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As the COVID-19 pandemic continues to spread, and research related to potential risk factors for COVID-19 mortality continues, it is becoming clear that individuals with underlying comorbidities have a greater risk of death from COVID-19. The exact contribution of different comorbidities is unclear, however. Now, a new study published in the journal PLOS ONE dissects this topic and may help to quantify the risk posed by specific conditions and offer help with the prognosis.
Study: Association of cardiovascular disease and 10 other pre-existing comorbidities with COVID-19 mortality: A systematic review and meta-analysis. Image Credit: SvetaZi / Shutterstock
Earlier Studies Yield Contradictory Results
With many different studies coming up, the contradictions multiply. While some say chronic disease increases the risk of COVID-19 and its severity, others disagree. The differences may arise because of the small number of studies, the variety of methods used, and the sources of bias. There is no doubt that the locales with the highest mortality rates are those regions with the highest prevalence of chronic illnesses.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters and infects human host cells using angiotensin-converting enzyme 2 (ACE2), an enzyme and receptor found in many tissues, such as the heart, kidney, and type II pneumocytes. Some researchers suggest that the use of angiotensin II type 1 receptor blockers (ARBs) may enhance the expression of ACE2 on the cell membranes and thus render the individual more susceptible to the infection and at a higher risk of developing progressive and severe disease. This would include people with hypertension and chronic cardiac failure who are being treated with ARBs.
Most studies carried out in this area so far have covered only certain countries, some of the research, and specific conditions. The presence of significant bias from various sources prevents their conclusions from gaining complete acceptance. To address this bias, the current study adopted a panoramic view of most major pre-existing chronic illnesses.
These include hypertension, cardiovascular disease, chronic kidney disease, chronic liver disease, cancer, asthma, chronic obstructive pulmonary disease, asthma, and HIV/AIDS. The researchers estimated the risk of dying from COVID-19-related conditions in individuals with these illnesses.
The researchers found 25 studies suitable for quantitative analysis, including ~65,500 patients. Almost four-fifths of the studies were from China. The median patient age was 61 years, and 57% of the patients were male. The study also had a median score of 7, indicating a reasonable quality standard.
Cardiovascular Disease and Mortality in COVID-19
In half the studies that reported this risk, there was a significant negative or positive association, with the estimated risk of mortality being anywhere from ~30% less to ~9 times higher than expected in an uninfected population. The pooling of the studies showed an overall doubling of the risk of death.
Other Chronic Illnesses and COVID-19 Mortality
The researchers showed that the risk of death was ~80% higher in patients with hypertension, 1.5 times higher in diabetics and cancer patients, doubled in those with congestive heart failure, and threefold in patients with chronic kidney disease. Other conditions were not linked to a higher risk of death in COVID-19.
Sources of Bias
The researchers suspect the presence of publication bias for some conditions, notably cerebrovascular disease, cancer, and hypertension, with these receiving more attention compared to others. However, even after adjustment for this, hypertension remains a risk factor for mortality, but not cancer.
The findings of various studies diverged significantly as to whether these conditions were or were not linked to a high risk of mortality. However, examining only those conditions which were implicated in more than 10 studies, they found that neither age nor male sex was associated with a higher risk.
The risk that any single study might have an undue influence on the risk estimate was also ruled out by removing them one by one from the meta-analysis, which failed to show any significant change in the pooled risk.
The researchers, therefore, concluded that the presence of pre-existing cardiovascular disease, hypertension, diabetes, congestive heart failure, chronic kidney disease, and cancer in patients with COVID-19 who are hospitalized confer a higher risk of death from the infection. This agrees with earlier studies showing that individuals with cardiovascular disease, chronic kidney disease, and cancer have a higher mortality risk with COVID-19.
However, the risk with cerebrovascular disease was not significantly raised, unlike the conclusion of an earlier study. This may be because of the larger size of the sample in this study, as well as the opportunity to use the data from recent studies.
Why this effect?
The researchers think these chronic illnesses may be related to a higher risk of mortality because the body’s functioning is already under stress from the pre-existing illness. The body’s endocrine system is in disarray and the sympathetic nervous system and immune system. Since these are responsible for homeostasis, chronic stress on them causes a slow and progressive wearing down of regulatory capability.
The eventual outcome of dysregulated metabolism is the build-up of pro-inflammatory cytokines, which triggers an abnormal immune response. This is widely held to be responsible for the severe complications that are called severe or critical COVID-19, as observed before with the flu, SARS, and MERS.
The study concludes that patients with COVID-19 with six specific pre-existing chronic conditions are at a greater risk of death from this disease compared to those who do not. This may indicate the role of sheltering such individuals and targeted treatment early in the course of infection, or preferential administration of a vaccine, for this high-risk group.
Implications for research and clinical practice
Renin-angiotensin-aldosterone system (RAAS) blockers are used by most patients with heart or vascular disease, hypertension, diabetes, chronic kidney disease, and congestive cardiac failure. These have not been found to increase the proportion of COVID-19 patients who die of the disease, even though experiments have shown that they may increase the levels of the host receptor molecule ACE2. Thus, these drugs remain an optimal choice for treating high blood pressure and other cardiovascular conditions, even with COVID-19.
The current study, therefore, shows the need to prioritize vaccinations when a vaccine becomes available, in order to reduce the mortality rate. This has been termed targeted vaccination and is a strategy supported by history, especially concerning the flu. Similar to this latter illness, SARS-CoV-2 may become a seasonal virus requiring annual vaccinations, predict some researchers.