Because the symptoms of COVID-19 can take up to 3 weeks to develop fully [1–4], the early identification of patients at higher risk of severe disease is important to implement timely medical strategies. This could save time and energy in the context of the exhausted healthcare systems. Therefore, this study aimed to identify the factors associated with severe COVID-19 and evaluate the current antiviral drugs, especially in severe patients. The results suggest that age ≥ 60 years, D-dimer > 0.243 µg/ml, and lower oxygenation index were associated with severe COVID-19. Therefore, the patients presenting those characteristics could be more aggressively managed from start in order to prevent complications. In addition, arbidol might provide more clinical benefits in treating patients with severe COVID-19 compared with other antiviral drugs.
A total of 550 patients diagnosed with COVID-19 were included in this study. Inconsistent with the literature, there were more females (53.1%) than males in the present study [1–4], but there were more male patients among the severe cases. This discrepancy can be due to many factors, including the transmission route, willingness to undergo screening, and socioeconomical factors. Epidemiology tracing identified 170 (30.9%) of patients with 2019-nCoV having a history of contact with an infected individual and 38 (6.9%) due to a recent visit to a COVID-19-designated hospital. The remaining of the patients had no clear source of infection. Those results highlight the need for refraining from having contacts and to enforce physical distancing, to avoid visiting hospitals known to treat COVID-19 and visiting other hospitals, and that many patients might have been infected through asymptomatic patients, either because those patients were asymptomatic carriers or because symptom onset sis not occur yet. This will have to be examined in future studies.
In this study, 42.3% of the non-severe patients did not have fever at diagnosis, which was lower than what was reported by Guan et al. [4]. Upon hospital admission, 42.7% of the patients who eventually progressed to severe COVID-19 had the typical triple signs (fever, cough, and dyspnea), while the triple signs were observed in only 14.5% of the non-severe patients. Unsurprisingly, severe patients often had more comorbidities. Hypertension, diabetes, cardiovascular diseases, and malignancy were the most common underlying diseases observed in patients with severe COVID-19. Older age was also observed to be associated with severe COVID-19, but whether this is because older patients can be more frail and weaker or because older individuals often have more comorbidities is still unknown.
As for the laboratory tests, 66.7% of the patients in the study had normal leukocyte count, and a quarter of the patients had decreased WBC counts. For 9.6% of patients who had an elevated WBC, secondary infections were often the cause of the elevated WBC. In addition, 49.8% of the patients presented with decreased lymphocyte counts, of which 52.0% (130/250) were severe cases. The incidence of anemia and thrombocytopenia was 36.9% and 6.8%, respectively, without differences according to disease severity. Cardiac enzymes, troponin T, transaminase, creatinine, and other organ injury indicators were also increased to varying degrees in some patients. Both hsCRP and ESR were increased in most patients, especially in severe patients. This highlights the systemic nature of the disease and that the patients should be comprehensively assessed. The increased inflammatory indicators suggested that SARS-CoV-2 tips the balance of the immune system towards a cytokine storm that contributes to patient deterioration and mortality, as observed in various infections [21, 22]. Recent biopsy reports by Xu et al. [23] also indicated an increase of proinflammatory CCR4 + CCR6 + Th17 cells in the peripheral blood that might lead to systemic inflammatory responses and contribute to diffuse alveolar injury and pulmonary hyaline membrane formation. That evidence suggests that the systemic inflammatory response is an important factor leading to poor COVID-19 prognosis, as supported by the literature [21, 22]. Unfortunately, due to the limited conditions of the hospital, no cytokine or other related testing was performed in this study. Future studies should aim to carefully examine the various cytokines involved in COVID-19 and in relation to disease severity.
It has been estimated that the mortality rate in severe cases was over 50% [24]. Therefore, it is critical to identify patients with an increased risk of disease progression. In the present study, the multivariable logistic regression analysis showed that age ≥ 60 years, D-dimer > 0.243 µg/ml, and decreased OI might be risk factors for patient deterioration. The importance of aging in determining the COVID-19 prognosis was consistent with previous studies that aimed to identify prognosis factors for SARS or MERS infections [25–28]. The coagulation dysfunction we observed in this study was consistent with previous studies [1–3, 5]. Severe patients were more likely to develop coagulation and fibrinolysis disorders, especially the elevation of D-dimer levels. Similar to other severe viral pneumonia, the cause might be the sepsis-induced inflammatory cytokine storm affecting multiple endogenous and exogenous coagulation pathways and fibrinolysis that ultimately lead to thrombosis formation [16, 21]. Therefore, special attention should be paid to severe patients with long-term bed rest, advanced age, and complicated underlying diseases, especially in the presence of coagulation abnormalities. Appropriate anticoagulant treatment might be considered in such patients in order to prevent the occurrence of deep vein thrombosis (DVT) and related complications [29–31]. In the present study, a reduction in OI was associated with increased mortality. Similarly, Liu et al. [32] found that the lung injury Murray score and OI could predict the prognosis of COVID-19. Therefore, early recognition of these three indicators upon hospital admission is critical, so appropriate medical strategies can be adjusted, and more importantly, the nearly exhausted medical support force can be redistributed. This is especially important because when the patients are admitted, the exact interval between infection and symptom onset is unknown and the exact time until an eventual disease progression is also unknown.
In this study, 435 patients (79.1%) received at least one antibiotic in the hospital, but only 110 (20.0%) of them were confirmed with secondary bacterial infection (some cases were accompanied by fungal infection). Therefore, more attention should be paid to the indication of antibiotic use and avoid antibiotic overuse. Prophylaxis for eventual complicating secondary bacterial or fungal infections can be indicated in some cases, but additional studies are necessary to determine who they might be. In addition, 122 severe patients received intravenous or oral glucocorticoid treatment. Among these patients, 79 had an improved condition but 43 eventually died. Nevertheless, the rate of improvement was relatively high (83.9% vs. 64.8%, P = 0.009) in severe patients who did not receive glucocorticoids. It is important to point out that the patients who received glucocorticoids also had a higher rate of secondary infections compared with patients who did not receive glucocorticoids (36.9% vs. 19.6%, P = 0.021). This is consistent with several recent studies that suggested that glucocorticoids are not beneficial for patients with ARDS and viral infections [33, 34], but contradicts recent findings that suggest that corticosteroids decrease the mortality of COVID-19, but the level of evidence is low [35]. Even though this study was not powered to analyze the benefit and risks of using glucocorticoids in COVID-19, the data suggest that glucocorticoids failed to improve the prognosis and increased the risk of secondary infection.
Another important feature of this study was the assessment of current antiviral drugs. The antiviral drugs used during the study period were arbidol, oseltamivir, ribavirin, lopinavir/ritonavir, and α- interferon. The results suggest that arbidol might provide more benefits compared with ribavirin in severe patients treated with monotherapy, but the difference between arbidol and oseltamivir was not significant (P = 0.391). At the same time, in severe patients who received combination therapy, the combinations that included arbidol showed better benefits. A multicenter randomized controlled clinical trial published on medRxiv recently showed that patients treated with favipiravir had a better recovery rate (71.4% vs. 55.9% P = 0.0199) but more side effects were observed compared with arbidol [15, 17]. There are multiple antiviral drugs being evaluated and tested in trials currently [18], but before better options can be justified, the use of arbidol might be recommended for its relative safety and effectiveness profile.
Using the MuLBSTA scoring system, 46 (88.5%) patients were correctly classified as at high-risk for death (score > 12), but only 22 (42.3%) were correctly classified as high-risk (score ≥ 2) when using the CURB-65 scoring system. This suggests that the MuLBSTA scoring system is more effective in the mortality risk assessment of patients with COVID-19 (P < 0.001) on the early-stage of the disease. This is consistent with a previous study [36]. We speculated that the reason why the MuLBSTA scoring system was more effective is that its scoring criteria (age ≥ 60, smoking status/smoking cessation history, hypertension history, imaging showing multiple lobar infiltrations, lymphocyte counts ≤ 0.8 × 109/L, or combined with a bacterial infection) can be achieved and evaluated at the early stage of the disease. On the other hand, the parameters analyzed in CURB-65 may not be elevated in the early stage of the disease in the high-risk population. If necessary, an attempt might be made to lower the scoring criteria and set 1 as a cut-off point to improve its sensitivity (44/52, 84.6% vs. 46/52, 88.5%, P = 0.566). Despite that the 2009 IDSA/ATS guidelines recommended CURB-65 as a severity assessment form for community-acquired pneumonia (CAP) [37], the present study suggests that the MuLBSTA scoring system might be a better assessment tool for COVID-19.
Limitations
This study has several limitations. First, this was a retrospective study conducted at a single center, with a cohort of 550 patients treated after the arrival of the Hebei medical team, which might not necessarily represent the general population of patients. In addition, the false-negative rates of current SARS-CoV-19 tests are relatively high and might bias the results. Last but not least, due to the retrospective nature of this study and the lack of diverse drugs in the early stage of the epidemic, the observation of the benefits for different antiviral drugs needs to be further confirmed in future randomized controlled trials.