The Risk of COVID-19 Related Hospitalsation, Intensive Care Unit Admission and Mortality in People With Underlying Asthma or COPD: A Systematic Review and Meta-Analysis

Background: Several underlying diseases have been associated with unfavorable COVID-19 related outcomes including asthma and Chronic Obstructive Pulmonary Disease (COPD), however few studies have reported risks that are adjusted for confounding variables. This study aimed to examine the adjusted risk of COVID-19 related hospitalsation, intensive care unit (ICU) admission, and mortality in patients with vs. without asthma or COPD. Methods: A systematic review of major databases was undertaken for studies published between 1/12/2019 and 19/4/2021. Studies reporting the adjusted (for one or more confounder) risks of either hospitalsation, ICU admission, or mortality in asthmatics or COPD patients (control group = no asthma or no COPD) were identified. Risk of bias was determined via the QUIPS tool. A random effect meta-analysis was undertaken. Findings: 37 studies were eligible for analysis, with a total of 1,678,992 participants. The pooled ORs of COVID-19 hospitalsation in subjects with asthma and COPD was 0.91 (95% CI 0.76–1.09) and 1.37 (95% CI 1.29–1.46), respectively. For ICU admission, OR in subjects with asthma and COPD was 0.89 (95% CI 0.74–1.07) and 1.22 (95% CI 1.04–1.42), respectively. For mortality, ORs were 0.88 (95% CI 0.77–1.01) and 1.25 (95% CI 1.08–1.34) for asthma and COPD, respectively. Further, the pooled risk of mortality as measured via Cox regression was 0.93 (95% CI 0.87–1.00) for asthma and 1.30 (95% CI 1.17–1.44) for COPD. All of these findings were of a moderate level of certainty. Interpretation: COPD was significantly associated with COVID-19 related hospital admission, ICU admission, and mortality. Asthma was not associated with negative COVID-19 related health outcomes. Individuals with COPD should take precautions to limit the risk of COVID-19 exposure to negate these potential outcomes. Limitations include differing population types and adjustment for differing cofounding variables. Practitioners should note these findings when dealing with patients with these comorbidities. Review Protocol Registration: https://www.crd.york.ac.uk/prospero/.


INTRODUCTION
In March 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a global pandemic, and as of 3rd February 2021, over 103,000,000 confirmed cases have been diagnosed in more than 130 countries and areas, resulting in ∼2,238,000 deaths to date (1). Several risk factors associated with increasing severity of the disease have been reported, including age (2), obesity (3), and underlying conditions such as hypertension (4), and diabetes (5).
An important risk factor for unfavorable COVID-19 outcomes is Chronic Obstructive Pulmonary Disease (COPD); a group of lung conditions including emphysema and chronic bronchitis (6), primarily caused by tobacco smoking, with air pollution, genetic factors, diet and tuberculosis also contributing to the disease (7).
COPD has been associated with increased risks of unfavorable outcomes in non-COVID-19 related pneumonia (8). For COVID-19, some primary studies have questioned whether COPD is associated with worse outcomes (9), whilst the majority of reviews conclude that COPD patients yield significantly worse outcomes than those without (10)(11)(12)(13) and others report no effects (14).
An additional risk factor for COVID-19 related complications is the presence of asthma, a common allergy that can cause breathing difficulties including coughing, wheezing, breathlessness and a tight chest (15). Asthma exacerbations have been shown to be strongly associated with other respiratory viral infections, including previous coronaviruses (16,17). Although some primary studies have reported associations between asthma and negative COVID-19 outcomes, the majority of reviews that have examined associations of COVID-19 outcomes and asthma have concluded a lack of association between asthma and negative COVID-19 outcomes (18,19).
One limitation of all of the systematic reviews, to date, on COVID-19 outcomes and asthma or COPD is that they report on risk that has not been adjusted for any potential confounding factors, making the true risks of these comorbidities, and subsequent clinical implications, difficult (20)-indeed, of the 16 similar meta-analyses that were published in 2021 (as of April 2021), none of them reported exclusively on adjusted risks; they either report unadjusted risks or the inclusion of adjusted or unadjusted risks is unclear. Several primary studies report on adjusted risks that are lower than the unadjusted risks in several COVID-19 related outcomes, including in asthma (21) and COPD (22). Furthermore, several studies advocate the use of pooling adjusted effect sizes (23,24), especially in the case of determining COVID-19 related risks (20,25).
The aim of this review was to examine the risks of negative COVID-19 outcomes in subjects with asthma or COPD, that have been adjusted for one or more COVID-19 related risk factor, including age, sex, smoking status (20,25), or comorbid disease. Specifically our aims were to assess: 1. Adjusted risk of COVID-19 related hospitalsation in subjects with vs. without asthma or COPD. 2. Adjusted risk of COVID-19 related intensive care unit (ICU) admission in subjects with vs. without asthma or COPD. 3. Adjusted risk of COVID-19 related overall mortality in subjects with vs. without asthma or COPD.
This review has the potential to inform clinicians regarding the true risks of unfavorable COVID-19 outcomes in patients with asthma and COPD, increase awareness in people of the potential risks should they contract COVID-19 and to inform healthcare and public health policies.

Study Registration
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (26), and was registered on 29th June 2020 with the international prospective register of systematic reviews (PROSPERO: protocol ID CRD42020194155)-note that the full PRIMSA checklist can be found in Supplementary Table 1

Study Selection
Two researchers (MV,SW) independently screened titles and abstracts of all identified studies after duplicates were removed. Discrepancies between reviewers were resolved by discussion before screening full texts independently against the inclusion criteria. If it was not possible to determine whether a study met the inclusion criteria from the title and/or abstract, it was marked for a full paper review. Where necessary, the reviewers contacted corresponding authors to request missing information or clarification. All references were imported to Mendeley.

Study Inclusion and Exclusion
Two reviewers (MV & SW) independently screened all titles and abstracts. The relevance of each study was assessed according to the inclusion and exclusion criteria. Studies were included if they met the following criteria.

Population
Studies including humans with COPD and/or asthma and a confirmed case (via polymerase chain reaction or antibody test) of COVID-19 were included in this review. Children <18 yrs and animal studies were excluded from this review. We also excluded studies on previous human coronaviruses: 229E, NL63, OC43, HKU1, MERS-CoV, and SARS-CoV.

Intervention
Observational studies, including case-control and cohort studies were included. Randomized studies that reported the prognostic role of asthma/COPD in post-hoc analyses (e.g., Cox regression models) were also included.

Comparison
Comparator groups include humans with confirmed COVID-19 and no evidence of COPD and/or asthma.

Outcomes
Studies had to report one or more of the following: adjusted for more than one COVID-19 related covariate) related to the stated outcomes.

Data Extraction
Data was extracted by two reviewers (MT & MV) and included: first author, study title, date of study, dates in which study data were collected, country, aim/objective, study type, number of participants, disease investigated, method of disease diagnoses, method of COVID-19 diagnosis, outcome type, sample size, participant characteristics, adjusted OR and 95% confidence intervals (CIs) (or raw data in which an adjusted odds ratio could be calculated), details of confounding variables the OR was adjusted for. Where data was missing, required clarification or particular variables of interest were not reported in the paper, corresponding authors were contacted to enable inclusion in the meta-analysis, and given 2 weeks to respond. If no response was received within 2 weeks, or the data was unavailable, these studies were excluded.

Quality Assessment
Risk of bias was assessed by two independent researchers (MT & MV) using the Quality In Prognosis Studies (QUIPS) tool (27). The QUIPS is a non-scoring appraisal tool for assessing the scientific validity of articles, which requires the identification of whether or not relevant information is present in each article using a yes, no or not applicable rating, with an overall verdict of "low, " "medium, " or "high" risk of bias. Any discrepancies over the final risk of bias verdict was made by consensus, with involvement of a third review author (SP) where necessary.

Statistical Analysis
Due to anticipated heterogeneity, a random-effects model was conducted using the DerSimonian and Laird method, with studies weighted according the inverse variance, using Comprehensive Meta-Analysis (28). The meta-analysis was conducted using the following steps: (1) Adjusted odds ratios (aORs), or adjusted Hazard Ratios (aHRs) and 95% CIs were inputted (with significance set as p = 0.05). Note that if the raw data were available, a binary logistic regression was conducted. (2) Heterogeneity between studies was assessed using the I² statistic (29). If high (>50%) heterogeneity was found, subgroup analyses were conducted based on total participants (>10 vs. <10k participants). (3) Publication bias was assessed with a visual inspection of funnel plots and with the Egger bias test (30). As per the recommendations by Fu et al. (31) and Sterne et al. (32), these tests were only conducted if the number of studies in each analysis exceeded ten. (4) Sensitivity analyses were conducted to assess the robustness of the pooled effect sizes through the one study removed method.

Certainty of Evidence
To ascertain the certainty of the evidence, the Grading of Recommendations, Assessment, Development and Evaluations (33) (GRADE) framework was used.

RESULTS
The literature search yielded 3,701 results, of which 780 were duplicates and were automatically removed, leaving 2,921 studies to be screened using the title and abstract. Of these studies, 416 full-texts were screened, where five extra studies were     obtained by way of reference lists, resulting in 421 full texts that were finally screened. Thirty-eight studies appeared to be eligible for inclusion, however one (34) was excluded because the reported 95% CIs were not symmetrical, and therefore could not be pooled, leaving 37 finally eligible for inclusion (21,. The full PRISMA flowchart is shown in Figure 1, and a full list of excluded studies with reasons for exclusion can be found in Supplementary Table 2. There were a total of 1,678,992 participants across the included studies, with a mean age range of 45.7-81.9 years. Of the included studies, 10 (38, 42, 46, 48, 51, 55, 56, 58, 66, 69) examined outcomes in both asthma and COPD, seven (21,43,50,52,63,64) examined outcomes exclusively in asthma, and the remaining 20 studies (37, 39-41, 44, 45, 47, 49, 53, 57, 59-62, 65, 67, 68, 70, 71) reported on outcomes exclusively regarding COPD. All but one study was classified as having low risk of bias (see Supplementary Table 4 for full QUIPS scoring). Full descriptive characteristics of included studies are shown in Table 1.

Risk of COVID-19 Related Hospitalsation
When adjusted for one or more comorbidity, the pooled aOR was 0.87 (95% CI 0.73-1.05; p = 0.15; I 2 = 85.36) for asthma and 1.39 (95% CI 1.31-1.48; p = <0.001; I 2 = 4.24) for COPD (see Table 2 and Figure 2). The sensitivity analysis found that the removal of any one study did not significantly change the direction of results for either asthma or COPD (see Supplementary Figures 1, 2 for full details).

Risk of COVID-19 Related ICU Admission
When adjusted for one or more comorbidity, the pooled aOR was 0.75 (95% CI 0.55-1.02; p = 0.07; I 2 = 87.20) for asthma and 1.34 (95% CI 1.14-1.57; p =< 0.001; I 2 = 66.64) for COPD (see Table 2 and Figure 3). The sensitivity analysis found that for asthma the aOR became significant with the removal of one study (46) (OR = 0.65 95% CI 0.44-0.97 p = 0.04). The removal of any one study did not significantly change the direction of results for COPD (see Supplementary Figures 3, 4 for full details).

Risk of COVID-19 Related Mortality
When adjusted for one or more comorbidity, the pooled aOR was 0.83 (95% CI 0.71-0.96; p = 0.01; I 2 = 61.48) for asthma and 1.28 (95% CI 1.18-1.39; p = <0.001; I 2 = 34.51) for COPD (see Table 2 and Figure 4). The sensitivity analysis found that for asthma the aOR became non-significant with the removal of one study (46) (OR = 0.83 95% CI 0.66-1.05 p = 0.118), and the results did not significantly change for COPD when any one study was removed (see Supplementary Figures 5, 6 for full details).
Regarding studies that reported aHRs in the form of Cox regression models, the pooled risk of mortality was 0.93 (95% CI 0.87-1.00; p = 0.049; I 2 = 64.18) for asthma and 1.30 (95% CI 1.17-1.44; p =< 0.001; I 2 = 88.39) for COPD (see Table 2 and Figure 5). The sensitivity analysis found that the removal of any one study did not significantly change the direction of results for COPD, and the removal of any one of three studies  (56, 58, 69) changed the significance of results in asthma (see Supplementary Figures 7, 8 for full details).

Certainty of Evidence Using the GRADE Approach
Using the GRADE (33) approach, all of the results were rated as being a "moderate" level of certainty. The two reasons why the level of evidence was not rated as "high" was because of either (1) high heterogeneity, or (2) the presence of publication bias.

Sub-Group Analyses
When sub-grouped between studies with >10 vs. <10k participants, no significant changes were found, except for in  risk of mortality (as measured by Cox regression) in participants with COPD. It was found that studies with >10k participants yielded significantly lower (p = 0.001) risk of mortality (aHR = 1.13 95% CI 1.10-1.17) when compared to studies that had <10k participants (aHR = 1.59 95% CI 1.31-1.94), and also yielded lower heterogeneity in this subgroup (>10k = 36.19%; <10k = 58.32%). Although the differences between sub-groups were significant, both pooled aHRs were still, respectively, statistically significant. Full information can be found in Table 3 and in Supplementary Figures 9-16.

DISCUSSION
This meta-analysis included 37 studies examined the adjusted risks of COVID-19 related hospitalsation, ICU-admission, and mortality in populations with and without either asthma or COPD. The analysis suggests with a moderate level of certainty that COPD is a significant risk factor for COVID-19 related hospitalsation, ICU admission, or mortality when the risks were adjusted for at least one comorbidity. Furthermore, with a moderate level of certainty, asthma was not shown to be a significant risk factor for COVID-19 related hospitalsation, ICU admission, or mortality when adjusted for at least one comorbidity.
COPD was shown to be a significant risk factor in all three outcomes, with the sensitivity analysis reporting robustness in all outcomes. These results broadly agree with previous meta-analyses exploring similar outcomes in this population (10)(11)(12)(13)(14). When directly comparing reported risks, this study shows a marked decrease in mortality risk (5.69 vs. 1.25) when compared to Lippi and Henry (10), which would be expected. Although the mechanisms that underpin this risk are not clear, several hypotheses, including the increased expression of the angiotensin-converting enzyme 2 (ACE-2) in COPD patients, have been reported as COVID-19's route of entry into susceptible cells (73). Furthermore, it has been reported that morbidity and mortality in COPD patients are frequently related to acute exacerbation (12), and severe respiratory failure (67) which may add to already compromised respiratory capacity among COVID-19 patients (12,74,75). Moreover, the effect of smoking could be a reason why people with COPD appear to have increased COVID-19 risks; indeed, a recent systematic review and meta-analysis (76) reported that both current and former smokers have increased risks of COVID-19 related deaths, although these risks do not appear to have been adjusted for any co-variates. Further exploration into adjusted smoking risk, in particular adjusted for COPD and/or asthma presence, would be beneficial.
Other comorbidities have also been shown to be significant risk factors for unfavorable COVID-19 related outcomes including (but not limited to), hypertension (4), diabetes (5), and obesity (3). It is difficult to directly compare our results with previous data as these previous estimates report unadjusted data making true risks of each comorbidity hard to compare. We agree with Jordan et al. (20) and recommend that future studies aim to report risks based on adjustments for, at the very least, age, sex, and smoking status so that true risks can be determined. It is recommended that clinicians continue to consider COPD patients to be at greater risk of COVID-19 related morbid outcomes. Individuals with COPD should take extra precautions to ensure that exposure to COVID-19 is minimal.
Although asthma has been related to worse outcomes in other viral infections, including other forms of coronavirus (16,17), our analysis did not suggest asthma as a significant risk factor for any of the outcomes measured in this review, apart from mortality (measured as a non-time dependent OR), however sensitivity analysis suggested that the significance of this outcome was subject to the influence of one large study. These results broadly agree with previous meta-analyses that concluded that asthma was not a significant risk factor for either mortality or "severe" health outcomes (14,18,35,77). When directly comparing reported risks across these metaanalyses, this study's mortality risk is lower (0.83 and 0.93 vs. 0.96 and 1.03) (35,77), which is an expected result given we pooled adjusted ORs and the other meta-analyses were not adjusted for any other covariates. These results, however, need to be interpreted with caution as the included studies have used asthma as an umbrella term and did not differentiate between different types or severities of the disease. The National Health Service (NHS) in the UK has severe asthma listed "high risk of severe outcomes, " and other severities at "moderate risk" of COVID-19 (78), and although this study does not support this, more data is required to differentiate between different severity of asthma, and, as such, individuals with asthma should still aim to minimize their risk of COVID-19 exposure. Although this is the first review to systematically examine risks of unfavorable COVID-19 outcomes in populations with asthma or COPD with effect sizes adjusted for at least one covariate, our results should be considered within its limitations. Firstly, although the majority were deemed as low risk of bias, the effect of methodological bias cannot be ruled out. Secondly, the pooling of adjusted ORs (with different studies adjusting for different covariates) inherently creates a degree of inconsistency, meaning that the results should be treated only as indicative. Thirdly, there was considerable heterogeneity in some of the reported analyses, especially in the asthmatic populations, which could not be explained by the presence of large studies vs. smaller ones. One probable reason for this is the different asthma diagnosis methods, in particular regarding the type and severity of asthma.
Furthermore, there was some evidence of publication bias, which could not be explained. Lastly, meta-analyses have inherent limitations: their findings are dependent on estimates selected from each primary study and thus are dependent on the accuracy of primary studies (79).

CONCLUSIONS
COPD is significantly associated with worse COVID-19 related, hospital admission, ICU admission and mortality, even when adjusted for at least one comorbidity. Asthma, when pooling risks were adjusted for other comorbidities, was not associated with a higher risk of COVID-19 related hospitalsation, ICU admission and mortality. Clinicians should note these findings when dealing with patients with these comorbidities. Furthermore, individuals with COPD should take special precautions to limit the risk of COVID-19 exposure to negate these potential outcomes.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
MT and MV acquisition and analysis. MT, MV, and SP drafted the work. MT and MV verified the underlying data. All authors made substantial contributions to the conception, design of the work, interpretation of data for the work, revising it critically for important intellectual content and final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.