key: cord-0728590-707w8otq
authors: Alay, Handan; Laloglu, Esra
title: The role of angiopoietin‐2 and surfactant protein‐D levels in SARS‐CoV‐2‐related lung injury: A prospective, observational, cohort study
date: 2021-07-16
journal: J Med Virol
DOI: 10.1002/jmv.27184
sha: 5768eca9a0661fe26f8cec24e4d4fb229b8932ec
doc_id: 728590
cord_uid: 707w8otq

INTRODUCTION: Coronavirus disease‐2019 (COVID‐19) is a respiratory disease whose clinical manifestation ranges from asymptomatic to severe respiratory failure. The purpose of this study was to investigate the place of serum surfactant‐D (SP‐D) and angiopoetin‐2 (Ang‐2) levels in predicting severity of disease in patients diagnosed with COVID‐19. METHODS: Sixty‐four patients diagnosed with COVID‐19 between September 2020 and February 2021, 50 patients diagnosed with community‐acquired pneumonia and a 50‐member healthy control group were included in the study. Plasma samples and clinical data were collected within 72 h after admission, during hospital stay. Serum SP‐D and Ang‐2 concentrations were measured using the enzyme‐linked immunosorbent assay. RESULTS: SP‐D and Ang‐2 levels were significantly higher in the mild–moderate pneumonia and severe/critical patient groups compared to the asymptomatic and noncomplicated COVID‐19 patients (p < 0.001 for all groups). Serum SP‐D and Ang‐2 levels of severe‐critical COVID‐19 patients were significantly higher than CAP patients (p < 0.001). Powerful correlation was present between clinical severity of COVID‐19 and SP‐D and Ang‐2 levels (r = 0.885 p < 0.001 and r = 0.913 p < 0.001, respectively). Cut‐off values of 37.7 ng/ml (AUC = 0.763, p < 0.001, 95% confidence interval [CI] = 0.667–0.860) for SP‐D and 4208.3 pg/ml (AUC = 0.659, p = 0.004, 95% CI = 0.554–0.763) for Ang‐2 were identified as predictors of COVID‐19 disease at receiver operating characteristic curve analysis. CONCLUSION: SP‐D and Ang‐2 are predictive factors in differentiating COVID‐19 patients and determining severity of disease. These data may be important for the initiation of treatment in the early stage of the disease in patients with COVID‐19.

A novel coronavirus was identified as the agent in a series of cases of pneumonia in the Chinese city of Wuhan in the province of Hubei in late 2019. The virus responsible for the outbreak in China subsequently spread rapidly across the entire world. The virus responsible for 2019 Coronavirus disease was given the name Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 1 Infected patients may be asymptomatic, or else the condition may manifest from a mild clinic form to severe respiratory failure accompanied by symptoms such as sore throat, fatigue, joint pain, and loss of smell and taste. and extrapulmonary capillary bed. 6 Endothelial damage is a common cause of thrombosis, a cause of morbidity and mortality in COVID-19 patients, ARDS, and multiple organ failure. 7 Angiopoietin-2 (Ang-2) increases endothelial inflammation and permeability by acting as an Ang-1 and Tie2 signaling antagonist. 8 Higher serum Ang-2 levels have been reported as a result of induction of endothelial permeability occurring in pneumonia and ARDS compared to healthy individuals, and Ang-2 levels have been shown to be correlated with the severity of sepsis and pneumonia. 9, 10 Several parameters are employed as prognostic factors in However, these parameters are not specific in COVID-19 infection. The purpose of the present study was therefore to evaluate serum SP-D and Ang-2 levels, showing endothelial dysfunction and respiratory failure, for predicting disease severity in COVID-19 patients at time of presentation and for differentiating these from patients with community-acquired pneumonia (CAP). 

Group 1 consisted of patients aged over 18 tested for SARS-CoV-2 infections using nasopharyngeal swabs, reported as reversetranscription polymerase chain reaction (RT-PCR) positive, and diagnosed with COVID-19 based on the Turkish Ministry of Health COVID-19 Adult Patient Treatment Guideline and literature. [12] [13] [14] These were divided into four subgroups based on clinical characteristics-asymptomatic, uncomplicated, mild-moderate pneumonia, and severe pneumonia/critical. Clinical evaluation of all patients was performed using thoracic computed tomography (CT) scanning and laboratory assessments.

Asymptomatic patients can develop symptoms in a median 4 days (3-7 days) after a positive RT-PCR test. 15 Patients with no symptoms 4 days after first RT-PCR positivity were therefore regarded as asymptomatic in this study.

Uncomplicated patients consisted of individuals with findings of fever, muscle/joint pains, cough, sore throat, and nasal congestion, without respiratory distress, tachypnea, or SPO 2 < 93%, with no poor prognostic criteria at blood tests (blood lymphocyte count 800 cells/ µl or ferritin >500 ng/ml or D-dimer >1000 ng/ml, etc.), and with normal lung radiographs.

Patients with mild-moderate pneumonia were defined as individuals with findings such as fever, muscle/joint pain, cough, and sore throat, with a respiratory rate <30/min, SpO2 levels in room air >90%, and mild-moderate pneumonia findings on lung X-rays or tomography.

Patients with severe pneumonia had findings such as fever, muscle/joint pain, cough, and sore throat, with tachypnea (≥30/min), SpO2 levels in room air ≤90%, and findings of diffuse bilateral pneumonia on X-rays or tomography.

Group 2 consisted of patients with fever (>38.3°), cough, and phlegm, with chest X-rays compatible with infiltration (lobar consolidation) and leukocytosis, diagnosed with community-acquired bacterial pneumonia, 16 and with CAP but identified as SARS-CoV-2 infection-negative with nasopharyngeal swabs. These had no history of COVID-19 patients. Table 1 . The groups' routine laboratory parameters are shown in Table 2 .

SP-D and Ang-2 levels were compared among the patients in Group 1 according to their clinical severity. SP-D and Ang-2 levels were significantly higher in the mild-moderate pneumonia and severe/critical patient groups compared to the asymptomatic and uncomplicated COVID-19 patients (p < 0.001 for all groups. In addition, severe/critical COVID-19 patients have higher serum SP-D and Ang-2 than CAP patients. (p < 0.001) ( Table 3 ).

Significant, powerful positive correlation was also determined be- from wide cohorts emphasizes that it is a prognostic marker of clinical flare-ups and COPD progression. 19 In addition, it has been shown to be useful in predicting the risk of poorer outcomes in critical patients A/ H1N1 virus infection. 20 Lymphopenia is most frequently observed, although leukocytosis or leukopenia have also been reported. 25 Lymphopenia is a maker used in the hospitalization of COVID-19 patients and in determining disease severity. 26 One meta-analysis reported that severe COVID-19 may be associated with a high WBC count and a lower lymphocyte count. 27 WBC values were lower in COVID-19 patients than in the CAP and control groups in the present study, while WBC levels in patients with CAP were higher than in the COVID-19 and control groups. Severe acute respiratory syndrome coronavirus (SARS-Cov) resulted in significant morbidity and mortality in humans in previous years. Studies have reported that no significant difference between patients with SARS and those with bacterial pneumonia in terms of pulmonary infiltration, chest X-ray scores, thrombocytopenia and leukocytopenia.

However, higher serum SP-D levels have been shown compared to CAP patients and healthy controls. 26 One study evaluating serum SP-D levels in patients with CAP reported below-normal values at the time of patients' presentation to hospital. Initially low SP-D levels were then observed to peak on the fifth day of follow-up. That study also reported no correlation between SP-D and CRP concentrations, and that these molecules respond independently to bacterial infection. 28 Higher serum SP-D levels have been reported in COVID-19 patients compared to a control group, and in patients developing ARDS and macrophage activation syndrome. The increase in SP-D levels was described as associated with the clinical severity of the disease. 29 In the present study, severe/critical COVID-19 patients have higher serum SP-D and Ang-2 than CAP patients. In addition, we also determined in 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The authors declare that there are no conflict of interests. 

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How to cite this article: Alay H, Laloglu E.. The role of angiopoietin-2 and surfactant protein-D levels in SARS-CoV-2-related lung injury: A prospective, observational, cohort study

http://orcid.org/0000-0002-4406-014XEsra Laloglu http://orcid.org/0000-0001-5189-3564