Predictive factors of severe coronavirus disease 2019 in previously healthy young adults: a single-center, retrospective study

From December 2019 to March 2020, coronavirus disease 2019 (COVID-19) has been considered an epidemic in China, specifically in Wuhan City, Hubei Province, where this disease initially emerged [1]. According to data, this disease has already been considered a global epidemic because more than 200 countries have been affected, with more than 970,000 patients infected and 50,000+ deaths [2]. Hence, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which caused COVID-19, shows stronger infectivity than SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, although, the mortality rate of COVID-19 is lower than SARS and MERS [3]. Nevertheless, COVID-19 should be given careful attention considering that its mortality rate is increasing [4]. The previous study has reported that elderly men, specifically those with chronic comorbidities, tend to develop a more severe COVID-19 which may be fatal compared with young men [5], considering that these elderly men have impaired immune response and incomplete functional organs. However, several previously healthy young adults who developed severe COVID-19, required superior oxygen therapy, including high-flow nasal cannula (HFNC), noninvasive positive-pressure ventilation (NPPV), invasive positive-pressure ventilation (IPPV), and even extracorporeal membrane oxygenation (ECMO). The reason this happened remains unclear. Thus, we used our hospital’s data to determine the factors affecting patients’ clinical outcomes using an appropriate statistical model.

Coronaviruses are known because of the previously encountered SARS-CoV and MERS-CoV epidemics, and both are zoonotic viruses [8]. Similar to the previous two coronavirus outbreaks, fever and cough were the most common symptoms with viral pneumonia [9]. Our study showed that patients with severe COVID-19 had higher febrile temperatures with a large number of them in the overall population. For those previously healthy young adults with sound immunity, the occurrence of high fever after viral infection indicates the body’s rapid response against the invaded pathogen. It revealed that a fierce inflammatory reaction in patients was one of the factors leading to the “severe” status. Anorexia also showed significance in our study; we presumed that it co-occurred as a symptom with fever. Patients with high fever accompanied by anorexia could be discriminated more strongly from those with ordinary fever (P = 0.001). The previous study showed that dyspnea and chest tightness were indicators of severe COVID-19 [10]. Inversely, we found that both symptoms were insignificant to distinguish severe COVID-19 in previously healthy young adults. In fact, only seven patients (two in the severe group and five in the mild group) had dyspnea and 39 patients had chest tightness (11 in the severe group and 28 in the mild group) on admission. Owing to the relatively good state of the lungs, we inferred that there was less probability of respiratory decompensation on admission. Besides, a great sample size was needed for a more powerful prove. Furthermore, a larger cohort would be required to validate these associations. Additionally, we found that older patients would need to beware of aggravation of the disease because an older age indicates the decline in organ function as well as ability of the body to self-regulate.

Our study showed that the estimated rate of COVID-19 severity in patients was 22.76%, which was lower than that of the previous study [11]. This is possibly attributed to the single-center design of this study, and we collected the previously healthy young part of patients, causing possible bias in patient distribution. Moreover, based on the results of our study, the sex difference was not associated with the development of severe COVID-19, a result consistent with the previous study [11].

It is believed that previously healthy young adults usually have a sound immune system; thus, they can immediately and accurately respond to invading pathogens and viruses. However, the reasons they quickly develop respiratory failure or acute respiratory distress syndrome (ARDS) after being infected with SARS-Co-2 are still unclear. We presume that the first reason is possibly attributed to the pathophysiology of the viral load. Tiny viral loads allow the immune system to produce antibodies whether any clinical symptoms are experienced by the body or not [12]. However, when a significant number of viruses invade the body in a short time, the immune system will be overwhelmed, resulting in massive cytokine reaction that ultimately damages the lung’s tiny vessels. It will subsequently result in pulmonary edema, providing significant burden to the circulatory system, eventually crushing the heart and lungs as well as causing coagulation and massive tiny thromboses in the tiny vessels of the whole body. Recently, Zou et al. have proven the presence of viral load of the upper respiratory tract that was detected in the asymptomatic patient was similar to that in the symptomatic patients [13]. According to another previous study, the lower respiratory tract specimens usually have significantly higher viral loads and genome fractions than the upper respiratory tract specimens [14]. The second reason is possibly attributed to the different inflammatory responses of each individual, which also play a crucial role in coronavirus-induced lung injury and ARDS. CRP is a nonspecific marker of inflammation which was widely used as a biochemical indicator for reflecting the acute severe systemic inflammatory response caused by a viral infection, such that our research illustrated that the severe COVID-19 patients had a high value than mild ones. In 2003, corticosteroid was widely administered in the treatment of SARS to control pulmonary inflammatory edema by regulating the immunity responses toward SARS-CoV. Russell et al. announced that corticosteroids should be administered before an inflammatory storm occurs to prevent lung injury [15]. However, recently, most studies have reported that corticosteroids could only delay viral clearance [16] and are insignificantly associated with the mortality rate in severe viral pneumonia [17]. According to Wang et al.’s study [18] in comprising 46 COVID-19 patients, low-dose and short-term administration of corticosteroids was associated with a faster improvement of clinical symptoms and absorption of lung focus. However, patients may significantly benefit when the medication is administered at the right time with a reasonable dose.

Elevated D-dimer levels in COVID-19 patients, associated with poor clinical outcomes has been proven [19]. Tiny thromboses are produced by inflammatory cascade, blocking the pulmonary vessel, which might result in disseminated intravascular coagulation (DIC) without stopping inflammation. In fact, in clinical practice, low-molecular-weight heparin (LMWH) is administered to prevent thrombosis if the D-dimer levels at > 4 μg/ml. The inflammatory reaction includes a cytokine storm, resulting in internal environmental disruption and inducing coagulation maladjustment. Patients in the intensive care unit (ICU) or those who died may present a final phase of body decompensation, with elevated D-dimer. The study we conducted could be an early phase before coagulation decompensation. The increase in Fib levels and decrease in PLT counts could be a coagulation compensation before D-dimer elevating.

Lymphopenia is commonly assessed in most viral infections, specifically, type A and B influenza [20]. According to a previous study, lymphopenia was also observed in SARS and MERS [21]. Coronavirus infection usually induces an immune response, resulting in decreased CD4 count and immunosuppression [22, 23]. Simultaneously, the virus also damages the epithelial walls, and disrupts surfactant in the airways, providing access to rapid bacterial growth and resulting in a secondary bacterial infection, adversely affecting immunosuppressed patients.

Our study also has limitations. Firstly, considering this was a single-center, retrospective study with limited sample size, avoiding bias regarding patient distribution is considered difficult. Secondly, lymphopenia was observed in contribution to severe prognosis in this study, but data regarding CD4 and CD8 counts and other inflammatory biomarkers were not assessed; these biomarkers may also possibly associate with the patients’severe prognosis .

In summary, this is the first study to systematically describe the clinical symptoms and laboratory biomarkers of COVID-19 in mild and severe groups of previously healthy young adults. If the patients who were admitted to the hospital had higher fever and symptoms of anorexia, biochemical examination showed higher CRP and lymphopenia; the patients is then more likely to progress to severe COVID-19. Furthermore, lymphopenia was considered as the strongest predictor of severe prognosis. Our study findings are possibly beneficial for physicians to comprehensively understand the predictive factors associated with disease severity for COVID-19, allowing them to immediately and accurately provide supportive treatment, preventing the rapid development of the disease and decreasing the mortality rate. However, additional multicenter, prospective studies are required to further assess the clinical outcomes of severe COVID-19.

In conclusion, lymphopenia is considered the strongest predictor of severe prognosis in previously healthy young adults diagnosed with COVID-19. For them, proper supervision and supportive treatment combined with superior oxygen therapy are required.