Comorbidities for fatal outcome among the COVID-19 patients: A hospital-based case-control study.

Dear Editor,

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., however, with the extent of the risk remained controversial.2, 3, 4, 5, 6 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. 1 A and Table S2).

Fig. 1

Distribution of comorbidities and ORs for fatal outcome of the COVID-19 patients.

Association between each comorbidity and risk of fatal outcome was shown in Panel A, and association between multiple coexisting comorbidities and risk of fatal outcome was shown in Panel B. The numbers of multiple coexisting comorbidities are classified as zero, one, two, three, and four or more. The number of the COVID-19 patients is shown to the left of column. The dots are the odd ratios (ORs) and the error bars are the 95% confidence intervals; the red color represents P < 0.05 and the gray color represents P ≥ 0.05. For the model with all the patients, the adjusted ORs are calculated with the use of multivariate logistic regression model by adjusting age, sex and the delay from symptom onset to hospital admission. For the models with the patients stratified by age, only sex and the delay from symptom onset to hospital admission are adjusted. Three age groups are stratified as ≤ 60 years, 60–70 years, and > 70 years. The dotted line indicates an OR of 1. DM, diabetes mellitus; CHD, chronic heart diseases; CVD, cerebrovascular diseases; CKD, chronic kidney diseases; COPD, chronic obstructive pulmonary diseases; CVH, chronic viral hepatitis.

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. 2 A–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).

Fig. 2

Coagulation and inflammation-related biomarkers in the patients of COVID-19 and among the COVID-19 patients with hypertension under three different medications.

The gray, red, and blue boxes represent the COVID-19 patients without any of the eight comorbidities, only with hypertension, and only with diabetes above the black line, respectively; the gray, red, and blue boxes represent no drug use, calcium channel blocker (CCB) drugs treatment, and other antihypertensive drugs treatment in the COVID-19 patients with hypertension under the black line, respectively. A, fibrinogen (FIB); B, activation of partial thrombin time (APTT); C, prothrombin time (PT); D, interleukin 6 (IL-6); E, D-Dimer; F, fibrinogen degradation products (FDP); G, lactate dehydrogenase (LDH); H, neutrophil percent; I, lymphocyte percent; J, fibrinogen degradation products (FDP); K, D-dimer; L, C reactive protein (CRP); M, interleukin 6 (IL-6); N, lactate dehydrogenase (LDH); O, white blood cell (WBC); P, lymphocyte percent; Q, neutrophil percent. The star (*) means P<0.05 between two groups. Three stages were classified based on the days from symptom onset: 1–10 days, 11–20 days and 21–30 days. Other antihypertensive drugs include angiotensin receptor blockers, angiotensin converting enzyme inhibitors, β-blockers, and thiazide.

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 syndrome and the Middle East respiratory syndrome. 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. , 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.

Declaration of Competing Interest

Authors not named here have disclosed no conflicts of interest.