Risk factors associated with disease severity and length of hospital stay in COVID-19 patients
Authors: Xiaofan Liu, Hong Zhou, Yilu Zhou, Xiaojun Wu, Yang Zhao, Yang Lu, Weijun Tan, Mingli Yuan, Xuhong Ding, Jinjing Zou, Ruiyun Li, Hailing Liu, Rob M. Ewing, Yi Hu, Hanxiang Nie, Yihua Wang
Journal: Journal of Infection (2020)

We read with interest the article in this journal which revealed the critical role of timely supply of medical resources for COVID-19 patients.1Zhang Z. Yao W. Wang Y. Long C. Fu X. Wuhan and hubei COVID-19 mortality analysis reveals the critical role of timely supply of medical resources.J Infect. 2020; (PubMed PMID:32209384)Google Scholar The pandemic of COVID-19 has placed an enormous burden on health authorities across the world. The virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously known as 2019-nCoV), causes acute respiratory disease with common signs of infection being respiratory symptoms, fever, cough and breathing difficulties. In more severe cases, infection causes pneumonia, lung failure, septic shock, organ failure and risk of death. The WHO reports that 80% of those infected will develop mild symptoms, 14% severe symptoms and 6% will become critically ill. Given the wide clinical spectrum of COVID-19, a key challenge faced by frontline clinical staff is prioritisation of stretched resources. Thus, there is a critical need for robust risk assessment for clinical management. To address this, we identified consecutive patients with moderate or severe COVID-19 discharged from the general wards of Renmin Hospital of Wuhan University between 5 February 2020 to 14 March 2020 (Ethics approval No: WDRY2020-K124). All patients had been diagnosed with COVID-19 according to WHO interim guidance and had radiologic evidence of pneumonia or infiltrates on chest CT scan according. The criteria for patient discharge was the absence of fever for at least 3 days, substantial improvement in both lungs on chest CT, clinical remission of respiratory symptoms, and two throat-swab samples negative for viral RNA obtained at least 24 h apart. In total, 99 patients (61 pneumonia and 38 severe pneumonia) with key information in their medical records were included in this study. Demographic, clinical, laboratory, and treatment data were extracted from electronic medical records. Risk factors that affect disease severity and length of hospital stay were investigated with appropriate statistical methods using R (V3.6.1) or GraphPad Prism (V8.2.1). To explore the risk factors associated with disease severity, univariate and multivariate logistic regression models were used. In univariate analysis, hypertension, lymphopenia, elevated neutrophil count, lactate dehydrogenase (LDH), C-reactive protein (CRP), and symptoms such as dyspnea, fatigue, and anorexia/lethargy were all associated with severe cases (Fig. 1a; p < 0.05). In the multivariable logistic regression model, we included 90 patients (56 pneumonia and 34 severe pneumonia) with complete data for those significant variables from univariate analysis. We identified hypertension (Odds ratio: 3.59; p = 0.048), increased CRP (Odds ratio: 1.38; p = 0.01) and lymphocyte count (Odds ratio: 0.10; p = 0.004) as independent predictors of severe pneumonia (Fig. 1b). In this cohort, all the patients were discharged. As expected, COVID-19 patients with pneumonia were discharged sooner than those with severe cases (Fig. 2a, p = 0.016). The median length of hospital stay for pneumonia patients was 22 days, ranging from 9 to 46; while in severe pneumonia patients, it was 25, ranging from 14 to 44. To investigate whether there were any demographic, laboratory and treatments associated with length of hospital stay, log-rank test or Spearman's Rank-Order correlation was used as appropriate (summarised in Fig. 2b). We found length of hospital stay in COVID-19 patients with lymphopenia was prolonged (Fig. 2c, p = 0.027). In addition, glucocorticoids use in COVID-19 patients caused prolonged length of hospital stay (Fig. 2d, p = 0.002). Cytopathic effects and inflammatory response induced by virus as well as viral evasion of host immune responses are thought to play critical roles in disease severity.2Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. et al.COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; (PubMed PMID:32192578)Abstract Full Text Full Text PDF Scopus (6441) Google Scholar,3Qin C. Zhou L. Hu Z. Zhang S. Yang S. Tao Y. et al.Dysregulation of immune response in patients with COVID-19 in Wuhan, China.Clin Infect Dis Off Publ Infect Dis Soc Am. 2020; (PubMed PMID:32161940)Google Scholar Consistent with this, we identified increased CRP and lymphopenia as independent risk factors for disease severity, while lymphopenia is also a risk factor for prolonged hospital stay. As a result, we recommend surveillance of CRP and lymphocyte counts in the early screening of critical illness in COVID-19 patients. It has been confirmed that SARS-CoV2 utilizes angiotensin-converting enzyme 2 (ACE2) as receptor for viral cell entry. Given that ACE2 levels are increased in hypertensive patients treated with ACE inhibitors (ACEIs) and angiotensin II type-I receptor blockers (ARBs),4Furuhashi M. Moniwa N. Mita T. Fuseya T. Ishimura S. Ohno K. et al.Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by Olmesartan, an angiotensin ii receptor blocker.Am J Hypertens. 2015; 28 (PubMed PMID:24842388): 15-21Crossref PubMed Scopus (207) Google Scholar,5Ferrario C.M. Jessup J. Chappell M.C. Averill D.B. Brosnihan K.B. Tallant E.A. et al.Effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme 2.Circulation. 2005; 111 (PubMed PMID:15897343): 2605-2610Crossref PubMed Scopus (1238) Google Scholar Fang and colleagues proposed the hypothesis that ACE2-stimulating drugs could potentially increase the risk of developing severe and fatal COVID-19.6Fang L. Karakiulakis G. Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; (PubMed PMID:32171062)Abstract Full Text Full Text PDF Scopus (2013) Google Scholar In this study, we found hypertension is a risk factor for severe cases, independent of age and other variables. We managed to trace 34 hypertensive patients in this cohort. We found 1 out of 14 COVID-19 patients with pneumonia and 4 out of 20 COVID-19 patients with severe pneumonia are on ACEIs/ARBs. The impact of ACEIs/ARBs on disease severity is inconclusive due to small number, but it does suggest a larger cohort study is demanded. The use of corticosteroids in COVID-19 patients is controversial.7Shang L. Zhao J. Hu Y. Du R. Cao B. On the use of corticosteroids for 2019-nCoV pneumonia.Lancet. 2020; 395 (PubMed PMID:32122468): 683-684Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 8Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020 Feb 15; 395 (PubMed PMID:32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1490) Google Scholar, 9Zhou W. Liu Y. Tian D. Wang C. Wang S. Cheng J. et al.Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia.Signal Transduct Target Ther. 2020; 5 (PubMed PMID:32133159Pubmed Central PMCID:7035340): 18Crossref PubMed Scopus (182) Google Scholar The Chinese Thoracic Society has developed an expert consensus statement on the use of corticosteroids in COVID-19 patients,10Zhao J.P. Hu Y. Du R.H. Chen Z.S. Jin Y. Zhou M. et al.[Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia].Zhonghua Jie He He Hu Xi Za Zhi. 2020 Feb 8; 43 (PubMed PMID:32034899): E007PubMed Google Scholar in which low-to-moderate dose of corticosteroids in short courses for critically ill COVID-19 patients is recommended. However, there are potential risks associated with corticosteroids, such as secondary infections and prolonged virus shedding.8Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020 Feb 15; 395 (PubMed PMID:32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1490) Google Scholar In our study, the log-rank test suggested glucocorticoids use led to a prolonged length of hospital stay in COVID-19 patients, which discourages its use. There are several limitations in this study. First, not all laboratory examinations were done in all patients due to the retrospective nature of this study. In addition, interpretation of our findings might be limited by the sample size. Despite these limitations, with appropriate statistical tools we are able to identify several risk factors to predict disease severity and length of hospital stay in COVID-19 patients. Taking together, we report hypertension, increased CRP and lymphopenia as independent risk factors for disease severity. COVID-19 patients with lymphopenia have longer length of hospital stay. In addition, our data do not support corticosteroid treatment for COVID-19 patients. None. This project was funded by a Key Project of Science and Technology on COVID-19 of Hubei Province [No. 2020FCA002] and partly by Medical Research Council (UK) [MR/S025480/1]. YZ was supported by an Institute for Life Sciences (University of Southampton) PhD Studentship. We acknowledge all the patients involved in this study, and appreciate all the frontline medical and nursing staff involved in the diagnosis and treatment of patients in Wuhan. We thank Prof Donna E. Davies and Dr Mark G. Jones for critical reading.