Comorbidities for fatal outcome among the COVID-19 patients: A hospital-based case-control study
Authors: Qing-Bin Lu, Wan-Li Jiang, Xin Zhang, Hui-Jun Li, Xiao-Ai Zhang, Hao-Long Zeng, Juan Du, Guo-Liang Yang, Lei-Ke Zhang, Rui Li, Li-Qun Fang, Hao Li, Wei Liu
Journal: Journal of Infection (2020)

Since the discovery of coronavirus disease 2019 (COVID-19), there have been numerous evidences supporting the pathogenic role of chronic comorbidities in the prognosis of infections, including the study by Galloway et al.,1Galloway J.B. Norton S. Barker R.D. Brookes A. Carey I. Clarke B.D. et al.A clinical risk score to identify patients with COVID-19 at high risk of critical care admission or death: an observational cohort study.J Infect. 2020; (PubMed PMID: 32479771. Pubmed Central PMCID: PMC7258846 interest form and report no conflicts of interest. Epub 2020/06/02)Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar however, with the extent of the risk remained controversial.2WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)2020.Google Scholar, 3Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the chinese center for disease control and prevention.JAMA. 2020; (PubMed PMID: 32091533. Epub 2020/02/25)Crossref Scopus (12457) Google Scholar, 4Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. et al.Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.JAMA Intern Med. 2020; (PubMed PMID: 32167524. Pubmed Central PMCID: PMC7070509. Epub 2020/03/14)Crossref Scopus (5718) Google Scholar, 5Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395 (PubMed PMID: 32171076. Epub 2020/03/15): 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18527) Google Scholar, 6Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.Lancet Respir Med. 2020; (PubMed PMID: 32105632. Pubmed Central PMCID: PMC7102538. Epub 2020/02/28)Abstract Full Text Full Text PDF Scopus (6897) Google Scholar The existing univariate models do not adequately distinguish between risk due to age and that due to increased presence of co-morbidities in older patients, thus these assessments of real effect from comorbidities are inevitably confounded. Here by performing a retrospective multi-center study, we try to evaluate the adjusted effect of the common preexisting comorbidities on COVID-19 related death, based on which, the therapy effect of three widely used anti-hypertension drugs were assessed. From 18 January to 24 February 2020, 1138 confirmed COVID-19 patients consisting of 920 survivals and 218 deaths from three designated hospitals for COVID-19 treatment in Hubei province were included for analysis (Table S1). The presence of comorbidities was reported in 49.12% (559/1138) of the total patients, with significantly higher frequency in the deceased than in the survivals (77.06% vs. 42.50%, P < 0.001; Table S1). As a whole, hypertension was the most prevalent comorbidity (32.95%), followed by diabetes mellitus (DM, 15.64%) and chronic heart diseases (CHD, 9.31%). The chronic obstructive pulmonary diseases (COPD), malignancy, cerebrovascular diseases (CVD), chronic kidney diseases (CKD), and chronic viral hepatitis (CVH) were less frequent, with prevalence ranging from 2.11% to 6.41%. By multivariate logistic regression model adjusting age, sex, and delay from symptom onset to hospital admission, six comorbidities showed significant associations with the disease outcome, with malignancy exhibiting the highest risk of death, followed by CKD, CVD, hypertension, CHD, and DM (Fig. 1A and Table S2). An age-stratified analysis revealed the effect of comorbidities on death was reduced as the age increased. Among the patients ≤60 years, CVD had the highest effect on death, followed by hypertension. Among the patients aged 60–70 years, only malignancy and DM were related to fatal outcome. Among the patients aged >70 years, none of the eight comorbidities demonstrated the significant association with fatal outcome. The sex-stratified analysis disclosed that male patients presenting with any of the three comorbidities (hypertension, DM, or CVD) had an increased risk of developing fatal outcome, in contrast, female patients presenting any of the four comorbidities (CHD, COPD, malignancy, or CKD) had an increased risk of fatal outcome (Table S3). For patients with isolated DM, four parameters displayed significantly higher abnormal levels than those without any comorbidity, i.e., fibrinogen, activated partial thromboplastin time, prothrombin time and IL-6 (Fig. 2A–D). For patients with isolated hypertension than those without, five laboratory indicators were deviated from normal value with greater extent, i.e., higher levels of D-dimer, fibrinogen degradation products, lactic dehydrogenase (LDH) and neutrophil percentage, and lower lymphocyte percentage (Fig. 2E–I). Among the 1138 patients, 149 (13.09%) had two coexisting comorbidities (Table S1), with hypertension-DM most frequently observed (Table S4). Fifty-seven (5.01%) had three coexisting comorbidities, and 27 (2.37%) had four or more. The coexisting of multiple comorbidities had significantly increased the risk of death (Fig. 1B and Table S5). In the multivariate analysis, over 4-fold risk of death was observed in the patients with ≥3 comorbidities. Age-stratified analysis again revealed the effect of comorbidities on death was reduced as the age increased. Forty-one (50.00%) of 82 fatal patients had taken calcium channel blocker (CCB) drugs, significantly lower than those among the survived (68.15%, 92/135; Table S6). The effect of CCB drugs on reducing fatal outcome was shown to be significant. The use of angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs) was comparable between the fatal patients (24.39%, 20/82) and the survivals (24.44%, 33/135), showing no effect in reducing risk of death. Decreased levels of fibrin degradation product, D-dimer, C-reactive protein, IL-6 and LDH, less incidence of leukocytosis, and more rapid recovery of lymphocytes and neutrophils percentages were observed in the patients with CCB drugs treatment (Fig. 2J–Q). The patients who regularly received oral hypoglycemic agents or insulin treatment had over 70% reduced risk of death without significance (Table S6). As is known, mechanisms that lead to hypertension, DM, and CVD were increasingly recognized to overlap with pathways that regulate immune function. Most importantly, older age is an important risk factor for these conditions and the effect of aging on immune function was equally important for COVID-19 severity. Therefore, the effect of age was mixed with those from the comorbidities, resulting in heterogenicity of effects among age groups. For those aged >70 years, none of the underlying condition played role in affecting the outcome any more. It's suggested that old age had exerted the strongest effect on death, that all effects from the comorbidities could be compromised when the patients are old enough. DM was found to be a strong risk factor for adverse outcome, with its risky effect also observed in those aged 60–70 years, which was reported for the two earlier CoV infections, severe acute respiratory syndrome7Chan-Yeung M. Xu R.H. SARS: epidemiology.Respirology. 2003; 8 (PubMed PMID: 15018127. Epub 2004/03/17)Google Scholar and the Middle East respiratory syndrome.8Morra M.E. Van Thanh L. Kamel M.G. Ghazy A.A. Altibi A.M.A. Dat L.M. et al.Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis.Rev Med Virol. 2018; 28 (PubMed PMID: 29664167. Epub 2018/04/18): e1977Crossref PubMed Scopus (134) Google Scholar In this study, inflammation-related biomarker such as IL-6, was elevated to a significantly higher level among the DM patients, indicating more intense induction of inflammatory storm. It is suggested accordingly that the anti-inflammatory drugs in treating diabetes-COVID-19 should be proposed. Moreover, the higher risk of diabetes-COVID-19 death could also be reduced by good glycaemic control, as displayed by the therapy effect of insulin. RAAS blockade might decrease proinflammatory activity of Ang II, decreasing the risk of ARDS, myocarditis, or mortality in COVID-19.9Vaduganathan M. Vardeny O. Michel T. McMurray J.J.V. Pfeffer M.A. Solomon S.D. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; (PubMed PMID: 32227760. Epub 2020/04/01)Crossref PubMed Scopus (1563) Google Scholar,10Hanff T.C. Harhay M.O. Brown T.S. Cohen J.B. Mohareb A.M. Is there an association between COVID-19 mortality and the renin-angiotensin system-a call for epidemiologic investigations.Clin Infect Dis. 2020; (PubMed PMID: 32215613. Epub 2020/03/28)Crossref Scopus (208) Google Scholar We provided evidence that CCB drugs offered beneficial effect of reducing risk for fatal outcome in hypertension-COVID-19 patients, mostly mediated through enhancing the recovery of abnormal parameters and reducing host inflammatory response that had been proven to aggravate the disease severity. Hence the current study provided further pharmacoepidemiologic data supporting the effect of CCBs in treating SARS-CoV-2 infection combined with hypertension. In conclusion, the comorbidities significantly affected the outcome of OCVID-19 but were age-dependent. The anti-hypertensive treatment, especially CCBs can offer beneficial effect in reducing the mortality of COVID-19. Authors not named here have disclosed no conflicts of interest. None. This study was funded by the China Mega-Project on Infectious Disease Prevention (Nos. 2018ZX10713002, 2018ZX10101003 and 2017ZX10103004) and the National Natural Science Funds (Nos. 81825019 and 81722041).