key: cord-0754388-ki7ab5ha
authors: Tisminetzky, Mayra; Delude, Christopher; Hebert, Tara; Carr, Catherine; Goldberg, Robert J; Gurwitz, Jerry H
title: Age, Multiple Chronic Conditions, and COVID-19: A literature review
date: 2020-12-24
journal: J Gerontol A Biol Sci Med Sci
DOI: 10.1093/gerona/glaa320
sha: e705f1f82fbb23141febf2feb7dab00bcd28794d
doc_id: 754388
cord_uid: ki7ab5ha

BACKGROUND: Various patient demographic and clinical characteristics have been associated with poor outcomes for individuals with coronavirus disease 2019 (COVID-19). To describe the importance of age and chronic conditions in predicting COVID-19 related outcomes. METHODS: Search strategies were conducted in PubMed/MEDLINE. Daily alerts were created. RESULTS: A total of 28 studies met our inclusion criteria. Studies varied broadly in sample size (n=21 to more than 17,000,000). Participants mean age ranged from 48 years to 80 years and the proportion of male participants ranged from 44%-82%. The most prevalent underlying conditions in patients with COVID-19 were hypertension (range: 15% - 69%), diabetes (8% - 40%), cardiovascular disease (4% - 61%), chronic pulmonary disease (1% - 33%), and chronic kidney disease (range 1% - 48%). These conditions were each associated with an increased in-hospital case fatality rate ranging from 1% to 56%. Overall, older adults have a substantially higher case fatality rate (CFR) as compared with younger individuals affected by COVID-19 (42% for those <65 vs 65% > 65 years ). Only one study examined the association of chronic conditions and the risk of dying across different age groups; their findings suggested similar trends of increased risk in those < 65 and those > 65 years as compared to those without these conditions. CONCLUSIONS: There has been a traditional, single condition approach to consideration of how chronic conditions and advancing age relate to COVID-19 outcomes. A more complete picture of the impact of burden of multimorbidity and advancing patient age is needed.

The first known cases of pneumonia identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), (1) or COVID-19, were identified in Wuhan, China in December 2019. COVID-19 has unfortunately spread rapidly throughout the world since that time. (2) As of November 23, 2020, the number of cases in the United States has increased to more than 11.8 million with more than 250,000 deaths attributed to COVID-19.(3) Based on recent CDC reports, approximately 8 out of every 10 COVID-19-related deaths in the United States have been among adults aged 65 years and older. (4) Some early case reports and small clinical studies suggested a greater impact of COVID-19 in older adults with underlying chronic conditions as compared with younger individuals without these conditions. (5) (6) (7) (8) Numerous studies have that COVID-19 positive older adults presenting with specific conditions such as diabetes, cardiovascular disease, and obesity are at a higher risk for hospitalization and mortality than older adults without these chronic conditions. (6, (9) (10) (11) (12) The overall aim of this literature review was to summarize the rapidly evolving literature on the patient characteristics associated with poor outcomes for individuals with coronavirus disease 2019 (COVID-19), specifically focusing on the relative importance of age and burden of multiple chronic conditions, with a specific focus on their interaction, in predicting COVID-19 related outcomes.

This rapid review followed the basic Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. (13) "Rapid reviews 'are literature reviews that use methods to accelerate or streamline traditional *systematic review+ processes' in order to meet the needs and timelines of the end-users (health care institutions, health professionals, and patient associations')."

In keeping with the methodology of a rapid review, it was conducted with a shortened timeline and A c c e p t e d M a n u s c r i p t 4 omitted stages of the PRISMA systematic review process, but the process maintained transparent and used reproducible methods. (14) A health sciences librarian (C.C.) developed the search strategies and conducted unique searches in PubMed/MEDLINE. Major concepts included, but were not limited to, severe acute respiratory syndrome coronavirus 2, COVID-19, mortality, case fatality rate, hospitalization, chronic conditions, comorbidity, diabetes mellitus, cardiovascular disease, chronic lung disease, obesity, aged and older adults.

A combination of medical subject heading (MeSH) terms and text words was created to search PubMed. The full search algorithm is detailed in Supplement eMethods 1. Due to the evolving COVID-19 situation, a PubMed alert was set up using the original search strategy to capture relevant and significant newly published literature. Daily monitoring of these results contributed to a selection of studies being included until October 30, 2020. Bibliographic references were hand searched to identify additional possible studies to include.

Studies were included if (i) the articles were published between December 1, 2019 and October 30, 2020, (ii) cases of COVID-19 were confirmed, (iii) patients' demographic and clinical characteristics were described, and (iv) prevalence of chronic conditions were included and the (v) articles were written in English.

A detailed data abstraction form was developed a priori allowing two reviewers to independently abstract data in duplicate from these studies. Data abstraction began when there was a minimum of 80% agreement between reviewers in the sample of pilot studies; any disagreements were resolved either by consensus or by consulting a third reviewer.

A c c e p t e d M a n u s c r i p t

A total of 70 studies were identified in our initial literature search. Among these, 31 studies were removed based on abstract review, leaving 39 studies for detailed review. Of these 39 studies, 28 met our inclusion criteria and were included in this review Supplement eFigure 1. Studies were excluded if they included less than 10 patients, did not report the prevalence of comorbidities, did not report adverse outcomes, or were not published in the English language.

The characteristics of the reviewed studies are detailed in Table 1 . Thirteen studies were case series, (5, 7, 8, 10, (15) (16) (17) (18) (19) (20) (21) (22) (23) fourteen were retrospective cohort investigations, (6, 9, 11, 12, 16 ,24-33) and

one was a prospective cohort study. Four studies were based in Italy, (6, 8, 17, 33) one in Korea, (7) and two in the United Kingdom. (9, 11) Study sample sizes ranged from 21 (5) to 17,278,392 (11) patients. Five out of 28 studies had less than 100 participants,(5,7,10,18,24) 11 studies had between 100 and 1,000 participants, (8, 12, 15, 16, 23, 25, (30) (31) (32) 34, 35) 10 studies had between 1,000 and 1,000,000 participants, (6, 9, 10, 21, (26) (27) (28) (29) 33 ) and 2 studies had more than 1,000,000 participants. (11, 22) Participants age varied widely among the included studies with the mean age ranging from 48 years (10) to 61% (29), chronic obstructive pulmonary disease (COPD) (5) (6) (7) (9) (10) (11) 15, 16, 18 ,20-24,26-30,32,33) ranging from 1% (24) to 33%, (5) and chronic kidney disease (5) (6) (7) (9) (10) (11) 15, 16, (20) (21) (22) (23) 26 ,27,29,30,32,33) with a prevalence ranging from 1% (10,16,29,31) to 48%. (5) Association between comorbidities and risk of dying All but two studies reported overall case-fatality rates during hospitalization for COVID-19 (Supplement eTable 1). (5) (6) (7) (8) (9) (10) (11) 15, (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) 28 ,30-34,39) Case-fatality rates (CFRs) ranged from less than 1% (7) to 56% (31) during a follow-up period of 28 days post-hospital admission.

Thirteen studies reported in-hospital CFRs related to particular chronic conditions (Supplement eTable 1). (6, 10, 11, 17, 22, 26, 28, (30) (31) (32) 34, 39) The most common conditions associated with high CFRs were hypertension, cardiovascular disease (CVD), diabetes, COPD, chronic kidney disease and heart A c c e p t e d M a n u s c r i p t failure (HF). There was a considerable variation in the CFRs associated with each particular condition, as an example CFRs for those with hypertension ranged from 0.1% (11) to 78% (31) CFRs for those individuals with diabetes ranged from 0.2% (11) to 81% (31) and CFRs for those with chronic kidney disease ranged from 0.4% (11) to 100%. (16, 32) Fourteen studies reported CFRs across different age groups (Supplement eTable 1).(6-8,10-12,16,21,25,26,28,34) Case fatality rates for those aged <65 years ranged from 0% (11) to 42%; (6) and for those aged > 65 years ranged 0% (11) to 56%. (6) Only one study reported CFRs by age group and compared those with and without underlying conditions.(22) The CFRs during COVID-19 hospitalization for those presenting with at least one comorbidity were 8%, 17%, 32% and 50% for individuals aged 50-59 years, 60-69, 70-79, and > 80 years old, respectively. (22) Eleven out of the 28 included studies examined the association between underlying conditions and the risk of dying during hospitalization for COVID-19 (Table 2) . (6, (9) (10) (11) (12) 26 ,28,30-32,34) Among these studies, 9 out of 12 examined the association between hypertension and the risk of dying; (6, (9) (10) (11) 28 ,30,32-34) risks ranged from a HR of 0.89 (95% CI 0.85;0.93) (11) to an OR of 4.08 (95% CI 1.58; 10.5).(34) Ten out of 12 studies (6,9-11,26,28,30-33) examined the association between diabetes and the risk of dying; risks ranged from RR 1.23 (95% CI 0.77; 1.95) (28) to OR 2.85 (95% CI 1.35; 6.05).(32) The association between COPD and the risk of dying was examined in 8 out of 12 studies; (6, (9) (10) (11) 26 Ten out of the 12 studies reported an association between older age and increased mortality in individuals with COVID-19 (Supplement eTable 2). (6, 9, 11, 12, 23, 26, 28, 30, 32, 34) Four of the 12 A c c e p t e d M a n u s c r i p t 8 studies examined the risk of dying using age as a stratified variable. (6, 9, 11, 28 Association between comorbidity burden and mortality by age group Only one study included in our literature review reported the association between the burden of multimorbidity and risk of dying during hospitalization for COVID-19 further stratified by the patient's age (Table 3) .(10) This study included 1,590 confirmed COVID-19 cases hospitalized across China (mean age: 49 years 43% women). The most prevalent chronic conditions in this cohort were hypertension (17%) and diabetes (8%) and, 8% of the study sample reported having two or more chronic conditions. Among individuals aged <65 years, risks of dying were two times and three times higher for those with one and two or more chronic conditions as compared with those < 65 years without comorbidities, respectively.(10) The risks of dying during hospitalization for those 65 years and older were 1.8 and 2.7 times higher for those with one and two or more chronic conditions as compared to those >65 years without comorbidities, respectively (Table 3 ).(10) One study reported the association between more prevalent chronic conditions and the risk of dying across different age groups. The study included 31,461 (mean age 50; 54.5% women) COVID-19 patients hospitalized in 24 healthcare organizations across the US.(26) The most common comorbidities were chronic pulmonary disease (17.5%) and diabetes mellitus (15.0%).(26) Among individuals less than 70 years old, the risk of dying was 1.6, 1.4 and twice the risk in those presenting with heart failure, pulmonary A c c e p t e d M a n u s c r i p t 9 disease, and renal disease as compared to those without these chronic conditions, respectively. The risks of dying in those >= 70 years were 1.3, and 1.9 times higher in those with heart failure and renal disease, as compared to those without these conditions, respectively.(26) Somewhat similar results were reported in a recent investigation that examined the association of obesity and risk of dying at 21 days after hospital admission among 6,916 patients with COVID-19 (mean age: 49 years; 45% men) at Kaiser Permanente Southern California.(28) The risk of dying was most striking among those aged 60 years or younger, with a 12 times higher risk of dying in individuals <60 years and a BMI of >45 kg/m 2 as compared to those in the same age group with a BMI of less than 24 kg/m 2 . (28) The risk of dying for those older than 60 years was three times higher for those in the highest BMI group as compared to those with a BMI of less than 24 kg/m 2 .(28)

The reviewed literature suggests a high prevalence of chronic conditions in patients with COVID-19 and a significant association between chronic conditions and adverse outcomes in this population. In this rapid review, we found a significant prevalence of chronic conditions in individuals hospitalized with COVID-19; the most frequent morbidities reported were hypertension, diabetes mellitus, cardiovascular disease, chronic pulmonary disease, and chronic kidney disease. Most of the studies included in our review described very sick hospitalized populations. Inasmuch, the findings from these studies might be not generalizable to community-based settings. Differing lengths of follow-up may have also resulted in heterogeneity, and studies that were deemed to have an inadequate length of follow-up may have missed events and biased the results towards smaller effect sizes. Finally, since more than half of the included studies were from early reports in Wuhan, China, the generalizability of these findings to other race/ethnic groups may be limited. Future studies should examine potential racial and ethnic differences in the magnitude and impact of multimorbidity on mortality in older adults hospitalized with COVID-19.

A c c e p t e d M a n u s c r i p t 12

There has been a traditional, siloed, single condition approach to consideration of how chronic conditions and advancing age relate to COVID-19 outcomes. A more complete picture of the impact of burden of multimorbidity and the interaction with advancing patient age is needed. Table 3 : Association between comorbidity burden or BMI and risk of dying during hospitalization for COVID-19 by age group o Body mass index (BMI); No comorbidity, 18.5-24 kg/m 2 , no heart failure, no pulmonary disease, no diabetes, no kidney disease are the referent groups respectively M a n u s c r i p t 22 

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A c c e p t e d M a n u s c r i p t M a n u s c r i p t 20 M a n u s c r i p t 23