The association of hypertension with the severity and mortality of COVID-19 patients: Evidence based on adjusted effect estimates
Authors: Xuan Liang, Li Shi, Ying Wang, Wenwei Xiao, Guangcai Duan, Haiyan Yang, Yadong Wang
Journal: Journal of Infection (2020)

Previous studies have shown that common comorbidities were significantly associated with the increased risk of adverse outcomes in patients with coronavirus disease 2019 (COVID-19)1Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. et al.Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.JAMA. 2020; (Feb 7)https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16038) Google Scholar. As we know, hypertension was the most common comorbidities among COVID-19 patients2Yang J. Zheng Y. Gou X. Pu K. Chen Z. Guo Q. et al.Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis.Int J Infect Dis IJID. 2020; 94 (official publication of the International Society for Infectious DiseasesMay): 91-95https://doi.org/10.1016/j.ijid.2020.03.017Abstract Full Text Full Text PDF PubMed Scopus (2681) Google Scholar. Recently, a paper in the Journal of Infection by Zheng et al.3Zheng Z. Peng F. Xu B. Zhao J. Liu H. Peng J. et al.Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis.J Infect. 2020; (Apr 23)https://doi.org/10.1016/j.jinf.2020.04.021Abstract Full Text Full Text PDF Scopus (1507) Google Scholar has reported that the proportion of hypertension was significantly higher in critical/mortal patients compared to the non-critical patients (odds ratio (OR) = 2.72, 95% confidence interval (CI) [1.60–4.64], P = 0.0002). However, the findings were based on unadjusted effect estimates. It was worth mentioning that the data based on unadjusted effect estimates indicated hypertension was an important risk factor for the adverse outcomes of COVID-19 patients, but the pooled effects based on adjusted effect estimates were significantly reduced or even disappeared in several studies4Chen F. Sun W. Sun S. Li Z. Wang Z. Yu L. Clinical characteristics and risk factors for mortality among inpatients with COVID-19 in Wuhan, China.Clin Transl Med. 2020; (Jun 4)https://doi.org/10.1002/ctm2.40Crossref Google Scholar, 5Cummings M.J. Baldwin M.R. Abrams D. Jacobson S.D. Meyer B.J. Balough E.M. et al.Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.Lancet. 2020; 395 (Jun 6): 1763-1770https://doi.org/10.1016/s0140-6736(20)31189-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Phipps M.M. Barraza L.H. LaSota E.D. Sobieszczyk M.E. Pereira M.R. Zheng E.X. et al.Acute liver injury in COVID-19: prevalence and association with clinical outcomes in a large US cohort.Hepatology. 2020; (May 30)https://doi.org/10.1002/hep.31404Crossref PubMed Scopus (229) Google Scholar, 7Wang D. Yin Y. Hu C. Liu X. Zhang X. Zhou S. et al.Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China.Crit Care. 2020; 24 (Apr 30): 188https://doi.org/10.1186/s13054-020-02895-6Crossref PubMed Scopus (242) Google Scholar, 8Wang G. Wu C. Zhang Q. Wu F. Yu B. Lv J. et al.C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation.Open Forum Infect Dis. 2020; 7 (Mayofaa153)https://doi.org/10.1093/ofid/ofaa153Crossref Scopus (164) Google Scholar. For instance, in the study of Wang et al., univariate analysis showed that hypertension was a risk factor for death in patients with COVID-19 (OR = 5.000, 95% CI [1.748–14.301]), while multivariate analysis showed that hypertension was not significantly associated with the risk of mortality (OR= 1.099, 95% CI [0.264–4.580])7Wang D. Yin Y. Hu C. Liu X. Zhang X. Zhou S. et al.Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China.Crit Care. 2020; 24 (Apr 30): 188https://doi.org/10.1186/s13054-020-02895-6Crossref PubMed Scopus (242) Google Scholar. Similarly, univariate analysis in Cummings et al. indicated that hypertension was significantly associated with patients' death (hazard ratio (HR) = 2.24, 95% CI [1.40–3.59]), but this association disappeared in the multivariate analysis (HR = 1.58, 95% CI [0.89–2.81])5Cummings M.J. Baldwin M.R. Abrams D. Jacobson S.D. Meyer B.J. Balough E.M. et al.Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.Lancet. 2020; 395 (Jun 6): 1763-1770https://doi.org/10.1016/s0140-6736(20)31189-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. The same findings were also observed in Wang et al.'s study8Wang G. Wu C. Zhang Q. Wu F. Yu B. Lv J. et al.C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation.Open Forum Infect Dis. 2020; 7 (Mayofaa153)https://doi.org/10.1093/ofid/ofaa153Crossref Scopus (164) Google Scholar. This meant that the association of hypertension with the adverse outcomes of COVID-19 patients might be affected by various factors such as age, gender and other comorbidities. Therefore, it is urgently required to clarify the association between hypertension and the adverse outcomes of COVID-19 patients by a systematically quantitative meta-analysis on the basis of the published studies reporting the adjusted effect estimates. Therefore, we systematically searched the electronic databases, including Web of Science, Chinese National Knowledge Infrastructure (CNKI) and PubMed to identify all observational studies published between January 1, 2020 and June 15, 2020 that compared outcomes in hospitalized COVID-19 patients with and without hypertension. These search engines used the following two sets of keywords to capture available literature: "Coronavirus 2019, 2019-nCoV, SARS-CoV-2, COVID-19″ and "Hypertension". Only articles that reported adjusted effect estimates of hypertension and adverse outcomes (severity including severe and critical, and mortality) in patients with COVID-19 were qualified. All calculations were implemented with Stata 11. 2 software. The pooled OR and pooled HR with their corresponding 95% CI were used to evaluate the risk of adverse outcomes in patients with COVID-19 and hypertension. The degree of heterogeneity between studies was tested using I2 statistics. The I2 values were 25%, 50%, and 75%, indicating low, medium, and high heterogeneity, respectively9Higgins J.P. Thompson S.G. Deeks J.J. Altman D.G. Measuring inconsistency in meta-analyses.BMJ (Clin Res Ed). 2003; 327 (Sep 6): 557-560https://doi.org/10.1136/bmj.327.7414.557Crossref PubMed Scopus (44448) Google Scholar. If there was no evidence of between-studies heterogeneity (I2 ≤ 50%), a fixed-effects model was used to calculate the combined effects. Otherwise, a random-effects model was selected10Greenland S. Quantitative methods in the review of epidemiologic literature.Epidemiol Rev. 1987; 9: 1-30https://doi.org/10.1093/oxfordjournals.epirev.a036298Crossref PubMed Scopus (1464) Google Scholar. The sensitivity analysis was used to evaluate the robustness of the results. Both Begg's test and Egger's test were used to evaluate publication bias. Overall, 521 documents were initially identified according to our search criteria, and the final analysis included 19 studies of 15,302 patients4Chen F. Sun W. Sun S. Li Z. Wang Z. Yu L. Clinical characteristics and risk factors for mortality among inpatients with COVID-19 in Wuhan, China.Clin Transl Med. 2020; (Jun 4)https://doi.org/10.1002/ctm2.40Crossref Google Scholar, 5Cummings M.J. Baldwin M.R. Abrams D. Jacobson S.D. Meyer B.J. Balough E.M. et al.Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.Lancet. 2020; 395 (Jun 6): 1763-1770https://doi.org/10.1016/s0140-6736(20)31189-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Phipps M.M. Barraza L.H. LaSota E.D. Sobieszczyk M.E. Pereira M.R. Zheng E.X. et al.Acute liver injury in COVID-19: prevalence and association with clinical outcomes in a large US cohort.Hepatology. 2020; (May 30)https://doi.org/10.1002/hep.31404Crossref PubMed Scopus (229) Google Scholar, 7Wang D. Yin Y. Hu C. Liu X. Zhang X. Zhou S. et al.Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China.Crit Care. 2020; 24 (Apr 30): 188https://doi.org/10.1186/s13054-020-02895-6Crossref PubMed Scopus (242) Google Scholar, 8Wang G. Wu C. Zhang Q. Wu F. Yu B. 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Seventeen studies were retrospective and two prospective.Table 1Characteristics of the included studies.AuthorLocationCaseAge (years)Male (%)Study designHTNAdjusted effect estimate(95%CI)ConfoundersChen C [12]China15059(16)84(56)R49(32.6)OR 2.586(0.609–10.980)Age, gender, NT-proBNP, cTnI, hs-CRP, creatinine, CHDWang D [7]China10751(31–65)57(53.3)R26(24.3)OR 1.099(0.264–4.580)Age, gender, CVD, creatinine concentrationSun H [21]China244NR137(54.5)R138(56.6)OR 0.82(0.24–2.75)Age, gender, vital signs, previous respiratory diseases, laboratory valuesShi S [20]China67163(50–72)322(48)R199(29.7)HR 1.07(0.46–2.53)Age, gender, diabetes, CHD, chronic renal disease, chronic heart failure, atrial fibrillation, CVD, COPD, procalcitonin, CRPYan X [23]China1004NR493(49.1)R235(23.4)OR 2.606(0.988–6.870)NLR, hs-CRP, NT-proBNP, BUN, respiratory failure, digestive system disease, CVDWang G [8]China209NR105(50.2)R27(12.9)OR 0.357(0.078–1.639)Age, gender, creatine kinase, lymphocyte, AST, CRPCummings MJ [5]America25762(51–72)171(67)P162(63)HR 1.58(0.89–2.81)Age, gender, symptom duration before hospital presentation, chronic cardiac disease, COPD or interstitial lung disease, diabetes, interleukin-6, d-dimerPhipps MM [6]America227365(52–76)1297(57)R1375(60)OR 1.15(0.85–1.56)Age, peak ALT, BMI >35, diabetes, intubation, renal replacement therapyGalloway JB [14]UK115771(57–82)666(57.6)R611(52.9)HR 1.53(1.24–1.90)Age, genderHuang S [16]China31062(40–70)174(56.1)R113(36.5)OR 1.562(0.929–2.625)Age, genderEscalera-Antezana JP [13]Bolivia10743.9(17.6)55(51.4)R10(9.35)OR 3.284(1.276–6.291)AgeGao C [15]China2877NR1479(51.1)R850(29.5)HR 2.06(1.10–3.83)Age, gender, medical history of diabetes, insulin-treated diabetes, myocardial infarction, underwent PCI/CABG, renal failure, stroke, heart failure, COPDZhao M [24]China100061(46–70)466(46.6)R282(28.2)HR 1.974(1.297–3.003)AgeSabri A [19]Iran6354.1(15.5)NRR15(23.8)OR 1.42(1.13–1.71)History of heart disease, pericardial effusion, blood oxygen saturationLim JH [18]Korea160NR86(53.8)R77(48.1)HR 1.34(0.71–2.52)Acute kidney injury network, age, gender, diabetesChen F [4]China66055(34–68)295(44.7)R230(34.8)OR 0.920(0.420–2.016)Age, cerebral infarction, SOFA, CRP, LDHTargher G [22]China31047149(48.1)RNROR 2.68(1.20–5.98)Age, genderLala A [17]America273666.40(15.8)1630(59.6)R1065(38.9)OR 0.99(0.79–1.23)Age, gender, troponin strata, race, ethnicity, coronary artery disease, diabetes, heart failure, atrial fibrillation, chronic kidney diseaseCen Y [11]China100761 (49–68)493(49.0)P270(26.8)HR 1.442(1.109–1.876)Age, gender, smoking, diabetes, chronic obstructive lung disease, coronary artery disease, duration of anti-viral therapyAll values are n (%), mean (SD) or median (IQR); NR, not reported; HTN, hypertension; P, prospective; R, retrospective; HR, hazard ratio; OR, odds ratio; NT-proBNP, amino-terminal pro-brain natriuretic peptide; cTnI, cardiac troponin I; hs-CRP, high-sensitivity C-reactive protein; CHD, Coronary heart disease; CVD, cardiovascular or cerebrovascular disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; SOFA, Sequential Organ Failure Assessment; PCI/CABG, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); LDH, lactate dehydrogenase. Open table in a new tab All values are n (%), mean (SD) or median (IQR); NR, not reported; HTN, hypertension; P, prospective; R, retrospective; HR, hazard ratio; OR, odds ratio; NT-proBNP, amino-terminal pro-brain natriuretic peptide; cTnI, cardiac troponin I; hs-CRP, high-sensitivity C-reactive protein; CHD, Coronary heart disease; CVD, cardiovascular or cerebrovascular disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; SOFA, Sequential Organ Failure Assessment; PCI/CABG, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); LDH, lactate dehydrogenase. Totally, our meta-analysis showed that hypertension was significantly associated with the increased risk of adverse outcomes in COVID-19 patients on the basis of 19 studies with 15,302 cases (OR= 1.44, 95% CI [1.24–1.66]; I2 = 41.4%, random-effects model) (Fig. 1A). Of the 19 studies, 12 reported adjusted OR and 7 reported adjusted HR. Therefore, we conducted a subgroup analysis based on the adjusted OR and adjusted HR. We also found a significant correlation between hypertension and adverse outcomes on the basis of both 12 OR-adjusted studies with 8173 cases (OR= 1.37, 95% CI [1.08–1.72]; I2 = 51.9%) and 7 HR-adjusted studies with 7129 cases (HR= 1.55, 95% CI [1.35–1.78]; I2 = 0.0%) (Fig. 1A). As shown by the sensitivity analysis, none of the studies had a significant impact on the overall results, which proves the robustness of our results (Fig. 1B). No publication bias was detected in Begg's test (P = 0.889) or Egger's test (P = 0.432). Previous studies have suggested that hypertension was a risk factor for adverse outcomes of COVID-19 patients, but the studies did not consider the effects of confounding factors on the findings2Yang J. Zheng Y. Gou X. Pu K. Chen Z. Guo Q. et al.Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis.Int J Infect Dis IJID. 2020; 94 (official publication of the International Society for Infectious DiseasesMay): 91-95https://doi.org/10.1016/j.ijid.2020.03.017Abstract Full Text Full Text PDF PubMed Scopus (2681) Google Scholar,25Zuin M. Rigatelli G. Zuliani G. Rigatelli A. Mazza A. Roncon L. Arterial hypertension and risk of death in patients with COVID-19 infection: Systematic review and meta-analysis.J Infect. 2020; 81: e84-e86https://doi.org/10.1016/j.jinf.2020.03.059Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 26Pranata R. Lim M.A. Huang I. Raharjo S.B. Lukito A.A. 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Presently, our results showed that hypertension was significantly associated with the increased risk of adverse outcomes in COVID-19 patients on the basis of the adjusted effect estimates, which suggests that hypertension is an independent risk factor for predicting the severity and mortality of COVID-19 patients. Thus, COVID-19 patients with hypertension deserve more clinical attention. It should be acknowledged that some limitations existed in our study. Firstly, the judgment criteria of adverse results in the included studies were not uniform. Secondly, all the included studies reported the adjusted effect estimates, but the confounding factors adjusted in each study were not entirely consistent. Thirdly, the stage of hypertension and whether it is controlled or poorly controlled are also unknown. The included studies did not adequately report data on chronic hypertension medications and therefore these could not be analyzed. In summary, our meta-analysis demonstrated for the first time that hypertension was an independent risk factor for predicting the adverse outcomes of patients with COVID-19. Further well-designed studies with larger sample sizes are required to verify the findings of our present study. All authors report that they have no potential conflicts of interest. This study was supported by a grant from the National Natural Science Foundation of China (No. 81973105).