Clinical characteristics of Egyptian male patients with COVID‐19 acute respiratory distress syndrome

Background Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in severe cases associated with acute respiratory distress syndrome (ARDS). Objective To describe the clinical characteristics of patients with ARDS-COVID-19. Materials and methods This study involved 197 male Egyptian participants, among them111 COVID-19 patients presented with ARDS, 60 COVID-19 patients presented with non-ARDS, and 26 Non-COVID-19 patients. We reported the analysis results of clinical and laboratory information, including blood routine tests, blood biochemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine and C‐reactive protein (CRP)], thrombotic activity (D‐dimer) and serum ferritin and lactate dehydrogenase (LDH). Results The levels of hemoglobin, AST, creatinine, monocyte count, monocyte %, RBC count, TLC, and platelet count were not significantly different among the groups. The lymphopenia and increased CRP, ALT, D-dimer, ferritin, and LDH were observed in patients with ARDS-COVID-19. Conclusion COVID-19 patients with ARDS presented with lymphopenia, increased thrombotic activity, increased CRP, LDH, and ferritin levels. The results revealed that CRP, D-dimer, LDH levels, and lymphopenia have a significant association with the COVID-19 severity and can be used as biomarkers to predict the disease severity.

Introduction A novel coronavirus, coronavirus disease 2019 (COVID- 19), was first recognized in Wuhan (the capital of Hubei Province), China, in December 2019 [1][2][3] . The main routes of virus transmission between people are contact routes and respiratory droplets [4]. In this disease, most patients develop mild respiratory tract infection symptoms, with some people rapidly developed acute respiratory distress syndrome (ARDS) that requires hospitalization, respiratory support, and oxygen therapy [5]. Criteria for ARDS diagnosis include a progression of pulmonary findings, and bilateral pulmonary infiltrates on chest imaging, absence of cardiogenic respiratory failure, and profound hypoxemia [6]. Patients with COVID-19 ARDS have inflammatory lung, mucus production in the airways, higher proinflammatory cytokines levels, and pulmonary microthrombosis [7]. The diagnosis, control, prevention, and treatment are very critical subjects in COVID-19. So, early diagnosis and effective and timely treatment are very crucial. Delayed diagnosis of COVID-19 leads to a rapid spread of infection with increased risk for ARDS [8]. In the current study, we investigated hematological and coagulation characteristics in Egyptian patients. Moreover, the predictive values and diagnostic efficacy of clinical laboratory data were analyzed for ARDS-COVID-19 patients.

Patients and study design
This retrospective study was conducted on male Egyptian participants with or without COVID-19 at Fayoum University Hospital (Fayoum, Egypt), from May 11, 2020, to June 18, 2020. One hundred and ninety-seven male participants aged 22 to 75 years, with a median age of 40 years (interquartile range [IQR], 30-50), were participated in this study. We considered male subjects only to neglect the effect of fluctuation of female's menstrual cycle that may affect some of the clinical laboratory tests as creatine kinase, c-reactive protein, white blood cell, and others [9]. Of 197 suspected male cases, 171 (86.8%) patients were positive for COVID-19, and 26 (13.2%) were negative. Nasopharyngeal swabs were collected by a health care professional and tested for COVID-19 by real-time reverse transcription-polymerase chain reaction (rRT-PCR). The COVID-19 patients were divided into two groups, comprising 111 (64.9%) patients diagnosed with ARDS and 60 (35.1%) with non-ARDS. Blood samples from each adult male patient were collected and used for hematological investigations.
This study was performed in accordance with the ethical principles of the 1975 Declaration of Helsinki and approved by the Ethics Committee of Fayoum University Hospital, and written informed consent was obtained from each patient before clinical and laboratory investigations for the involvement of anonymous patients' data in scientific research for the current retrospective study.

Statistical analysis
All statistical analyses were performed using GraphPad Prism (GraphPad Prism 8.0 Software, San Diego, CA, USA). All data were presented as median and IQR. For comparing more than two groups, both one-way ANOVA and Tukey's multiple comparisons post-hoc test were used while Student's t-test was used, if two different groups were compared. Differences were considered significant at P-value < 0.05. The diagnostic potential was compared among tested parameters using receiver operating characteristic (ROC) curve analysis.

Clinical laboratory data
The hematological features of the patients are shown in Table 2. The levels of hemoglobin, AST, creatinine, monocyte count, monocyte %, RBC count, TLC, and platelet count were not significantly different (p > 0.05) among the groups. The level of CRP (mg/L) was significantly higher in the ARDS-COVID-19 group  The level of LDH (U/L) was significantly (p < 0.05) higher in the ARDS-COVID-19 [331.5 (241.5-521. 5

ROC curve analysis
ROC curves were used to evaluate the diagnostic efficiency of CRP, D-dimer, ferritin, and LDH levels. The total accuracy and sensitivity of CRP, D-dimer, ferritin, and LDH at the selected cutoff values are in Table 3. The sensitivity of CRP, D-dimer, ferritin, and LDH were 74.38%, 80.0%, 62.62% and 76.42%, respectively.
As shown in Table 3
In the current study, we reported the analysis results of blood routine, blood biochemistry parameters, thrombotic activity, serum ferritin, and lactate dehydrogenase of 197 Egyptian male patients tested for coronavirus by rRT-PCR after being admitted to the Fayoum University Hospital emergency room as suspected COVID-19 cases. Of them, 171 tested positive, whereas 26 tested negatives.
The results revealed that TLC, monocyte count, monocyte%, hemoglobin, and RBC count were not significantly different between the ARDS-COVID-19 group and the Non-ARDS--COVID-19 group. The lymphocyte count was significantly lower in the ARDS-COVID-19 group when compared to non-ARDS-COVID-19 and suspected non-COVID-19 groups. In accordance with Huang et al. [7] who described low lymphocyte counts in most patients. Lymphopenia is a prominent characteristic of critically ill patients with COVID-19, resulting from the direct destruction of lymphocytes, especially CD4 + T and CD8 + T cells [15], or cytokinemediated lymphocyte destruction [16]. Conversely, Gao et al. [1] found that lymphocyte count was not significantly different between patients with severe and mild COVID-19, and this may be attributed to variability in the population, gender difference as the current study selected male subjects while the Chinese one uses data of both male and female patients, and sample size (Gao et al. [1] study involved smaller sample size).
This study revealed that thrombotic activity (D-dimer) was significantly elevated in ARDS--COVID-19 group  [17]. Gao et al. [1] found a significant difference in D-dimer level between patients with severe and mild COVID-19, which suggests that elevated D-dimer levels have a significant association with the COVID-19 severity. Our results revealed that COVID-19 patients with ARDS would have abnormal coagulation, and the acute lung inflammatory response may have been associated with increased thrombotic activity [18].
This study demonstrated that the median platelet counts in the ARDS-COVID-19 group were within the normal range. This result is in agreement with a previous study in China [19]. On the other hand, Yin et al. [20] reported a significant elevation in platelet count in patients with severe pneumonia induced by COVID-19 than in those induced by non-COVID-19. There was no significant difference (p > 0.05) regarding kidney functions among the groups. On the other hand, ALT showed a significant difference (p < 0.05) between the ARDS--COVID-19 group and the non-ARDS-COVID-19 group.
In this study, COVID-19 patients showed elevated LDH, ferritin, and CRP levels compared to the suspected non-COVID-19 group. Huang et al. and Wang et al. [7,21] found LDH level was significantly elevated in COVID-19 cases, which required intensive care unit (ICU) care compared to cases that did not require ICU care in China. Severe COVID-19 infections may cause cytokine-mediated lung tissue damage and LDH enzyme release [22]. Since LDH isoenzyme-3 (LDH-3) is present in lung tissue, patients with severe ARDS can be expected to release LDH in greater amounts in the circulation.
Statistical analysis in this study showed that the ferritin level was significantly (p < 0.05) elevated in ARDS-COVID- 19   the disease severity (Table 2). This result was in agreement with Lin et al. [23], who reported an increase of ferritin level in Chinese patients with severe COVID-19 than patients with nonsevere COVID-19 disease. Raised ferritin levels in circulation could indicate severe inflammatory reaction in ARDS-COVID-19, and elevated ferritin levels in circulation may play an important role by contributing to cytokine storm development resulting in pulmonary edema and ARDS [24].
Results of the current study revealed a positive association between CRP level and lung disorders in COVID-19 patients. This result was in agreement with Wang [25], who reported an increase in CRP level in Chinese patients with critical and severe COVID-19 than patients with moderate and mild COVID-19.
ROC curves were used to evaluate the sensitivity and specificity of different biomarkers in ARDS-COVID-19 patients. The AUCs of CRP, D-dimer, and LDH were 0.80, 0.79, and 0.89, respectively, while the AUC of ferritin was 0.72, below 0.750, unlikely to be an acceptable predictive value. The results revealed that the levels of CRP, D-dimer, and LDH, AUC more than 0.75, were valuable diagnostic biomarkers for distinguishing ARDS-COVID-19 from non-ARDS-COVID-19.

Conclusion
COVID-19 Egyptian patients with ARDS showed lymphopenia, increased thrombotic activity, elevated CRP, LDH, and ferritin levels. Furthermore, elevated CRP, D-dimer, and LDH levels as well as lymphopenia have a significant association with the COVID-19 severity and can be used as valuable biomarkers to predict the disease severity.