Prognostic factors for COVID-19 pneumonia with severe acute respiratory distress syndrome: An observational study.

Objective: To identify the prognostic factors of the coronavirus disease 2019 (Covid-19) pneumonia patients with severe acute respiratory distress syndrome (ARDS). Design and methods: 45 Covid-19 pneumonia patients with ARDS were included, who were hospitalized at The First Affiliated Hospital of Yangtze University in Jingzhou, Hubei, China, between January 22, 2020, and March 6, 2020. Clinical data and outcomes were reviewed and analyzed according to the Berlin definition. Results: Males were more likely to develop severe ARDS (11 [91.7%] in males vs. 1 [8.3%] in females). Several factors related to the development of Severe ARDS had been found in this study, which included sex (male) (HR, 13.75; 95% CI, 1.45-130.24), Neutrophil Count (HR, 55.00; 95% CI, 5.02-602.15), Lymphocyte Counts (HR, 40.00; 95% CI, 4.83-331.00), Pro-Thrombin Time (HR, 12.14; 95% CI, 1.19-123.62), D-Dimer (HR, 11.00; 95% CI, 1.16-103.94), Total Bilirubin (HR, 5.00; 95% CI, 0.93-26.79), Albumin (HR, 17.5; 95% CI, 2.67-114.85), Blood Urea Nitrogen (HR, 28.60; 95% CI, 2.89-283.06), Lactate Dehydrogenase (HR, 6.00; 95% CI, 1.17-30.73), C-Reactive Protein (HR, 15.87; 95% CI, 2.40-111.11). Conclusion: Laboratory tests such as neutrophil count and lymphocyte Counts could play an important role in the diagnosis of severe ARDS and guide treatment decision-making for ARDS patients.

Clinically, patients with ARDS develop severe hypoxemia and/or hypercapnia, and most die of sepsis or multiorgan failure rather than from refractory respiratory failure. Hospital mortality of 40% has been reported in patients with ARDS [7,8]. The Berlin definition divides ARDS into three severity of levels based on degree of hypoxemia: mild, moderate, and severe ARDS, and severe ARDS has the highest mortality rate. However, prognostic factors for COVID-19 pneumonia with severe ARDS are still uncertain. In this study, we evaluated ARDS patients with confirmed Covid-19 who were admitted to The First Affiliated Hospital of Yangtze University in Jingzhou, Hubei, China. The objective of this case series was to identify the prognostic factors of Covid-19 pneumonia patients with severe acute respiratory distress syndrome (ARDS) according to the Berlin definition [9].The baseline ARDS morbidity and mortality reported in this study will be of considerable value for the early identification of individuals who are at risk of developing severe ARDS and who are most likely to benefit from further treatment.

Design and participants
This single-center, retrospective, observational study was conducted at The First Affiliated Hospital of Yangtze University, located in Jing Zhou, Hubei Province, which is responsible for the treatment of Covid-19 patients assigned by the government. In this study, we retrospectively analyzed data from 45 Covid-19 patients that developed ARDS between January 23 and March 6, 2020, Laboratory confirmation of Covid-19 was performed at The First Affiliated Hospital of Yangtze University according to WHO interim guidelines (WHO, 2020), while ARDS diagnosis was performed according to the Berlin definitions [9].Patients died within 24 h of receiving a diagnosis of ARDS were excluded; no children or adolescents were enrolled in the study. At final, 15 patients with mild ARDS, 18 with moderate ARDS, and 12 with severe ARDS patients were included. All chest CT images were reviewed by experienced radiologists. The severity of the ARDS was determined based on the degree of hypoxemia as mild (200 mmHg<PF ratio≤ 300 mmHg), moderate (100 mmHg<PF ratio≤ 200 mmHg), or severe (PF ratio<100 mmHg). This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Yangtze University (No. K20200102). Verbal consent was obtained from all patients.

Data collection
We reviewed the electronic medical records of all patients with laboratory-confirmed Covid-19. Recorded data included demographic information, medical history, exposure history, comorbidities, symptoms, signs, laboratory findings, treatments, and outcomes. The majority of clinical data regarding Systolic Pressure, Respiratory Rate, Blood Routine Blood Test, Coagulation, Biochemical Tests, Chest CT Scans, as well as Partial Pressure of Arterial Oxygen (PaO2)/fraction of inspired oxygen (FIO2) were obtained within 24 hours of ARDS diagnosis. Shock was defined according to the guidelines of WHO for novel coronavirus disease 2019 (COVID-19), while acute kidney injury was diagnosed based on serum creatinine levels [4,10,11]. Cardiac injury was diagnosed if the serum concentration of hypersensitive cardiac troponin I (hsTNI) was above the upper limit of the reference range (34.2 pg/mL) [4]. All clinical data were reviewed by an experienced team of physicians. Any missing or uncertain records were collected and clarified through direct communication with involved health-care providers and the families of the patients.

Statistical analysis
Continuous variables were expressed as median and interquartile range (IQR), and comparisons were performed using the Kruskal-Wallis H test. Categorical variables were expressed as number (%) and compared using the chi-squared test or Fisher's exact test among patients with mild, moderate, and severe ARDS. We used a Kaplan Meier plot for survival data. Mantel-Cox (log-rank) tests were performed to compare survival curves. Multivariate Cox proportional hazard ratio (HR) models were used to determine HRs and 95% CIs between individual factors on the development of ARDS. All statistical tests were two-sided, with the significance threshold set at α<0.05. Statistical analyses were conducted using the SPSS software, version 17.0.

Clinical characteristics and symptoms
In this study, we retrospectively analyzed data from 45 Covid-19 patients that developed ARDS between January 23 and March 6, 2020; no children or adolescents were enrolled in the study. All study participants were residents of Jing Zhou City. The median age was 64 years (IQR, 53-73; range, 18-88 years; p>0.929). 22(48.9%) were older than 65 years, 6 of whom had mild ARDS, 9 had moderate ARDS, and 7 had severe ARDS; 29 (64.4%) patients were males, while the remaining 16

Comorbidities and prognosis
The median systolic pressure, respiratory rate, pH, PO 2 Table 2).
Compared with patients with mild ARDS and moderate ARDS, patients with severe ARDS were more likely to require invasive mechanical ventilation (p=0.005), prone position ventilation (p=0.001), antibacterial agents (p=0.004), and interferon (p=0.017). Although antiviral agents (n=12; 100%) and glucocorticoids (n=11; 91.7%) were widely used in patients with severe ARDS, there was no significant difference in the frequency of the use of these agents among the different groups (Table 2).
In this cohort, among discharged patients (n=16), the median hospital stay was 29 days (IQR, 19.0-38.0). Among patients that died of ARDS (n=7), the median duration from admission to death was 14 (IQR, 7-17) days. Kaplan Meier survival curves for different severity of ARDS patients showed significant difference between three groups (log-rank tests, p=0.034) (Figure 1).

Discussion
It has become evident that Covid-19 patients are at risk of developing ARDS [4][5][6]. Severe ARDS has the highest mortality rate among three severity levels of ARDS [9]. However, Prognostic factors for COVID-19 pneumonia with severe acute respiratory distress syndrome are still uncertain.
In this single-centered, retrospective, observational study, we stratified patients into three groups (mild, moderate, and severe ARDS) according to Berlin severity definitions. We assessed differences in clinical characteristics and outcomes among the different patient groups and found that male patients were more likely to develop severe ARDS. We also found that patients with severe ARDS were more likely to experience severe respiratory failure, sepsis, cardiac injury, and shock. Laboratory findings, including high neutrophil counts, low lymphocyte count, low albumin levels, prolonged prothrombin time, as well as high D-dimer, lactate dehydrogenase, blood urea nitrogen, and C-reactive protein levels. Laboratory tests such as neutrophil count and lymphocyte Counts could play an important role in the diagnosis of severe ARDS and guide treatment decision-making for ARDS patients.
Several studies reported that nearly 70% of patients confirmed with Covid-19 were men [1,2]. Moreover, elderly patients have a higher Covid-19-associated mortality rate compared with younger individuals [4]. These findings suggest that older, male patients are the most susceptible to Covid-19 infection [2]. Consistently, we found that of the 45 enrolled ARDS patients, a high proportion included elderly or male patients. Furthermore, we found that males were more likely to develop severe ARDS compared to females (p=0.044). However, the mechanism underlying this phenomenon remains unclear.
Wu et al. found that several factors that were associated with the development of ARDS, including fever, comorbidities, AST, creatinine, and glucose levels, were not associated with mortality [12,13]. In this study, we could not find an association between ARDS severity and disease Signs and Symptoms, Including Fever, Dry Cough, Vomiting, Fatigue, Chest Pain, Hemoptysis, Dorsalgia, and Diarrhea). The presence of chronic diseases, including diabetes, hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and cancer, were also not linked to the risk of severe ARDS development. Additionally, we found no association between ARDS severity and organ dysfunction, including acute kidney injury, liver dysfunction, and hyperglycemia.
In this study, we found that the incidence of severe ARDS was higher in patients with low lymphocyte count, high white blood cell count, and high neutrophil count. Neutrophilia has been observed both in the peripheral blood and lungs of patients with Covid-19, and neutrophils were identified as the primary Lu/ Zhu/ Xiong/ et al.
source of chemokines and cytokines [14][15][16]. Patients with severe ARDS had a significantly higher neutrophil count compared with patients with mild or moderate ARDS. Elevated neutrophil numbers were likely due to host immune responses against the virus, contributing to cytokine storm. Lymphopenia has also been reported in patients with Covid-19 and has been suggested as a critical factor associated with disease severity [2,5,16,17]. Consistent with previous reports that lymphopenia could increase inflammation, we found that compared to patients with mild or moderate ARDS, patients with severe ARDS had higher levels of C-reactive protein, a marker of generalized inflammation [18].
Low albumin levels, prolonged prothrombin time, and high Ddimer, lactate dehydrogenase, total bilirubin, and blood urea nitrogen levels were associated with high mortality in ARDS patients [4,12]. The predictive value of albumin and lactate dehydrogenase levels may be higher in monitoring the severity and course of ARDS in critically ill patients [19]. Previous studies demonstrated that prolonged prothrombin time and high D-dimer were associated with excessive thrombin generation, inhibition of fibrinolysis, endothelial damage, and capillary leakage, which could increase the severity of ARDS [20]. Consistent with these results, we found that low albumin and prolonged prothrombin time, as well as high D-dimer, total bilirubin, lactate dehydrogenase, and blood urea nitrogen were all factors significantly associated with risk of severe ARDS development. These results suggest that laboratory findings could provide a powerful tool guiding severe ARDS diagnosis.
In this study, we found that ARDS development was associated with the presence of various dysfunctions and complications, such as severe respiratory failure, hypoxemia, sepsis, multiple systemic organ failure, and shock. We also found that the respiratory rate and pH were significantly higher in patients with severe ARDS, while the median PO 2 and PO 2 /FiO 2 were lower. The incidence of dyspnea was significantly higher in patients with severe ARDS, who required mechanical ventilation more frequently. Additionally, cardiac injury and shock were more prevalent among patients with severe ARDS. As patients with ARDS often develop severe hypoxemia and hypercapnia and most die of sepsis or multiorgan failure rather than refractory respiratory failure, future studies are needed to explore the prognostic value of SOFA scores in Covid-19 patients [7,8].
This study has several limitations. Importantly, this was a single-center study with a limited sample size. Potential selection bias may have been introduced when identifying factors that influence clinical outcomes, and large multi-center studies are required to further define the clinical characteristics and risk factors of ARDS development in Covid-19 patients. Furthermore, this was a retrospective study; hence, the data of this study permit a preliminary assessment of the clinical course and outcomes of ARDS patients with Covid-19, and further studies are required to confirm our findings.

Conclusion
In conclusion, the mortality Covid-19 patients with severe ARDS are considerably higher compared with patients with mild ARDS symptoms. Male patients with low lymphocyte count, high neutrophil count, prolonged prothrombin time, low albumin, as well as high D-dimer, lactate dehydrogenase, total bilirubin, blood urea nitrogen, and C-reactive protein levels have a higher risk of developing severe ARDS. Laboratory tests could play an important role in the diagnosis of severe ARDS and guide treatment decision-making for ARDS patients.