key: cord-1050778-gjc35wl0 authors: Kuluöztürk, Mutlu; İn, Erdal; Telo, Selda; Karabulut, Ercan; Geçkil, Ayşegül Altıntop title: Efficacy of copeptin in distinguishing COVID‐19 pneumonia from community‐acquired pneumonia date: 2021-02-17 journal: J Med Virol DOI: 10.1002/jmv.26870 sha: c8fc0727b0da48a2b8af15057bd5d944f8ba21e3 doc_id: 1050778 cord_uid: gjc35wl0 The clinical symptoms of community‐acquired pneumonia (CAP) and coronavirus disease 2019 (COVID‐19)‐associated pneumonia are similar. Effective predictive markers are needed to differentiate COVID‐19 pneumonia from CAP in the current pandemic conditions. Copeptin, a 39‐aminoacid glycopeptide, is a C‐terminal part of the precursor pre‐provasopressin (pre‐proAVP). The activation of the AVP system stimulates copeptin secretion in equimolar amounts with AVP. This study aims to determine serum copeptin levels in patients with CAP and COVID‐19 pneumonia and to analyze the power of copeptin in predicting COVID‐19 pneumonia. The study consists of 98 patients with COVID‐19 and 44 patients with CAP. The basic demographic and clinical data of all patients were recorded, and blood samples were collected. The receiver operating characteristic (ROC) curve was generated and the area under the ROC curve (AUC) was measured to evaluate the discriminative ability. Serum copeptin levels were significantly higher in COVID‐19 patients compared to CAP patients (10.2 ± 4.4 ng/ml and 7.1 ± 3.1 ng/ml; p < .001). Serum copeptin levels were positively correlated with leukocyte, neutrophil, and platelet count (r = −.21, p = .012; r = −.21, p = .013; r = −.20, p = .018; respectively). The multivariable logistic regression analysis revealed that increased copeptin (odds ratio [OR] = 1.183, 95% confidence interval [CI], 1.033–1.354; p = .015) and CK‐MB (OR = 1.052, 95% CI, 1.013–1.092; p = .008) levels and decreased leukocyte count (OR = 0.829, 95% CI, 0.730–0.940; p = .004) were independent predictors of COVID‐19 pneumonia. A cut‐off value of 6.83 ng/ml for copeptin predicted COVID‐19 with a sensitivity of 78% and a specificity of 73% (AUC: 0.764% 95 Cl: 0.671–0.856, p < .001). Copeptin could be a promising and useful biomarker to be used to distinguish COVID‐19 patients from CAP patients. . 1 A total of more than 90 million COVID-19 cases and more than 2 million deaths have been reported worldwide as of January 15, 2021. 2 Copeptin is an arginine-vasopressin (AVP) glycopeptide composed of 39 amino acids, and it is derived from the C-terminal part of pre-pro-AVP, which is the AVP precursor molecule. Copeptin is released from the neurohypophysis simultaneously by osmotic or hemodynamic stimulation with AVP and its plasma levels correlate well. AVP is an antidiuretic and vasoconstrictive hormone. It shows the endogenous stress response and its release is increased by stimuli, such as hypotension, hypoxia, hyperosmolarity, acidosis, and infections. However, its circadian rhythm, short half-life, and being an unstable molecule make it impossible to use it as a biomarker. Copeptin is a more stable peptide and its level in the blood can be easily detected. [3] [4] [5] Community-acquired pneumonia (CAP) is a pulmonary parenchymal infection acquired outside of a healthcare setting and it is one of the leading causes of morbidity and mortality worldwide. Bacterial infections are responsible for most of the CAP and the most commonly detected pathogens are Streptococcus pneumoniae, Haemophilus influenzae, atypical bacteria, and viruses. 6, 7 The clinical symptoms of CAP and COVID-19-associated pneumonia are generally similar. The gold standard test used to confirm the diagnosis of COVID-19 disease is the reverse transcriptase polymerase chain reaction (RT-PCR). However, it has been reported that the sensitivity of RT-PCR may not be high enough for the early diagnosis and treatment of patients. In addition, these tests may not be available in a state of emergency and it takes time for the result to come out. It has been demonstrated in various studies that thoracic computed tomography (CT), which is easily accessible in many hospitals, is a useful test that can be used in the diagnosis of COVID-19 pneumonia. However, one of the biggest problems in current pandemic conditions is the difficulty of performing CT scans for every patient who is suspected of pneumonia due to excessive patient load. In addition, thorax CT may not provide a clear distinction between COVID-19 and pneumonia due to other factors in every case. Peripheral ground-glass opacities observed on thoracic CT are characteristic for COVID-19 pneumonia and have a high sensitivity. However, this measurement has low specificity in distinguishing COVID-19 from other types of pneumonia, and false-positive cases are not rare. [8] [9] [10] It has been shown that some laboratory tests, such as leukocyte count, lymphocyte count, and C-reactive protein (CRP) used routinely, can be useful in distinguishing COVID-19 pneumonia from CAP. 11, 12 Copeptin levels are known to increase with infectious stimuli. It has been shown in the studies that serum copeptin levels increase in infectious diseases, such as CAP, ventilator-associated pneumonia, lower respiratory tract infections, and sepsis, and this increase is associated with poor prognosis. 13 guideline. 19 All patients with CAP had negative RT-PCR results for SARS-COV-2. Also, patients whose chest radiography and/or CT results were typical for COVID-19 pneumonia were not included in the study, even if their PCR tests were negative. Clinical parameters and demographic data were documented. After the questioning of the medical histories and physical examinations of the subjects, blood samples were collected from patients diagnosed with COVID-19 and CAP before the treatment. Patients with acute myocardial infarction, acute coronary syndrome, heart failure, renal failure, peripheral artery disease, chronic obstructive pulmonary disease, interstitial lung disease, any organ malignancy or immunosuppression (HIV infection, solid organ or stem cell transplantation, or any immunosuppressive treatment), and pregnancy were excluded from the study. The study was conducted in accordance with the Helsinki Declaration, and it was approved by the Ethical Committee of the Medicine Faculty of Firat University (issue: 403647/27.07.2020). The subjects who participated in the study provided their written consent to be included in the study. The serum was separated by centrifuging the samples at 4000 g for 10 min and freezing at −80°C for further analysis. The serum copeptin levels were measured using a double-antibody sandwich enzyme-linked immunosorbent assay kit (Catalog No.: 201-12-5463 Human copeptin Elisa Kit: Sunred Biological Technology Co. Ltd.). The assay sensitivity was 0.067 ng/ml. The inter-assay and intraassay calculation values were <12% and <10%, respectively. The detection range of copeptin was 0.07-20 ng/ml. The statistical analyses were conducted by using IBM SPSS Statistics 21 (Statistical Product and Service Solutions version 21, authorization code: d91314f638c364094170) software. The results were presented as mean ± SD. The statistical significance level was determined to be p < .05. The Student t test was used for comparing two independent samples. A one-way analysis of variance test was conducted for multiple sample comparisons. In addition, the Tukey test was conducted to determine the importance of any significant difference detected. The χ 2 test was used to compare the gender distribution between the groups, while the Pearson correlation test was used in the evaluation of the parametric values. Binary logistic regression analyses were used for univariate and multivariate analysis to assess which variables were predictive of COVID-19 pneumonia, and odds ratios (ORs) were calculated with a 95% confidence interval (CI). The cut-off value for copeptin was determined by using the "receiver operating characteristic" (ROC) analysis method, and sensitivity and specificity values for copeptin were determined according to this value. "Area under curve" (AUC) value was determined with the ROC curve. The minimum required sample size was estimated as 26 for each group based on large effect size (Cohen's d = 0.80) expectation between groups in terms of copeptin levels (α = .05, 1 − β = .80). Gpower package version 3.6.1 was used for sample size estimations. The study population consists of 98 hospitalized patients with COVID-19 pneumonia and 44 hospitalized patients with CAP. The median age was 59.3 years, and 62.2% of the patients were men for COVID-19 patients. The median age was 66.6 years and 63.8% of the patients were men for CAP patients. No statistically significant difference was determined among the two groups in terms of sex (p = .87, χ 2 =0.025) while the ages of patients in CAP were significantly higher compared to COVID-19 patients (p = .02). Patients with COVID-19 showed a significantly lower leukocyte, neutrophil, lymphocyte, and platelet count compared to CAP patients in terms of complete blood count parameters (p = .018 for lymphocyte, p < .001 for others) An analysis of the basic biochemical data of patients revealed that the COVID-19 group had significantly higher aspartate transaminase (AST) and D-dimer levels compared to the CAP group (p < .001 and p = .019; respectively). An analysis of cardiac and inflammatory markers revealed that creatine kinase (CK) and CK-MB levels were significantly higher (p = .006 and p < .001; respectively), and procalcitonin levels were significantly lower in the COVID-19 group (p = .012). Additionally, oxygen saturation (SaO 2 ) levels were significantly lower in the COVID-19 group compared to the CAP group (p < .001). The demographical and laboratory data of the COVID-19 group and the CAP group are presented in Table 1 . The mean serum copeptin levels of COVID-19 and CAP patients were 10.2 ± 4.4 ng/ml and 7.1 ± 3.1 ng/ml, respectively. Serum copeptin levels were significantly higher in the COVID-19 group compared to the CAP group according to these results (p < .001). Figure 1 shows the serum copeptin levels of the two groups. There was a negative correlation between the serum copeptin levels and leukocyte, neutrophil, and platelet count (r = −.21, p = .012; r = −.21, p = .013; r = −.20, p = .018 respectively) ( Figure 2 ). The results of binary logistic regression analysis of the potential predictors of COVID-19 pneumonia are shown in Levels of copeptin for the prediction of COVID-19 was evaluated by ROC analysis. Accordingly, when the cut-off value for copeptin in distinguishing COVID-19 patients from CAP patients was determined to be 6.83 ng/ml, the sensitivity was determined as 78% while the specificity was 73% (AUC: 0.764%; 95 Cl, 0.671-0.856, p < .001) (Figure 3 ). The results of the present study indicate that serum copeptin levels were significantly higher in the COVID-19 group compared to the CAP group. Furthermore, multivariable logistic regression analysis revealed that increased copeptin level was an independent predictor of COVID-19 pneumonia. In addition, copeptin was found to have a reasonable sensitivity (78%) and specificity (73%) in distinguishing COVID-19 patients from CAP patients. pneumonia were found to have significantly lower leukocyte, neutrophil, and lymphocyte counts compared to patients to CAP in our study. In addition, procalcitonin levels were found to be lower in the COVID-19 group, while there was no statistical difference between the two groups in terms of CRP levels. But these results are not surprising. Different inflammatory responses are expected in infections with different types of pathogens, and this may explain important differences in laboratory data. Bacterial infections are often the main pathogen in CAP patients, and these patients have higher leukocyte counts, neutrophils, and procalcitonin levels. 21, 22 In addition, previous studies have shown that lymphopenia is a typical feature in COVID-19 patients and may be related to the severity of the disease. 20, 23 In addition, a negative correlation was found between copeptin levels and the number of leukocytes, neutrophils, and platelets in our study. A positive correlation was found between disease severity and copeptin levels in the CAP patients in a previous study. 15 No classification of severity was made for both pneumonia groups in our study. However, correlations between copeptin levels and leukocyte, neutrophil, and platelet counts seem to be related to disease severity. One of the most important problems in COVID-19 patients is the dynamic changes in platelet count and platelet-related parameters. There is no evidence that the SARS-CoV-2 virus has its own procoagulant effects. The coagulopathy observed in COVID-19 patients is likely the result of a severe inflammatory T A B L E 1 Comparison of the demographic and laboratory data of COVID-19 pneumonia and community-acquired pneumonia groups F I G U R E 3 ROC curve analysis of the utility of copeptin in distinguishing COVID-19 patients from community-acquired pneumonia patients. ROC, receiver operating characteristic CK-MB levels were significantly higher in COVID-19 patients compared to CAP patients in our study, consistent with the literature. The physiological functions of AVP in regulating fluid balance, vascular tone, and endocrine stress response are well known. Copeptin is released simultaneously with AVP from the neurohypophysis due to osmotic, hemodynamic, and stress-related stimuli. Copeptin release is stimulated by many physiological and pathological stimuli, such as pain, infection, hypoglycemia, hypoxemia, exercise, stroke, and shock. [3] [4] [5] Evidence suggests that copeptin is superior to cortisone in determining stress levels. Copeptin has been shown to have an active role in lung diseases, such as pneumonia, and in being superior to traditional inflammatory markers as a prognostic marker in CAP patients. 4, 30 It was determined in a study conducted in children that serum copeptin levels were higher in children with pneumonia compared to the healthy control group, and copeptin was a reliable marker that can be used to evaluate the severity and prognosis of pneumonia in this disease group. 31 Similarly, Du et al. 32 reported that copeptin reflected the severity of pneumonia in children and was associated with pneumonia complications. Copeptin has also been shown to be a useful biomarker for predicting severity and complications in pneumonia patients in studies conducted in adults. 33 study. When the optimal cut-off value of copeptin in terms of distinguishing COVID-19 pneumonia from CAP was determined as 6.83 ng/ml, its sensitivity and its specificity were found to be 78% and 73%, respectively. Also, it is shown that copeptin was found an independent predictor of COVID-19 pneumonia according to multivariable logistic regression analysis. Copeptin may be a simple and useful marker that can be used to distinguish COVID-19 pneumonia from CAP, has reasonable sensitivity and specificity, and gives quick results according to the results obtained from our study. However, our study is the first study conducted in this field, and studies with larger series are needed to support the findings of our study. There were some limitations to this study. The primary limitation of our study is the lack of follow-up data. The importance of copeptin in these disease groups could be demonstrated more clearly if the serum copeptin levels were also examined during the follow-up and posttreatment period. Second, the value of copeptin in critical patients could not be determined since patients requiring intensive care were not included in the study. Lastly, the number of patients in the CAP group in our study is relatively low and the healthy control group was not included in the study. In conclusion, it was determined in this study that serum copeptin levels were higher in COVID-19 pneumonia patients compared to CAP patients, and copeptin distinguished COVID-19 pneumonia with a reasonable level of sensitivity and specificity. Copeptin can be a useful biomarker that can be used for distinguishing COVID-19 pneumonia patients from CAP patients. KULUÖZTÜRK ET AL. Understanding of COVID-19 based on current evidence Coronavirus COVID-19 Global Cases by Johns Hopkins CSSE Copeptin in the diagnosis of vasopressindependent disorders of fluid homeostasis Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level Copeptin and its potential role in diagnosis and prognosis of various diseases Update in adult community-acquired pneumonia Diagnosis and treatment of adults with community-acquired pneumonia Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases Sensitivity of chest CT for COVID-19: comparison to RT-PCR Coronavirus disease 2019 (COVID-19): a perspective from China Comparison of clinical characteristics between coronavirus disease 2019 pneumonia and communityacquired pneumonia Can routine laboratory tests discriminate SARS-CoV-2-infected pneumonia from other causes of communityacquired pneumonia? Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired pneumonia: results from the German competence network CAPNETZ Midregional pro A-type natriuretic peptide and carboxy-terminal provasopressin may predict prognosis in community-acquired pneumonia The vasopressin and copeptin response to infection, severe sepsis, and septic shock Copeptin, a novel prognostic biomarker in ventilatorassociated pneumonia National Health Commission of the People's Republic of China (2020) Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America Clinical features of patients infected with 2019 novel coronavirus in Wuhan Community-acquired pneumonia Advances in the causes and management of community-acquired pneumonia in adults Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study COVID-19 and its implications for thrombosis and anticoagulation Coagulation abnormalities and thrombosis in patients with COVID-19 Platelet functions and activities as potential hematologic parameters related to Coronavirus Disease 2019 (Covid-19) Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis Myocardial injury and COVID-19: possible mechanisms Cardiac injury associated with severe disease or ICU admission and death in hospitalized patients with COVID-19: a meta-analysis and systematic review Copeptin: a new and promising diagnostic and prognostic marker Predictive value of copeptin as a severity marker of community-acquired pneumonia Relationship between plasma copeptin levels and complications of community-acquired pneumonia in preschool children Proadrenomedullin to predict severity and outcome in communityacquired pneumonia Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin Extrapulmonary manifestations of COVID-19 The cytokine storm and COVID-19 Characterization of the Inflammatory Response to Severe COVID-19 Illness Contribution of acute-phase reaction proteins to the diagnosis and treatment of 2019 novel coronavirus disease (COVID-19) Covid-19 does not lead to a "typical" acute respiratory distress syndrome Association between hypoxemia and mortality in patients with COVID-19 Efficacy of copeptin in distinguishing COVID-19 pneumonia from community-acquired pneumonia