key: cord-0905636-uerrq5mm authors: Kerget, Buğra; Kerget, Ferhan; Koçak, Abdullah Osman; Akbaş, İlker; Araz, Ömer; Uçar, Elif Yılmazel; Akgün, Metin title: Is endogenous carboxyhaemoglobin level a useful biomarker of clinical course and prognosis in COVID‐19 patients? date: 2021-08-06 journal: Int J Clin Pract DOI: 10.1111/ijcp.14680 sha: 5d82410da9d91e21d7b715004a8d8bfded0dd46f doc_id: 905636 cord_uid: uerrq5mm OBJECTIVE: SARS‐CoV‐2 has caused nearly 4 million confirmed cases of COVID‐19 worldwide in the approximately 4 months since it emerged in Wuhan, China in December 2019. Comorbidities increase morbidity and mortality in COVID‐19, and many laboratory parameters have been associated with mortality. The aim of the present study was to identify the relationship between endogenous carboxyhaemoglobin (COHb) level and the clinical course and prognosis of COVID‐19. METHODS: The study included 48 non‐smokers or ex‐smokers aged 18 years or older who presented to the emergency department, were diagnosed with COVID‐19 by real‐time PCR analysis of nasopharyngeal swab sample and were treated in the pulmonary diseases ward of the Atatürk University hospital after 24 March 2020 and 15 April 2020. The patients’ laboratory parameters and demographic data were analysed retrospectively. RESULTS: Prothrombin time and C‐reactive protein (CRP), troponin‐I, and D‐dimer levels decreased in COVID‐19 patients during follow‐up (P = .024, P = .001, P = .001, P = .001), while PaO(2)/FiO(2) ratio and COHb increased (P = .002, P = .001). COHb level at admission was significantly lower in patients who developed macrophage activation syndrome (MAS), acute respiratory distress syndrome (ARDS), and those who died compared with the other patients (P = .002, P = .001). COHb level on day 5 of treatment was significantly higher in patients with ARDS and patients who died (P = .001, P = .001). Significant correlations were detected between COHb level and CRP (r=−0.425, P = .001), ferritin (r = −.395, P = .001) and PaO(2)/FiO(2) ratio (r = .431, P = .001). CONCLUSIONS: COHb level may be an easily accessible biomarker that guides early follow‐up and treatment planning to avoid ARDS, MAS and mortality in COVID‐19. treatment, but evaluation of correlation with clinical condition revealed a relationship with macrophage activation syndrome (MAS), which is among the most important causes of mortality. This led to the investigation of parameters that can be associated with mortality in this emerging disease. 2, 3 Carbon monoxide (CO) is naturally synthesised in the body and plays an important role in the regulation of physiological functions such as vasodilation, angiogenesis, vascular remodelling, protection against tissue damage and modulation of the inflammatory response. Approximately 85% of CO is produced by haeme oxygenase and is excreted from the body through the respiratory system. 4, 5 In critical diseases such as acute respiratory failure, chronic obstructive pulmonary disease, acute pulmonary embolism and acute myocardial infarction, low initial endogenous carboxyhaemoglobin (COHb) level has been associated with high mortality and poor prognosis. The leading causes of morbidity and mortality in COVID-19 are acute respiratory failure, microthombi and cardiac involvement. [5] [6] [7] [8] COVID-19 is a new disease that does not have specific laboratory findings as in other known diseases, and as such is the focus of intense research. The aim of the present study was to determine the value of COHb levels measured at admission and follow-up in the prediction of clinical course and prognosis in COVID-19 patients who develop MAS and acute respiratory failure. The study included patients aged 18 years or older who presented to the Atatürk University emergency department from 24 March 2020 (the date of admission of the first COVID-19-positive patient to our centre) to 15 April 2020 with fever, cough, dyspnoea, fatigue and/or sudden attenuation of taste and smell and had contact with a suspected COVID-19 patient in the past 14 days. Local ethics committee approval was obtained to use patients' records for our retrospective study. As standard procedure, high-resolution computed tomography (HRCT) was performed for high-risk patients with COVID-19. Patients with typical HRCT findings (bilateral ground-glass opacity with primarily peripheral distribution, subsegmental consolidation or linear opacities, cobblestone pattern and inverse halo sign) and patients with atypical radiological findings but consistent clinical presentation were hospitalised. 9 Nasopharyngeal swab samples were obtained from the patients and COVID-19 diagnosis was established using real-time PCR analysis. Patients in the study who did not develop acute respiratory distress syndrome (ARDS) and/or MAS were followed in the respiratory ward, while those who developed MAS and/or ARDS were followed in the respiratory intensive care unit. Haematological parameters, biochemical parameters including liver and kidney function tests, coagulation parameters, ferritin, D-dimer, troponin-I, C-reactive protein (CRP) and arterial blood gas parameters were analysed at admission and daily thereafter. The 48 patients in the study were divided into three groups: patients without ARDS and MAS at admission and during follow-up (n = 22), patients who had ARDS at admission or developed ARDS during follow-up (n = 26), and patients who developed MAS during follow-up (all patients who developed MAS also had ARDS) (n = 13). Patients with chronic or clinically significant infectious or inflammatory conditions in the last month, current smoking, uncontrolled asthma, chronic obstructive pulmonary disease (COPD), malignancy, invasive surgery in the last month, uncontrolled hypertension, high fasting blood glucose and newly developed cerebrovascular disease, kidney disease and coronary artery disease were excluded. History and laboratory parameters obtained at admission were used to evaluate patients in terms of the exclusion criteria. The presence of coronary artery disease, asthma, COPD and diabetes was determined through consultation with the cardiology, pulmonology and internal medicine departments. • Carbon monoxide (CO) is naturally synthesised in the body and plays an important role in the regulation of physiological functions such as vasodilation, angiogenesis, vascular remodelling, protection against tissue damage and modulation of the inflammatory response. • Approximately 85% of CO is produced by haeme oxygenase and is excreted from the body through the respiratory system. • In critical diseases such as acute respiratory failure, chronic obstructive pulmonary disease, acute pulmonary embolism, and acute myocardial infarction, low initial endogenous carboxyhaemoglobin (COHb) level has been associated with high mortality and poor prognosis. • The leading causes of morbidity and mortality in COVID-19 are acute respiratory failure, microthombi and cardiac involvement. • Low COHb level at admission in COVID-19 patients may be an easily accessible biomarker that guides early follow-up and treatment planning to avoid ARDS, MAS and mortality. Fever was defined as an axillary temperature of 37.3°C or higher. Positive endotracheal aspirate or lower respiratory tract sputum culture with signs and symptoms of bacteraemia or pneumonia was considered a secondary bacterial infection. Treatment of patients diagnosed as having ventilator-associated or hospital-acquired pneumonia was planned based on available guidelines. Diagnosis and grading of ARDS were done according to Berlin 2015 diagnostic criteria. If the patients' daily cardiac-specific troponin level was above normal, echocardiography was performed to evaluate for the development of new cardiac pathologies. Coagulopathy was defined as a prothrombin time more than 3 seconds higher than normal and par- Statistical analyses were performed using IBM SPSS Statistics for Windows version 22.0 (IBM Corp., Armonk, NY). Between-group comparisons were performed using Pearson's chi-square test for parametric data and Mann-Whitney U test for non-normally distributed numerical data. The groups' demographic data and laboratory parameters were compared using independent-samples t test. Wilcoxon analysis was performed to compare repeated measures for laboratory parameters within groups. Pearson correlation analysis was used to evaluate the correlation between COHb and CRP, ferritin, D-dimer level, lymphocyte count and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ). A P-value <.05 was considered statistically significant. The mean age of the 48 patients included in the study was 57.6 ± 17.6 years. Twenty-two of the patients were women (mean age 55.8 ± 18.3 years) and 26 were men (mean age 59.1 ± 17.3 years). Twenty-eight of the patients had HT, 12 had DM, 4 had asthma, and In the present study, we determined that the COHb levels of COVID-19 patients treated in our centre were low at admission and increased with treatment. In particular, we observed that low COHb The level of CO naturally synthesised in the body can be measured using COHb, the product of its high-affinity binding to haemoglobin. In addition to its anti-inflammatory activity, it also plays an important role in vascular remodelling and prevention of tissue damage. Endogenous COHb is generated in the body when haeme oxygenase-1 (HOX-1) converts haeme to biliverdin. COHb released as a result of HOX-1 activation is eliminated by the respiratory system and can be measured in exhaled breath. HOX-1 has an important role in the reduction of reactive oxygen radicals and induction of enzymes that are cytoprotective for many organ and tissue epithelia, primarily the respiratory tract epithelium. 16 Low COHb level was found to be associated with high mortality in studies of intensive care patients. In addition, low COHb levels were shown to be correlated with poor prognosis in patients presenting with community-acquired pneumonia, myocardial infarction, stroke and acute pulmonary thromboembolism. [5] [6] [7] [8] 17 In this study, we observed that COVID-19 patients' COHb levels were low at admission and progressively increased with treatment. Furthermore, COHb levels were even lower in patients who developed MAS and ARDS, for which early treatment is of great importance. In non-surviving patients who developed ARDS, COHb levels on day 5 of treatment were higher than in surviving patients who did not develop ARDS. Patients who developed MAS exhibited greater changes in COHb on day 5 of treatment relative to patients who did not. In addition, we observed in our study that patients who developed ARDS and MAS had a higher respiratory rate at the time of hospital admission compared with those who did not. The higher respiratory rate in these patients may have been responsible for their initially low levels of CO, which is removed while breathing. The low PaCO 2 values measured in these patients' arterial blood gas analysis also showed that their ventilation capacity was not impaired at admission and that conditions were suitable for CO excretion. A study of patients who developed ARDS because of acute pulmonary thromboembolism showed that CO level was correlated with oxygen saturation, providing further evidence that CO level may fall because TA B L E 2 Comparison of laboratory parameters at admission and on day 5 among COVID-19 patients who did and did not develop macrophage activation syndrome (MAS) p: Comparison of parameters at the time of admission and day 5 of treatment between groups. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; COHb, carboxyhaemoglobin; GGT, gamma-glutamyl transferase; LDH, lactate dehydrogenase; NLR, neutrophil/lymphocyte ratio; WBC, white blood cells. Correlation analysis of COHb level with CRP and PaO 2 /FiO 2 levels in COVID-19 patients anti-inflammatory activity. CRP, ferritin, troponin and PaO 2 /FiO 2 ratio have been shown to be closely associated with MAS and mortality, and the correlations observed between these parameters and COHb support previous studies as well as our present findings. The main limitation of this study was that the number of nonsurviving patients in our sample was too small to establish an association between COHb level and mortality. However, our finding that COHb levels in patients who developed ARDS and MAS were consistent with those of non-surviving patients suggests that our results can be generalised. In conclusion, low COHb level at admission in COVID-19 patients may be an easily accessible biomarker that guides early follow-up and treatment planning to avoid ARDS, MAS and mortality. The authors received no financial support for the research and/or authorship of this article. The authors declare that they have no conflict of interest in the publication of this article. The data that support the findings of this study are available from the corresponding author upon reasonable request. 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