The association of cardiovascular disease and other pre-existing comorbidities with COVID-19 mortality: A systematic review and meta-analysis

Importance. Exploring the association of coronavirus-2019 disease (COVID-19) mortality with chronic pre-existing conditions may promote the importance of targeting these populations during this pandemic in order to optimize survival. Objective. To explore the association of pre-existing conditions with COVID-19 mortality. Data Sources. MEDLINE, the OVID databases, SCOPUS, and Cochrane Register of Controlled Trials were searched for the period October 1, 2019 to May 1, 2020. Snowballing was used to identify additional studies. Study Selection. Observational studies (n=19) reporting on 61,455 patients with relative risks (RR) or hazard ratios or odds ratios that reported the risk of mortality in patients with COVID-19 and comorbid conditions were included for the current study. Data Extraction and Synthesis. Two independent reviewers extracted data and assessed the risk of bias. All analyses were performed using random-effects models and heterogeneity was quantified. Main Outcomes and Measures The outcome of interest was the risk of COVID-19 mortality in patients with and without pre-existing conditions, reported as RR. Comorbidities explored were cardiovascular diseases (coronary artery disease, hypertension, cardiac arrhythmias, and congestive heart failure), chronic obstructive pulmonary disease, type 2 diabetes, cancer, chronic kidney disease, chronic liver disease, and stroke. Results. Ten chronic conditions from 19 studies were included in the meta-analysis (n=61,455 patients with COVID-19; mean age, 61 years; 57% male). Any cardiovascular disease, coronary heart disease, hypertension, congestive heart failure, and cancer significantly increased the risk of mortality from COVID-19. Cardiovascular disease was associated with a 135% higher risk of COVID-19 mortality (RR=2.35, 95%CI 1.44-3.84 n=9). The risk of mortality from COVID-19 in patients with coronary heart disease was 2.4 times as high as those without coronary heart disease (RR= 2.40, 95%CI=1.71-3.37, n=5) and twice as high in patients with hypertension as high as that compared to those without hypertension (RR=1.89, 95%CI= 1.58-2.27, n=9). Patients with cancer also were at twice the risk of mortality from COVID-19 compared to those without cancer (RR=1.93 95%CI 1.15-3.24, n=4), and those with congestive heart failure were at 2.5 times the risk of mortality compared to those without congestive heart failure (RR=2.66, 95%CI 1.58-4.48, n=3). Conclusions and Relevance COVID-19 patients with all any cardiovascular disease, coronary heart disease, hypertension, congestive heart failure, and cancer have an increased risk of mortality. Tailored infection prevention and treatment strategies targeting this high-risk population are warranted to optimize survival.


Introduction
The number of total cases of the coronavirus-2019 disease  continues to rise quickly, threatening thousands to millions of individuals with preexisting chronic conditions who are disproportionately affected. 1 To date, May 5, 2020, the John Hopkins coronavirus resource center reported that worldwide more than 180 countries have been affected with COVID-19 with more than three million confirmed cases and more than 250,000 deaths (https://coronavirus.jhu.edu/). As research related to potential risk factors for COVID-19 mortality continues, it is becoming clear that individuals with underlying conditions, such as cardiovascular disease (coronary artery disease, heart failure, hypertension, and cardiac arrhythmias), cancer, chronic obstructive pulmonary disease (COPD), type 2 diabetes, chronic kidney disease (CKD), and chronic liver disease (CLD), all may be at an increased risk of death. 1-3 As the number of published studies increase, there is a widening gap due to inconsistent findings with respect to the influence that types of pre-existing comorbidities have on COVID-19 mortality. Some studies report an association between preexisting conditions and COVID-19 mortality, whereas others report no association. With this being said, it is clear that regions experiencing the highest mortality rates, such as the United States, Europe, and China, also have the greatest burden of these preexisting chronic conditions. 4 The novel virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, interacts with angiotensin-converting enzyme 2 (ACE2), a cellular receptor expressed in the heart, kidney, pulmonary alveolar type II cells. 5 It has been postulated, though not confirmed, that preexisting use of angiotensin II type 1 receptor blockers (ARBs) may heart failure taking ARBs may be more susceptible to severity of SARS-CoV-2 including mortality.
To date, limited reviews only have studied cardiovascular disease and COVID-19 mortality alone, 7 or only in China involving a few patients. 8 We took a comprehensive approach and explored the association of major preexisting chronic conditions, including cardiovascular diseases such as coronary artery disease, heart failure, stroke, hypertension, and cardiac arrhythmia, type 2 diabetes, COPD, Asthma, cancer, HIV, chronic kidney, liver disease, and stroke and the risk of mortality from COVID-19. Although the majority of studies occurred in China, we identified additional studies involving patients from Europe and North America. We hypothesize that the risk of mortality in COVID-19 patients is higher in patients with preexisting chronic conditions. We believe that this set of meta-analyses will emphasize the increased risk within this population, in hopes of decreasing the burden that these individuals are actively experiencing.

Methods
We performed a systematic literature search of PubMed (MEDLINE), OVID (MEDLINE, HEALTHSTAR), SCOPUS, EMBASE, and Cochrane Library, using search criteria provided in the supplemental material (Supplemental Document 1). We followed the standards of the Metaanalysis of Observational Studies in Epidemiology (MOOSE, Supplemental Table 1). 9 This initial search was supplemented by scanning of the references lists of relevant publications, and identifying their citations through the Web of Sciences (snowballing). We identified all studies published between October 1, 2019 and May 1st, 2020 reporting the risk of mortality in patients with COVID-19. Our search criteria included the following keywords and MesH terms: ("COVID-19" OR "Coronavirus" or "Sars-cov-2") AND ("Mortality") AND ("cardiovascular All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 14, 2020. . disease" OR "chronic obstructive pulmonary disease" OR "asthma" OR "Coronary heart disease" OR "hypertension" OR "T2D" or "DM" or "diabetes" or "cancer" or "chronic kidney disease" or "chronic liver disease" or "comorbidities" or "chronic disease"). Two reviewers (ESH and AES) independently screened titles and abstracts of the studies for inclusion eligibility.

Inclusion criteria
Studies were included in the analysis if they met the following inclusion criteria: COVID-19 was diagnosed on the basis of the World Health Organization guidance; 10 study examined the association of any of the preexisting comorbidities and COVID-19; the risk point estimates reported as odds ratios (ORs), relative risks (RRs), or hazard rations (HRs) or the data was presented such that the OR, (RR), or HR could be calculated; the 95% CI was reported, or the data were presented such that the 95% CI could be calculated. We excluded studies not conducted on humans, or not having reported the numbers or risk of mortality with any comorbidities. Studies not published in English were translated when possible. Review papers, meta-analyses, literature reviews, commentaries, and meeting abstracts were excluded as well.
All excluded studies were documented with reasons for their exclusion.

Quality Assessment and Data Extraction
Since all of our studies were nonrandomized observational studies, we used the Newcastle-Ottawa Scale (NOS) for quality assessment (Supplemental Document 2 and 3). 11 Studies were first screened based on titles and abstracts by AES and ESH. If they met the inclusion criteria, then full-text was obtained and they were screened. In the event of disagreement, a third researcher (PS) was recruited in order to reach a consensus. Information extracted from included studies included title, year of publication, country, number of participants with each comorbidity who died and did not die, the RR/OR/HR of mortality of COVID-19 with each underlying condition, the mean or median age, proportion that was male, and other findings of interest.

Data analysis
We adopted a narrative approach to describe the number of studies, study settings, diagnoses criteria for COVID-19, and the proportion of gender and race from each study. Our primary outcome was the risk of mortality in COVID-19 associated with preexisting chronic diseases.
According to the previous study, if the outcome is rare in all populations and subgroups, the distinctions among different measures of RRs (e.g., odds ratios, rate ratios, and risk ratios) can be ignored 12 , thus we combined RRs and HRs with ORs in the present meta-analysis and reported the pooled effect size as RRs as common risk estimates for all studies. We used the reported ORs, RRs, or HRs as the measures of the association between preexisting chronic conditions and the risk of mortality in COVID-19. For studies without measures of associations, we used generalized linear mixed model to calculate the odds ratios using number of events and the sample size of each study group. 13 We combined RRs and HRs with ORs in the present metaanalysis and reported the pooled effect size as RRs as common risk estimates for all studies. We first log-transform all the reported effect size data to normalize the distributions. We calculated standard errors (SEs) via the following equations 14 . Lower = log (lower 95% CI) and upper = log (upper 95% CI), and SE = (upper -lower)/3.92. To assess the associations between preexisting conditions and the risk of mortality, we pooled the RR estimates for the presence versus absence of preexisting conditions from each study, weighted by the inverse of their variances (inter-study plus intra-study variances). We applied the metagen function from the R package meta to calculate the pooled effect estimates using random-effects models. 15 We invoked random-effects models to pool study results for the association between preexisting 19. Those with cardiovascular disease had twice the risk of mortality from COVID-19 as compared to those without cardiovascular disease (risk ratio: RR: 2.35 95%CI 1.44-3.84).

The risk of mortality from COVID-19 in patients with chronic obstructive pulmonary disease (COPD)
Three of seven studies found that patients with COPD were at a significantly higher risk of mortality from COVID-19 compared to patients without COPD (figure 2B). The risk ratio ranged from 0.37 to 5.40. The pulled risk of mortality from Covid-19 in patients with COPD was 1.76 (95% CI 0.92-3.36), indicating that these patients were not at significantly increased risk of mortality from COVID-19.

The risk of mortality from COVID-10 in patients with coronary artery disease
Coronary artery disease significantly increased patient's risk of mortality from COVID-19 ( Figure 2C). Five studies reported the risk ratio of dying from COVID-19 with underlying coronary heart disease. Four studies were from China and one international study including patients from \the USA. The risk of dying from COVID-19 with coronary heart disease ranged from 1.3 to 3.2. The overall risk was significant, indicating that patients with coronary heart disease were about 2 times as likely to die from COVID-19 compared to patients without coronary heart disease (RR=1.89 95%CI= 1.58-2.27). The between study heterogeneity was very low, with I 2 = 0%.

The risk of mortality from COVID-10 in patients with hypertension
Eight studies from China, and one from Italy, reported the risk of mortality from COVID-19 in patients with hypertension ( Figure 3A). Patients with hypertension were twice as likely to die from COVID-19 compared to patients without hypertension (RR= 1.89 95%CI 1.58-2.27). The between study heterogeneity, I 2 was equal to 0%.

The risk of mortality from COVID-10 in patients with type 2 diabetes
Twelve studies reported the risk of mortality from COVID-19 in patients with type 2 diabetes ( Figure 3B). However, only four studies found that patients with type 2 diabetes were at a significantly higher risk of morality. Using random-effect models in our pooled analysis, we found that those with type 2 diabetes were not at an increased risk of mortality from COVID-19 (RR=1.37, 95%CI =0.85-2.20).

The risk of mortality from COVID-10 in patients with cancer
Four studies reported the COVID-19 mortality risk in patients with cancer ( Figure 3C). Feng and colleagues and Guan and colleagues found that those with cancer were 2.5-3.5 times as likely to die from COVID-19 compared to those without cancer, however other studies found that there was no significant difference in the COVID-19 mortality risk. Our pooled analysis using the random effects model found that those with cancer were 2 times as likely to die from COVID-19 compared to those without (RR=1.93, 95%CI -1.15-3.24). All rights reserved. No reuse allowed without permission.
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The risk of mortality from COVID-10 in patients with chronic kidney disease (CKD)
Four studies reported the risk of mortality from COVID-19 in patients with chronic kidney disease ( Figure 4A). One of these studies found that patients with chronic kidney disease were at increased of mortality from COVID-19. However, our pooled analysis on 2172 patients with CKD indicated that these patients were not at a significantly higher risk of COVID-19 mortality (RR=2.36 95% 0.97-5.77).

The risk of mortality from COVID-10 in patients with chronic liver disease (CLD)
Two reports explored whether chronic liver disease (CLD) increased patients' risk of mortality from COVID-19 ( Figure 4B). Both studies found that patients with CLD were not at an increased risk of mortality. Our pooled analysis confirmed these findings (RR=1.57 95%CI 0.70-3.50).
More studies are urgently needed to further explore this relationship.

The risk of mortality from COVID-10 in patients with congestive heart failure (CHF)
We found that patients with congestive heart failure had 2.7 times the risk of mortality from COVID-19 compared to those without CHF ( Figure 4C, RR=2.66, 95%CI 1.58-4.48). Among the three studies reporting the risk of mortality from COVID-19 in patients with CHF, the risk ratio ranged from 2.44 to 3.89. The between-study heterogeneity was 0%.

The risk of mortality from COVID-10 in patients with stroke
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The copyright holder for this preprint this version posted May 14, 2020. . https://doi.org/10. 1101/2020 Three studies from China explored whether patients with a history of stroke were at an increased risk of COVID-19 mortality ( Figure 4D). Two of the three studies found that patients with stroke were at a significantly higher risk of mortality, resulting in a pooled RR of 2.72, 95%CI 0.90-8.21.
Lastly, one study reported the association of arrhythmia and COVID-19 mortality. 1 Those with arrhythmia were 95% more likely to die compare to those without. OR: (1.95 (1.33-2.86) All rights reserved. No reuse allowed without permission.
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Discussion
To the best of our knowledge, this is the first systematic review and meta-analysis to include COVID-19 cases from across Europe, Asia and North America, while also having the largest sample size (N=61,455) and number of studies (n=19). This meta-analysis was based on data from 19 studies with laboratory-confirmed COVID-19. Our findings suggest that patients with preexisting chronic conditions had a higher risk of death from COVID-19, particularly any cardiovascular disease, hypertension, coronary heart disease, congestive heart failure and cancer.
Our findings further highlight two important points. First, the failure of allostasis caused by preexisting conditions may in part explain the increased risk of mortality among COVID-19 patients. Second, a need for optimization of COVID-19 survival and limited health resources by employing focused vaccination for individuals with cardiovascular disease, chronic kidney disease, and cancer.
A probable hypothesis of the pathophysiological mechanism related to the increased risk of mortality among COVID-19 patients may be explained by the allostatic load imposed on the body by cardiovascular and other preexisting conditions. Chronic conditions cause dysregulation of major physiological systems, including the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system, and the immune system. 33 The chronic nature of such conditions induces the ''wear and tear'' on body's regulatory systems, 34 leading to accumulation of proinflammatory cytokines and effect of the cellular immune system. As a result of the reduced immunity, these individuals become very susceptible to severe complications of SARS-CoV-2 and death. However, such an association with this type of virus is not relatively new. Seasonal influenza, SARS-CoV, and Middle Eastern respiratory syndrome (MERS)-CoV, have also been associated with increased severity and mortality in patients with preexisting conditions. 26,35 As the race towards acquiring a vaccination against COVID-19 intensifies, the question remains as to which group of individuals should be prioritized for this vaccine. Our findings suggest that those with preexisting cardiovascular disease, hypertension and cancer may benefit from vaccination to optimize both survival and limited resources. Targeted public health vaccination intervention strategy for influenza vaccination are recommended by the Advisory Committee on Immunization Practices against seasonal influenza. 36 In the population with chronic comorbidities, annual influenza vaccination significantly reduces mortality and morbidity. 37 It is postulated that SARS-CoV-2 may become seasonal requiring annual vaccination.
Lastly, although the specific mechanisms are uncertain, SARS-CoV-2 is thought to infect host cells through ACE2 to cause COVID-19, while also causing damage to the myocardium. 38 Majority of patients with preexisting cardiovascular disease use renin-angiotensin system (RAS) blockers, which are postulated to increase the risk of developing a severe and fatal SARSCoV-2 infection. 39 In animal studies, Ferrario and colleagues reported ACE inhibitors or ARBs increased the levels of Ace2 mRNA compared with placebo. 40 Particularly, cardiac levels of Ace2 mRNA increased by 4.7-fold or 2.8-fold with either lisinopril (an ACE inhibitor) or losartan (an ARB), respectively. However, it remains a controversial whether patients with COVID-19 and pre-existing cardiovascular disease who are taking an ACE inhibitor or ARB should switch to another antihypertensive drug. 6 Nevertheless, particular attention should be given to cardiovascular protection during treatment for COVID-19.

Strengths and Limitations
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As COVID-19 is still a relatively new phenomenon, there has been a limited number of comprehensive and conclusive studies related to mortality in diverse populations. Therefore, data from Africa and Australia were not included in this meta-analysis. We are hopeful that in the future, further research will be published that explores the association between COVID-19 mortality and preexisting chronic conditions in these regions. In addition to this, we were unable to explore the influence that cancer, HIV, and asthma may have on COVID-19 mortality. As mentioned above, further research is necessary to conclusively determine if individuals with these preexisting chronic conditions in these regions are at an increased risk for death from COVID-19.
As previously mentioned, this meta-analysis employed a large number of studies, which allowed for a relatively large sample size (n=61,455). By doing this, we were able to explore a broad scope of chronic conditions, with over seven comorbidities included. This allows our meta-analysis to comprehensively cover a multitude of prevalent conditions throughout populations.

Conclusion
Our findings suggest that of the major comorbidities analyzed, cardiovascular disease, coronary heart disease, hypertension, congestive heart failure, and cancer carry the strongest risk of death from COVID-19. This research highlights the importance of conducting further research related to the association between preexisting chronic conditions and COVID-19 mortality, in order to explore potential mechanisms to decrease this burden.
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The copyright holder for this preprint this version posted May 14, 2020. . a  d  a  w  i  A  ,  R  y  o  o  S  G  .  P  r  e  v  a  l  e  n  c  e  o  f  c  o  m  o  r  b  i  d  i  t  i  e  s  i  n  t  h  e  M  i  d  d  l  e  E  a  s  t  r  e  s  p  i  r  a  t  o  r  y   s  y  n  d  r  o  m  e  c  o  r  o  n  a  v  i  r  u  s  (  M  E  R  S  -C  o  V  )  :  a  s  y  s  t  e  m  a  t  i  c  r  e  v  i  e  w  a  n  d  m  e  t  a  -a  n  a  l  y  s  i  s  .   I  n  t  e  r  n  a  t  i  o  n  a  l  J  o  u  r  n  a  l  o  f  I  n  f  e  c  t  i  o  u  s  D  i  s  e  a  s  e  s  .   2  0  1  6  ;  4  9  :  1  2  9  -1  3 3 . All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 14, 2020. . All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.