Age, Comorbidities, and Mortality Correlation in COVID-19 Patients: A Review

Background: The risk of death due to COVID-19 among hospitalized patients is known to be higher in older adults and those with underlying health conditions. Understanding the proportion of patients who are at increased risk of death due to COVID-19 and how this varies between age groups will inform the healthcare community as to how to evaluate the risk of COVID-19 and better design healthcare and economic policies. Methods: We conducted a literature search for studies published between December 2019 and May 16, 2020 in PubMed, Embase, and Cochrane (CENTRAL). Descriptive statistics were performed. Results: We reviewed 14 studies, of which 13 were retrospective and one of which was prospective. Eleven studies were conducted in Wuhan, China. A grand total of 11,938 COVID-19 confirmed patients were reviewed. Among these patients, 7,637 (64%) were males. Our review reported hypertension (41%), diabetes (21%), cardiac diseases (14%), chronic obstructive pulmonary disease (8%), chronic kidney disease (4%), and cerebrovascular disease (10%) as the most common underlying diseases among patients who died during hospitalization due to COVID-19. The total number of patients who died in the hospital was 1,744 (15%). Among patients who died in the hospital, 1% of patients were 30– 39 years old, 16% patients were 40–59 years old, and 83% patients were more than 60 years old. Conclusions: Older patients with underlying diseases appear to be at higher risk of mortality due to COVID-19. Co-morbidities are significant predictors of mortality in COVID-19 patients. There is an urgent need to know the epidemiology of the novel virus and characterize its potential impact.


Introduction
The first case of severe acute respiratory syndromerelated coronavirus-2 (SARS-CoV-2) was reported in Wuhan, China in December 2019.The World Health Organization (WHO) recognized this virus as a global pandemic on March 11, 2020.[1] It is caused by a positive-sense RNA virus.It is a highly infectious virus, and has been reported to have 1-5% mortality rate or more.[2] Individuals from all age groups are susceptible to SARS-CoV-2 infection.Coronavirus disease-2019 (COVID- 19) is the syndrome caused by this virus, and is associated with higher mortality than influenza.[3] It is difficult to estimate the COVID-19 global mortality, given the high variability in testing and management strategies adopted in different countries.The COVID-19 mortality rate is calculated as the number of deaths due to COVID-19 divided by the total COVID-19 cases.The total cases available to count are those who are evaluated either test positive or are clinically diagnosed despite a negative test.However, it's a challenge to capture the total cases of COVID-19, because it is difficult to trace asymptomatic cases, especially with limited resources and inadequate testing in some parts of the world.[4] The mortality rate due to COVID-19 varies among different age groups in different countries.[5] The age-related mortality risk cannot be estimated accurately with the current limited information regarding prevalence, mortality and overall epidemiology of COVID-19.[6] There is an urgent need to know the epidemiology of the novel virus and characterize its potential impact.This information is essential for the healthcare community to evaluate the risk of COVID-19 in patients, and design health and economic policies.We will describe the mortality in COVID-19 patients as they relate to different age groups and comorbidities in this review.

Data sources and search strategy
We conducted a literature search for articles published (including ahead of print) until May 16, 2020 in PubMed, Embase, and Cochrane (CENTRAL).The search was conducted on May 14, 2020.Articles reporting mortality rates from COVID-19 were included in the review.We searched articles by using keywords with combinations of "COVID-19" AND "mortality", "coronavirus" AND "mortality", "SARS-CoV-2" AND "mortality".Studies that did not report data about mortality or death rate due to COVID-19 were excluded from this review.Studies conducted in hospital, outpatient, or intensive care unit (ICU) were included.Duplicate publications, reviews, editorials, case reports, letters, surveillance, non-English and articles predicting mortality were not included.A flow diagram of literature search is shown in Figure 1.

Data extraction
Two authors independently reviewed each article by reviewing title and abstract using Rayyan.[7] The full text of included articles was reviewed.Any conflict between two authors for selecting studies for this review were resolved through discussion and review by a third author.The following variables were extracted: author, study type, date, age, gender, total number of participants, comorbidities, mortality rate.
We identified a total of 704 articles.After removing duplicates, the authors checked the title, abstract and full articles of included studies.The primary outcome of our analysis was in-hospital mortality.Studies that reported mortality rate not stratified by comorbidities or by age group were excluded.Out of these, we found fourteen studies where mortality rate was stratified by comorbidities or by age groups.These studies were included into this review.

Results
We reviewed 14 studies, which included 13 retrospective and one prospective study.Eleven studies were conducted in Wuhan, China.A total of 11,938 confirmed COVID-19 patients were included in the review.Among these total patients, 7637 (64%) were males.All patients included in the review were hospitalized patients with confirmed diagnosis of COVID-19.The diagnostic test used for confirmation was reverse transcriptase-polymerase chain reaction assay of nasal or pharyngeal swabs.
Our review reported hypertension, diabetes, cardiac diseases as the most common underlying diseases among patients who died during hospitalization due to COVID-19.Chronic cardiac diseases included chronic heart disease and coronary heart disease.Social history of current smoking was present in 13% of patients.
The total number of patients who died in the hospital was 1744 (15%).Among the patients who died in the hospital, 1% were 30-39 years old, 16% were 40-59 years and 82% were more than 60 years of age.

Discussion
The analysis from this manuscript demonstrates that age and presence of underlying diseases correlate with risk of death from COVID-19.The severity of disease presentation increases with age.The most common comorbidity was hypertension among hospitalized patients who died from SARS-CoV2.Patients with cardiovascular disease and diabetes were also at high risk of death from this pathogen.Interestingly, our data also demonstrates that male sex was associated with higher mortality.
Multiple studies have corroborated our findings that elderly patients are at a higher risk of mortality from COVID-19.[22] Approximately 80% of deaths occurred among adults over the age of 60-years.One mechanism of this phenomenon is that older age can lead to defects in T cell and B cell function, causing an excess inflammatory response contributing to worse outcomes.[8] Furthermore, several studies have demon-strated that hypertension and cardiovascular disease portends poor prognosis.[23] Patients with a history of hypertension have 2.5-fold higher risk of fatal COVID-19, especially older age groups when compared to patients without hypertension.[24] Another study demonstrates that the presence of cardiovascular risk factors does not increase the likelihood of developing the infection but are associated with an increased COVID-19-related mortality.[2,23] One potential mechanism of cardiovascular events from SARS-CoV-2 is from the release of cytokines and chemokines that can precipitate vascular inflammation, plaque instability and myocardial inflammation.[25] A recent study reported myocardial injury in 20% of patients confirmed with COVID-19, and who were associated with a higher mortality rate.[26] Our data suggest that diabetes is a prominent comorbid condition that increases the risk of COVID-19 related morbidity.Diabetic patients are more likely to be older than non-diabetes patients, whereas older age is also associated with higher mortality due to COVID-19.[27] Previous studies have also reported an association of diabetes with poor prognosis in other viral infections like seasonal influenza, H1N1 influenza, and Severe Acute Respiratory Syndrome (SARS).[28,29,30] There is scarce data about glucose metabolism and the development of acute complications of diabetes like ketoacidosis in patients with COVID-19.Infection due to SARS-CoV-2 in patients with diabetes possibly triggers higher stress conditions by releasing hyperglycemic hormones like glucocorticoids and catecholamines that can lead to increased blood glucose levels.[31] In diabetic patients, COVID-19 can progress rapidly to acute respiratory distress syndrome, septic shock and organ failure.[31] Diabetes causes impaired neutrophil chemotaxis and phagocytosis which predisposes diabetic patients to infections in general.[32] Our study also demonstrates that male sex was associated with higher mortality.A recent case study conducted at a hospital in Wuhan, China also showed a higher percentage of males died compared to females.This study showed that men were approximately two times more likely than females to die from COVID-19, and that sex is an independent risk factor for severity and mortality in COVID-19 patients.[22] ULJRI | https://ir.library.louisville.edu/jri/vol4/iss1/69 Our review has few limitations.As most of the studies are from China and may present a location bias in the results.Furthermore, not all case studies reported comorbid conditions related to COVID-19 mortality.Our study only utilized descriptive statistics and did not calculate if co-morbid conditions or age were independent predictors of outcomes.Because of the descriptive nature of these data, attack rates among patients with and without underlying health conditions could not be compared, and thus the risk difference of severe disease with COVID-19 between these groups could not be estimated.However, this is one of the few studies to review the risk of age and co-morbidities from COVID-19.Future prospective studies will be essential to corroborate these findings.
In conclusion, older patients with underlying disease appear to be at a higher risk of mortality from COVID-19.Comorbidities are significant predictors of mortality in COVID-19 patients.More studies are needed to understand underlying pathophysiological mechanisms of risk-factors and age in association with COVID-19.

Table 1 .
Studies characteristics included in analysis.

Table 2 .
Mortality reported in studies stratified by comorbidities.

Table 3 .
Mortality reported in studies stratified by age.