MO, Gulen M, et al. Retrospective analysis of pediatric trauma cases admitted to the emergency medicine department. Journal of Academic Emergency Medicine. 2013;12(1):8-12.
8. Demir OF, Aydin K, Turan F, Yurtseven A, Erbil B, Gulalp B. Analysis of pediatric forensic cases presented to emergency department. Türk Pediatri Arşivi. 2013;48(3):235-240.
9. Oliver J, Avraham J, Frangos S, Tomita S, DiMaggio C. The epidemiology of inpatient pediatric trauma in United States hospitals 2000 to 2011. J Pediatr Surg. 2018;53(4):758-764.
10. Nesje E, Valoy NN, Kruger AJ, Uleberg O. Epidemiology of paediatric trauma in Norway: A single-trauma centre observational study. Int J Emerg Med. 2019;12(1):18.
11. Jalalvandi F, Arasteh P, Faramani RS, Esmaeilivand M. Epidemiology of pediatric trauma and its patterns in Western Iran: A hospital based experience. Global journal of health science. 2016;8(6):139.
12. Herbert HK, van As AB, Bachani AM, Mtambeka P, Stevens KA, Millar AJ, et al. Patterns of pediatric injury in South Africa: An analysis of hospital data between 1997 and 2006. J Trauma Acute Care Surg. 2012;73(1):168-74.
13. Bayreuther J, Wagener S, Woodford M, Edwards A, Lecky F, Bouamra O, et al. Paediatric trauma: Injury pattern and mortality in the UK. Arch Dis Child Educ Pract Ed. 2009;94(2):37-41.
14. Peden M, McGee K, Krug E. Injury: A leading cause of the global burden of disease, 2000. World Health Organization; 2002.
15. Spady DW, Saunders DL, Schopflocher DP, Svenson LW. Patterns of injury in children: A population-based approach. Pediatrics. 2004;113(3 Pt 1):522-9.
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Nurgül Akça, Ömer Faruk Demir, Secdegül Coşkun Yaş. The epidemiology of pediatric trauma in the emergency department of a trauma center: An observational study. Ann Clin Anal Med 2024;15(6):394-398
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Is there a relationship between knee osteoarthritis and osteoporosis?
Hatice Ağır
Department of Physical Medicine and Rehabilitation, Şanlıurfa Training and Research Hospital, Şanlıurfa, Turkey
DOI: 10.4328/ACAM.22085 Received: 2023-12-27 Accepted: 2024-02-12 Published Online: 2024-04-04 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):399-403
Corresponding Author: Hatice Ağır, Department of Physical Medicine and Rehabilitation, Şanlıurfa Training and Research Hospital, Eyyübiye, Şanlıurfa, Turkey. E-mail: haticeagir10@hotmail.com P: +90 554 115 25 90 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1606-9224
This study was approved by the Ethics Committee of Harran University, Faculty of Medicine (Date: 2023-11-15, No: HRU/21.20.12)
Aim: Osteoarthritis (OA) and osteoporosis (OP) are two metabolic bone diseases associated with old age. Recently, the hypothesis that there may be a relationship between OP and OA and that the degree of OA will change with the degree of OP has been emphasized. In this cross-sectional study, the relationship between knee OA and bone mineral density (BMD) in female patients was investigated.
Material and Methods: In this cross-sectional study of 324 patients with knee pain and radiological diagnosis of knee OA, the severity of knee OA was evaluated according to Kellgren-Lawrence (K-L) radiographic criteria and joint space distance (JSD). BMD of the femur and lumbar spine was measured by dual-energy X-ray absorptiometry (DXA). K-L grade and the relationship between JSD and BMD were examined.
Results: T scores of femoral neck, femoral trochanter, femoral intertrochanter, total hip were highest in K-L stage 2 group and lowest in K-L stage 4 group. Femoral T scores were found to be significantly lower in BMD in the C-L stage 3 and 4 group compared to the C-L stage 1 and 2 group (p <0.001). No significant correlation was found between K-L stage and L1-L4 T score.
Discussion: Although there is an inverse relationship between OP and the presence of knee OA, the relationship between the two is not linear. In order to evaluate patients better, it is necessary to know the relationship between the two diseases.
Keywords: Osteoarthritis, Osteoporosis, Bone Mineral Density
Introduction
Osteoarthritis (OA) and osteoporosis (OP) are two metabolic diseases that increase in frequency with age, are very common in society, negatively affect the patient’s quality of life and cause functional disability in the patient. Osteoporosis is a skeletal disease characterized by decreased bone mineral density (BMD), causing deterioration in bone microarchitecture and reduction in bone mass [1]. Osteoarthritis, on the other hand, is a degenerative skeletal disease that can affect all joints, characterized by the deterioration of articular cartilage and new bone formation [2, 3]. The relationship between these two diseases is quite complex in terms of bone loss, new bone formation, fracture risk, mechanical loading and systemic causes. Although recent publications are trying to explain the relationship between the two, this relationship has not been clearly demonstrated and is still controversial [4, 5]. Bone turnover plays a very important role in the common pathophysiology of OA and OP diseases. It has been reported that there is a relationship between high bone turnover and the progression of OA levels in osteoporosis. In some studies, it has been found that patients with severe knee OA have higher bone turnover biomarkers and lower bone mineral density [6]. In rabbit experiments to explain the relationship between OP and OA; It has been emphasized that the deterioration in the microarchitecture of the subchondral bone caused by osteoporosis increases the severity of osteoarthritis. There are cross-sectional and experimental studies examining the relationship between BMD and knee OA over the Kellgren-Lawrence (K-L) grade. In a study on women; BMD scores were found to be higher in the C-L grade 2 and above group compared to the group without OA [5, 7]. In some studies, it has been shown that high BMD is protective in terms of OA severity [8, 9].
In this study, it was aimed to examine the relationship between radiological knee OA severity and ipsilateral proximal femur and L1-L4 lumbar spine T score in postmenopausal women.
Material and Methods
This cross-sectional study included 324 postmenopausal women patients who applied to the Physical Medicine and Rehabilitation outpatient clinic with knee pain between January 2020 and January 2021 and were diagnosed with knee OA according to American Collage of Rheumatology (ACR) criteria [10].
Demographic data such as age and BMI (kg/m2) were recorded. Radiologic staging of knee OA by Kellgren Lawrence (K-L) and BMD measurement by dual-energy X-ray absorptiometry (DXA) [11]. were done for each patient [12]. Femoral neck, thoracantary femur, interthoracantary femur, total hip and L1-L4 lumbar spine total T scores of all participating patients in the study were measured by DXA. The severity of knee OA was evaluated according to K-L radiographic criteria and joint space distance (JSD). JSD was measured by anteroposterior (AP) knee radiography. K-L grade and the relationship between JSD and BMD were investigated.
Inclusion criteria were to be ages between 50-75 postmenopausal women and OA staging of K-L between 1 to 4 for knee OA. Exclusion criteria; K-L grade 0, had a surgical procedure related to the knee, valgus alignment (≥3° valgus), inflammatory joint disease, congenital knee joint deformity, endocrinological disease, and disease affecting bone metabolism were not included in the study. Diagnoses of lumbar spondylosis and coxarthrosis, which may affect DXA measurement results, were excluded.
Assessment Radiographic Knee OA
Radiologic evaluation of osteoarthritis was performed according to K-L staging. K-Lstaging; Anteroposterior and lateral radiographs of both knees taken while standing were evaluated (at 30° flexion). Knee OA staging was classified radiographically by a physiatrist according to the K-L criteria: These stages are as follows: Stage 0: Normal; Stage I: Suspected osteophytes, normal joint spacing; Stage 2: Definite osteophyte, suspicious narrowing of joint space; Stage 3: Moderately numerous osteophytes, definite narrowing of joint space, mild sclerosis; Stage 4: Large osteophytes, significant sclerosis and cysts, severe joint space narrowing, definite deformity of the bone ends [13].
Measure of the Joint Space Distance
Knee joint spacing was measured as recommended in the literature. Patients were asked to slightly bend their knees at 30 degrees of flexion, with their weight evenly distributed on both knees. The patella was positioned at the lower end of the femur. The beam was standardized 2.5 cm below the apex of the patella. The mechanical axis of the knee was recorded as the line formed between the center of the femoral head, the medial plateau of the tibia and the ankle joint. The X-ray was applied parallel to the tibial plateau. JSD was measured as the maximum height in the middle of the medial and lateral compartments of each knee. In other words, the gap in the radiolucent area between the radiopaque edges of the tibio-femoral joint surfaces was measured (Figure 1) [14].
BMD Measurement
DXA measurements were done by Hologic Horizon Wi S/N 201290 at the education and research hospital radiology unit. T-scores below -2.5 for lumber total, femur neck and femur total, femur inerthoracanteric BMDs were accepted as OP referring to World Health Organization (WHO) classification criteria. The BMD value of the discrete/crushed vertebrae corpus was subtracted from the value of total lumbar BMD for not causing a wrong decision. According to the WHO classification, T scores between -1 and -2.5 were considered osteopenia, and those below -2.5 were considered OP [15].
Statistical Analysis
SPSS 20 program was used for statistical analysis and p value <0.05 was considered statistically significant. Correlation analysis was performed to analyze the relationship between JSN and T scores (femoral neck, femoral trochanter, femoral intertrochanter, total hip, and spine) in knee AP images. Analysis of Covariance (ANCOVA) was used to evaluate the relationship between T scores in K-L stage category groups.
Ethical Approval
This study was approved by the ethics committee of Harran University, Faculty of Medicine (Date: 2023-11-15, No: HRU/21.20.12). All participants provided written informed consent for participation in the survey and the use of their data for research purposes.
Results
The mean age of 342 postmenopozal women patients participating in the study was 66.47±8.10 (50–73) years, and the mean BMI was 28.07±3.04(20.49–39.43) kg/m2. The mean value of the JSD was measured as 2.05±1.65(0–7.40) mm. According to K-L stage, 52 (15.20%) of the patients were K-L stage 1, 38 (11.11%) K-L stage 2, 89 (26.02%) K-L stage 3 and 163 (47.66%) K-L stage was 4. Demographic and clinical data of the patients are given in A significant correlation was found between JSD and T scores of the femoral neck, femoral trochanter, femoral intertrochanter, and total hip (p=0.042, r=0.152; p=0.000, r=0.262; p=0.000, r=0.305; p=0.001, r=0.230 respectively). However, no relationship was found between JSD and spinal L1-L4 T scores (p=0.181, r=0.105) (Table 2). T scores of femoral neck, femoral trochanter, femoral intertrochanter, total hip were highest in K-L stage 2 group and lowest in K-L stage 4 group. Femoral T scores were found to be significantly lower in BMD in the K-L stage 3 and 4 group compared to the K-L stage 1 and 2 group (p < 0.001). No significant correlation was found between K-L stage and spinal L1-L4 T score (Table 3).
Discussion
The relationship between OA and OP has not been clearly explained [15, 16]. Due to the factors affecting the pathophysiology of OA and OP, the extent of the relationship between the severity of OP and the degree of OA needs to be addressed from different perspectives. It is not a correct approach to evaluate and treat OA and OP diagnoses separately in clinical practice. It would be an appropriate approach to evaluate and treat both diagnoses together. We think that this study is important in terms of raising awareness on this issue.
In this cross-sectional study, there was a relationship between JSD and K-L staging and hip BMD; however, there was no correlation between spinal BMD. At the same time, it was observed that there was no linear relationship between knee OA and BMD. That is, while the hip T score was highest in patients with K-L stage 2, it was found to be the lowest in stage 4 patients. The results of this study show some similarities and differences with previous studies.
In the Framingham study; it was found that the femoral BMD value was higher in the female patient group with knee OA compared to the group without OA. However, unlike our study, it was shown that there was no relationship between BMD and JSD [17]. There is also a study showing a negative relationship between OP density and K-L staging of OA [4].
In a study similar to ours, BMD was found to be higher in K-L stage 2 and lower in K-L stage 3 compared to K-L stage 0 in women. In the study, higher BMD levels were observed with increasing K-L stage [18]. In the study, higher BMD levels were observed as the K-L stage increased. In a study of 473 geriatric women, patients with K-L grades 1 and 2 had a higher BMD than those without OA; lower BMD was found in K-L grades 3 and 4 [19].
In a multicenter OA study, higher BMD was observed in knees without OA and was associated with increases in the degree of joint space narrowing. However, the relationship between OA progression and BMD in knees with OA was not found to be significant [20]. Contrary to all these studies, in the study conducted by Sezer et al., no statistically significant relationship was found between BMD and the degree of knee OA [21].
Similarly, in a large-scale study conducted in the Korean population, the relationship between BMD and knee OA was investigated. Consistent with our study, in knee OA (K-L grades 2, 3 and 4), femoral neck and total hip BMD decreased as K-L grade increased, while spinal BMD did not differ significantly [22].
In a study investigating the relationship between BMD and OA in postmenopausal female patients; lumbar spine BMD levels were statistically higher in the non-OA group than in the OA group. However, there was no difference between the groups in terms of femoral BMD values. As a result, it has been emphasized that OA may be protective against OP [23].
Various contributing factors such as metabolic, mechanical, genetic or endocrinological in the etiology of OA and OP reveal the complex relationship between these two diseases. It has been argued that subchondral bone density may cause progressive chondrocyte dysfunction in the early stages of cartilage destruction. Increased mechanical stress of weight-bearing cartilages with high BMD is aggravating for OA [24].
The results of this article make a clinical contribution to the literature. First of all, this is the first study in the literature to evaluate knee OA patients with both K-L stage and JSD and to examine the relationship between both and BMD.
At the same time, the higher T score in patients with mild OA in the study suggests that bone quality may be misinterpreted in this group. In OA patients, it is also a situation that we should pay attention to when treating OP; It would not be very accurate to evaluate a high T score as an indicator of good bone quality. It can be interpreted as a temporary increase in the T score due to the high amount of subchondral bone. It is important to inform patients that OP is more likely to exacerbate, as the T score decreases significantly with the progression of OA in patients with OA.
It was concluded from this study that OP should be more effectively prevented and treated in patients with early stage OA. In mild OA, BMD results may not accurately reflect bone quality, as the T-score may increase as a result of bone sclerosis. We think that a different measurement tool should be used to more accurately measure bone quality in clinical practice and more research is needed in this area.
The spine and hip, designated as standard BMD measurement sites, are affected by the subcondal bone in the knee joint, which is a load-bearing joint. Therefore, we think that knee BMD can also be deduced from hip and spine values. More patient and multicenter studies are needed on this subject. We wanted to emphasize the importance of evaluating patients with OA or OP holistically, predicting the risk of OA or OP in patients, and providing appropriate clinical treatment to prevent them in daily practice.
Limitation
This study has some limitations. First of all, the number of patients participating in the study is not sufficient. Second, comorbidities affecting BMD scores were ignored. Third, only patients with radiological OA were included in the study. Its relationship to patients with symptomatic knee pain has not been evaluated.
Conclusion
As a result, this study is an attempt to explain the relationship between OA and OP in more detail. While BMD scores were higher in mild knee OA cases, they were significantly lower in moderate and severe OA. We also hypothesized that it would be possible to deduce the bone quality of the knee from hip and spine BMD, which are the standard regions routinely used for BMD measurement. Because the hip and spine are also stimulated by load bearing similar to the subchondral bone of the knee.
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. Zhu Z, Zhang T, Shen Y, Shan PF. The burden of fracture in China from 1990 to 2019. Arch Osteoporos. 2023;19(1):1.
2. Man GS, Mologhianu G. Osteoarthritis pathogenesis – a complex process that involves the entire joint. J Med Life. 2014;7:37-41.
3. Apold H, Meyer HE, Nordsletten L, Furnes O, Baste V, Flugsrud GB. Risk factors for knee replacement due to primary osteoarthritis, a population-based, prospective cohort study of 315,495 individuals. BMC Muscoskel Disord. 2014;15:217.
4. Özövez GA, Alp A. Correlation of Femoral Cartilage Thickness and osteoporosis in patients with knee osteoarthritis. 2021;27(2): 96-102.
5. Akamatsu Y, Mitsugi N, Taki N, Takeuchi R, Saito T. Relationship between low bone mineral density and varus deformity in postmenopausal women with knee osteoarthritis. J Rheumatol. 2009;36(3):592-597.
6. Bellido M, Lugo L, Roman-Blas JA, Castañeda S, Caeiro JR, Dapia S, et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis. Arthritis Res Ther. 2010;12(4):152.
7. Choi ES, Shin HD, Sim JA, Na YG, Choi WJ, Shin DD, et al. Relationship of bone mineral density and knee osteoarthritis (Kellgren-Lawrence Grade): Fifth Korea National Health and Nutrition Examination Survey. Clin Orthop Surg. 2021;13(1):60-66.
8. Im GI, Kwon OJ, Kim CH. The relationship between osteoarthritis of the knee and bone mineral density of proximal femur: A cross-sectional study from a Korean population in women. Clin Orthop Surg. 2014;6(4):420-425.
9. Zhang Y, Hannan MT, Chaisson CE, McAlindon TE, Evans SR, Aliabadi P, et al. Bone mineral density and risk of incident and progressive radiographic knee osteoarthritis in women: the Framingham Study. J Rheumatol. 2000;27:1032-7.
10. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986;29:1039-49.
11. Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA. Age-related changes in bone marrow mesenchymal stromal cells: A potential impact on osteoporosis and osteoarthritis development. Cell Transplant. 2017;26(9):1520-9.
12. Messina C, Sconfienza LM, Bandirali M, Guglielmi G, Ulivieri FM. Adult dual-energy X-ray absorptiometry in clinical practice: How ı report it. Semin Musculoskelet Radiol. 2016;20(3):246-253.
13. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16:494-502.
14. Anas I, Musa TA, Kabiru I, Yisau AA, Kazaure IS, Abba SM, et al. Digital radiographic measurement of normal knee joint space in adults at Kano, Nigeria. Egypt J Radiol Nucl Med. 2013;44(2):253–8.
15. Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA. Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transplant. 2017;26(9):1520-9.
16. Geusens PP, van den Bergh JP. Osteoporosis and osteoarthritis: Shared mechanisms and epidemiology. Curr Opin Rheumatol. 2016;28(2):97-103.
17. Alkhatatba M, Abualadas J, Tabar MAA, Abueed M, Alghzawi AA, Abualadas R, et al. Is there a role for ordering a DEXA (Dual Energy X-Ray Absorptiometry) scan for patients with symptomatic advanced knee osteoarthritis?. Acta Inform Med. 2023;31(2):111-114.
18. Zamzam M, Alamri MS, Aldarsouni FG, Al Zaid H, Al Ofair AA. Impact of osteoporosis in postmenopausal women with primary knee osteoarthritis. Cureus. 2023;15(6):e40645.
19. Zhang Y, Hannan MT, Chaisson CE, McAlindon TE, Evans SR, Aliabadi P, et al. Bone mineral density and risk of incident and progressive radiographic knee osteoarthritis in women: the Framingham Study. J Rheumatol. 2000;27(4):1032-7.
20. Nevitt MC, Zhang Y, Javaid MK, Neogi T, Curtis JR, Niu J, et al. High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study. Ann Rheum Dis. 2010;69(1):163-8.
21. Sezer I, Illeez OG, Tuna SD, Balci N. The relationship between knee osteoarthritis and osteoporosis. Eurasian J Med. 2010;42(3):124-127.
22. Kim YH, Lee JS, Park JH. Association between bone mineral density and knee osteoarthritis in Koreans: the Fourth and Fifth Korea National Health and Nutrition Examination Surveys. Osteoarthritis Cartilage. 2018;26(11):1511-1517.
23. Lin L, Luo P, Yang M, Wang J, Hou W, Xu P. Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study. Front Endocrinol (Lausanne). 2022;13:1011246.
24. Xu J, Wang WZ, Fan X, Wang L, Zhang M. Correlation between osteoarthritis and osteoporosis in men. Sichuan Da Xue Xue Bao Yi Xue Ban. 2023;54(2):439-443.
Download attachments: 10.4328.ACAM.22085
Hatice Ağır. Is there a relationship between knee osteoarthritis and osteoporosis? Ann Clin Anal Med 2024;15(6):399-403
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Extracellular vesicles mirna-126: A potential therapeutic role in type i diabetic rat model
Shaimaa Saeed Ahmed Ahmed Mostafa 1, Maha Abdel Kader Hegazi 1, Doaa A. Abdelmonsif 2, Seham Z. Nassar 1, Samiha Mahmoud Ahmed Elsayed 1
1 Department of Physiology, 2 Department of Biochemistry, Faculty of Medicine, Alexandria University, Alexnadria, Egypt
DOI: 10.4328/ACAM.22113 Received: 2024-01-16 Accepted: 2024-03-05 Published Online: 2024-04-04 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):404-408
Corresponding Author: Shaimaa Saeed Ahmed Ahmed Mostafa, Department of Physiology, Faculty of Medicine, Alexandria University, 21561, Alexnadria, Egypt. E-mail: shimaa.ahmed@alexmed.edu.eg P: +20 114 995 69 32 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2772-5143
Other Authors ORCID ID: Maha Abdel Kader Hegazi, https://orcid.org/0000-0002- 8240-3852 . Doaa A. Abdelmonsif, https://orcid.org/0000-0002-6859-1156 . Seham Z. Nassar, https://orcid.org/0000-0002-8129-034X . Samiha Mahmoud Ahmed Elsayed, https://orcid.org/0000-0002-3793-1613
This study was approved by the Ethics Committee of Alexandria Faculty of Medicine (Date: 2021-6-27, IRB No: 00012098- FWA No: 00018699)
Aim: Type 1 diabetes mellitus (TIDM) is a metabolic disorder of an unknown etiology caused mainly by autoimmune or viral destruction of pancreatic β-cells. So far, the main therapy is insulin administration with no curable treatment. The aim of the current study was to evaluate the therapeutic effect of extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BM-MSCs) and transfected with miRNA126 in treatment of TIDM in rats. Moreover, to compare transfected EVs effect versus their parent BM-MSCs and untransfected EVs.
Material and Methods: The induction of diabetes in rats was done by intraperitoneal (i.p) injection of streptozotocin (STZ). Rats were divided randomly into groups that received either BM-MSCs or EVs or miRNA-126 mimic transfected EVs or miRNA-126 inhibitor transfected EVs.
Results: miRNA-126 mimic transfected EVs, BM-MSCs, EVs treated groups resulted in lowering of blood glucose level and increase in plasma insulin level significantly compared to diabetic untreated group with significantly higher miRNA126 level in pancreatic tissue of miRNA126 mimic-EVs treated group compared to diabetic group. Results were superior in miRNA-126 treated group compared to BM-MSCs treated.
Discussion: miRNA-126 transfected EVs were found to be superior to BM-MSCs in the treatment of STZ induced type-1 DM. MSCsderived EVs may represent a novel cell-free treatment strategy with a potential implication of miRNA-126.
Keywords: miRNA-126, Extracellular Vesicles, Bone Marrow Mesenchymal Stem Cells, Diabetes Mellitus
Introduction
Type 1 DM (TIDM) is considered as one of the most common metabolic disorders in childhood. Different treatment modalities were developed for the treatment of TIDM ,however due to patient inconvenience and reported their complications and patient inconvenience more studies is needed to eradicate the disease [1].
Bone marrow mesenchymal stem cells (BM-MSCs) are non-hematopoietic stem cells which can produce and secrete wide spectrum of cytokines, chemokines, and growth factors in a paracrine fashion that affect the action of nearby cells [2].
Extracellular vehicles (EVs) derived from MSCs is considered as one of the promising paracrine mechanisms of stem cells that could effectively mimic the beneficial effects of MSCs. EVs mainly contribute to the action of stem cells transferring proteins, lipids, and RNA species between cells. Many studies have assessed the potential therapeutic of MSCs derived EVs in TIDM due to their immunoregulatory actions [3].
MicroRNAs (miRNAs) are considered as a non‑coding small-molecule RNAs that control gene expression by attaching to complementary target sequences of the 3’ untranslated regions (3’‑UTR) of miRNAs [4]. miRNAs may have cross-talks with mRNAs in pancreatic tissues of TIDM [5].
MiRNA-126 is profusely found in endothelial cells in and performs an important role in regulating vascular integrity and angiogenesis regulation. Hence, several studies have investigated its potential therapeutic role in decreasing the consequences of diabetic vascular complications in various types of DM [6]. However, no study, up to now, have studied the potential paracrine role of miR-126 on pancreatic tissue regeneration and insulin production.
The current study aimed to assess the potential therapeutic role of EVs secreted from bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of TIDM as compared to BM-MSCs alone. Moreover, to study miR-126 as a potential molecular mechanism by which EVs communicate with pancreatic tissue. As far as we know, this is the first study to assess the use of BM-MSCs- derived EVs in the treatment of DM with the implication of miRNA 126.
Material and Methods
Laboratory animals
The present study included sixty adult male Wister albino rats (150-180 g, 7-8 weeks). Rats were housed under a standard condition as 14 to 10 h light-dark cycle at 25 ± 2 ℃ with free access to food and water, at the institutional Animal House of Physiology Department. Experiments were done in compliance with the approved guidelines set by the institutional Research
Ethics Committee, the National Institutes of Health guide for the care and use of laboratory animals.
Experimental design
Bone marrow isolation
Two male Wistar albino rats (25-35 g, 3 weeks) were sacrificed for bone marrow extraction. The femur and tibia were dissected, disinfected, and flushed with PBS. The proximal and distal ends of the tibiae and femurs were cut [7].
Preparation of bone marrow derived mesenchymal stem cells (BM-MSCs)
The cells obtained from the tibia and femur bones were layered on Ficoll-Paque
(Gibco-Invitrogen). The cells were collected, washed, and seeded in T flasks. The cells were characterized by morphology, adherence, and flowcytometry assessment using CD44, CD90 and
CD45 surface markers.
EVs isolation and characterization protocol
EVs were isolated from MSCs supernatant. After filtration, ultracentrifugation was done at 120,000 x g for 70 minutes at 4°C (Thermo Fisher Micro Ultracentrifuge MX 120+, Medical Research Institute- Alexandria University), pellets were discarded, re-suspended in PBS, and stored for -80ºC. Transmission Electron Microscope (TEM) with an accelerating voltage of 120 kV (JEM-1400 series 120kV Transmission Electron Microscope, USA) was used for EVs characterization.
miRNA-126 Analysis
The extraction of total RNA from BM-MSCs and their EVs was done under completely sterile and RNAse-free conditions in accordance with the manufacturer’s instructions of miRNeasy Mini Kit (Qiagen, Hilden, Germany). The evaluation of the concentration of the extracted RNA samples was done using NanoDrop 1000 Spectrophotometer (Thermo Scientific, USA). Quantitative RT-PCR analysis for miRNA-126 was next done twice over using TaqMan microRNA assays and TaqMan Universal PCR Master Mix II (Applied Biosystems, USA) [8]. StepOne real-time PCR system (Applied Biosystems, USA) was used for amplification. StepOneTM Software v2.3 was used for data analysis [9].
BM-MSCs transfection protocol
One day before transfection, BM-MSCs were cultured 2–8 x 104 cells per well in a 24-well plate. On the day of transfection, 37.5 ng miRNA-inhibitor/mimic was mixed with 2 μL of lipofectamine 2000 transfection reagent (Invitrogen Cat No. 11668-030). After incubation, the complexes were added to the cells and re-incubated for 72 h. qRT-PCR analysis was done as previously described.
The induction of TIDM was done by single intraperitoneal (I.P) injection of streptozotocin (STZ) in a dose of 50 mg/Kg [7]. Healthy untreated rats received an equal volume of phosphate buffer saline (PBS) intraperitoneal and served as controls (group I, control group)(n=10). Diabetic rats were randomly divided into five groups each containing 10 rats. Group II: untreated diabetic group, Group III: Diabetic rats treated with single I.P. injection of BM-MSCs in a dose of 106 cells per rat [10].
Group IV: Diabetic rats received a single I.P. injection of
BM-MSCs derived extracellular vesicles at a dose of 1000 μg/ml in a frozen pellet,
Group V: Diabetic rats received single I.P. injection of BM-MSCs derived extracellular vesicles expressing miR-126 mimic with a dose of 1000 μg/ml in a frozen pellet [10].
Group VI: Diabetic rats received single I.P. injection of BM-MSCs derived extracellular vesicles expressing miR-126 inhibitor with a dose of 1000 μg/ml in a frozen pellet.
Animal scarification was done by cervical dislocation at the end of the study. Blood samples were taken from the aorta in EDTA tubes (10 μl of 0.1 M EDTA for 200-400 μl of blood); plasma was separated for the assessment of insulin level and stored at – 80 °C.
Biochemical analysis:
Plasma insulin level
Plasma insulin level was determined by ELISA according to the manufacturer instructions (Insulin ELISA kit Thermo Fisher, USA). Once rats’ plasma insulin level became below 9 µIU/ml, they were considered diabetic.
Blood glucose level (Fasting/ Random)
Blood glucose level was measured weekly using samples from venous blood glucocheck strips.
Histopathological examination of the pancreas
After sacrifice, the pancreatic tissues were harvested, fixed, and processed into paraffin blocks. Four to five microns sections were cut using a manual rotatory microtome. Hematoxylin and eosin (H&E) stained section were then assessed for histopathologic changes [11].
Statistical Analysis
All statistical analysis was done by SPSS software version 20.0. (Armonk, NY: IBM Corp). Mean and standard deviation were used to summarize the data. Analysis of variance (ANOVA) test was done for comparison between two groups with post hoc test (Tukey’s) for pairwise comparison. Post Hoc Test (adjusted Bonferroni) for pairwise comparisons was done to compare between two durations. Statistical significance was considered at p values ≤0.05.
Ethical Approval
This study was approved by the Ethics Committee of Alexandria Faculty of Medicine (Date: 2021-6-27, IRB No: 00012098- FWA No: 00018699).
Results
Characterization of Bone marrow mesenchymal stem cells (BM-MSCs)
MSCs were characterized by their fibroblast spindle-shape using inverted contrast phase microscope (Olympus CKX41SF, Japan) (Fig. 1 A-D). Flowcytometric analysis of cultured BM-MSCs showed the positive expression of the mesenchymal surface markers CD44 and CD90 as well as negative expression of CD45 (Fig. 1E-F)
Characterization of Extracellular vesicles
TEM was used to visualize the isolated EVs, showing spherical structures with lipid bilayer of different sizes ranging from 50.92 to 67.03 nm. Showing that most of extracellular vesicles were exosomes (Fig. 1G).
Quantification of miRNA-126 level in BM-MSCs and their EVs
miRNA-126 expression in BM-MSCs and their derived EVs as compared to un-transfected BM-MSCs and BM-MSCs transfected with miRNA-126 inhibitor (in Vitro)
Cells transfected with miRNA-126 mimic showed 17-fold higher miRNA-126 expression than BM-MSCs. Additionally, miRNA-126 dropped by 4 folds following transfection with miRNA-126 inhibitor (Fig. 2A).
Evaluation of Therapeutic Effect of BM-MSCs and Their EVs
Plasma insulin level
There was a significant increase in the level of plasma insulin in BM-MSCs, EVS and
EVs – miRNA-126 mimic treated groups as compared to untreated diabetic group and EVs-miRNA-126 inhibitor group (P ≤ 0.001). (Fig. 2B).
Blood glucose level
There was significant decrease in blood glucose levels in the BM-MSCs, EVs and miRNA-126 mimic treated groups compared to untreated diabetic, and miR-126 inhibitor treated groups (P ≤ 0.001). (Fig. 2C).
Histopathological Assessment
Pancreatic tissues of rats treated with miRNA-126 mimic, BM-MSCs and EVs stained with hematoxylin and eosin (H&E) showed improvement compared to untreated diabetic and miRNA-126 inhibitor. Diabetic group showing degenerative changes seen as mononuclear infiltration (red arrow) and diffuse cytoplasmic vacuolation of islets cells (yellow arrow) (x400) (Fig 3B)
BM-MSCs treated group showed improvement in endocrine cell histology where vacuolation is only focally seen (yellow arrow) with residual mono nuclear cells are seen (red arrow) (x400) (Fig 3C). EVs treated group showed improvement in endocrine cell histology where vacuolation is only focally seen (yellow arrow) (Fig 3D). EVs with mimic showed an increased number of islet cells.
Discussion
TIDM treatment is considered a challenge mainly due to the early onset of the disease and its unknown exact etiology. Many different treatment modalities were used for the treatment of TIDM [1]. BM-MSCs have been recognized as a hopeful agent for the treatment of TIDM because of their ability to differentiate into islets-like cells. MSCs regenerative ability can be attained through certain paracrine factors released from them, which include extracellular vesicles (EVs). EVs derived from MSCs have immunomodulatory effects through induction of T-regulatory cells and suppressing autoreactive immune cells [12]. MiRNAs may have shown an important role in many aspects of diabetes as they modulate the expression of many genes associated with the pathophysiological process. In the current work, EVs were used as cargo for miRNA-126 mimic and inhibitor to prevent their digestion by different nucleases and avoid their modification [13].
In the current work, TIDM was induced by STZ injection. Many previous studies have used STZ for induction of TIDM because of its cytotoxic effect in β-cells through inflammation activation, production of excessive amount of reactive oxygen species, and cell apoptosis [14, 15].
In the present study, TIDM was confirmed by high blood glucose >300 mg/dl and decreased plasma insulin level and histopathological pancreatic changes. These results were consistent with previous studies that reported the confirmation of TIDM was done by fasting blood glucose level >300 mg/dl and histopathological pancreatic changes [15-16-17].
The results of the present work revealed that cultured BM- MSCs were characterized by their morphology and surface markers (Fig. 1 A-F) which was consistent with a previous study by Kobolak et al. [18] EVs were also characterized by their morphology (Fig 1G) which agreed with previous study that denotes the size of EVs derived from BM-MSCs were ranged 100 nm in diameter with typical spherical shape [7].
The study results documented that BM-MSCs treated group showed significant lowering in blood glucose levels and an elevation in plasma insulin levels, as well as improvement in histopathological pancreatic tissue findings. This may be due to their immunomodulatory effects, their homing capabilities [4, 12]. These findings are in agreement with previous studies that revealed the decline in blood glucose level and elevation in plasma insulin level after injection BM-MSCs in TIDM rats [7, 19].
Regarding the other group that received EVs, they showed decrease in blood glucose level, increase in plasma insulin level and improvement in histological findings in pancreatic tissue. However, EVs results were superior to those of BM-MSCs results which may be due to the immunomodulatory ability of EVs through inhibition of reactive T cells and reduction of inflammatory cytokines levels [20].
Rani et al. [21] stated that exosomes can be used as a novel substitute to whole cell therapies. Exosomes may provide a better safety profile when compared to their parent cells. The previously mentioned study could provide explanation for the mechanism of improvement that occurred in our present work in EVs treated group [21].
The findings of the present study demonstrated that miRNA-126 mimic treatment has improved fasting blood glucose, plasma insulin levels and pancreatic tissue histopathology, which denoted possible therapeutic effects. Other previous study had reported the anti-an inflammatory role of miRNA-126 as denoted by intravitreal injection of miRNA-126 mimic has improved diabetic retinopathy by enhancing retinal tissue histopathology and inflammation by inhibiting specific inflammatory pathways [22].
Another previous study suggested that the increase in expression of miRNA-126 may paly anti-inflammatory role, antiapoptotic role in cardiomyopathy thus this could explain the mechanism of miRNA-126 in reversing cytotoxic effects of STZ on islets cells [23].
Zhang and his colleagues [24] have revealed the angiogenic role of miRNA-126 as they reported that diabetic wounds treated with negative pressure wound therapy (NPWT) revealed large increases in miR-126, which controls VEGF-induced angiogenesis [24]. Thus these previously mentioned findings may be provide a possible explanation to the results in our present study in terms of improvement of β-islet cell mass after treatment of miRNA-126 through angiogenesis.
Conclusion
The current study highlights miRNA-126 mimic- transfected EVs as a promising, safe, cell-free treatment strategy for T1DM. In addition, molecular action of EVs could be mediated by miRNA-126 in T1DM rat model. However, the exact molecular pathways and mechanisms of miRNA-126 should be further investigated.
Acknowledgment
Authors would like to acknowledge the Center of Excellence for Research in Regenerative Medicine and its Applications (CERRMA) for providing the adequate facilities and environment for the processing and characterization of the BM-MSCs under completely sterile conditions.
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. Kahanovitz L, Sluss PM, Russell SJ. Type 1 Diabetes – A clinical perspective. Point Care. 2017;16(1):37-40.
2. Moravej A, Karimi MH, Geramizadeh B, Azarpira N, Zarnani AH, Yaghobi R, et al. Mesenchymal stem cells upregulate the expression of PD-L1 But Not VDR in dendritic cells. Immunol Invest. 2017;46(1):80-96.
3. Garcia-Contreras M, Brooks RW, Boccuzzi L, Robbins PD, Ricordi C. Exosomes as biomarkers and therapeutic tools for type 1 diabetes mellitus. Eur Rev Med Pharmacol Sci. 2017;21(12):2940-56.
4. Negi S, Rutman AK, Paraskevas S. Extracellular Vesicles in Type 1 Diabetes: Messengers and regulators. Curr Diab Rep. 2019;19(9):69.
5. Hashimoto N, Tanaka T. Role of miRNAs in the pathogenesis and susceptibility of diabetes mellitus. J Hum Genet. 2017;62(2):141-50.
6. Pishavar E, Behravan J. miR-126 as a therapeutic agent for diabetes mellitus. Curr Pharm Des. 2017;23(22):3309-14.
7. Sabry D, Marzouk S, Zakaria R, Ibrahim HA, Samir M. Correction to: The effect of exosomes derived from mesenchymal stem cells in the treatment of induced type 1 diabetes mellitus in rats. Biotechnol Lett. 2020;42(12):2761-2.
8. Xiao GY, Cheng CC, Chiang YS, Cheng WT, Liu IH, Wu SC. Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Sci Rep. 2016;6:23120.
9. Lin Q, Di YP. Determination and quantification of bacterial virulent gene expression using quantitative real-time PCR. Methods Mol Biol. 2020;2102:177-93.
10. Braun RK, Chetty C, Balasubramaniam V, Centanni R, Haraldsdottir K, Hematti P, et al. Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia. Biochem Biophys Res Commun. 2018;503(4):2653-8.
11. Alturkistani HA, Tashkandi FM, Mohammedsaleh ZM. Histological stains: A literature review and case study. Glob J Health Sci. 2015;8(3):72-9.
12. Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: Therapeutic outlook for inflammatory and degenerative diseases. Front Immunol. 2020;11:591065.
13. Martellucci S, Orefice NS, Angelucci A, Luce A, Caraglia M, Zappavigna S. Extracellular vesicles: New endogenous shuttles for miRNAs in cancer diagnosis and therapy? Int J Mol Sci. 2020;21(18):6486.
14. Chandirasegaran G, Elanchezhiyan C, Ghosh K, Sethupathy S. Berberine chloride ameliorates oxidative stress, inflammation and apoptosis in the pancreas of Streptozotocin induced diabetic rats. Biomed Pharmacother. 2017;95:175-85.
15. Mostafa-Hedeab G, Hassan ME, Sabry D, Ali RI. Anti-diabetic therapeutic efficacy of mesenchymal stem cells-derived exosomes. Int J Pharm. 2020;16(6):437-46.
16. Nurdiana S, Goh YM, Ahmad H, Dom SM, Syimal’ain Azmi N, Noor Mohamad Zin NS, et al. Changes in pancreatic histology, insulin secretion and oxidative status in diabetic rats following treatment with Ficus deltoidea and vitexin. BMC Complement Altern Med. 2017;17(1):290.
17. Yousef HN, Sakr SM, Sabry SA. Mesenchymal stem cells ameliorate hyperglycemia in type I diabetic developing male rats. Stem Cells Int. 2022;2022:7556278.
18. Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A. Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods. 2016;99:62-8.
19. Hussien NI, Ebrahim N, Mohammed OM, Sabry D. Combination of obestatin and bone marrow mesenchymal stem cells prevents aggravation of endocrine pancreatic damage in type II diabetic rats. Int J Stem Cells. 2017;10(2):129-43.
20. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64(4):831-40.
21. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: Toward cell-free therapeutic applications. Mol Ther. 2015;23(5):812-23.
22. Zheng Y, Liu Y, Wang L, Xu H, Lu Z, Xuan Y, et al. MicroRNA‑126 suppresses the proliferation and migration of endothelial cells in experimental diabetic retinopathy by targeting polo‑like kinase 4. Int J Mol Med. 2021;47(1):151-60.
23. Suresh Babu S, Thandavarayan RA, Joladarashi D, Jeyabal P, Krishnamurthy S, Bhimaraj A, et al. MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes. Sci Rep. 2016;6:36207.
24. Zhang D, Li Z, Wang Z, Zeng F, Xiao W, Yu A. MicroRNA-126: A promising biomarker for angiogenesis of diabetic wounds treated with negative pressure wound therapy. Diabetes Metab Syndr Obes. 2019;12:1685-96.
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Shaimaa Saeed Ahmed Ahmed Mostafa, Maha Abdel Kader Hegazi, Doaa A. Abdelmonsif, Seham Z. Nassar, Samiha Mahmoud Ahmed Elsayed. Extracellular vesicles mirna-126: A potential therapeutic role in type i diabetic rat model. Ann Clin Anal Med 2024;15(6):404-408
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Predictive factors of lymph node metastasis in patients with 2014 figo stage Ib1-IIa2 cervical squamous cell cancer: A multicentric study
Okan Aytekin 1, Necim Yalcin 2, Hande Esra Koca Yildirim 3, Mehmet Unsal 1, Okan Oktar 3, Fatih Celik 1, Abdurrahman Alp Tokalioglu 1, Mustafa Gokkaya 2, Dilek Yuksel 3, Caner Cakir 3, Cigdem Kilic 3, Ilker Selcuk 1, Gunsu Kimyon Comert 1, Tayfun Toptas 2, Vakkas Korkmaz 3, Isin Ureyen 2, Alper Karalok 4, Derman Basaran 5, Sevgi Koc 3, Tolga Tasci 6, Taner Turan 1
1 Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, 2 Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Antalya Training and Research Hospital, Antalya, 3 Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Etlik Zubeyde Hanim Women’s Health Training and Research Hospital, Ankara, 4 Department of Gynecologic Oncology, Ulus Lıv Hospital, Istanbul, 5 Department of Gynecologic Oncology, Faculty of Medicine, Hacettepe University, Ankara, 6 Department of Gynecologic Oncology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey
DOI: 10.4328/ACAM.22128 Received: 2024-01-29 Accepted: 2024-03-19 Published Online: 2024-04-26 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):409-413
Corresponding Author: Okan Aytekin, Department of Gynecologic Oncology, Faculty of Medicine, Ankara Bilkent City Hospital, University of Health Sciences, 06800, Ankara, Turkey. E-mail: okanaytekin13@hotmail.com P: +90 536 662 49 59 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6430-4607
Other Authors ORCID ID: Necim Yalcin, https://orcid.org/0000-0001-5980-3244 . Hande Esra Koca Yildirim, https://orcid.org/0000-0002-3715-9424 . Mehmet Unsal, https://orcid.org/0000-0002-9920-6804 . Okan Oktar, https://orcid.org/0000-0002-9696-7886 . Fatih Celik, https://orcid.org/0000-0002-9523-180X . Abdurrahman Alp Tokalioglu, https://orcid.org/0000-0002-1776-2744 . Mustafa Gokkaya, https://orcid.org/0000-0002-0477-157X .Dilek Yuksel, https://orcid.org/0000-0002-2366-8412 . Caner Cakir, https://orcid.org/0000-0003-2559-9104 . Cigdem Kilic, https://orcid.org/0000-0002-4433-8068 . Ilker Selcuk, https://orcid.org/0000-0003-0499-5722 . Gunsu Kimyon Comert, https://orcid.org/0000-0003-0178-4196 . Tayfun Toptas, https://orcid.org/0000-0002-6706-6915 . Vakkas Korkmaz, https://orcid.org/0000-0001-8895-6864 . Isin Ureyen, https://orcid.org/0000-0002-3491-4682 . Alper Karalok, https://orcid.org/0000-0002-0059-8773 . Derman Basaran, https://orcid.org/0000-0002-2689-1417 . Sevgi Koc, https://orcid.org/0000-0002-1703-0690 . Tolga Tasci, https://orcid.org/0000-0001-8645-4385 . Taner Turan, https://orcid.org/0000-0001-8120-1143
This study was approved by the Ethics Committee of Ankara City Hospital (Date: 2022-11-09, No: E2-22-2777)
Aim: The objective of this study is to identify the risk variables associated with lymph node metastasis (LNM) in individuals diagnosed with cervical squamous cell carcinoma (SCC).
Material and Methods: Cervical cancer patients who underwent type II/III radical hysterectomy and pelvic lymphadenectomy +/- para-aortic lymphadenectomy were analyzed.
Results: In total, 422 SCC patients were included in the cohort. Three hundred-twenty-three (76.5%) patients were stage IB1, 59 (14%) were stage IB2, 33 (7.8%) were stage IIA1, and 7 (1.7%) were stage IIA2. Eighty-seven (20.6%) patients had LNM only in the pelvic region, 2 (0.5%) patients in the paraaortic region, and 8 (1.9%) patients in both regions. In the multivariate logistic analysis, parametrial invasion (hazard ratio [HR]: 2.182, 95% confidence interval [CI]: 1.090–4.366, p=0.027), lymphovascular space invasion (LVSI) (HR: 6.300, 95% CI: 2.968–13.370, p<0.001) and deep stromal invasion (HR: 2.122, 95% CI: 1.088–4.139, p=0.027) were identified as significant risk factors for LNM.
Discussion: In summary, age, FIGO stage, tumor size, vaginal invasion, surgical border involvement, and uterine involvement were not identified as independent risk factors for LNM. However, parametrial invasion, LVSI, and deep stromal invasion are independent risk factors for LNM in stage IB1-IIA2 cervical SCC patients.
Keywords: Cervical Cancer, Lymph Node Metastasis, Parametrial Invasion, Deep Stromal Invasion, Lymphovascular Space Invasion
Introduction
Cervical cancer is a prominent malignancy affecting women globally, occupying the fourth position in terms of prevalence [1]. Squamous cell carcinoma (SCC) is the most prevalent histologic subtype of cervical cancer. Radical hysterectomy with pelvic lymphadenectomy is the standard approach for early-stage disease, while chemoradiotherapy is the standard treatment for advanced stages of the disease [2]. The addition of pelvic lymphadenectomy in the surgical management of early-stage cervical cancer is widely accepted. However, the appropriateness of para-aortic lymphadenectomy remains a subject of debate due to the associated risk of severe complications and the requirement for a high degree of surgical proficiency [3, 4].
Cervical cancer can spread directly to the vagina, parametrium, uterus, and nearby organs, such as the rectum and bladder. Furthermore, it disseminates through the lymphatic vessels to the nearby lymph nodes, such as the obturator, external iliac, and internal iliac nodes, and subsequently to the common iliac and paraaortic nodes. A late manifestation of the disease is hematogenous metastasis to the lungs, liver, and skeleton [5].
The presence of lymph node metastasis (LNM) is an important factor of prognosis in patients with cervical cancer [6]. The occurrence of pelvic LNM in individuals diagnosed with early-stage cervical cancer (stages IA1-IB1) has been documented to be approximately 15-20% [7, 8]. These patients have a poorer prognosis, and their 5-year survival rates are lower than those of patients without LNM [9, 10]. LNM is associated with the histological subtype, tumor size, parametrial invasion, deep stromal invasion, and lymphovascular space invasion (LVSI) [10, 11]. LNM was not included in the International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system until 2018. In the latest classification, evaluation of lymph nodes by imaging and/or pathology is incorporated as stage IIIC disease. Stage IIIC1 is defined if LNM is in the pelvic lymph nodes, and stage IIIC2 if LNM is in the para-aortic lymph nodes [12].
In the present study, patients with stages IB1, IB2, IIA1 and IIA2 SCC had radical hysterectomy and pelvic ± paraaortic lymphadenectomy. Our objective was to identify the prognostic markers associated with lymph node metastasis in patients with cervical SCC.
Material and Methods
The study was designed retrospectively. Cervical cancer patients who underwent type II/III radical hysterectomy and pelvic lymphadenectomy +/- para-aortic lymphadenectomy were analyzed at 6 gynecologic oncology centers between 1993 and 2022. The electronic database system, medical files, and pathology reports were utilized to obtain patient information. Patients who were not treated with a radical hysterectomy, those with microinvasive cancer, a non-squamous cell component in their tumors, synchronous primary tumors, and those receiving neo-adjuvant chemotherapy were excluded.
The following clinical data were collected: age, FIGO stage, the pathologic data (parametrial invasion, vaginal invasion, surgical border involvement, depth of stromal invasion, LVSI, uterine invasion, size of the tumor, lymph node status, adnexal metastasis). The tumor size was determined by the greatest tumor diameters. The clinical stage was evaluated in accordance with the FIGO 2014 criteria. Deep stromal invasion was defined as ≥½ stromal invasion. In hematoxylin and eosin stained pathologic sections, LVSI was described as tumor cells or cell clusters adhering to vascular walls containing both tumor and surrounding healthy tissue. The spread of the disease to the endometrium and/or myometrium above the level of the internal ostium has been defined as uterine invasion. The criterion for surgical border involvement was established as a measurement of less than 0.5 cm between the tumor and the termination point of the specimen. In contrast, vaginal metastasis was defined as the detection of the tumor in any location within the vagina. The decision to include a bilateral salpingo-oophorectomy in the surgical procedure was based on factors such as the patient’s age, the state of the ovaries, and the professional judgment of the surgeon. Depending on the presence of suspicious lymph nodes in the paraaortic region and the preference of the senior surgeon, paraaortic lymphadenectomy was added to the surgical procedure and was performed up to the level of the inferior mesenteric artery or left renal vein. All surgical procedures were performed by gynecological oncologists.
The effects of categorical variables on LNM were evaluated using Fisher’s exact test or Pearson’s Chi-square test, as applicable, to see whether they were statistically significant. With factors that were statistically significant in univariate analysis, a model for multivariate analysis was developed. Backward stepwise multivariate Cox proportional hazard regression analysis was utilized to identify the effects of LNM-influencing variables. A p-value less than 0.05 was determined to be statistically significant for the obtained results. Statistical Package for the Social Sciences (SPSS) for Windows version 22.0 was used to conduct statistical analyses.
Ethical Approval
This study was approved by the Ethics Committee of Ankara City Hospital (Date: 2022-11-09, No: E2-22-2777).
Results
In total, 422 SCC patients were included in the cohort. The size of the median tumor was 30 mm (range, 6-80) and the mean age of the patients was 52±10.2 years (range, 26-80). Three hundred twenty-three (76.5%) patients were stage IB1, 59 (14%) were stage IB2, 33 (7.8%) were stage IIA1, and 7 (1.7%) were stage IIA2. All patients underwent pelvic lymphadenectomy, while 389 patients (92.2%) underwent paraaortic lymphadenectomy. The median number of lymph nodes excised was 44. Ninety-seven (23%) patients had metastatic lymph nodes. The mean number of metastatic lymph nodes was 3±4.1 (range, 1-31). Eighty-seven (20.6%) patients had LNM only in the pelvic region, 2 (0.5%) patients in the paraaortic region, and 8 (1.9%) patients in both regions. Bilateral salpingo-oophorectomy was performed in 339 (80.3%) patients. There were 64 (15.2%) cases with positive parametrial invasion, 24 (5.7%) with surgical border involvement, 70 (16.6%) with vaginal invasion, 57 (13.5%) uterine invasion, 241 (57.1%) with LVSI, and 265 (62.8%) with deep stromal invasion. The clinical characteristics and surgical pathological outcomes of the patients were detailed in Table 1.
In the univariate analysis, parametrial invasion, surgical border involvement, uterine invasion, deep stromal invasion, and positive LVSI were found to be associated with LNM (Table 2). However, age, tumor size, FIGO stage, and vaginal involvement were not associated with LNM. In the multivariate logistic analysis, parametrial invasion (hazard ratio [HR]: 2.182, 95% confidence interval [CI]: 1.090–4.366, p=0.027), LVSI (HR: 6.300, 95% CI: 2.968–13.370, p<0.001) and deep stromal invasion (HR: 2.122, 95% CI: 1.088–4.139, p=0.027) were identified as significant risk factors for LNM (Table 2).
Discussion
This investigation analyzes the clinical and pathological characteristics of 422 patients diagnosed with stage IB1-IIA2 cervical SCC who underwent radical hysterectomy and lymphadenectomy. Additionally, the study investigates the relationship between LNM and these parameters. Deep stromal invasion, LVSI, and parametrial invasion were independent factors for LNM. Deep stromal invasion, LVSI, and parametrial invasion increased the incidence of LNM by more than twofold, sixfold, and twofold, respectively.
As predictors of LNM in cervical cancer, the following have been identified: The advanced stage [8, 13, 14], histology [8], larger tumor size [8, 13-17], LVSI [8, 13-18], deep stromal invasion [13-16, 18], parametrial invasion [13, 15, 18], older age [13, 17] and high level serum squamous cell carcinoma antigens (SCC-Ag) [13, 16]. In contrast, our study found no association between age, tumor size or FIGO stage and LNM.
The present study examined the prevalence of lymph node metastasis (LNM) in patients diagnosed with stage IB1, IB2, IIA1, and IIA2 cervical squamous cell carcinoma (SCC). The findings revealed LNM rates of 22.3%, 23.7%, 30.3%, and 14.3% for each stage. In the cervical SCC study presented by Yang et al., LNM metastases rates in stage IB1-2 and IIA1-2 were similar to our study [13]. In contrast to previous studies [8, 13, 14], stage was not found to be associated with LNM in our study. This may be explained by the fact that the stage IA2 group, where LNM is rarely seen, was not included in our study.
Tumors larger than 2 cm were associated with an increased risk of LNM in a study by Togami et al. of patients with stages IA2-IIB cervical cancer [19]. Yang et al. found that a tumor diameter greater than 2 cm was statistically significant in the univariate analysis for LNM but not in the multivariate analysis [13]. In our study, however, tumor diameter was not found to be significant.
In accordance with our study, Wang et al. reported that deep stromal invasion and LVSI were significantly associated with LNM in a multivariate analysis of cervical SCC [16]. Similarly, Zhou et al. demonstrated in a multivariate study of stages IA2, IB1, and IIA1 epithelial cervical carcinoma that deep stromal invasion and LVSI had a significant association with LNM [14].
In a multivariate analysis of cervical cancer, Nanthamongkolkul et al. and Togami et al. also reported that parametrial invasion was significantly associated with LNM [15, 19]. According to the study by Benedetti-Panici et al.[20], the parametrium is the initial location of extracervical spread, which could explain these results.
Limitation
The main limitation of this study is its retrospective design. In addition, the locations of lymph node involvement (external iliac, internal iliac, obturator, common iliac, and paraaortic nodes) are not specified. However, the study’s strengths are its multicentric design and large patient population. Secondly, patients with only squamous cell types were included, whereas microinvasive patients were excluded. Thirdly, all surgical procedures were conducted by gynecological oncology specialists, and pathologic assessments were performed by expert gyneco-pathologists.
Conclusion
In summary, age, FIGO stage, tumor size, vaginal invasion, surgical border involvement, and uterine involvement were not identified as independent risk factors for LNM. However, parametrial invasion, LVSI, and deep stromal invasion are independent risk factors for LNM in stage IB1-IIA2 cervical SCC patients. Further clinical research can help to strengthen these results.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. The Lancet Global Health. 2020;8(2):e191-e203.
2. Cibula D, Pötter R, Planchamp F, Avall-Lundqvist E, Fischerova D, Haie-Meder C, et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Virchows Archiv. 2018;472(6):919-36.
3. Rob L, Pluta M, Strnad P, Hrehorcak M, Chmel R, Skapa P, et al. A less radical treatment option to the fertility-sparing radical trachelectomy in patients with stage I cervical cancer. Gynecologic oncology. 2008;111(2):S116-S20.
4. Koh W, Abu-Rustum N, Bean S. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cervical Cancer Version 1. 2018.
5. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri: 2021 update. International Journal of Gynecology & Obstetrics. 2021;155:28-44.
6. Huang B-x, Fang F. Progress in the study of lymph node metastasis in early-stage cervical cancer. Current medical science. 2018;38(4):567-74.
7. Salvo G, Ramirez PT, Levenback CF, Munsell MF, Euscher ED, Soliman PT, et al. Sensitivity and negative predictive value for sentinel lymph node biopsy in women with early-stage cervical cancer. Gynecologic oncology. 2017;145(1):96-101.
8. Ferrandina G, Pedone Anchora L, Gallotta V, Fagotti A, Vizza E, Chiantera V, et al. Can we define the risk of lymph node metastasis in early-stage cervical cancer patients? A large-scale, retrospective study. Annals of Surgical Oncology. 2017;24(8):2311-8.
9. Li A, Wang L, Jiang Q, Wu W, Huang B, Zhu H. Risk stratification based on metastatic pelvic lymph node status in stage IIIC1p cervical cancer. Cancer Management and Research. 2020;12:6431.
10. Sakuragi N. Up-to-date management of lymph node metastasis and the role of tailored lymphadenectomy in cervical cancer. International journal of clinical oncology. 2007;12(3):165-75.
11. Sakuragi N, Satoh C, Takeda N, Hareyama H, Takeda M, Yamamoto R, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer: Interdisciplinary International Journal of the American Cancer Society. 1999;85(7):1547-54.
12. Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri. International Journal of Gynecology & Obstetrics. 2019;145(1):129-35.
13. Yang S, Zhao J, Zhao H, Hu Y, Zhu H. Development of a nomogram for predicting pelvic lymph node metastasis in cervical squamous cell carcinoma. International Journal of Gynecology & Obstetrics. 2022.
14. Zhou J, Ran J, He Z-Y, Quan S, Chen Q-H, Wu S-G, et al. Tailoring pelvic lymphadenectomy for patients with stage IA2, IB1, and IIA1 uterine cervical cancer. Journal of Cancer. 2015;6(4):377.
15. Nanthamongkolkul K, Hanprasertpong J. Predictive factors of pelvic lymph node metastasis in early-stage cervical cancer. Oncology Research and Treatment. 2018;41(4):194-8.
16. Wang Y, Yao T, Yu J, Li J, Chen Q, Lin Z. Can pelvic lymphadenectomy be omitted in patients with stage IA2, IB1, and IIA1 squamous cell cervical cancer? SpringerPlus. 2016;5(1):1-7.
17. Aziz MF, Andrijono A, Nuranna L, Purbadi S, Mangunkusumo RT, Siregar B, et al. Clinical-pathologic factors, as predictor of lymph nodes metastasis in cervical cancer stage IB and IIA. Medical Journal of Indonesia. 2004;13(2):113-8.
18. Turan T, Yüksel N, Kıyka Ş, Özer S, Tulunay G, Boran N, et al. Erken evre serviks kanserinde lenf nodu tutulumunu belirleyen faktörler [Factors determining lymph node involvement in early stage cervical cancer]. Türk Jinekolojik Onkoloji Dergisi. 2007;10(1):9-15.
19. Togami S, Kamio M, Yanazume S, Yoshinaga M, Douchi T. Can pelvic lymphadenectomy be omitted in stage IA2 to IIB uterine cervical cancer? International Journal of Gynecologic Cancer. 2014;24(6).
20. Benedetti‐Panici P, Maneschi F, D’Andrea G, Cutillo G, Rabitti C, Congiu M, et al. Early cervical carcinoma: The natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer. 2000;88(10):2267-74.
Download attachments: 10.4328.ACAM.22128
Okan Aytekin, Necim Yalcin, Hande Esra Koca Yildirim, Mehmet Unsal, Okan Oktar, Fatih Celik, Abdurrahman Alp Tokalioglu, Mustafa Gokkaya, Dilek Yuksel, Caner Cakir, Cigdem Kilic, Ilker Selcuk, Gunsu Kimyon Comert, Tayfun Toptas, Vakkas Korkmaz, Isin Ureyen, Alper Karalok, Derman Basaran, Sevgi Koc, Tolga Tasci, Taner Turan. Predictive factors of lymph node metastasis in patients with 2014 figo stage ib1-iia2 cervical squamous cell cancer: A multicentric study. Ann Clin Anal Med 2024;15(6):409-413
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Factors ınfluencing mortality after cardiopulmonary resuscitation; never give up!
Elvan Tekir Yılmaz 1, Bilge Olgun Keleş 1, İskender Aksoy 2
1 Department of Anesthesiology and Reanimation, 2 Department of Emergency Medicine, Faculty of Medicine, Giresun University, Giresun, Turkey
DOI: 10.4328/ACAM.22134 Received: 2024-02-01 Accepted: 2024-03-19 Published Online: 2024-04-03 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):414-419
Corresponding Author: Elvan Tekir Yilmaz, Department of Anesthesiology and Reanimation, Faculty of Medicine, Giresun University, Giresun, Turkey. E-mail: elvanty28@hotmail.com P: +90 505 646 64 85 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8631-2520
Other Authors ORCID ID: Bilge Olgun Keleş, https://orcid.org/0000-0002-8912-6317 . İskender Aksoy, https://orcid.org/0000-0002-4426-3342
This study was approved by the Ethics Committee of Giresun University Training Research Hospital (Date: 2023-12-04, No: 26)
Aim: The study aims to evaluate the prognostic factors affecting mortality and neurological recovery in patients with restored circulation in in-hospital cardiac arrest (IHCA).
Material and Methods: For this retrospective study, patients who survived after cardiac arrest and followed up in the intensive care unit of our hospital between 2021 and 2023 were investigated. Sixty-one patients with in-hospital cardiac arrest were included in the study. Laboratory data and epicrises of the patients were analysed. Demographic characteristics, cardiopulmonary resuscitation (CPR) duration, mechanical ventilation (MV) duration, the intensive care unit length of stay, mortality, cerebral performance category (CPC) scores, tracheotomy and percutaneous endoscopic gastrostomy (PEG) status, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow coma scale (GCS) were recorded. Patients who survived were classified as GL and those who died were classified as GM.
Results: In the current study, 22 patients were discharged from the intensive care unit. Potassium and N-terminal pro-brain natriuretic peptides were found to be predictors of mortality (p=0.006, p=.0.025). Mechanical ventilation duration, MCV, gamma glutamyl transpeptidase (GGT), CPR duration, tracheotomy and PEG status were positively correlated with CPC score (p=0.011, p=0.017, p=0.013, p=0.007, p=0.007, p=0.000, p=0.000). In GM, lactate, urea, creatinine, NT-pro-BNP and potassium values were statistically significantly higher (p=0.022, p=0.016, p=0.003, p<0.001, p=0.008, respectively).
Discussion: NT-proBNP and potassium were found to be predictors of mortality in patients with return of spontaneous circulation after IHCA. In addition, a positive correlation was found between CPR duration and CPC score. We suggested that these parameters could be included in prognostic scoring systems.
Keywords: Cardiac Arrest, Cardio-Pulmonary Resuscitation, Mortality
Introduction
The follow-up and management of patients after cardiac arrest is one of the most challenging situations faced by physicians and paramedics. In particular, there is controversy about which of these patients have a good prognosis. Whether or not patients should be accepted as Do- Not- Resuscitate (DNR) after cardiac arrest can be a problem in terms of ethics, culture and even belief. Some studies have shown that there is no significant difference in mortality between in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA). However, patients with IHCA are more fortunate to receive basic and advanced life support than patients with OHCA. Because they can access intervention in a shorter time.
In studies, survival after IHCA ranges between 15-20% and almost half of these patients have good cerebral performance scores, meaning that they are neurologically intact or have mild neurological deficits [1-4]. In order to improve survival and neurological status in IHCA patients, it is necessary to determine prognostic factors. Many studies have published models to predict prognostic factors after resuscitation in IHCA patients. PAM, PAR, and GO-FAR are the most important ones. The most acceptable of these models is GO-FAR [5]. These models, which mostly focus on the comorbidities of the patients before the arrest, do not include the characteristics during or after admission to the intensive care ünit (ICU).
The most common cause of cardiac arrest is cardiac diseases with 50-60%, followed by respiratory failure with 15-40% [6-8]. In our study, we excluded coronary intensive care unit patients and patients with OHCA. The reason for excluding coronary ICU patients was to rule out patients with cardiovascular causes. Unlike other studies, we evaluated the mortality and cerebral performance category (CPC) score of patients with IHCA who were followed up in the ICU by adding laboratory parameters, mechanical ventilator and ICU length of stay. Our aim was to evaluate the probability of survival in these patients and to determine the determinants of good prognosis. Thus, we targeted to enable physicians to exhibit more scientific approaches in terms of performance orientations and informing patients’ relatives about death and survival.
Material and Methods
Inclusion criteria
A retrospective review of 3956 patients who were admitted to the intensive care unit of our hospital between January 2021 and December 2023 was performed. We identified 196 patients with return of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR). Rhythm on the monitor and manual pulse control were considered the gold standard for ROSC decision. We excluded 135 patients with OHCA or followed up in coronary ICU (Figure 1). We searched the data of 61 patients with in-hospital cardiac arrests from the hospital information system and patient files. Patients whose blood gas, haemogram, biochemistry, procalcitonin and NT-pro-BNP levels were measured within the first two hours after ROCS were included in the study.
Patients who survived were classified as GL and those who died were classified as GM.
Analysed data
Age, gender, comorbidities (Diabetes mellitus, hypertension, congestive heart failure, neurological disease, pulmonary dısease, acute renal faılure, chronic renal failure) duration of CPR, duration of mechanical ventilation, duration of intensive care unit stay, tracheostomy and percutaneous endoscopıc gastrostomy (PEG), Acute Pysiology and Chronic Health Evaluation II (APACHE II), Glasgow Coma Scale (GCS) were recorded. Blood gas pH, PaO2, PaCO2, HCO3-, BE, lactate values were recorded. Glucose, urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), troponin, procalcitonin, N-terminal pro-brain natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), albumin, potassium, calcium, lymphocyte, neutrophil, red blood cell (RBC), (WBC), haemoglobin (Hb), haematocrit (Htc), platelet, mean corpuscular volume (MCV) values and mortality status were recorded.
Neurological evaluation
Neurological outcomes were assessed using the CPC scale, which evaluates brain recovery functionally and cognitively [9]. The CPC scale is a 5-point scale; 1 good brain performance, 2 moderate neurological defect, 3 severe cerebral disability, 4 coma or vegetative state, 5 brain death. A favourable neurological outcome was defined as a CPC score of 1 or 2 at discharge, and CPC 3 and above was considered a poor neurological outcome.
Statistical Analysis
Statistical analyses were performed with IBM SPSS v23. Normality analysis of the data was performed with Shapiro Wilk test. The comparison of normally distributed data was performed with independent sample t-test, and the comparison of non-normally distributed data was performed with Mann Whitney U test. A comparison of qualitative data was performed with Pearson Chi-square test. Logistic regression analysis was used to analyze the factors affecting survival. The relationship between CPC score and parameters was analyzed by Pearson correlation analysis. Data are presented as n (%) and mean (95% CI). Statistical significance was accepted as p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Giresun University Training Research Hospital (Date: 2023-12-04, No: 26)
Results
We retrospectively reviewed 3956 patients admitted to the anaesthesia intensive care unit between January 2021 and December 2023. We identified 196 patients with ROSC, of whom 135 patients (incomplete data set, OHCA or coronary ICU) were excluded. This study included 61 IHCA patients with a complete data set within the first 2 hours after ROSC.Thirty-nine patients died during intensive care unit follow-up. Twenty-two patients were discharged. At the time of discharge, six patients had a CPC score of 1 and two patients had a CPC score of 2.
Patient Characteristics
The mean age of the surviving patients was 66.7 years, and 73.3 years of the patients who died. There was no statistically significant difference between the two groups (p=0.183) (Table 1). MV duration was 42.8 days in GL and 15.6 days in GM. The duration of ICU stay was 48 days in GL and 16 days in GM. The duration of MV and ICU stay was statistically significantly higher in GL ( p=0.006, p=0.001). CPR duration, APACHE II, expected mortality and GCS were not different between the two groups (p>0.05) (Table 1).
The number of male patients was higher in both groups, but there was no significant difference in terms of gender (Fig.1). When the comorbidities of the patients were analysed, there was no difference between the two groups in terms of DM, HT, congestive heart failure, neurological disease, acute and chronic renal failure and lung disease (p>0.05) (Table 2). The proportion of patients with tracheotomy and PEG was statistically significantly higher in GL (p=0.004, p<0.001) (Figure 2).
Laboratory Results
The median value of lactate was 3.3 mmol/L in GL and 5.6 mmol/L in GM. The median value of urea was 70.1mg/dL in GL and 99.6mg/dL in GM. Creatinine was 1.16 mg/dL in GL and 2.12 mg/dL in GM Potassium was 4 mEq/L in GL and 4.5 mEq/L in GM Pro- BNP was 3362 pg/ml in GL, 16388 pg/ml in GM. In GM, lactate, urea, creatinine, pro-BNP and potassium values were statistically significantly higher (p=0.022, p=0.016, p=0.003, p<0.001, p=0.008, respectively) (Table 1).
There was no significant difference between the groups in pH, pO2, pCO2, HCO3-, BE, lymphocyte, neutrophil, RBC, WBC, haemoglobin, haemotocrit, platelet, MCV, glucose, AST, ALT, GGT, LDH, ALP, troponin, procalcitonin, CRP, albumin and calcium values (Table 1).
Neurological evaluation and factors affecting CPC score and mortality
Six patients had a CPC score of 1 at discharge. Two patients had a CPC score of 2. In the correlation analysis, the effects of the characteristics of the surviving patients on the cerebral performance category (CPC) score were analysed (Table 2). A positive correlation was found between MCV, GGT, MV duration, CPR duration, tracheotomy and PEG with CPC score (Table 2). Before discharge from the ICU, 63.9% of patients with ROCS died. When the relationship between the independent variables and mortality was analysed by univariate and multivariate logistic regression analysis, a positive correlation was found between NT-pro-BNP and potassium with mortality and a negative correlation with PEG (Table 3).
Discussion
The possibility of survival after CPR and discharge with a good neurological outcome (CPC score;1 or 2) confronts physicians with the choice of which patients to resuscitate and which patients to accept as DNR. Patients after CPR are generally considered to have a low likelihood of survival during follow-up and the decision to DNR may be made earlier than in the general population. Therefore, effective parameters are needed to predict mortality in this patient population. However, it is important to remember that no parameter or scoring system alone can be effective in making this decision. In this study, we have examined survival and discharge with a good CPC score in a group of patients who were followed up in the ICU after CPR. In 64% of the patients, death occurred before they were discharged from the intensive care unit. NT-pro-BNP and potassium elevation were directly correlated with mortality. Of the survivors, 36.4% were discharged with a good neurological outcome. The CPC score also increased as the duration of CPR, MCV and GGT increased.
IHCA is a common and difficult-to-treat condition. Previous studies and meta-analyses have identified groups with high and low survival rates after IHCA and reported that advanced age, malignancy, impaired renal function and dependent functional status are associated with mortality. Survival has been reported to be higher in patients with cardiovascular diagnosis [4, 5, 9]. Survival rate in IHCA varies between 15-25% [4, 9-11]. In our study, 36% of patients with ROCS survived. We found a higher survival rate compared to other studies.Age has been found to be a risk factor for mortality in many studies [4, 5, 12]. In our study, although the mean age was higher in the mortality group, no significant difference was found. Male gender has been found as a prognostic factor for mortality in some studies [13]. In this study, male gender was predominant in both groups, but no difference was found between the groups.
Considering the comorbidities of the patients, some studies have reported that chronic obstructive pulmonary disease, cirrhotic liver disease, CRF and HF worsen survival [10, 14-17]. In our study, no significant difference was found between the two groups in terms of comorbidity. However, it was observed that patients with impaired renal function had a more mortal course. In patients with ROCS, urea creatinine and potassium levels in blood samples taken within 2 hours were significantly higher in the mortality group. In addition, potassium elevation was determined as a predictive factor for mortality in the multivariation analysis.
NT-pro-BNP is secreted by the heart and vessels in response to myocardial stretch and is used in the diagnosis of heart failure [18]. Satyan et al [19] reported that NT-pro-BNP is associated with left ventricular systolic dysfunction and is a stronger predictor of mortality than troponin-t level in haemodialysis patients. In the studies, diagnosed heart failure is included among the comorbidities affecting mortality after CPR. In our study, 44.2% of patients with ROCS were previously diagnosed with heart failure. NT-pro-BNP was significantly higher in the mortal group. In the multivariate analysis, NT-pro-BNP was found to be a predictor of mortality independent of other factors.
Lactate is used as an important indicator of perfusion. After cardiac arrest, lactate and pH values may change during the period of no blood flow. Increased lactate levels have been found to be associated with mortality. In our study, similarly, lactate level was significantly higher in the mortality group [20, 21]. PEG and tracheotomy status was higher in surviving patients. We think that this is due to the fact that the need for these interventions arises more in patients who survive for a long time.
The CPC score is used to assess functional outcomes in patients after cardiac arrest [22]. It has been shown to have good validity and reliability [23]. In previous studies, more than half of the patients who survived after IHCA were intact or had mild neurological deficits at discharge [3, 4]. In our study, 36.4% of the surviving patients were discharged from the ICU with a CPC score of 1 or 2. Undoubtedly, the level of hypoxia has an effect on good neurological outcomes. Therefore, CPR efficacy and duration are determinants of hypoxia. However, there is not much information about the neurological predictive value of CPR duration. Rohlin et al. Rohlin et al. reported that the chance of 30-day survival decreased markedly as the duration of CPR increased [24]. While neurological conditions are the major cause of death in OHCA patients, this ratio is about one in four in IHCA. In IHCA, mortality is mostly determined by multiorgan failure[25]. Similarly, in our study, increased CPR time was not associated with mortality in IHCA cases, whereas there was a moderate positive correlation with CPC score. In addition, CPC score increased as MV duration, tracheotomy and PEG status increased. However, since we could not evaluate these parameters at baseline, we think that their value as predictors is limited. It may be considered that prolonged MV duration during clinical follow-up may contribute to decision making.
Scoring systems such as Pre-arrest Morbidity Score (PAM – Score), Prognosis After Resuscitation Score (PAR – Score), Good Outcome Following Attempted Resuscitation Score (GOFAR – Score) are scoring systems developed to evaluate survival and mortality after resuscitation. In our study, urea, creatinine, potassium and NT-pro-BNP were found to be higher in the mortal group. NT-pro-BNP and potassium were found to be independent predictors of mortality. We think that potassium and NT-pro-BNP are important parameters alone in post-CPR evaluations and can be included in scoring systems used to predict mortality.
Study Limitations
Limitations of our study include the retrospective design and therefore missing data on patients in the post-CPR period.
Conclusion
In-hospital cardiac arrests and the subsequent support process are considered challenging for clinicians and the healthcare system. It is important to determine the factors affecting survival and good neurological outcomes for the management of the process and clinical care with correct decisions in surviving patients. We think that potassium, NT-pro-BNP and duration of CPR should be considered among these factors. Comprehensive studies are needed to increase the evidence that will shed light on new research.
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. Nolan JP, Sandroni C, Böttiger BW, Cariou A, Cronberg T, Friberg H, et al. European resuscitation council and european society of ıntensive care medicine guidelines 2021: Post-resuscitation care. Intensive Care Med. 2021;47(4):369-421.
2. Sandroni C, Nolan J, Cavallaro F, Antonelli M. In-hospital cardiac arrest: Incidence, prognosis and possible measures to improve survival. Intensive Care Med. 2007;33(2):237-45.
3. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, et al. Cardiopulmonary resuscitation of adults in the hospital: A report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003;58(3):297-308.
4. Ebell MH, Afonso AM. Pre-arrest predictors of failure to survive after in-hospital cardiopulmonary resuscitation: a meta-analysis. Fam Pract. 2011;28(5):505-15.
5. Grandbois van Ravenhorst C, Schluep M, Endeman H, Stolker RJ, Hoeks SE. Prognostic models for outcome prediction following in-hospital cardiac arrest using pre-arrest factors: A systematic review, meta-analysis and critical appraisal. Crit Care. 2023;27(1):32.
6. Perman SM, Stanton E, Soar J, Berg RA, Donnino MW, Mikkelsen ME, et al. American Heart Association’s Get With the Guidelines®—Resuscitation (formerly the National Registry of Cardiopulmonary Resuscitation) Investigators. Location of In-Hospital Cardiac Arrest in the United States-Variability in Event Rate and Outcomes. J Am Heart Assoc. 2016;5(10):e003638.
7. Wallmuller C, Meron G, Kurkciyan I, Schober A, Stratil P, Sterz F. Causes of in-hospital cardiac arrest and influence on outcome. Resuscitation. 2012;83(10):1206-11.
8. Radeschi G, Mina A, Berta G, Fassiola A, Roasio A, Urso F, et al. Piedmont IHCA Registry Initiative. Incidence and outcome of in-hospital cardiac arrest in Italy: A multicentre observational study in the Piedmont Region. Resuscitation. 2017;119:48-55.
9. Schluep M, Gravesteijn BY, Stolker RJ, Endeman H, Hoeks SE. One-year survival after in-hospital cardiac arrest: A systematic review and meta-analysis. Resuscitation. 2018;132:90-100.
10. Ebell MH, Jang W, Shen Y, Geocadin RG. Get With the Guidelines–Resuscitation Investigators. Development and validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) score to predict neurologically intact survival after in-hospital cardiopulmonary resuscitation. JAMA Intern Med. 2013;173(20):1872-8.
11. Jung J, Ryu JH, Shon S, Min M, Hyun TG, Chun M, et al. Predicting in-hospital cardiac arrest outcomes: CASPRI and GO-FAR scores. Sci Rep. 2023;13(1):18087.
12. Swindell WR, Gibson CG. A simple ABCD score to stratify patients with respect to the probability of survival following in-hospital cardiopulmonary resuscitation. J Community Hosp Intern Med Perspect. 2021;11(3):334-42.
13. Harrison DA, Patel K, Nixon E, Soar J, Smith GB, Gwinnutt C, et al. Development and validation of risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team. Resuscitation. 2014;85(8):993–1000.
14. Piscator E, Göransson K, Forsberg S, Bottai M, Ebell M, Herlitz J, et al. Prearrest prediction of favourable neurological survival following in-hospital cardiac arrest: the prediction of outcome for in-hospital cardiac arrest (PIHCA) score. Resuscitation. 2019;143:92–9.
15. Ebell MH, Afonso AM, Geocadin RG; American Heart Association’s Get With the Guidelines-Resuscitation (formerly National Registry of Cardiopulmonary Resuscitation) Investigators. Prediction of survival to discharge following cardiopulmonary resuscitation using classification and regression trees. Crit Care Med. 2013;41(12):2688-97.
16. Chan PS, Berg RA, Spertus JA, Schwamm LH, Bhatt DL, Fonarow GC, et al. Risk-standardizing survival for in-hospital cardiac arrest to facilitate hospital comparisons. J Am Coll Cardiol. 2013;62(7):601–9.
17. Larkin GL, Copes WS, Nathanson BH, Kaye W. Pre-resuscitation factors associated with mortality in 49,130 cases of in-hospital cardiac arrest: A report from the national registry for cardiopulmonary resuscitation. Resuscitation. 2010;81(3):302–11.
18. Gupta DK, Wang TJ. Natriuretic Peptides and Cardiometabolic Health. Circ J. 2015;79(8):1647-55.
19. Satyan S, Light RP, Agarwal R. Relationships of N-terminal pro-B-natriuretic peptide and cardiac troponin T to left ventricular mass and function and mortality in asymptomatic hemodialysis patients. Am J Kidney Dis. 2007;50(6):1009-19.
20. Issa MS, Grossestreuer AV, Patel H, Ntshinga L, Coker A, Yankama T, et al. Lactate and hypotension as predictors of mortality after in-hospital cardiac arrest. Resuscitation. 2021;158:208-14.
21. Haschemi J, Müller CT, Haurand JM, Oehler D, Spieker M, Polzin A, et al. Lactate to Albumin Ratio for Predicting Clinical Outcomes after In-Hospital Cardiac Arrest. J Clin Med. 2023;12(12):4136.
22. Raina KD, Callaway C, Rittenberger JC, Holm MB. Neurological and functional status following cardiac arrest: method and tool utility. Resuscitation. 2008;79(2):249-56.
23. Stiell IG, Nesbitt LP, Nichol G, Maloney J, Dreyer J, Beaudoin T, et al. OPALS Study Group. Comparison of the Cerebral Performance Category score and the Health Utilities Index for survivors of cardiac arrest. Ann Emerg Med. 2009;53(2):241-8.
24. Rohlin O, Taeri T, Netzereab S, Ullemark E, Djärv T. Duration of CPR and impact on 30-day survival after ROSC for in-hospital cardiac arrest: A Swedish cohort study. Resuscitation. 2018;132:1-5.
25. Witten L, Gardner R, Holmberg MJ, Wiberg S, Moskowitz A, Mehta S, et al. Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest. Resuscitation. 2019;136:93-9.
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Elvan Tekir Yılmaz, Bilge Olgun Keleş, İskender Aksoy. Factors ınfluencing mortality after cardiopulmonary resuscitation; never give up! Ann Clin Anal Med 2024;15(6):414-419
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Clinical-laboratory findings and risk factors in pulmonary embolism: A retrospective evaluation in the emergency service
Kürşat Kaan Kerimoğlu 1, Doğaç Niyazi Özüçelik 2, Akkan Avcı 3, Ahmet Çağdaş Acara 4
1 Department of Emergency Medicine, Alsancak Nevvar-Salih İşgören State Hospital, İzmir, 2 Department of Social Services, Faculty of Health Sciences, İstanbul Cerrahpaşa University, İstanbul, 3 Department of Emergency Medicine, Health Science University, Adana City Research and Training Hospital, Adana, 4 Department of Emergency Medicine, Faculty of Medicine, Dokuz Eylül University, İzmir, Türkiye
DOI: 10.4328/ACAM.22136 Received: 2024-02-02 Accepted: 2024-03-19 Published Online: 2024-04-29 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):420-424
Corresponding Author: Kürşat Kaan Kerimoğlu, Department of Emergency Medicine, Alsancak Nevvar-Salih İşgören State Hospital, İzmir, Türkiye. E-mail: k.kerimoglu@saglik.gov.tr P: +90 232 463 64 65 Corresponding Author ORCID ID: https://orcid.org/0009-0002-7519-5546
Other Authors ORCID ID: Doğaç Niyazi Özüçelik, https://orcid.org/0000-0002-7752-0667 . Akkan Avcı, https://orcid.org/0000-0002-4627-0909 . Ahmet Çağdaş Acara, https://orcid.org/0000-0001-6708-7946
This study was approved by the Ethics Committee of Bakırköy Dr. Sadi Konuk Training and Research Hospital (Date: 2011-04-18, No:2011/4-05)
Aim: The objective of this study is to retrospectively identify the demographic characteristics of patients diagnosed with pulmonary embolism in the emergency department, aiming to provide clinicians with new perspectives on the diagnosis of the disease. For this purpose, the clinical symptoms, risk factors, comorbid diseases, laboratory findings, and radiological results in those patients were detected.
Material and Methods: This single-center, retrospective, and observational study consisted of patients older than 18 years of age who presented to the emergency service with various complaints and were subsequently diagnosed with PE. Medical records, radiological results, and laboratory findings of the patients were documented for this research.
Results: A total of 37 cases were included in this study, with ages ranging from 25 to 89 (mean 66.24 ± 17.10). When evaluated based on the clinical symptoms, the most observed complaints were shortness of breath (n=24; 64.9%) and chest pain (n=16; 43.2%). The most frequently observed comorbidities were hypertension and diabetes, which were detected in 15 patients (40.5%) and 11 patients (29.7%), respectively.
Discussion: The findings of the present study revealed that in addition to typical clinical findings, PE may present with atypical symptoms that are not specific to the disease. In this context, the diagnosis of PE should not only be considered in the presence of typical symptoms but also taken into account when atypical symptoms that are not specific to PE exist.
Keywords: Emergency Department, Pulmonary Embolism, Comorbidity, Risk Factors, Clinical Symptoms
Introduction
Pulmonary embolism (PE), a remarkable disease highly associated with morbidity, is the third most common cause of in-hospital deaths after acute myocardial infarction and stroke [1]. Diagnosing PE is often challenging, and primarily suspicion of the disease is necessary before making the diagnosis [2]. Sudden-onset shortness of breath, chest pain, cyanosis, hemoptysis, and occasionally, pain accompanied by swelling in the legs are the most common symptoms of PE [1, 3].
Although previous studies have reported an increasing trend in annual PE incidence rates, current research draws attention to a significant decline in mortality rates attributed to PE [4]. The more frequent application of effective treatment methods is considered the main factor contributing to the observed positive changes in the prognosis of PE [5]. Due to the widespread use of advanced diagnostic methods, today clinically insignificant cases of PE that are not life-threatening are more frequently detected. This situation leads to an increase in the diagnosed cases of PE that consequently results in a relative decrease in mortality [6]. Another possible reason for the decrease in mortality rates in PE cases is that physicians working in emergency departments lately have been more frequently suspecting PE [7].
In previous studies regarding PE, it was suggested that approximately half of the PE patients admitted to the emergency department were not accurately diagnosed [8]. The difficulty in diagnosing PE arises from the fact that the disease can indicate classical symptoms such as shortness of breath and pleuritic chest pain, while it can also come up with atypical findings, such as syncope and slow-onset shortness of breath which are not characteristic of PE [9].
Diagnostic algorithms and techniques used in the diagnosis of PE have remained relatively unchanged in recent years, and the fundamental tool still employed for diagnosing the disease is computed tomography pulmonary angiography (CTPA) [10, 11]. In cases where clinical suspicion of PE is present, non-invasive diagnostic methods such as D-dimer blood test, clinical probability scoring, echocardiography, and serial ultrasonography of the legs are also utilized in addition to CTPA [4, 12]. This study aims to retrospectively identify the demographic characteristics of patients diagnosed with PE in the emergency department, aiming to provide clinicians with new perspectives in the diagnosis of the disease. The symptoms at the time of hospital admission, risk factors, comorbid diseases, laboratory findings, radiological results, risk classification scores, and prognoses in those patients were detected.
Material and Methods
Study Design: This single-center, retrospective, and observational study consisted of patients older than 18 years of age who presented to the Emergency Medicine Clinic of Bakırköy Dr. Sadi Konuk Training and Research Hospital with various complaints and symptoms between March 15, 2009, and March 15, 2011. Those patients were subsequently diagnosed with PE following advanced diagnostic investigations.
Study Protocol: To identify patients for inclusion in the study and to exclude those with incorrectly entered data, all patients for whom D-dimer analysis was requested were initially detected from laboratory records. The medical records and computed tomography (CT) findings of these identified patients were then reviewed for PE diagnosis. Following this examination, a total of 37 patients with confirmed PE diagnosis were included in the study.
Medical records, radiological results, and laboratory findings of the patients were documented in a research form prepared for this study. Hospital records of all patients were examined for clinical symptoms at the time of admission and the presence of risk factors for PE. In addition to demographic data, vital signs detected in the emergency department, existing comorbidities, electrocardiography (ECG) findings, radiological imaging results, blood gas analysis, troponin, and D-dimer values were recorded in the research form. In order to obtain data on the prognosis of the disease, the research form also included information concerning the duration of hospital stay, discharge details, and the treatment method applied. Furthermore, based on the available data, the Wells score was calculated for all patients.
Statistical Analysis: Statistical Package for the Social Sciences (SPSS) for Windows version 21.0 was used for the statistical analysis of the obtained data. Descriptive statistics such as mean, standard deviation, frequency, and ratio values were used for data that followed a normal distribution. The Kolmogorov-Smirnov test was utilized to assess the normality distribution of the parameters. Continuous variables were presented as mean ± standard deviation, whereas categorical values were expressed as absolute numbers and percentages.
Ethical Approval
This study was approved by the Ethics Committee of Bakırköy Dr. Sadi Konuk Training and Research Hospital (Date: 2011-04-18, No:2011/4-05).
Results
A total of 37 cases were included in this study, with ages ranging from 25 to 89 (mean 66.24 ± 17.10), including 22 females (59.5%) and 15 males (40.5%). Table 1 indicates clinical symptoms and signs of the cases of the patients presented at the emergency department. When evaluated based on the initial symptoms, shortness of breath (n=24; 64.9%) and chest pain (n=16; 43.2%) were the most observed complaints. In addition to these findings, pain or temperature change in the lower extremity (n=7, 18.9%), syncope (n=5; 13.5%), and confusion (n=4; 10.8%) were other frequently encountered symptoms. It is also noteworthy that non-specific symptoms such as headache (n=3; 8.1%), stomachache (n=3; 8.1%), lower back pain (n=2; 5.4%), dysuria (n=1; 2.7%), and speech disorder (n=1; 2.7%) were present in the patients included in the study. When evaluating the cases of PE in terms of risk factors, the most common ones identified were immobilization, swelling or temperature changes in one leg, recent history of surgery, or trauma (Table 2). The most frequently observed comorbidities, presented in Table 2, were hypertension and diabetes, which were detected in 15 patients (40.5%) and 11 patients (29.7%), respectively. In addition to these two pathologies, other diseases recorded were congestive heart failure, chronic obstructive pulmonary disease, coronary artery disease, and chronic kidney failure. No malignancy was detected in any of the patients included in the study.
When electrocardiography (ECG) findings were assessed (Table 2), sinus tachycardia was detected in 12 patients (32.4%), while an S1Q3T3 pattern was observed in only 1 patient (2.7%). Laboratory findings of the patients can be seen in Table 3. Evaluating the patients in terms of these average laboratory data, the results were as follows: D-dimer 6993.2 ± 7565.7 µg/L (0-500), troponin 0.3 ± 0.6 ng/L (0-0.4), pH 7.4 ± 0.1 (7.35-7.45), pO2 59.8 ± 29.7 mmHg (70-100), pCO2 38.3 ± 9.2 mmHg (35-45), HCO3 22.6 ± 4.6 mEq/L (22-28).
Examining the hospital records of the patients, it was determined that hospitalization was conducted for 20 patients (54.1%), and thrombolytic therapy was administered to 5 of these patients (13.5%). It was observed that 15 of the patients (40.5%) were referred to another healthcare institution, and 2 patients (5.4%) unfortunately passed away.
All patients diagnosed with PE were assessed for the risk of venous thromboembolism (VTE) according to the Wells scoring system. The presence of high risk was identified in 12 patients (Wells score > 6; 32.4%), moderate risk was recorded in 25 patients (Wells score: 2-6; 67.6%), whereas no patients were identified with low risk (Wells score < 2; 0%).
Discussion
PE remains a prevalent and life-threatening disease that is still underdiagnosed in contemporary healthcare. The risk of PE significantly increases with increased age, given the rising incidence of VTE [2]. In fact, in the current study, the average age of the patients diagnosed with PE was determined to be 66.24 ± 17.10. Similarly, in a study conducted by Le Gal et al. [2] involving 416 patients diagnosed with PE, the average age was found to be 60.50 ± 19.10. In contrast to these results, another study conducted by Hacıevliyagil et al. [13] analyzed 63 patients diagnosed with PE, revealing an average age of 49.40 ± 16.80. When compared to the findings of the present study, it is evident that the average age in this research is considerably lower. The reason for this difference may be attributed to the potential impacts of other factors except for age on the incidence of PE such as environmental effects, genetic predisposition, and individual habits. Consequently, when making age-related correlations with PE, it is crucial to consider these highlighted factors.
The current study found that 59.5% of the patients diagnosed with PE were female, while 40.5% were male. Similar to our findings, two different research conducted by Pribish et al. [14] and Hacıevliyagil et al. [13] also reported higher proportions of females diagnosed with PE compared to males. On the other hand, in general, PE is more frequently observed in males than females across all races and age groups [3]. In this manner, the findings of the present study were in contrast to the literature. In high-income countries, the rate of women giving birth at age 35 and above has been recently increasing [15]. The widely preferred use of oral contraceptives for birth control among women of reproductive age is one of the most common risk factors for VTE [4]. However, not only in women of reproductive age but also in postmenopausal women receiving hormone replacement therapy, the risk of VTE is significantly increased [4]. Therefore, these factors could be considered as probable reasons for the contrary findings of literature obtained in the present study.
The most observed symptoms in patients diagnosed with PE include sudden-onset shortness of breath, pleuritic chest pain, hemoptysis, cough, leg pain or swelling [1,4]. Similar symptoms were identified in the patients included in the current study where the most common symptoms upon emergency department admission were shortness of breath, chest pain, and pain or temperature change in the lower extremity. Despite not being the primary complaint, the presence of non-specific symptoms such as stomachache, dysuria, speech disorder, and lower back pain is noteworthy. Likewise, in the literature, some atypical symptoms such as diarrhea and loss of appetite [16], as well as dizziness [17] have been reported alongside the typical symptoms of PE. In this context, the diagnosis of PE should not only be considered in the presence of typical symptoms but also taken into account when atypical symptoms that are not specific to PE exist.
In the current study, hypertension and diabetes were found to be the highly observed comorbidities accompanying PE in the evaluated cases. In addition to the mentioned pathologies, congestive heart failure, chronic obstructive pulmonary disease, coronary artery disease, and chronic kidney disease were also identified, albeit with lower frequencies. Interestingly, unlike the literature, no cases of malignancy were observed in patients diagnosed with PE in the present study. Previously, comprehensive research conducted by Glise-Sandblad et al. [18] on 1.48 million patients identified malignancy (21.3%), congestive heart disease (18.3%), and ischemic heart disease (18.3%) as the most frequently associated diseases with PE. A different study by Ebner et al. [19] found that chronic kidney disease (34.2%), coronary artery disease (18.2%), and active malignancy (18.1%) were the most common comorbidities accompanying PE. In another study conducted by Huerta et al. [20], the presence of hypertension (24.95%), malignancy (15.87%), and asthma (14.11%) as comorbidities to PE was reported. While the distribution of comorbid diseases may vary when compared with the outcomes of our study, it could be concluded that malignancy, cardiac diseases, and respiratory system diseases are prominent. This phenomenon may be attributed to similar symptoms presented by cardio-pulmonary diseases and PE, leading clinicians to investigate PE in the differential diagnosis. A noteworthy finding in the current study, unlike other cited studies, is the absence of malignancy accompanying PE in any of the patients. Indeed, although patients in this study did not have a history of active malignancy at the time of PE diagnosis, Li et al. [21] emphasized that PE is an initial sign of cancer. For this reason, the possibility of PE as an early manifestation of cancer in patients should be considered. Thus, in PE-diagnosed patients with risk factors such as advanced age and a family history of malignancy, cancer screening tests are highly recommended.
The D-dimer test, commonly employed in the diagnosis of PE, exhibits a high-negative but a low-positive predictive value [4]. Therefore, a normal D-dimer level eliminates the likelihood of acute PE, while a high D-dimer level is not sufficient for confirming PE [12]. The average D-dimer levels of the patients included in the current study were determined to be 6993.2 ± 7565.7 µg/L (0-500), and a normal D-dimer level was found in 5.4% of the patients. D-dimer values can be measured using different methods in blood samples obtained from patients, and the sensitivity of these methods ranges from 95-99% [22]. Although a negative D-dimer result is considered to exclude the diagnosis of PE, the 5.4% rate of negative results observed in the current study may be attributed to this sensitivity range of the measurement methods. Therefore, even if D-dimer results are normal, in cases where clinical probability is high, applying for advanced imaging studies may be useful for the diagnosis of PE.
In PE, cardiac right ventricular dysfunction is a significant indicator of the prognosis of the disease [4]. Due to its indication of myocardial damage, cardiac troponin value is preferable for identifying high-risk patients [23]. In the current study, the average troponin level was determined to be 0.3 ± 0.6 ng/L (0-0.4), and it was found to be positive in 13.5% of the patients. Similar to the present research, former studies conducted by Douketis et al. [24] and Yalamanchili et al. [25] also reported positive troponin values in patients diagnosed with PE, with the positive patient rates being 13.5% and 16%, respectively.
The limitations of this study include its retrospective design, reliance on data collected from a single center, and its relatively small sample size. Although it has a small sample size, this study has identified atypical symptoms not specific to PE. We believe that our findings will provide guidance for further comprehensive studies.
Conclusion
PE is a remarkable illness highly associated with morbidity and diagnosing the disease is quite challenging. The findings of the present research revealed that in addition to typical clinical findings, PE may present with atypical symptoms that are not specific to the disease. Furthermore, while PE is more frequently observed in the elderly and male population, clinicians should always keep in mind that PE can also occur in low-risk patients due to environmental effects, and women’s more frequent use of oral contraceptives. Future studies would focus on comprehensive demographic data of PE by the application of multi-central research in different populations.
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. Ishaaya E, Tapson VF. Advances in the diagnosis of acute pulmonary embolism. F1000Res. 2020;9(F1000 Faculty Rev):44.
2. Le Gal G, Righini M, Roy P-M, Meyer G, Aujesky D, Perrier A, et al. Differential value of risk factors and clinical signs for diagnosing pulmonary embolism according to age. J Thromb Haemost. 2005;3:2457–64.
3. Örün S, Bol O, Aköz A. Determination of demographic changes of acute pulmonary embolism patients applied to emergency service: Retrospective analysis of 60 cases. Eurasian J Crit Care. 2022;4(1):8–11.
4. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543–603.
5. Jiménez D, Bikdeli B, Barrios D, Morillo R, Nieto R, Guerassimova I, et al. Management appropriateness and outcomes of patients with acute pulmonary embolism. Eur Respir J. 2018;51(5):1800445.
6. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: Evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831–7.
7. Konstantinides SV, Barco S, Lankeit M, Meyer G. Management of pulmonary embolism an update. J Am Coll Cardiol. 2016;67(8):976–90.
8. Kline JA, Hernandez-Nino J, Jones AE, Rose GA, Norton HJ, Camargo CA. Prospective study of the clinical features and outcomes of emergency department patients with delayed diagnosis of pulmonary embolism. Acad Emerg Med. 2007;14(7):592–8.
9. Prandoni P, Lensing AWA, Prins MH, Ciammaichella M, Perlati M, Mumoli N, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375(16):1524–31.
10. Howard L. Acute pulmonary embolism. Clin Med (Lon). 2019;19(3):243–7.
11. Zantonelli G, Cozzi D, Bindi A, Cavigli E, Moroni C, Luvarà S, et al. Acute pulmonary embolism: prognostic role of computed tomography pulmonary angiography (CTPA). Tomography. 2022;8(1):529–39.
12. Ten Wolde M, Hagen PJ, Macgillavry MR, Pollen IJ, Mairuhu ATA, Koopman MMW, et al. Non-invasive diagnostic work-up of patients with clinically suspected pulmonary embolism; results of a management study. J Thromb Haemost. 2004;2(7):1110-7.
13. Hacıevliyagil S, Mutlu L, Kızkın Ö, Günen H, Gülbaş G. Altmışüç pulmoner emboli olgusunun retrospektif değerlendirilmesi [A retrospective analysis of 63 cases of pulmonary embolism]. Solunum Hastalıkları. 2004;15:15–21.
14. Pribish AM, Beyer SE, Krawisz AK, Weinberg I, Carroll BJ, Secemsky EA. Sex differences in presentation, management, and outcomes among patients hospitalized with acute pulmonary embolism. Vasc Med. 2020;25(6):541–8.
15. Frick AP. Advanced maternal age and adverse pregnancy outcomes. Best Pract Res Clin Obstet Gynaecol. 2021;70:92–100.
16. Elavia N, Sharma N, Li S, Wang Y, Milekic B. An atypical presentation of acute pulmonary embolism with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. Cureus. 2020;12(5):e8249.
17. Jamil A, Shyam V, Neupane K. Atypical presentation of pulmonary embolism several months after COVID-19 infection. Cureus. 2021;13(1):e12863.
18. Sandblad KG, Rosengren A, Sörbo J, Jern S, Hansson PO. Pulmonary embolism and deep vein thrombosis—comorbidities and temporary provoking factors in a register-based study of 1.48 million people. Res Pract Thromb Haemost. 2022;6(4):e12714.
19. Ebner M, Sentler C, Harjola VP, Bueno H, Lerchbaumer MH, Hasenfuß G, et al. Outcome of patients with different clinical presentations of high-risk pulmonary embolism. Eur Heart J Acute Cardiovasc Care. 2021;10(7):787–96.
20. Huerta C, Johansson S, Wallander MA, Rodríguez LAG. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167(9):935–43.
21. Li Y, Shang Y, Wang W, Ning S, Chen H. Lung cancer and pulmonary embolism: What is the relationship? A review. J Cancer. 2018;9(17):3046–57.
22. Huisman MV, Klok FA. Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost. 2013;11(3):412–22.
23. Ebner M, Guddat N, Keller K, Merten MC, Lerchbaumer MH, Hasenfuß G, et al. High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism. ERJ Open Res. 2020;6(4):00625–2020.
24. Douketis JD, Leeuwenkamp O, Grobara P, Johnston M, Söhne M, Ten Wolde M, et al. The incidence and prognostic significance of elevated cardiac troponins in patients with submassive pulmonary embolism. J Thromb Haemost. 2005;3(3):508–13.
25. Yalamanchili K, Sukhija R, Aronow WS, Sinha N, Fleisher AG, Lehrman SG. Prevalence of increased cardiac troponin I levels in patients with and without acute pulmonary embolism and relation of increased cardiac troponin I levels with in-hospital mortality in patients with acute pulmonary embolism. Am J Cardiol. 2004;93(2):263–4.
Download attachments: 10.4328.ACAM.22136
Kürşat Kaan Kerimoğlu, Doğaç Niyazi Özüçelik, Akkan Avcı, Ahmet Çağdaş Acara. Clinical-laboratory findings and risk factors in pulmonary embolism: A retrospective evaluation in the emergency service. Ann Clin Anal Med 2024;15(6):420-424
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Clinical importance of SUPAR and Dickkopf-1 level in the etiology of pleural effusion
Aslinur Dogan 1, Atalay Sahin 2, İclal Hocanli 3
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, Adiyaman, 2 Department of Thoracic Surgery, Faculty of Medicine, Adiyaman University, Adiyaman, 3 Department of Pulmonary Diseases, Faculty of Medicine, Harran University, Sanliurfa, Turkey
DOI: 10.4328/ACAM.22139 Received: 2024-02-08 Accepted: 2024-04-02 Published Online: 2024-04-25 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):425-429
Corresponding Author: Atalay Sahin, Department of Thoracic Surgery, Faculty of Medicine, Adiyaman University, 02040, Adiyaman, Turkey. E-mail: atalaysahin44@yahoo.com P: +90 507 541 38 65 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0498-4935
Other Authors ORCID ID: Aslinur Dogan, https://orcid.org/0000-0002-2047-9229 . İclal Hocanli, https://orcid.org/0000-0003-3283-9639
This study was approved by the Ethics Committee of Harran University (Date: 2021-04-26, No: 2021.09.03)
Aim: Two distinct biomarkers, the soluble form of the urokinase-type plasminogen activator receptor (SUPAR) and Dickkopf-1 (DKK-1), play an important role in the mechanisms of inflammation, infection and malignancy. The aim of this study was to evaluate the prognostic value of two different biomarkers in patiants with a respiratory disease and investigate the association between combined multiple biomarkers reflecting different pathophysiological processes.
Material and Methods: We used serum and pleural fluid samples taken from patients diagnosed with pleural effusion by physical and radiological examination. The potential role of DKK-1, a Wnt signalling pathway inhibitor, and SUPAR in pleural effusion occurring due to different etiologies has been examined.
Results: The data show that SUPAR, and DKK-1 levels increased significantly compared to the control groups. It has been shown that SuPAR levels were lower in the pleural fluids and serums of patients with tuberculosis compared to patients with parapneumonic effusions, and that serum SUPAR levels of patients with malignancies were higher compared to patients with tuberculosis and lower compared to parapneumonic patients. It was determined that there was no significant difference in DKK-1 levels in serum and pleural fluids between patients with malignancy, tuberculosis and parapneumonic effusion.
Discussion: Overlapping clinical presentations led to delayed diagnosis and treatment initiation. This results in unnecessary diagnostic procedures. As an indicator, the use of concomitant biomarkers can reverse this situation.
Keywords: SUPAR, Dickkopf-1, Pleural Efusion
Introduction
Pleural effusion is a pathological condition known as the accumulation of fluid in the pleural space of the lung. The most common causes of this condition are congestive heart failure, pneumonia, pulmonary embolism and various types of cancer [1-3]. Studies show that the mortality rate in patients with non-malignant pleural effusion is between % 25-57 [4]. Pleural effusion, which is commonly seen in the presence of various disease states, has a wide range of differential diagnoses. Further evaluation of pleural effusion by distinguishing transudate and exudate using Light criteria helps determine diagnosis and treatment. However, these criteria are not always sufficient to make a diagnosis and determine the etiology. Therefore, invasive interventions are needed [2, 3]. This information shows that determining the etiology of pleural effusion is not easy.
Dickkopf-1 (DKK-1), which has been found as a new biomarker that causes endothelial cell damage by triggering the release of inflammatory cytokines, has been proven to be closely associated with some malignancies and chronic inflammatory diseases. This biomarker is defined as a secretory protein that can inhibit the Wnt signal transduction pathway [5]. It is well known that the Wnt signaling pathway plays an important role in embryogenesis, organogenesis, and homeostasis [6]. In particular, the discovery of new therapeutic drugs targeting the Wnt signaling pathway is considered promising agents for treating many diseases. DKK-1, defined as a secretory protein that can inhibit the Wnt signal transduction pathway, causes endothelial cell damage by triggering the secretion of inflammatory cytokines. Research shows that this biomarker is closely associated with various malignancies, chronic inflammatory diseases and neurological pathologies. It has been proven that DKK-1, which serves as a new biomarker that causes endothelial cell damage by supporting the release of inflammatory cytokines, is closely associated with various malignancies, chronic inflammatory diseases and neurological pathologies [7-10].
Soluble urokinase plasminogen activator receptor (SUPAR), defined as a different and new inflammatory biomarker, is found at high levels in plasma, serum and urine samples of patients with pneumonia, sepsis, tuberculosis and various cancers. Recent studies have shown that SUPAR levels are also high in pleural fluid [11-15].
As mentioned above, determining the etiology of pleural effusion is not easy or sufficient with current methods. The use of two effective biomarkers such as SuPAR, and DKK-1 to determine the etiology of pleural effusion without the need for invasive interventions is of great importance for scientific research. For this purpose, we aimed to investigate whether changes in serum and pleural fluid SUPAR, and DKK-1 levels can yield the evaluation of the diagnosis of pleural effusion and to evaluate the relationship between pleural effusion conditions that occur due to different etiological reasons and SUPAR, and DKK-1 levels in our study. We sought to examine the prognostic value of two distinct biomarkers in patients with PE and to evaluate combined multiple biomarkers reflecting different pathophysiological processes.
Material and Methods
Study population and experimental design
Peural fluid obtained by thoracentesis from patients over the age of 18 and malignancy, tuberculosis, and parapneumonic effusion with pleural effusion detected by physical examination and radiological findings and venous blood taken simultaneously between August 2021-March 2022. Pleural fluid samples were characterized as exudate or transudate using Light’s criteria. The samples obtained were divided into 4 groups: control, malignancy, tuberculosis and parapneumonic effusion.
Measurement of serum and pleural fluid DKK-1 and SuPAR Level
DKK-1 (Human Dickkopf-like Protein 1, Elisa Kit, SunRedBio, Shanghai, Chinese) and SUPAR (Human suPAR Elisa Kit, SunRedBio, Shanghai, Chinese) levels in serum and pleural fluid samples taken from the participants were determined using ELISA kits in accordance with the manufacturer’s instructions. Data analysis results in serum and pleural fluid are given in units of ng/ml or pg/ml.
Statistical analysis
Results are presented as mean ± standard derivation. Statistical analysis of the results was performed using Student’s t-test for comparison of pairs and between group comparisons of qualitative and quantitative variables wereperformed by using the Fisher exact test and Mann–Whitney U-test, respectively. One-way ANOVA was used for parametric variables and Kruskal–Wallis analysis for nonparametric variables (GraphPad Prism 8.0, USA). The p-value is considered statistically significant when it is less than 0.05.
Ethical Approval
This study was approved by the Ethics Committee of Harran University (Date: 2021-04-26, No: 2021.09.03).
Results
SuPAR levels of serum and pleural fluid
It was determined that SUPAR levels in serum samples of patients with malignancy, tuberculosis and parapneumonic effusion were significantly increased compared to control groups (Table 1). At the same time, the study showed that the serum SUPAR levels of patients with malignancy were higher compared to patients with tuberculosis, while the serum SUPAR levels of patients with parapneumonic effusion were found to be significantly higher than those of patients with malignancy and tuberculosis (Figure 1a). It was determined that SUPAR levels in the pleural fluids of patients with malignancy, tuberculosis and parapneumonic effusion increased significantly compared to control groups. At the same time, the study showed that the SUPAR levels in the pleural fluids of patients with tuberculosis and parapneumonic effusion did not change compared to patients with malignancy, while the SUPAR levels in the pleural fluids of patients with parapneumonic effusion were found to be significantly higher compared to patients with tuberculosis (Figure 1b).
DKK-1 levels of serum and pleural fluid
It was determined that DKK-1 levels in the serum samples of patients with malignancy and tuberculosis did not change compared to the control groups, but DKK-1 levels in the serum samples of patients with parapneumonic effusion increased significantly compared to the control groups. However, the study found that there was no significant difference in serum DKK-1 levels between patients with malignancy, tuberculosis and parapneumonic effusion. (Figure 1c). It was determined that DKK-1 levels in the pleural fluid of patients with malignancy, tuberculosis and parapneumonic effusion were significantly increased compared to control groups. However, the study found that there was no significant difference DKK-1 levels in pleura fluid between patients with malignancy, tuberculosis and parapneumonic effusion. (Figure 1d).
SuPAR levels of patients with malignancy, tuberculosis and parapneumonic effusion in the pleural fluids and serum samples
SUPAR levels in the pleural fluids of patients with malignancy, tuberculosis and parapneumonic effusion were found to be significantly higher than the SUPAR levels in serum samples (Figure 2).
DKK-1 levels of patients with malignancy, tuberculosis and parapneumonic effusionin the pleural fluids and serum samples
DKK-1 levels in the patients with malignancy, tuberculosis and parapneumonic effusion were not significantly changed between serum and pleura fluid samples (Figure 3).
Discussion
The pathogenesis of respiratory disorders is multifactorial. Many pathophysiological alterations have been described in inflammation, infection and malignancy. Various clinical conditions result in pleural effusions, which is associated with increased morbidity and mortality. Pleural effusion is a pathological condition known as the accumulation of fluid in the pleural space of the lung [1]. The most common causes of this condition are congestive heart failure, pneumonia, pulmonary embolism and various types of cancer. Further evaluation of pleural effusion by distinguishing transudate and exudate using criteria helps determine diagnosis and treatment. However, these criteria are not always sufficient to make a diagnosis and determine the etiology. In addition, invasive interventions are needed [2, 3]. As a biological response, the effects of biomarkers are observable and quantifiable biological changes in cellular components, processes, structures, or functions within the development and progression of diseases. They, therefore, can be assessed as indicators of a physiological or pathological biological process. In various human body fluid samples, biomarker effects can be objectively measured. Some biomarker tests have been evaluated for lung diseases. Multiple uses of biomarkers can contribute significant additive effects to give rise to diagnosis and treatment. We examined whether changes in serum and pleural fluid SUPAR, and DKK-1 levels could yield the evaluation of the diagnosis of pleural effusion and the relationship between pleural effusion conditions that occur due to different etiological reasons and SUPAR, and DKK-1 levels. It has been found that pleural SUPAR levels of patients with malignant pleural effusion are increased in the literature [16-18]. Similarly, it was found that SUPAR levels increased in the pleural fluid of patients with parapneumonic effusion [19]. Additionally, a recent study showed that serum SUPAR levels are associated with the severity of pneumonia and mortality rates [20-24]. Consistent with literature studies, in our study, it was determined that SUPAR levels in the pleural fluids of patients with malignancy, tuberculosis and parapneumonic effusion were significantly higher than the SUPAR levels in serum samples.
However, SUPAR levels in serum samples of patients with malignancy, tuberculosis and parapneumonic effusion were found to be significantly increased compared to control groups. At the same time, the study showed that the serum SUPAR levels of patients with malignancy were higher compared to patients with tuberculosis, while the serum SUPAR levels of patients with parapneumonic effusion were found to be significantly higher than those of patients with malignancy and tuberculosis. Similarly, SUPAR levels in the pleural fluids of patients with malignancy, tuberculosis and parapneumonic effusion were found to be significantly increased compared to control groups. At the same time, the study showed that the SUPAR levels in the pleural fluids of patients with tuberculosis and parapneumonic effusion did not change compared to patients with malignancy, while the SUPAR levels in the pleural fluids of patients with parapneumonic effusion were found to be significantly higher compared to patients with tuberculosis.
It was determined that DKK-1 levels in the serum samples of patients with malignancy and tuberculosis did not change compared to the control groups, but DKK-1 levels in the serum samples of patients with parapneumonic effusion increased significantly compared to the control groups. However, the study found that there was no significant difference in serum DKK-1 levels between patients with malignancy, tuberculosis and parapneumonic effusion. It was determined that DKK-1 levels in the pleural fluid of patients with malignancy, tuberculosis and parapneumonic effusion were significantly increased compared to control groups. However, the study found that there was no significant difference DKK-1 levels in pleura fluid between patients with malignancy, tuberculosis and parapneumonic effusion.
The results of our study will contribute to the literature in terms of identifying new biomarkers called SuPAR, and DKK-1 in determining the causes of fluid in the pleural space and providing a different perspective on the treatment course of the disease.
Conclusion
Considering that biomarkers are not specific and common in predicting diseases, we proposed that the use of biomarker combinations can lead to better clinical diagnostic criteria for pulmonary diseases. Whether more than one biomarker is connected to pulmonary diseases independently is unknown. Due to the correlation between many biomarker levels, measuring one biomarker may not always replace the relationship of another biomarker with respiratory disease. Our data indicates that employing multiple biomarkers may result in a more precise assessment of individual biomarker associations. According to our findings, more investigation is needed to fully explore both SUPAR, and DKK-1’s potential as a respiratory illness therapeutic agent. The study cannot be interpreted to suggest a direct benefit of combining biomarkers.
Acknowledgment
This work was supported by Adiyaman University Scientific Research Projects Unit with project number TIPFMAP/2022-0013.
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. Light RW. Pleural diseases. 5th Edition, New York: Lippincott Williams and Wilkins; 2007.p.2-6.
2. Wu AC, Kiley JP, Noel PJ, Amur S, Burchard EG, Clancy JP, et al. Current status and future opportunities in lung precision medicine research with a focus on biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement. Am J Respir Crit Care Med. 2018;198(12):e116-e136.
3. Aboudara M, Maldonado F. Update in the management of pleural effusions. Med Clin North Am. 2019;103(3):475-85.
4. Jany B, Welte T. Pleural effusion in adults-etiology, diagnosis, and treatment. Dtsch Arztebl Int. 2019;116(21):377–86.
5. Huang Y, Liu L, Liu A. Dickkopf-1: Current knowledge and related diseases. Life Sci. 2018;209(1):249-54.
6. Ueland T, Otterdal K, Lekva T, Halvorsen B, Gabrielsen A, Sandberg WJ, et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29(8):1228-34.
7. González-Sancho JM, Aguilera O, García JM, Pendás-Franco N, Peña C, Cal S, García de Herreros A, et al. The Wnt antagonist Dickkopf-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24(6):1098-103.
8. Kim MJ, Choe YH. Correlation of Dickkopf-1 with inflammation in Crohn disease. Indian Pediatr. 2019;56(11):929-32.
9. Zhu Z, Guo D, Zhong C, Wang A, Xie X, Xu T, et al. Serum Dkk-1 (Dickkopf-1) is a potential biomarker in the prediction of clinical outcomes among patients with acute ıschemic stroke. Arterioscler Thromb Vasc Biol. 2019;39(2):285-93.
10. Nourane Y, Azab NY, El-Mahalawy II, Agha MA, El-Shazly RM, Hilal AA. The value of the assessment of serum and pleural Dikkopf-1 concentrations in the differentiation between malignant and non-malignant pleural effusions. Egypt J Chest Dis Tuberc. 2016;65(1):193-7.
11. Thunø M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers. 2009;27(3):157-72.
12. Bakker OG, Hemmes SN, Backes Y, Determann RM, Schultz MJ. SuPAR in pleural fluid may function as a biological marker for infe ction in critically ill patients with pleural effusions. J Infect. 2014;68(6):607-9.
13. Matzkies LM, Raggam RB, Flick H, Rabensteiner J, Feierl G, Hoenigl M, et al. Prognostic and diagnostic potential of suPAR levels in pleural effusion. J Infect. 2017;75(5):465-7.
14. Ozsu S, Oztuna F, Mentese A, Abul Y, Ozlu T. Diagnostic value of suPAR in differentiating noncardiac pleural effusions from cardiac pleural effusions. Clin Respir J. 2016;10(1):61-6.
15. Zimmermann HW, Reuken PA, Koch A, Bartneck M, Adams DH, Trautwein C, et al. Soluble urokinase plasminogen activator recep tor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality. J Intern Med. 2013;274(1):86-100.
16. Ergün B, Küçük M, Yakar MN, Öztürk MC, Bayrak V, Emecen AN, et al. Clinical significance of pleural lactate measurement in critically ill patients with parapneumonic pleural effusion. Thorac Res Pract. 2023;24(5):245-52.
17. Dağli AF, Küçük S, Sezer M, Uçer O. Cytopathologic diagnosis in pleural effusion and cyto-histopathologic correlation. Turk Patoloji Derg. 2011;27(1):12-6.
18. Erdoğan Duzcu S, Ozturk S. Seven-year retrospective analysis of pleural effusion cytologies and cyto-histopathological correlation. Curr Thorac Surg. 2023;8(1):8-15.
19. Arnold DT, Hamilton FW, Elvers KT, Frankland SW, Zahan-Evans N, Patole S, et al. Pleural fluid suPAR levels predict the need for ınvasive management in parapneumonic effusions. Am J Respir Crit Care Med. 2020;201(12):1545-53.
20. Song S, Jia Q, Chen X, Lei Z, He X, Leng Zet al. Serum suPAR associated with disease severity and mortality in elderly patients with community-acquired pneumonia. Scand J Clin Lab Invest. 2020;80(6):515-22.
21. Indumati V, Vijay V, Krishnaswamy D, Rajeshwari V, Ramesh A, Shantala D, et al. Serum levels of soluble urokinase plasminogen activator receptor (suPAR) as a marker of tuberculosis treatment efficacy. Indian J Tuberc. 2017;64(3):206–11.
22. Langkilde A, Hansen TW, Ladelund S, Linneberg A, Andersen O, Haugaard SB, et al. Increased plasma soluble uPAR level is a risk marker of respiratory cancer in initially cancer-free individuals. Cancer Epidemiol Biomarkers Prev. 2011;20(4):609-18.
23. Cobos E, Jumper C, Lox C. Pretreatment determination of the serum urokinase plasminogen activator and its soluble receptor in advanced small-cell lung cancer or non-small-cell lung cancer. Clin Appl Thromb Hemost. 2003;9(3):241-6.
24. Yalcin S, Demir M, Ozturk R, Kılınç A, Suer H, Karahan I. Prognostic effects of SuPAR and neopterin levels on patients with lung cancer. pteridines. 2020;31:136-41.
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Aslinur Dogan, Atalay Sahin, İclal Hocanli. Clinical importance of SUPAR and Dickkopf-1 level in the etiology of pleural effusion. Ann Clin Anal Med 2024;15(6):425-429
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Retrospective analysis of sociodemographic, laboratory, and imaging characteristics in patients with acute appendicitis
Gülbin Aydoğdu Umaç 1, Vermi Değerli 2
1 Department of Emergency Medical Services, Manisa Provincial Ambulance Service Chief Physician, Manisa, 2 Dempartment of Emergency, University of Health Science, Izmir Bozyaka Teaching and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.22147 Received: 2024-02-13 Accepted: 2024-04-02 Published Online: 2024-04-22 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):430-433
Corresponding Author: Gülbin Aydoğdu Umaç, Department of Emergency Medical Services, Manisa Provincial Ambulance Service Chief Physician, Manisa, Turkey. E-mail: dr.gulbinaydogdu@gmail.com P: +90 507 443 18 70 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9874-0343
Other Author ORCID ID: Vermi Değerli, https://orcid.org/0000-0002-8656-1305
This study was approved by the Ethics Committee of İzmir Bozyaka Education and Research Hospital (Date: 2015-03-24, No: 11)
Aim: This study aims to analyze the demographic, clinical, and laboratory characteristics of patients diagnosed with acute appendicitis, as well as the findings from ultrasonography (USG) and computed tomography (CT), to identify critical parameters in the diagnosis and the significance of early detection.
Material and Methods: A retrospective review was conducted on 315 patients diagnosed with acute appendicitis at a tertiary care hospital’s emergency department between January 1, 2014, and December 31, 2014. Data on demographic characteristics, clinical presentations, laboratory results, and imaging findings from USG and CT were collected and analyzed. Statistical analyses were performed using SPSS version 15.0, with significance set at p<0.05.
Results: Of the 315 patients, 77.8% (n=245) were male, and the majority were within the 18-28 (49.8%, n=157) and 29-39 (21.6%, n=68) age groups, aligning with literature benchmarks. The anatomical location of the appendix was predominantly normal (49.8%, n=157) and retrocecal (40.6%, n=128). Increased white blood cell counts were significantly associated with male gender and acute appendicitis diagnosis, particularly in cases with complications. Imaging findings supported the diagnosis in the majority of cases, with CT being particularly valuable in complex cases.
Discussion: The study underscores the importance of comprehensive clinical evaluation combined with targeted use of USG and CT in diagnosing acute appendicitis, highlighting the role of demographic and clinical factors in risk assessment. Early diagnosis emerges as a critical factor in preventing complications, emphasizing the need for prompt and accurate diagnostic approaches.
Keywords: Acute Appendicitis, Computed Tomography, Ultrasonography
Introduction
The appendix vermiformis is a tubular structure that is continuous with the cecum and terminates with a blind end. The inflammation of this structure is referred to as appendicitis. Acute appendicitis is one of the most common causes of abdominal pain encountered in emergency medical clinics and is among the pathologies that most frequently require surgical intervention among acute abdominal conditions [1, 2].
The diagnosis of appendicitis is made through the physician’s clinical examination, nonspecific laboratory tests, and radiological imaging methods used in suspicious cases. Although patients’ histories and physical examinations are generally sufficient for diagnosis, about 20-33% of cases may exhibit atypical symptoms [3, 4].
Delays in diagnosis can lead to serious complications such as abscesses, gangrene, perforation, generalized peritonitis, and phlegmon, which can significantly increase morbidity and mortality rates. Medical or surgical treatment plans based on clinical findings can increase the risks of negative laparotomy and complications associated with appendicitis. Therefore, the use of imaging methods in cases of acute appendicitis has gained importance today. Among the most commonly used imaging methods are ultrasonography (USG) and computed tomography (CT). While USG has high sensitivity and specificity in the diagnosis of appendicitis, it can give false negative results in cases of retrocecal appendicitis. On the other hand, CT is frequently used in differential diagnosis and in reducing the rate of negative appendectomy, offering high accuracy rates in the diagnosis of appendicitis [5, 6].
This study retrospectively examined the sociodemographic, laboratory, and imaging characteristics of cases diagnosed with acute appendicitis at the emergency department.
Material and Methods
This study retrospectively examined the data of patients who presented to the emergency department of a tertiary care hospital between January 1, 2014, and December 31, 2014, and were diagnosed with acute appendicitis histopathologically. The inclusion criterion for the study was patients whose diagnosis of acute appendicitis was confirmed histopathologically. Individuals under 18 years of age, pregnant women, and those who received a diagnosis other than acute appendicitis upon histopathological examination were excluded from the study. The demographic information of the patients, clinical features, laboratory and imaging findings, treatment methods, and outcomes were examined in detail. The analysis of the data was conducted using information obtained from the hospital’s electronic health record system.
Statistical Analysis
Statistical analyses were performed using SPSS version 15.0 (Statistical Package for the Social Sciences for Windows) software. The conformity of variables to normal distribution was thoroughly examined using both visual (histograms) and analytical methods (Kolmogorov-Smirnov and Shapiro-Wilk tests). Descriptive analyses for variables that conformed to normal distribution were presented with mean and standard deviation values. The independent samples t-test was preferred for the comparison of two independent groups. The Chi-square test was used for the comparison of categorical variables between groups, and the Kruskal-Wallis analysis, a non-parametric test, was applied for evaluating differences between groups. Analyses for binary group comparisons were conducted using the Mann-Whitney U test. The level of statistical significance was accepted for results with a p-value below 0.05.
Ethical Approval
This study was approved by the Ethics Committee of İzmir Bozyaka Education and Research Hospital (Date: 2015-03-24, No: 11).
Results
In this study, data from 315 patients diagnosed with acute appendicitis were analyzed. When examining the demographic data of the patients by gender and age groups; 77.8% (n=245) were male, and 22.2% (n=70) were female. Of the total 315 patients; 4.8% (n=15) were aged 65 and over, while 95.2% (n=300) were under 65 years of age. Among the 15 patients aged 65 and over; 46.7% (n=7) were male, and 53.3% (n=8) were female. Of the total 300 patients under 65; 79.3% (n=238) were male, and 20.7% (n=62) were female. The distribution according to the second age grouping in the study was: young age rate 54.2% (n=225); middle age 23.8% (n=75), and old age 26.0% (n=15). The study divided appendicitis locations into three groups: appendicitis in its normal position, retrocecal appendicitis, and others, which included diagnoses of subhepatic, pre-ileal, post-ileal, pelvic, and paracecal appendicitis. In patients diagnosed with acute appendicitis, 49.8% (n=157) had appendicitis in its normal position, while 40.6% (n=128) had retrocecal appendicitis (Table 1).
A relationship between gender and the mean value of white blood cell (WBC) count was examined, and a statistically significant increase was found (p=0.045). The mean WBC count in males was found to be significantly higher than that in females (p=0.045). When the relationship between the ages of the patients included in the study and their WBC values was examined, a statistically significant difference emerged in terms of WBC levels (p<0.001). When WBC values were examined according to the location of appendicitis, the mean WBC count for those diagnosed with appendicitis in its normal position was 13,250/mm³, while for those with retrocecal appendicitis, the mean WBC count was 11,890/mm³. A significant difference was found in terms of mean WBC counts according to the location (p=0.007).
When evaluating the findings supporting the diagnosis of acute appendicitis detected by ultrasonography (USG) in terms of age: of the 300 patients under 65, USG was performed on 292 (97.3%), while direct CT imaging was done for 8 (2.7%) without USG. Of the 292 patients under 65 who had USG, 148 (50.7%) had USG findings supporting the diagnosis of acute appendicitis, whereas 144 (49.3%) had USG findings that did not support the diagnosis of acute appendicitis. There was no significant difference in terms of supportive findings in USG according to the location of appendicitis (p=0.526). Of the total 315 patients diagnosed with acute appendicitis, CT imaging was performed on 116 (35.8%), while 199 (63.2%) were given a surgical decision with USG without CT imaging (Table 2).
When evaluating the complications in patients, perforation occurred in 35 (11.1%), abscess developed in 4 (1.3%), and 276 (87.6%) did not develop any complications. In the 39 (12.4%) patients who developed complications, no significant difference was found in the type of complication (perforation, abscess) developed according to gender (p=0.141). A significant difference was observed between age groups in terms of the occurrence of complications (p<0.001). When analyzing those who developed complications according to the location of appendicitis: of the total 157 patients diagnosed with appendicitis in its normal position; 20 (12.7%) developed perforation, 2 (1.3%) developed an abscess, and 135 (86%) did not develop any complications. Of the total 128 patients diagnosed with retrocecal appendicitis; 8 (6.3%) developed perforation, while 125 (93.8%) did not develop any complications. The occurrence of complications was statistically significant in patients with appendicitis in its normal position compared to those with retrocecal appendicitis (p=0.034). No abscess development was observed in patients with retrocecal appendicitis (Table 3).
Discussion
This study encompasses a retrospective review of 315 patients who presented to an emergency medicine clinic and were histopathologically confirmed to have acute appendicitis following surgery. The findings indicate a majority of male patients (77.8%) and a significant proportion of young adults aged between 18-28 years (54.2%), which is consistent with the distribution reported in the literature [7-10]. Regarding the location of the appendix, 49.8% (157) of the cases were found to have the appendix in its normal position, while 40.6% (128) had retrocecal appendicitis, and these ratios are also in line with the prevalent literature [11,12].
The early diagnosis of acute appendicitis is of vital importance for patients, especially in preventing appendix perforation, one of the most common complications of appendicitis. Perforation can significantly increase morbidity and mortality rates in patients with appendicitis. Early diagnosis and prompt intervention can keep the inflammation localized, thereby preventing more serious complications such as peritonitis, abscess formation, and sepsis. Furthermore, early treatment reduces the length of hospital stay, decreases treatment costs, and facilitates faster recovery for patients. Therefore, making a rapid and accurate diagnosis in patients suspected of having acute appendicitis, timely applying optimal treatment methods, and preventing potential complications are of great significance. This process requires the effective use of clinical assessment, laboratory tests, and appropriate imaging techniques, thereby significantly improving patient outcomes through early intervention.
In this study, an increase in the frequency of appendicitis with a normal location was observed with age, a finding for which there are few studies in the literature. The analysis of leukocytosis by gender, where male patients’ mean WBC count was found to be statistically significantly higher than that of females, aligns with results found in the literature [13]. It is well-known that white blood cell count is commonly used in the diagnosis of acute appendicitis and is considered a reliable parameter [14].
The differences in WBC values between age groups appear to indicate an increased risk of complications with age. Young age, male gender, and high leukocytosis are recognized in the literature as determinant factors for the risk of acute appendicitis, and our study supports these findings [15]. When examining WBC values according to the location of appendicitis, it was found that the mean WBC count of cases with the appendix in its normal position was higher than that of retrocecal cases, and this difference was statistically significant.
In patients who developed perforation, WBC values were significantly higher compared to those who did not develop perforation; however, there are conflicting findings on this matter in the literature [16]. In the diagnosis of acute and perforated appendicitis, besides white blood cell levels, CRP and bilirubin values are also used as auxiliary biomarkers. It is known, however, that despite these markers having high specificity, their sensitivity is generally low [17].
Ultrasonography (USG) and computed tomography (CT) are used as primary examination methods in the diagnosis of acute appendicitis. In our study, an increase in the diagnostic value of USG and CT, especially in cases with complications, was observed. However, the fact that these imaging methods were not used in every patient represents a limitation of the study. The high rates of negative appendectomies and the high risk of complications mentioned in the literature highlight the importance of timing in surgical decisions and diagnostic approaches.
Limitation
Our study has several significant limitations. First, due to the retrospective design’s nature, factors such as missing data or recording errors in the records could affect the interpretation of our findings. Second, our study population possesses limited demographic characteristics, and special patient groups such as pregnant women and children were excluded from the study. This may limit the generalizability of our results. Additionally, since this study was conducted at a single center, caution should be exercised regarding the applicability of the findings to populations in different healthcare institutions or geographical regions.
Conclusion
This study has highlighted the determinative factors in the early diagnosis of the disease by presenting a retrospective analysis of demographic characteristics, clinical signs, laboratory parameters, and findings from USG and CT in patients diagnosed with acute appendicitis. It was particularly found that male gender and young adults are at a higher risk for acute appendicitis; the WBC count and the anatomical position of the appendix are of key importance in the diagnostic process. In cases at risk of complications, a significant increase in the diagnostic accuracy of USG and CT was observed. These findings support the importance of a multidisciplinary approach and early diagnosis strategies in the diagnosis of acute appendicitis, shedding light on critical decision-making points in patient management.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Tekyol D, Ak R, Hökenek NM, Kılıç M, Tekyol KK, Erdoğan D. A comparative study of the RIPASA and Alvarado scores in geriatric patients diagnosed with acute appendicitis. Rev Assoc Med Bras. 2022;68(9):1308-12.
2. Moris D, Paulson EK, Pappas TN. Diagnosis and management of acute appendicitis in adults: A Review. JAMA. 2021;326(22):2299-2311.
3. Lane MJ. Unenhanced helical BT for suspeBTed acute apandicitis. Am J Roentgenol. 1997;168(2):405-9.
4. Whitley S, Sookur P, McLean A, Power N. The appendix on CT. Clin Radiol. 2009;64(2):190-9.
5. Arruzza E, Milanese S, Li LSK, Dizon J. Diagnostic accuracy of computed tomography and ultrasound for the diagnosis of acute appendicitis: A systematic review and meta-analysis. Radiography (Lond). 2022;28(4):1127-41.
6. Hoffmann JC, Trimborn CP, Hoffmann M, Schröder R, Förster S, Dirks K, et al. Classification of acute appendicitis (CAA): Treatment directed new classification based on imaging (ultrasound, computed tomography) and pathology. Int J Colorectal Dis. 2021;36(11):2347-60.
7. Saaiq M, Niaz-Ud-Din, Jalil A, Zubair M, Shah SA. Diagnostic accuracy of leukocytosis in prediction of acute appendicitis. J Coll Physicians Surg Pak. 2014;24(1):67-9.
8. Patmano M, Çetin DA, Gümüş T. Akut apandisitte perforasyonu öngörmede kullanılan laboratuvar belirteçleri [Laboratory markers used in the prediction of perforation in acute appendicitis]. Ulus Travma Acil Cerrahi Derg. 2022;28(7):960-6.
9. Dzabic M, Boström L, Rahbar A. High prevalence of an active cytomegalovirus infection in the appendix of immunocompetent patients with acute appendicitis. Inflamm. Bowel Dis. 2008;14:236-41.
10. Walker A, Hatch Q, Drake T, W Nelson D, Fitzpatrick E, Bingham J, et al. Predictors of appendiceal perforation in an equal access system. J Surg Res. 2014;190(1):87-92.
11. Wakeley CP. The position of the vermiform appendix as ascertained by an analysis of 10,000 cases. J Anat. 1933;67:277-83.
12. Börekçi H, Karacabey S, Sipahi M, Özdemir ZT, Erkoç MF. A rare case: Retrocecal appendicitis adherent to the liver capsule. Turk J Surg. 2015;33(3):227-9.
13. Ak R, Doğanay F, Akoğlu EU, Akoğlu H, Uçar AB, Kurt E, et al. Predictive value of scoring systems for the diagnosis of acute appendicitis in emergency department patients: Is there an accurate one? Hong Kong J. Emerg. Med. 2019;27(5):262–9.
14. Howell EC, Dubina ED, Lee SL. Perforation risk in pediatric appendicitis: Assessment and management. Pediatric Health Med Ther. 2018;9:135-45.
15. Sharma P, Jain A, Shankar G, Jinkala S, Kumbhar US, Shamanna SG. Diagnostic accuracy of Alvarado, RIPASA and Tzanakis scoring system in acute appendicitis: A prospective observational study. Trop Doct. 2021;51(4):475-81.
16. Er S, Çomçalı B, Soykurt A, Cavit Yüksel B, Tez M. Diagnosis of appendicitis in patients with a normal white blood cell count; a cross-sectional study. Bull Emerg Trauma. 2018;6(2):128-32.
17. Zosimas D, Lykoudis PM, Strano G, Burke J, Al-Cerhan E, Shatkar V. Bilirubin is a specific marker for the diagnosis of acute appendicitis. Exp Ther Med. 2021;22(4):1056.
Download attachments: 10.4328.ACAM.22147
Gülbin Aydoğdu Umaç, Vermi Değerli. Retrospective analysis of sociodemographic, laboratory, and imaging characteristics in patients with acute appendicitis. Ann Clin Anal Med 2024;15(6):430-433
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An overview of the demographics, diagnoses, and analysis of patients transported by ambulance to the emergency department
Ergül Kozan 1, Özlem Güneysel 2
1 Department of Emergency Medicine, Kartal Dr. Lütfi Kırdar City Hospital, 2 Department of Emergency Medicine, Faculty of Medicine, Maltepe University, Istanbul, Turkey
DOI: 10.4328/ACAM.22164 Received: 2024-02-29 Accepted: 2024-04-02 Published Online: 2024-04-23 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):434-438
Corresponding Author: Ergül Kozan, Department of Emergency Medicine, Kartal Dr. Lütfi Kırdar City Hospital, Istanbul, Turkey. E-mail: dr.ergul@hotmail.com P: +90 530 516 08 44 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5268-805X
Other Authors ORCID ID: Özlem Güneysel, https://orcid.org/0000-0002-1833-2199
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2014-11-11, No: 3)
Aim: This study aims to analyze the demographic characteristics of patients transported by ambulance to the emergency department (ED), their preliminary diagnoses during the pre-hospital phase, and their initial diagnoses and hospital outcomes after evaluation in the hospital.
Material and Methods: This was a prospective, cross-sectional descriptive study. Data were obtained from the emergency medicine physician’s patient forms in the hospital information system. The analysis included patients’ demographic characteristics, admission times, and status at the ED.
Results: A total of 633 patients who met the inclusion criteria were examined in this study. The demographic breakdown included 56.5% male (n=358) and 43.5% female patients (n=275), with ages ranging from 1 to 110 years and a mean age of 53.10 ± 24.59 years. Approximately one-third of the cases were geriatric patients. Nearly half of the patient admissions to the ED occurred between 16:00 and 24:00. Trauma was the predominant reason for ambulance transports, with most cases originating from the patients’ homes. The majority were discharged as outpatients from the ED. Despite geriatric patients constituting a significant portion of ambulance transports, their admissions to the ED were evenly distributed throughout the 24-hour cycle. Ambulances were primarily used for trauma and neurological disorders. Admissions after midnight were significantly lower than those before midnight. Although diagnostic concordance between ambulance and ED was generally high, it was lowest among the elderly (over 85 years of age). Additionally, the level of diagnostic agreement was consistent across different EMS teams, regardless of whether they were physicians, paramedics, or EMTs.
Discussion: Pre-hospital diagnoses made by EMS personnel may be less accurate for older patients.
Keywords: Ambulance, Emergency Department, Prehospital, Outcome
Introduction
The rising life expectancy today underscores the importance of high-quality healthcare services. In this context, advancements in emergency health services are particularly beneficial. Emergency departments (EDs), known for their rapid and effective interventions, alongside ambulances equipped to provide emergency health services, bear significant responsibility. A pivotal element in swift response is the role of tertiary EDs, which manage complex cases, relying extensively on ambulances for patient transport.
According to the American College of Emergency Physicians, individuals who identify themselves as “emergency patients” and seek care in the ED should be classified as emergency cases [1]. The transportation of ill and injured persons is a critical component of emergency and first aid care, with the initial contact, diagnosis, and intervention being essential parts of the pre-hospital process. In terms of emergency medical services (EMS), Turkey follows the Anglo-American model, where ambulances, staffed with professional teams and equipped for emergencies, are dispatched by Command and Control Centers upon receiving a call (112). These teams are prepared to provide both basic and advanced life support to individuals outside of hospital settings in emergencies. Ambulances serve as a cornerstone of the healthcare system, staffed by paramedics, doctors, and emergency medical technicians (EMTs). However, ambulance drivers are not always healthcare professionals; their duties include patient and equipment transport, offering preliminary treatment for infectious diseases, and supporting emergency patient transport. Beyond their primary role in emergency medical care, these activities are crucial for disaster response efforts [2-4].
Ambulances are vehicles specifically designed and equipped with the necessary technical and medical equipment for emergency assistance and patient transportation. The pre-hospital ambulance service (112) plays a crucial role in transferring emergency patients—who are impaired or at risk of impairment—to hospitals, while monitoring vital signs and providing necessary interventions en route. Beyond emergency department (ED) treatment, pre-hospital health services ensure patients receive quality care before reaching the hospital. The demand for prehospital healthcare services is increasing daily [5, 6], placing a strain on available resources when utilized for non-emergency purposes. Factors influencing ambulance service usage rates may include socioeconomic status, age, and illness severity. EDs and prehospital services collaborate to deliver medical services under challenging conditions [7, 8]. The objective for clinicians working in EDs is to provide high-quality service and enhance the quality of life for both themselves and their patients in this demanding and complex environment [9]. Achieving this level of quality requires seamless integration of diagnosis and treatment.
This study aims to evaluate the effectiveness of the prehospital system and to ascertain the demographic, clinical, and hospital outcomes of patients transported by ambulance to the ED of a tertiary hospital.
Material and Methods
In this prospective cross-sectional study, 633 patients brought by ambulance to our ED between November 1, 2014, and November 30, 2014, were examined. The hospital features three distinct EDs: one for adults, one for pediatrics, and one for gynecology. The adult ED treats trauma patients and those older than 13 years, with a dedicated trauma area for patients of all ages.
The emergency medicine physician who first encountered the patients recorded and managed their information. Ambulance healthcare professionals made preliminary diagnoses and noted the patients’ pickup locations. This study included adult patients aged 18 and above, encompassing trauma cases, who were transported to the adult ED by ambulance. Parameters such as age, gender, and admission time were analyzed, along with the agreement between 112 health workers and ED staff on preliminary diagnoses and discharge statuses. Patients were divided into six age groups: 0-13, 14-25, 26-45, 46-65, and over 65 years old. The day was segmented into three intervals: 00:00-08:00, 08:00-16:00, and 16:00-24:00.
Patient origin locations were categorized as home, street, nursing home, other healthcare facility, and other. The outcomes for patients presenting to the ED were classified as discharge, ICU admission, ward hospitalization, treatment refusal-unauthorized abandonment, and death. Predicted diagnoses by ambulance and ED staff were organized by system. Exclusions from the study were patients with incomplete or inadequate records and those directed to pediatric and gynecological EDs.
Statistical analysis
Statistical analysis of the data collected from study participants was conducted using SPSS software for Windows (Version 29, Chicago, IL, USA). Descriptive statistics, including mean, standard deviation (SD), median, minimum and maximum values, frequency, and ratio, were employed to summarize the data. The distribution of the variables was assessed using point biserial correlation analysis. Logistic regression analysis was utilized for examining the dependent quantitative variables. Additionally, Pearson correlation analysis was applied to investigate the relationships between variables.
Ethical Approval
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2014-11-11, No: 3).
Results
Between November 1 and 30, 2014, a comprehensive analysis of 633 patients transported by ambulance to our ED was conducted. The demographic breakdown revealed a majority of male patients (56.5%, n=358) with a wide age range from 1 to 110 years, averaging at 53.10 years. The detailed distribution of preliminary diagnoses, highlighting trauma and neurological conditions as the most common, is summarized in Table 1. Transport origins showed a significant proportion of patients arriving from homes (54.2%, n=343), particularly older females, indicating a potential pattern in emergency calls and responses, as further elucidated in Table 1. Analysis of arrival times revealed a higher incidence of admissions during the latter half of the day (16:00-24:00, 42.8%, n=271), though no significant time-dependent variation in trauma rates was observed. The outcomes of these admissions, ranging from discharge to ICU admissions and deaths, are detailed in Table 2. Special attention was given to the elderly and advanced age groups, uncovering notable differences in gender distribution and diagnostic agreement rates between hospital and ambulance services for those over 65, as shown in Table 3. The composition of ambulance teams and their agreement with hospital diagnoses were also analyzed, showing no significant difference in diagnostic concordance across physician, EMT, and paramedic-led teams.
Discussion
In this study, we analyzed data from patients transported by ambulance to the ED of a tertiary education and research hospital. The data collected indicate that a majority of these cases involve male patients. The predominant patient demographics include the elderly and those suffering from trauma. A comparison between ambulance diagnoses and hospital diagnoses revealed that patients younger than 85 years exhibit higher concordance rates in diagnoses than those older than 85 years.
Nearly half of the cases belong to the geriatric age group, with a significant proportion (25%) being patients over the age of 85. Similar studies have identified a comparably high prevalence of elderly individuals [10-12]. Despite overall higher ambulance utilization rates among men, women over the age of 65 were more likely to use ambulance services. When comparing groups aged over 65 with those between 65-85 years and those aged over 85, the rate of ambulance use among women in the advanced age group was statistically higher than that among men. The ambulance utilization rates observed in this study are consistent with those reported in the literature [13]. Our data on trauma cases revealed a significantly higher male-to-female ratio. A study by Akoğlu et al. at Marmara University Hospital’s ED, located in proximity to our study site, reported a high percentage of male patients among trauma admissions [14].
This study revealed that prediagnosis agreement rates were significantly higher in patients who had experienced trauma compared to those who had not, upon comparing hospital and ambulance prediagnosis agreements. Further analysis of prediagnosis agreement rates between the age groups of 65–85 years and those over 85 years indicated that the agreement rate was significantly higher in the 65-85 year-old group.
We also discovered that ambulance admissions were statistically significantly lower between 24:00 and 8:00 hours compared to other times of the day. The majority of ambulance admissions occurred between 16:00 and 24:00; however, no significant difference was observed between the time intervals of 08:00-16:00 and 16:00-24:00. This finding aligns with the study conducted by Kıdak et al., which reported the highest number of emergency calls during evening hours and the lowest after midnight. Similarly, a study by Yaylacı et al., conducted in the same city, found no significant differences in ambulance admissions between on-hours and off-hours [15]. Even in a bustling city like Istanbul, where activity spans throughout the day, admissions dwindle after midnight, likely because the majority of people are asleep. The lack of distinction between working and non-working hours in Yaylacı’s study may be attributed to private health insurance coverage for ambulance-admitted patients. In our study, the majority of ambulance admissions originated from patients’ homes. Conversely, a study by Önge conducted in an Emergency Department in Adana, another city, found that most patients were transported from home by ambulance [16].
In our study, trauma patients comprised the majority of those transported by ambulance to the Emergency Department (ED), with diseases of the neurological and respiratory systems ranking second and third, respectively. This finding contrasts with Zenginol et al., who reported trauma, cardiovascular disease, and neurological disease as the most common reasons for ambulance transport [11]. Similarly, Oktay et al. identified trauma, cardiovascular disease, and neurologic disorders as the primary preliminary diagnoses [17]. The absence of a cardiology service at our hospital, coupled with our proximity to a specialized cardiology branch hospital, likely explains the reduced number of cardiovascular patients arriving by ambulance.
Our hospital is equipped with trauma-related specialities available 24 hours a day, enabling immediate, comprehensive surgical and multidisciplinary treatment of trauma cases. This capability underlies the high incidence of trauma admissions observed. Approximately two-thirds of trauma patients were discharged following outpatient interventions. Those requiring hospitalization were predominantly admitted to the orthopedics and general surgery wards, with trauma-related discharges representing a significantly larger fraction of total discharges. Interestingly, cases necessitating ICU hospitalization and those resulting in death exhibited a lower level of trauma severity. Despite a high percentage (79.1%) of geriatric patients requiring ICU hospitalization, no significant age-related differences were observed between the 65-85 and over-85 age groups. Furthermore, the majority of hospitalized patients who succumbed to their conditions were over the age of 65.
The study demonstrated that there was a significant concordance between the preliminary diagnoses made by ambulance paramedics and the final diagnoses confirmed by the hospital. This correlation was consistent regardless of whether the ambulance team was composed of doctors, paramedics, or Emergency Medical Technicians (EMTs).
Limitation
This study, while providing valuable insights into the concordance of preliminary diagnoses and the demographics of ambulance admissions, is not without its limitations. The reliance on ambulance-based data may not fully capture the spectrum of emergencies presented to the ED, particularly given the absence of a cardiology service at the hospital which potentially skews the type of cases being transported by ambulance. Furthermore, the findings regarding the impact of age on preliminary diagnosis accuracy and the non-uniform distribution of admission times suggest that these factors might influence the study’s outcomes. Additionally, the generalizability of these results may be limited by the study’s setting in a specific hospital and its proximity to specialized facilities, which might not reflect the broader emergency care context. Future research could benefit from a more comprehensive approach that includes a wider range of emergency services and accounts for the variations in healthcare delivery systems across different regions.
Conclusion
The analysis revealed that age may serve as a confounding factor in the accuracy of preliminary diagnoses made by clinicians during the prehospital phase for patients admitted to the ED via ambulance. Despite a predominant number of admissions being trauma-related, the distribution of admission times was found to be non-uniform.
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. Definition of emergency medicine and the emergency physician. American College of Emergency Physicians. Ann Emerg Med. 1986;15(10):1240-1.
2. Bresnahan KA, Fowler J. Emergency medical care in Turkey: Current status and future directions. Ann Emerg Med. 1995;26(3):357-60.
3. Yealy DM. Emergency Medical Services in Our Journal: 50 Years and Counting. Ann Emerg Med. 2022;80(6):481-3.
4. Yilmaz S, Coban GS, Colak FU, Karcioglu O. Coping with difficulties faced in pre-hospital healthcare amid pandemics. Signa Vitae. 2022;18(3);47-55.
5. Katayama Y, Kitamura T, Nakao S, Himura H, Deguchi R, Tai S, et al. Telephone triage for emergency patients reduces unnecessary ambulance use: A propensity score analysis with population-based data in Osaka City, Japan. Front Public Health. 2022;28(10):896506.
6. Razon N, Gottlieb LM, Fraze T. Essential not supplemental: Medicare advantage members’ use of non-emergency medical transportation (NEMT). J Gen Intern Med. 2023;38(16):3566-73.
7. Yılmaz S. Problems and overcoming methods of emergency medicine specialists working at border points. Disaster Med Public Health Prep. 2022;16(2):683-8.
8. Yilmaz S, Ak R, Hokenek NM, Yilmaz E, Tataroglu O. Comparison of trauma scores and total prehospital time in the prediction of clinical course in a plane crash: Does timing matter? Am J Emerg Med. 2021;50:301-8.
9. Orhan AF, Yılmaz S, Altındağ Orhan EA, Karcıoğlu Ö. The relationship between mindfulness and styles of coping with stress and depression in emergency medicine residents working in İstanbul. Glob Emerg Crit Care. 2022;1:70-5.
10. Shah MN, Bazarian JJ, Lerner EB, Fairbanks RJ, Barker WH, Peggy Auinger P, et al. The epidemiology of emergency medical services use by older adults: An analysis of the National Hospital Ambulatory Medical Care Survey. Acad Emerg Med. 2007;14(5):441-7.
11. Zenginol M, Al B, Gen S, Deveci İ, Yarbil P, Yılmaz D, et al. Gaziantep’ li 112 Acil ambulanslarinin 3 yillik çalisma sonuçlari [3 yearly study results of 112 emergency ambulances in the city of Gaziantep]. Eurasian J Emerg Med. 2011;10(1):27-32.
12. Kıdak L, Keskinoğlu P, Sofuoğlu T, Olmezoğlu Z. İzmir ilinde 112 acil ambulans hizmetlerinin kullanımının değerlendirilmesi [Evaluation of the use of 112 emergency ambulance services in Izmir province]. Genel Tıp Derg. 2009;19:113-9.
13. Nur N, Demir ÖF, Çetinkaya S, Tirek N. Yaşlılar Tarafından Kullanılan 112 acil sağlık hizmetlerinin değerlendirilmesi [Evaluation of 112 emergency health services used by the elderly]. Turk J Geriatr. 2008;11:7-11.
14. Akoğlu H, Denizbaşı A, Ünlüer E, Güneysel Ö, Onur Ö. Marmara üniversitesi hastanesi acil servisine başvuran travma hastalarının demografik özellikleri [Demographic characteristics of trauma patients admitted to Marmara University Hospital emergency department]. Marmara Med J. 2015;18:113–22.
15. Yaylacı S, Öztürk TC, Yılmazer SÇ. Acil servise ambulansla başvuran hastaların aciliyetinin retrospektif değerlendirilmesi [Retrospective evaluation of the urgency of patients applying to the emergency department by ambulance]. ACU Sağlık Bil. 2013;4:64-7.
16. Önge T, Satar S, Kozacı N, Açıkalın A, Köseoğlu Z, Gülen M, et al. Analysis of patients admitted to the emergency medicine department by the 112 emergency service. J Acad Emerg Med. 2013;12:150-4.
17. Oktay İ, Kayışoğlu N. Tekirdağ ili 112 acil sağlık hizmetlerinin değerlendirilmesi [Evaluation of 112 emergency health services in Tekirdağ province]. STED. 2005;14:35-7.
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Ergül Kozan, Özlem Güneysel. An overview of the demographics, diagnoses, and analysis of patients transported by ambulance to the emergency department. Ann Clin Anal Med 2024;15(6):434-438
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Evaluation of maternal and fetal outcomes in pregnant women with gestational thrombocytopenia
Nebahat Sunar 1, Mulaim Sizer 1, Hamdin Günsel 1, Gülten Çirkin Tekeş 2, Dicle Akkılıç Dönmez 3, Mehmet Sait İçen 4
1 Department of Obstetrics and Gynecology, Batman Training and Research Hospital, Batman, 2 Department of Perinatology, Etlik City Hospital, Ankara, 3 Department of Obstetrics and Gynecology, Dagkapi State Hospital, Diyarbakir, 4 Department of Obstetrics and Gynecology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
DOI: 10.4328/ACAM.22186 Received: 2024-03-20 Accepted: 2024-05-13 Published Online: 2024-05-30 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):439-443
Corresponding Author: Mulaim Sizer, Department of Obstetrics and Gynecology, Batman Training and Research Hospital, Batman, Turkey. E-mail: mulayimsizer@hotmail.com P: +90 506 856 42 85 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4864-7287
Other Authors ORCID ID: Nebahat Sunar, https://orcid.org/0000-0002-5404-1241. Hamdin Günsel, https://orcid.org/0000-0001-5963-1147 . Gülten Çirkin Tekeş, https://orcid.org/0000-0002-2564-2435 . Dicle Akkılıç Dönmez, https://orcid.org/0000-0002-0755-7480 . Mehmet Sait İçen, https://orcid.org/0000-0001-7982-1407
This study was approved by the Ethics Committee of the Dicle University, Faculty of Medicine Non-Invasive Clinical Research (Date: 2021-09-21, No:38)
Aim: Investigate the relationship between gestational thrombocytopenia (GT) and adverse maternal and fetal outcomes in pregnant women.
Material and Methods: 97 patients who were diagnosed with gestational thrombocytopenia during pregnancy, had no other disease that causes thrombocytopenia and delivered in our clinic were included in the study. The patients were divided into two groups according to their platelet values. Group-1 platelet count was <70.000/mm3 and Group-2 platelet count was 70.000- 150.000/mm3. In the analysis of negative perinatal outcomes, logistic regression analysis was performed. P <0.05 was considered significant in the analysis results.
Results: From the laboratory data of the patients diagnosed with gestational thrombocytopenia, the mean platelet count was 85.28±27.08 (min-max: 22-142) and mean hematocrit was 35.91±3.63 (min-max: 21-45). When the groups were evaluated considering their hematocrit values; the mean hematocrit value of the patients in Group-2 (36.42 ± 3.22) was higher than the mean hematocrit value (34.26 ± 4.39) of the patients in Group-1, and a significant difference was found between them (p:0.03). This significant difference was also present when the platelet value was taken as the limit of 110,000 (p:0.039).
Discussion: Apgar scores are lower in patients diagnosed with gestational thrombocytopenia and with platelet values below 70,000, and the need for blood transfusion (erythrocyte suspension, FFP (Fresh Frozen Plasma) and platelet product) is higher. The need for erythrocyte transfusion continues even when the platelet limit is 80,000, and the need for platelet transfusion is 100,000.
Keywords: Gestational Thrombocytopenia, Pregnancy, Adverse Maternal and Fetal Outcomes
Introduction
Thrombocytopenia is defined as a platelet count of less than 150.000/mm3 and is observed in 7-10% of pregnancies [1]. Thrombocytopenia can be classified as severe (<50.000/mm3), moderate (50-100.000/mm3) and mild (>100.000/mm3) according to platelet count. Although platelet count decreases slightly in normal pregnancies, the level remains within normal limits [2]. Most studies have reported a decrease in platelet count during pregnancy, leading to levels that are approximately 10% lower at term than pre-pregnancy levels [3, 4].
Thrombocytopenia is the most common hematologic disease after anemia in pregnancy. Although there are many causes of thrombocytopenia observed in pregnancy, the gestational week is very important in the differential diagnosis. Autoimmune causes are mostly involved in the etiology of thrombocytopenia observed in early gestational weeks [5]. Thrombocytopenia may be associated with pregnancy-related conditions such as preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), which account for approximately 18% of cases, or various diseases such as idiopathic thrombocytopenic purpura, which accounts for approximately 5% of cases [6]. Thrombocytopenia may cause some adverse perinatal outcomes. Babies of mothers with moderate and severe thrombocytopenia have a high risk of low 5th minute APGAR score, fetal growth restriction (FGR), and stillbirth [7, 8].
In our study, we aimed to investigate the maternal and fetal outcomes of gestational thrombocytopenia and the relationship between these outcomes and the degree of thrombocytopenia by forming subgroups according to platelet counts.
Material and Methods
This study is a hospital-based retrospective case study including pregnant women with gestational thrombocytopenia who were admitted to the Gynecology and Obstetrics Clinic of Dicle University Faculty of Medicine Hospital between January 2010 and May 2021 and whose delivery took place in our clinic. Demographic and laboratory data of the patients were analyzed. Patients were called by phone and information was obtained on whether they had a recurrence in the next pregnancy. Patients with a platelet count of <150.000/mm3 as a result of a complete blood count performed 2 times in our clinic were included in the study. Patients were divided into two groups according to platelet counts. Group-1 was formed as platelet count <70.000/mm3 and Group-2 as platelet count 70.000- 150.000/mm3, and the subgroups were compared among themselves.
Diagnosis of thrombocytopenia before pregnancy, bleeding profile disorder, ITP, use of acetic salicylic acid and/or low molecular weight heparin or unfractionated heparin, hepatic or renal dysfunction, venous thrombosis, hepatitis, sepsis, viral and/or bacterial infection, autoimmune disease, use of drugs affecting platelet function or production, Pregnant women with hereditary factor deficiency such as vWF, bone marrow diseases such as leukemia, lymphoma, patients receiving IVIG and/or steroids, pregnancy-induced preeclampsia, gestational cholestasis, HELLP, disseminated intravascular coagulation (DIC) and diseases affecting liver and kidney function were excluded. Spontaneous singleton pregnancies without fetal ultrasonographic and/or cytogenetic fetal anomalies were included in the study. Pregnant women with fetal anomalies, intracranial hemorrhage on ultrasound and/or fetal MRI, intrauterine fetal intervention and multiple pregnancies were excluded.
Statistical Analysis
The data obtained from the study were analyzed using the SPSS package program (Statistical Package for Social Sciences; IBM SPSS Statistics for Macintosh, Armonk, NY) version 25. Descriptive analyses were presented as number (n) and percentage (%) for categorical data and mean±standard deviation (mean±standard deviation) for continuous data. Pearson chi-square test was used to compare categorical variables between groups. The compatibility of continuous variables with normal distribution was evaluated by Kolmogorov-Smirnov test. Mann Whitney U-test was used to compare variables that did not show the normal distribution in two groups. In the comparison of more than two groups, One Way ANOVA test was used for parametric variables and Kruskal Wallis test was used for non-parametric variables. The statistical significance level was accepted as p<0.05 in the analyzes.
Ethical Approval
This study was approved by the Ethics Committee of the Dicle University, Faculty of Medicine Non-Invasive Clinical Research (Date: 2021-09-21, No:38).
Results
The mean age of all patients included in the study was 29.36 ± 5.32 (min-max: 18- 41) years. The mean gravida was 3.82 ± 2.31 (min-max: 1-11), parity 2.26 ± 1.96 (min-max: 0-10), abortion 0.58 ± 1.02 (min-max: 0-5) and number of live births 2.15 ± 1.79 (min-max: 0-8).
Of a total of 97 patients included in the study, 88.65% (n= 86) delivered between 37-42 weeks, i.e. at term, 10 patients (10.30%) delivered between 34-37 weeks (early term) and 1 patient (1.03%) delivered at <34 weeks, i.e. preterm. There were no obstetric complications in 90.70% (n= 88) of our patients. A total of 9 patients (9.30%) had complications, including preterm-early term labor and fetal distress in three patients each, an incomplete uterine rupture in two patients, and atony in one patient. Of our 97 patients, 91 (93.80%) did not require intensive care, while 6 (6.20%) patients required maternal intensive care. Patients’ gestational week of delivery, obstetric complication status and maternal intensive care needs are shown in Table 1.
Neonatal intensive care was not needed in 86 (88.60%) neonates, while 11 (11.40%) patients needed neonatal intensive care. When the neonatal platelet value was analyzed, it was determined that this information was not available for 5 babies, platelet value was above 150 thousand in 85 babies, whereas this value was lower than 150 thousand in 7 babies. Small for gestational age (SGA) was present in 7 of the newborns and 90 babies (92.80%) did not have SGA (Table 2). When the need for blood transfusion was analyzed in our study, it was determined that 75 (77.30%) patients did not receive blood transfusion and 22 (22.70%) patients received blood transfusion. Eythrocyte, FFP and platelet suspension were given as blood transfusions. When the distribution of these transfusions was analyzed, it was determined that 88 patients received no RBCs, 5 patients (5.2%) received one unit of RBCs, 2 patients (2.1%) received two units of RBCs, and one patient each received 3 and 6 units of RBCs. 92 patients received no FFP, 3 patients received 2 units, and one patient each received 3 and 4 units of FFP. 77 patients did not receive platelets, 12 patients received one unit, 5 patients received 2 units, 2 patients received 3 units and 1 patient received 5 units of platelets. The 1st and 5th minute APGAR scores of the babies born from the patients included in the study were analyzed. The mean 1st minute APGAR score was 6.1 ± 1.5 (min-max: 3-10), while the mean 5th minute APGAR score was 8.4 ± 1.0 (max: 6-10).
There was a significant difference in hematocrit values, and the mean hematocrit value of the patients in Group-2 (36.42 ± 3.22) was higher than the mean hematocrit value of the patients in Group-1 (34.26 ± 4.39) (p:0.03). Similarly, Group-2 ALT values (16.27 ± 10.89) were significantly higher than Group-1 ALT values (13.52 ± 9.57) (p:0.01). The mean APGAR at 5 minutes was significantly higher in Group-2 (8.49 ± 0.97) compared to Group-1 (7.96 ± 0.88) (p:0.01) ( Table-3).
We also compared the need for blood transfusion between Group 1 and Group 2 and which blood products were administered for transfusion in transfused patients. The rate of need for blood transfusion in Group-1 patients (60.90%) was significantly higher than in Group-2 patients (p: 0.001). The need for erythrocyte suspension in patients in Group-1 was statistically significantly higher (p: 0.033). Even when an 80,000 platelet count was taken as the limit, the need for erythrocyte transfusion was found to be significantly higher (p: 0.002).
Discussion
With this study, in parallel with the literature, we concluded that GT does not cause preterm delivery. In the study published by Sadulla et al. in 2020, which included 802 pregnant women who gave birth with a diagnosis of gestational thrombocytopenia, the mean age of the patients was found to be 27 years [9]. According to a study published in 2021 by Fogerty et al; 460 (12%) of 3691 women who gave birth were diagnosed with GT and compared with a control group of 3231 patients without thrombocytopenia, excluding these patients. The mean age of patients diagnosed with GT was 33 years. When compared with the control group, no significant difference was found between them in terms of maternal age and gravida status [10]. In a study published by Şahin et al. in 2019, in which 240 healthy pregnant women and 80 pregnant women diagnosed with gestational thrombocytopenia were compared, the mean age of patients diagnosed with GT was 29, mean gravida was 3, mean parity was 1.9, and no significant difference was found between the control group in terms of maternal age and gravidity-parity [11]. Low platelet count in GT was not associated with gravidity and parity. Vaginal delivery is recommended in GT cases and cesarean section should be decided according to obstetric indications [8]. In the study conducted by Fogerty et al. 460 patients with a diagnosis of GT 68% of the patients had NVB, 28% had C/S and 3% had vaginal delivery after cesarean section. When compared with the control group with normal platelet count, the mode of delivery was found to be similar [10]. In another study by Sadulla et al., it was reported that 572 (71.3%) of 802 pregnant women with a diagnosis of GT delivered vaginally. In contrast, 230 (28.7%) patients were delivered by cesarean section due to obstetric indications (non-progressive trauma, fetal distress, oligohydramnios, breech presentation and repeat cesarean section) [9]. In our study, it was found that 33 (34%) of 97 pregnant women underwent vaginal delivery and 64 (66%) underwent cesarean section (C/S). As in the literature, indications for cesarean section in our study were determined according to obstetric reasons. However, contrary to other studies, the reason why the cesarean section rate was higher than the normal delivery rate was that patients with a history of repeated cesarean sections were more likely to apply to our hospital, which is a tertiary center.
According to current guidelines, vaginal delivery is considered safe when the platelet count is>30,000/mm3. For operative vaginal delivery or cesarean section, the safe platelet count should be at least 50,000 mm3 [12].
Severe thrombocytopenia detected during pregnancy is not an indication of termination of pregnancy. With etiology-directed treatment, pregnancy can be followed up without any risk for the mother-fetus [13]. In a study conducted by Elveđi-Gašparović et al. and published in 2016, the platelet count was found to be 50,000/mm3-100,000/mm3 in 38 and <50,000/mm3 in 12 of 50 patients diagnosed with gestational thrombocytopenia. When compared with the control group with platelet counts within normal limits, it was found that GT had no significant effect on mode of delivery and preterm delivery, although the platelet counts of the patients with GT included in the study were <100.000/mm3 [14].
Although there was a statistically significant difference, we think that platelet count was not related to ALT values because the values were within the normal range. We found that the mean APGAR score was within the normal range in both groups. There was a significant difference in APGAR 5 min score at a platelet count of 70.000/mm3, whereas there was no statistically significant difference when the cut-off value was 80.000/mm3. Therefore, we think that a platelet count of 70.000/mm3 can be accepted as the cut-off value for APGAR 5 min.
In our study even when a platelet count of 50.000/mm3 was taken as the cut-off value, no significant difference was observed in terms of neonatal thrombocytopenia. As a result of the findings of our study, we concluded that GT may cause neonatal thrombocytopenia but maternal platelet count did not affect neonatal thrombocytopenia.
In addition, although there is no data in the literature on blood transfusion (erythrocyte-platelet-FFP) in pregnant women diagnosed with gestational thrombocytopenia in the intrapartum or early postpartum period, in our study, it was observed that platelet transfusion was needed in patients with plt<100.000, erythrocyte transfusion was needed in the patient group with <80.000, and FFP transfusion was needed in those with <70.000. We think that in patients with gestational thrombocytopenia, a platelet count of 80.000 can be considered as the cut-off value for the need for erythrocyte transfusion, a platelet count of 100.000 for platelet product transfusion and a platelet count of 70.000 for FFP transfusion.
Limitation
The findings of our study are consistent with the literature and the features that increase the power of our study are that the study was conducted in a single center, focused specifically on gestational thrombocytopenia, and was one of the studies that included a large number of patients (n=97) grouped according to platelet counts. The main limitations of our study are its retrospective nature and the lack of a control group.
Conclusion
Since there is an increase in the need for platelet transfusion in patients with platelet count <100.000/mm3, erythrocyte transfusion in patients with platelet count <80.000/mm3, and FFP transfusion in patients with platelet count <70.000/mm3, delivery in a more equipped center where blood can be obtained will minimize the risks for mother and baby.
Acknowledgment
The authors would like to thank Dr. Erhan Okuyan contribution.
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. Myers B. Diagnosis and management of maternal thrombocytopenia in pregnancy. Br J Haematol. 2012;158(1):3-15.
2. Adams TM, Allaf MB, Vintzileos AM. Maternal thrombocytopenia in pregnancy: Diagnosis and management. Clin Lab Med. 2013;33(2):327–4.
3. Boehlen F, Hohlfeld P, Extermann P, Perneger TV, De Moerloose P. Platelet count at term pregnancy: A reappraisal of the threshold. Obstet Gynecol. 2000;95(1):29-33.
4. Jensen JD, Wiedmeier SE, Henry E, Silver RM, Christensen RD. Linking maternal platelet counts with neonatal platelet counts and outcomes using the data repositories of a multihospital health care system. Am J Perinatol. 2011;28(8):597-604.
5. Özsürmeli M, Sucu M, Çetin C, Khatib G, Demir C. Gebelikte Trombositopeni [thrombocytopenia in pregnancy]. Arşiv Kaynak Tarama Derg. 2016;25(3):420–32.
6. Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol. 2000;37(3):275-89.
7. Parnas M, Sheiner E, Shoham-Vardi I, Burstein E, Yermiahu T, Levi I, et al. Moderate to severe thrombocytopenia during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2006;128(1–2):163–8.
8. Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003;102(13):4306-11.
9. Sadulla SMS, Mahmood AY, Shamdeen MY. Gestational thrombocytopenia: maternal and fetal outcomes in Duhok. Duhok Med J. 2020;14(2):86–96.
10. Fogerty AE, Dzik W. Gestational thrombocytopenia: a case–control study of over 3,500 pregnancies. Br J Haematol. 2021;194(2):433–8.
11. Şahin ME, Şahin E, Madendağ Y, Çöl İ, Açmaz G. Effect of gestational thrombocytopenia on negative fetal and maternal outcomes in low-risk pregnancies. Cumhur Med J. 2019;41(3):620–5.
12. Ekéus C, Högberg U, Norman M. Vacuum assisted birth and risk for cerebral complications in term newborn infants: A population-based cohort study. BMC Pregnancy Childbirth. 2014;14(1):1–10.
13. Wang DP, Liang MY, Wang SM. Clinical analysis of pregnancy complicated with severe thrombocytopenia. Zhonghua Fu Chan Ke Za Zhi. 2010;45(6):401-5.
14. Elveđi-Gašparović V, Beljan P, Gverić-Ahmetašević S, Schuster S, Škrablin S. Fetalmaternal complications and their association with gestational thrombocytopenia. Ginekol Pol. 2016;87(6):454–9.
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Nebahat Sunar, Mulaim Sizer, Hamdin Günsel, Gülten Çirkin Tekeş, Dicle Akkılıç Dönmez, Mehmet Sait İçen. Evaluation of maternal and fetal outcomes in pregnant women with gestational thrombocytopenia. Ann Clin Anal Med 2024;15(6):439-443
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An investigation of procalcitonin/albumin ratio as a predictor of mortality in patients with sepsis
Ertuğrul Altuğ 1, Doğanay Can 1, Adem Çakır 2, Kemal Şener 3, Mücahit Kapcı 1, Ramazan Güven 1
1 Department of Emergency Medicine, Başakşehir Çam and Sakura City Hospital, Istanbul, 2 Department of Emergency Medicine, Mehmet Akif Ersoy State Hospital, Canakkale, 3 Department of Emergency Medicine, Mersin City Hospital, Mersin, Turkey
DOI: 10.4328/ACAM.22203 Received: 2024-03-28 Accepted: 2024-05-20 Published Online: 2024-05-25 Printed: 2024-06-01 Ann Clin Anal Med 2024;15(6):444-448
Corresponding Author: Ertuğrul Altuğ, Department of Emergency Medicine, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey. E-mail: ertugrulaltug42@gmail.com P: +90 535 656 84 42 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6807-643X
Other Authors ORCID ID: Doğanay Can, https://orcid.org/0000-0002-9544-2340 . Adem Çakir, https://orcid.org/0000-0002-4966-4882 . Kemal Şener, https://orcid.org/0000-0002-8579-6663 . Mücahit Kapci, https://orcid.org/0000-0002-6191-7336 . Ramazan Güven, https://orcid.org/0000-0003-4129-8985
This study was approved by the Ethics Committee of Basaksehir Cam and Sakura City Hospital (Date: 2021-12-29, No: 2021.12.304)
Aim: Sepsis is a condition that results in mortality as a result of multiorgan failure associated with infection. Therefore, a number of parameters are used to determine the prognosis of sepsis. Accordingly, the ratio of procalcitonin and albumin found recent use for the above purpose. The present study aimed to investigate the value of the procalcitonin/albumin ratio to determine the prognosis of sepsis patients.
Material and Methods: The present study was designed as a single-center, prospective research. The study included patients admitted to the intensive care unit upon diagnosed with pneumosepsis and met the inclusion criteria. Patients with pneumonic infiltration in the lungs supported by computed tomography images and a qSOFA score≥2 were considered to have pneumosepsis.
Results: The present study included 299 patients, who were admitted to the intensive care unit upon pneumosepsis diagnosis. The procalcitonin/albumin ratio in the mortality group and survivors was 0.42 and 0.004, respectively. The sensitivity and specificity for mortality were 87.4% and 77.6%, respectively, for a cut-off value of 0.010 for the procalcitonin/albumin ratio.
Discussion: The results of the present study were indicative of the fact that elevated procalcitonin/albumin ratio was significant in predicting prognosis in patients, who were admitted to the intensive care unit upon pneumosepsis diagnosis. This suggested that procalcitonin/albumin ratio might serve as a prognostic indicator on the grounds that the severity of sepsis was associated with the change in acute phase reactants.
Keywords: Sepsis, Procalcitonin/Albumin Ratio, Mortality, Acute Phase Reactants
Introduction
Sepsis is a clinical condition characterized by excessive release of inflammatory mediators and cytokines as induced by the uncontrolled response of the host against infection, which may lead to life-threatening organ dysfunction, specifically involving the heart and kidneys. There has been an increase in the incidence of sepsis especially in recent years [1]. In the US, approximately 3% of patients, who are admitted to hospital, are diagnosed with sepsis. The focus is pneumonia in most patients diagnosed with sepsis. Half of such patients would require admission to the intensive care unit (ICU) [2]. The outcome of the majority of pneumosepsis patients, who are admitted to the ICU, is mortality. Furthermore, the cost of sepsis treatment increases each day due to the prolonged treatment process [2].
Procalcitonin (PCT) is a peptide produced in thyroid C cells and adipose tissue [3]. While it is at a low level under physiologic conditions, serum PCT level increases upon production by a number of tissues especially in case of systematic inflammation, including bacterial infection [4]. In addition, PCT levels increase in certain noninflammatory conditions, such as shock, trauma, surgery, burns, and chronic renal failure (CRF) [4]. Recently, PCT has been adopted as a biomarker by clinicians in the diagnosis of sepsis [5]. Albumin (ALB) is a protein synthesized by liver hepatocytes and considered the most abundant protein in circulation. Despite the fact that ALB is generally used as an indicator of nutrition, ALB levels also decrease in cases of excessive alcohol intake, cirrhosis, hepatitis, and liver failure [6, 7]. Previous studies recently suggested that ALB was an indicator of inflammation due to the occurrence of hypoalbuminemia in case of inflammation [8].
The PCT/ALB ratio (PAR) is a parameter calculated by dividing the PCT level by the ALB level. This parameter is indicative of both the inflammatory state of the body and the nutritional status. Recent studies demonstrated that PAR was a marker of poor prognosis in patients with sepsis [9]. Another study reported that PAR contributed to the determination of prognosis in sepsis [10]. Accordingly, PAR can be used as a quick, easy and simple marker of sepsis to reduce costs incurred by the healthcare system.
It is critical that prognosis is determined rapidly and accurately in patients, who have been diagnosed with sepsis. Therefore, the present study aimed to identify a reliable predictive biomarker to effectively assess the prognosis in patients with sepsis and to rapidly diagnose those patients and start their treatment earlier.
Material and Methods
Study design
This study was designed as a retrospective and single-center research. The study included patients, who were admitted to the respiratory ICU upon diagnosis with pneumosepsis. Patients with pneumonic infiltration and ground-glass appearance on thoracic computed tomography and who met the qSOFA (abnormal state of consciousness, respiratory rate ≥22/min, and systolic blood pressure ≤100 mmHg) criteria used for the diagnosis of sepsis in the surviving sepsis campaign: 2021 [11] guidelines were included in the study. Demographic characteristics, laboratory results, PCT, ALB, and PAR values as well as 28-day mortality status were captured on the case form.
Setting and selection of participants
The study included patients, who were admitted to the respiratory ICU with a diagnosis of pneumonia and had qSOFA scores of ≥2 points. Patients, who met the following criteria were excluded from the study:
– under 18 years of age,
– pregnant,
– incomplete patient data,
– history of malignancy,
– history of hematologic disease,
– bone marrow pathology,
– use of anti-inflammatory or immunosuppressive drugs,
– history of liver failure and cirrhosis,
– trauma patient,
– burn patient,
– history of CRF,
– history of surgery within the last 6 months,
– qSOFA score of <2 points. Patients diagnosed with pneumosepsis and not falling in the above criteria were included in the study
Eligible patients were identified upon review of the automation system [Hospital Information Management System (HIMS)]. All the patients, who were admitted to the respiratory ICU in the last 2 years, were included in the analyses. There were 423 patients with sepsis upon HIMS review. Of the 423 patients, 35 had a history of CRF, 22 had incomplete data, 21 had a qSOFA score of <2, 18 had a history of malignancy, 17 had liver failure or cirrhosis, 6 had a history of surgery, and 5 had a history of hematologic disease, and therefore excluded from the study. The remaining 299 patients were included in the study (Figure 1).
Demographic characteristics (age, sex) and clinical data (vital signs, laboratory values, outcomes and PCT, ALB, PAR ratio) of the patients included in the study were captured. For the clinical data of the patients, the values at admission were captured.
Data calculation
Calculations were made based on the results from the cases in the study. Accordingly, the neutrophil-to-lymphocyte ratio (NLR) and PAR ratios were calculated. The formulas were as follows: NLR = Neutrophil/Lymphocyte ratio and PAR = Procalcitonin/Albumin ratio. Due to the retrospective design of the study, the endpoints (discharge, exitus) during hospitalization were assessed.
Statistical analysis
The Statistical Package for the Social Sciences software, Version 24.0 was used for data analyses. Numbers, percentage, mean, standard deviation, median, median, minimum, and maximum values were used for the presentation of descriptive data. The Kolmogorov-Smirnov test was used to see if the hypothesis of normal distribution of the data was met. The continuous variables without normal distribution upon univariate analysis were expressed as median (IQR) and compared using the Mann–Whitney U test. The Pearson Chi-Squared test was used to analyze the categorical variables. Fisher’s Exact test was used when there were <5 categorical variables. The receiver operating characteristic (ROC) curve analysis was used for diagnostic accuracy purposes; and further, sensitivity, specificity, and area under the curve were calculated and the results presented.
A p-value of <0.05 was considered statistically significant.
Ethical Approval
The study was approved by the Ethics Committee of Basaksehir Cam and Sakura City Hospital (Date: 2021-12-29, No: 2021.12.304).
Results
The study included 299 cases. 53.8% (n = 161) of the patients were men and 46.2% (n = 138) were women. The median age of the patients was 66 (57.0–76.0) years. As regards the endpoints, 41.8% of the patients were discharged, where the rate of mortality was 58.2%. The median length of hospital stays of the patients was 6 (3–18) days. The IQR values of the vital parameters from the patients included in the study are given in Table 1. Age, length of hospital stays, and vital and laboratory values were analyzed vis-à-vis the endpoints. Based on the study data, the median age was significantly higher in nonsurvivors. The systolic blood pressure, diastolic blood pressure, and saturation were significantly lower in nonsurvivors compared to survivors in terms of vital parameters. There were no differences in pulse rate, temperature, and respiratory rate by the outcome. The length of hospital stays was significantly higher in nonsurvivors (Table 2).
As regards the laboratory results, the lymphocyte values were significantly higher in the survivor patients, while there was no significant difference in white blood cell, neutrophil, and platelet values. Furthermore, the median procalcitonin value was significantly higher and the median albumin value was significantly lower in nonsurvivors compared to survivors (Table 2).
The median values of the PAR calculated by outcome were compared and accordingly these values were statistically significantly higher in nonsurvivor patients (Table 2). The NLR rate was compared by the outcome of the cases. The results indicated that the NLR rate was significantly higher in nonsurvivor cases (Table 2).
A review of the results of the ROC analysis aimed to determine mortality by procalcitonin/albumin ratio indicated that the sensitivity and specificity of the procalcitonin/albumin ratio for a cut-off value of 0.010 were 87.4% and 77.6%, respectively, and the area under the curve (AUC) was 0.876. Upon analysis to test the success of the NLR value in predicting mortality, sensitivity and specificity were 37.9% and 83.2% for a cut-off value of 23.15, respectively, with an AUC of 0.607. In this context, upon review of the analyzed values the PAR was a promising parameter to use in determining mortality (Table 3 and Figure 2). The factors affecting mortality in the cases were analyzed and the effects of those factors were investigated. Upon univariate and multivariate regression analyses, decreases in albumin level and saturation had a significant effect on mortality. The factors, which increased the rate of mortality included decreased albumin level (OR = 1.148; 95% CI = 1.055–1.247; p = 0.001) and decreased saturation (OR = 1.240; 95% CI = 1.098–1.399; p = 0.001).
Discussion
Pneumosepsis is a disease associated with high rates of mortality due to multiorgan dysfunction induced by lung parenchymal involvement. Determining the prognosis of this disease can have an impact on the treatment process and mortality rate. Especially recently PAR finds use to determine prognosis in patients with sepsis [12]. To the best of our knowledge, there was no previous study in the relevant literature on applying PAR to determine the prognosis of patients diagnosed with adult pneumosepsis. In the present study, the sensitivity and specificity rates of PAR at ICU admission as an indicator of mortality in pneumosepsis patients were 87.4% and 77.6%, respectively.
In this study, the median age of patients diagnosed with pneumosepsis was 66.0 years (57.0–76.0). Of the 299 patients included in the study, 53.8% were men and 41.8% were discharged. In a study with 590 patients, 60.6% were men and the mean age was 65.6 ± 14.9 years [13]. Another study reported the mortality rate as 41.9% [12]. The age, sex, and mortality rates in our study are similar to the previous studies in the relevant literature. The fact that the most important reason for the progression of pneumonia to sepsis is advanced age and decreased lung capacity may account for this similarity.
In the present study, there was a significant difference between the survivor and nonsurvivor patient groups by age, systolic blood pressure (SBP), and saturation values at ICU admission. Similarly, a study by Çekiç et al. reported that the mean age of the nonsurvivors compared to the survivors [13]. This may be due to the fact that elderly patients are more susceptible to sepsis. A retrospective study by Boonmee et al., reported that SDB was significant as an indicator of mortality [14]. Another study found a significant difference between survivor and nonsurvivor patients with sepsis using SBP [15]. This might be associated with the impairment of vascular permeability due to sepsis. There was no previous study reported on saturation. This might be due to the fact that lung involvement was more prevalent in the nonsurvivor group.
PCT demonstrates higher specificity in bacterial infections compared to other proinflammatory markers [16]. Another study suggested that PCT was important for confirming the prognosis of bacterial sepsis [17]. Another study found that PCT was a better indicator than CRP in bacterial infections [18]. Although hypoalbuminemia in community-acquired pneumonia is a predictor of mortality, it has been reported to be an indicator of the severity of sepsis of abdominal origin but not significant as a predictor of mortality [19]. In addition, many previous studies confirmed that PCT and ALB were associated with the prognosis of sepsis [20]. In the present study, PCT was significantly higher and ALB was significantly lower in the nonsurvivor group. This may be due to the rapid spread of pneumosepsis in geriatric patients with an aggressive progression and that albumin is a negative acute phase reactant.
PAR assesses the infective and nutritional statuses. This increases its value in predicting prognosis in patients with pneumosepsis. A study on patients with acute respiratory distress syndrome suggested that PAR could be used as an independent predictor of 28-day mortality [21]. Consistently, Luo et al. suggested that PAR was an early predictor in patients with sepsis [22]. Another study, reported that PAR was higher in the nonsurvivor group [12]. PAR was confirmed as an important predictor of 28-day mortality in a study of 128 adult patients with sepsis [23]. In the present study, consistent with the relevant literature, PAR in the nonsurvivor group was significantly higher compared to the survivor patients. This may be especially due to the combination of early elevation of PCT in bacterial infections and nutritional imbalance as a result of increased catabolism in sepsis.
In the present study, the sensitivity and specificity values of PAR as a predictor of mortality in patients with pneumosepsis with a cut-off value of 0.01 were 87.4% and 77.6%, respectively. Cekiç et al. reported that PAR had a cut-off value of 0.008 in patients with sepsis and it had a sensitivity of 70.7% and a specificity of 70.6% as a predictor of mortality [13]. Li et al. showed that the cut-off value of PAR as a mortality predictor was 0.256 with a sensitivity of 43.1% and a specificity of 81.5% in a study on patients with sepsis [12]. For the present study, we suggest that high PAR may be used as a predictor of mortality, especially in patients with severe sepsis, including pneumosepsis.
Limitation
There are some limitations associated with the present study. The most important limitation was that the study was designed as a retrospective, single-center research. Another limitation was the comparatively limited size of the sample. Therefore, future prospective and multicenter studies with a larger sample group will contribute to a better understanding of the issue.
Conclusion
Procalcitonin/albumin ratio can be used to determine the prognosis of patients, who are admitted to the ICU with a diagnosis of pneumosepsis as an easy, inexpensive, and rapid parameter. Therefore, pneumosepsis treatment can be started earlier and the mortality rate can be reduced.
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. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801-10.
2. Xie J, Wang H, Kang Y, Zhou L, Liu Z, Qin B, et al. the epidemiology of sepsis in Chinese icus: A national cross-sectional survey. Crit Care Med. 2020;48(3):e209-e218.
3. Paudel R, Dogra P, Montgomery-Yates AA, Coz Yataco A. Procalcitonin: A promising tool or just another overhyped test?. Int J Med Sci. 2020;17(3):332-337.
4. Gilbert DN. Role of procalcitonin in the management of infected patients in the intensive care unit. Infect Dis Clin North Am. 2017;31(3):435-453.
5. Mohsen AH, Kamel BA. Predictive values for procalcitonin in the diagnosis of neonatal sepsis. Electron Physician. 2015;7(4):1190-1195.
6. Fagenson AM, Gleeson EM, Pitt HA, Lau KN. Albumin-Bilirubin Score vs Model for End-Stage Liver Disease in Predicting Post-Hepatectomy Outcomes. J Am Coll Surg. 2020;230(4):637-645.
7. Baldassarre M, Naldi M, Zaccherini G, Bartoletti M, Antognoli A, Laggetta M, et al. Determination of effective albumin in patients with decompensated cirrhosis: Clinical and prognostic implications. Hepatology. 2021;74(4):2058-2073.
8. Gui Y, Xu Y, Yang P. Predictive Value of the Platelet-to-Albumin Ratio (PAR) on the risk of death at admission in patients suffering from severe fever with thrombocytopenia syndrome. J Inflamm Res. 2021;14:5647-5652.
9. Chen L, Wu X, Qin H, Zhu H. The PCT to albumin ratio predicts mortality in patients with acute kidney injury caused by abdominal infection-evoked sepsis. Front Nutr. 2021;8:584461.
10. Li T, Li X, Liu X, Zhu Z, Zhang M, Xu Z, et al. Association of procalcitonin to albumin ratio with the presence and severity of sepsis in neonates. J Inflamm Res. 2022;15:2313-2321.
11. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Inten Care Med. 2021;47(11):1181-1247.
12. Li F, Ye Z, Zhu J, Gu S, Peng S, Fang Y, et al. Early lactate/albumin and procalcitonin/albumin ratios as predictors of 28-day mortality in ICU-admitted sepsis patients: A retrospective cohort study. Med Sci Monit. 2023;29:e940654.
13. Cekic D, Issever K, Genc AC, Yaylaci S, Genc AB, Tamer A. Association of C-reactive protein/albumin, procalcitonin/albumin, platelet/lymphocyte, and lymphocyte/monocyte ratio with mortality in hospitalized COVID-19 patients. J Coll Physicians Surg Pak. 2022;32(9):1191-1195.
14. Boonmee P, Ruangsomboon O, Limsuwat C, Chakorn T. Predictors of mortality in elderly and very elderly emergency patients with sepsis: A retrospective study. West J Emerg Med. 2020;21(6):210-218.
15. Zhu F, Baczynski M, Kharrat A, Ye XY, Weisz D, Jain A. Blood pressure, organ dysfunction, and mortality in preterm neonates with late-onset sepsis. Pediatr Res. 2022;92:562-572.
16. Yan ST, Sun LC, Jia HB, Gao W, Yang JP, Zhang GQ. Procalcitonin levels in bloodstream infections caused by different sources and species of bacteria. Am J Emerg Med. 2017;35(4):579-583.
17. Ljungström L, Pernestig AK, Jacobsson G, Andersson R, Usener B, Tilevik D. Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis. PLoS One. 2017;12(7):e0181704.
18. Schuetz P, Birkhahn R, Sherwin R, Jones AE, Singer A, Kline JA, et al. Serial procalcitonin predicts mortality in severe sepsis patients: results from the multicenter procalcitonin monitoring sepsis (MOSES) study. Crit Care Med. 2017;45(5):781-789.
19. Godinez-Vidal AR, Correa-Montoya A, Enriquez-Santos D, Perez-Escobedo SU, Lopez-Romero SC, Gracida-Mancilla NI. Is albumin a predictor of severity and mortality in patients with abdominal sepsis?. Cir Cir. 2019;87(5):485–489.
20. Arnau-Barrés I, Güerri-Fernández R, Luque S, Sorli L, Vázquez O, Miralles R. Serum albumin is a strong predictor of sepsis outcome in elderly patients. Eur J Clin Microbiol Infect Dis. 2019;38(4):743-746.
21. Chen H, Liu Q, Wang L. An analysis of the 28-day mortality risk factors in acute respiratory distress syndrome patients and the establishment of prediction models. Am J Transl Res. 2021;13(6):6937-6944.
22. Luo X, Yang X, Li J, Zou G, Lin Y, Qing G, et al. The procalcitonin/albumin ratio as an early diagnostic predictor in discriminating urosepsis from patients with febrile urinary tract infection. Medicine (Baltimore). 2018;97(28):e11078.
23. Wang X, Jing M, Li L, Xu Q. The prognostic value of procalcitonin clearance and procalcitonin to albumin ratio in sepsis patients. Clin Lab. 2023;69(3):51.
Download attachments: 10.4328.ACAM.22203
Ertuğrul Altuğ, Doğanay Can, Adem Çakır, Kemal Şener, Mücahit Kapcı, Ramazan Güven. An investigation of procalcitonin/albumin ratio as a predictor of mortality in patients with sepsis. Ann Clin Anal Med 2024;15(6):444-448
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