|SYSTEMATIC REVIEW ARTICLE
|Year : 2021 | Volume
| Issue : 1 | Page : 10-28
Impact of chronic obstructive pulmonary disease on severity and outcomes in COVID-19 patients: A systematic review
Ashutosh Nath Aggarwal, Ritesh Agarwal, Sahajal Dhooria, Kuruswamy Thurai Prasad, Inderpaul Singh Sehgal, Valliappan Muthu
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||04-Mar-2020|
|Date of Acceptance||06-Mar-2021|
|Date of Web Publication||21-Apr-2021|
Dr. Ashutosh Nath Aggarwal
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012
Source of Support: None, Conflict of Interest: None
We conducted this systematic review to evaluate whether comorbid chronic obstructive pulmonary disease (COPD) increases the risk of severe disease and adverse outcomes among patients with coronavirus disease (COVID-19). We queried the PubMed and Embase databases for studies indexed till December 2020. We included studies that provided data on severe disease, hospitalization, intensive care unit (ICU) care, need for mechanical ventilation, or mortality among COVID-19 patients with and without COPD. We calculated the relative risk (RR) for each reported outcome of interest from each study and used a random-effects model to summarize our data. We retrieved 997 citations and included 110 studies published in 2020, in our review. Most publications reported the data retrieved from electronic records of retrospective patient cohorts. Only 27 studies were judged to be of high quality. COPD patients with COVID-19 had a significantly higher risk of severe disease (summary RR 2.44, 95% confidence interval [CI] 1.93–3.09), hospitalization (summary RR 1.91, 95% CI 1.70–2.14), ICU admission (summary RR 1.81, 95% CI 1.35–2.43), mechanical ventilation (summary RR 1.75, 95% CI 1.35–2.28), and mortality (summary RR 2.40, 95% CI 1.93–2.51), as compared to COVID-19 patients without COPD. All analyses showed significant between-study heterogeneity. We conclude that comorbid COPD significantly increases the risk of severe disease and adverse outcomes among COVID-19 patients.
Keywords: Chronic obstructive pulmonary disease, coronavirus disease, mortality, risk, severity, systematic review
|How to cite this article:|
Aggarwal AN, Agarwal R, Dhooria S, Prasad KT, Sehgal IS, Muthu V. Impact of chronic obstructive pulmonary disease on severity and outcomes in COVID-19 patients: A systematic review. Int J Non-Commun Dis 2021;6:10-28
|How to cite this URL:|
Aggarwal AN, Agarwal R, Dhooria S, Prasad KT, Sehgal IS, Muthu V. Impact of chronic obstructive pulmonary disease on severity and outcomes in COVID-19 patients: A systematic review. Int J Non-Commun Dis [serial online] 2021 [cited 2021 Jun 19];6:10-28. Available from: https://www.ijncd.org/text.asp?2021/6/1/10/314211
| Introduction|| |
The ongoing 2019 coronavirus disease (COVID-19) pandemic, resulting from infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected early 110 million people worldwide so far and continues to spread. As opposed to some other common respiratory viral infections, COVID-19 more often manifests as severe pneumonia. Thus, COVID-19 is associated with worse patient outcomes, especially among the elderly and in those with pre-existing comorbidities. Obesity, diabetes mellitus, hypertension, and cardiovascular disorders are quite prevalent among COVID-19 patients and are widely recognized to influence prognosis negatively.,,,,,,
Patients with chronic obstructive pulmonary disease (COPD) have long-standing respiratory impairment and low pulmonary reserve. Viral and other respiratory infections are an important cause of recurrent disease exacerbations in COPD. COPD patients are therefore widely perceived to be at a higher risk of acquiring COVID-19 and of progression to severe disease and even death. There are data to suggest that patients with chronic respiratory diseases may be at a higher risk of COVID-19–related mortality.,,,,,,,, However, the evidence is conflicting for outcomes other than mortality, with previous reviews exploring this subject reporting equivocal findings, or even suggesting a protective effect for COPD.,,,,,,,, Some studies also point to an overall low prevalence of COPD among patients with COVID-19.,,, We, therefore, conducted this systematic review to evaluate if comorbid COPD increases the risk of severe disease, hospitalization, intensive care unit (ICU) care, need for mechanical ventilation, or mortality among patients with COVID-19.
| Methods|| |
We preregistered our study protocol with the PROSPERO database (registration number CRD42021230307). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for this review., An approval from the institutional review board was not necessary as we extracted only summary information from previously published articles.
We conducted an online search for publications indexed till December 31, 2020, in the electronic databases PubMed and EMBASE, without any temporal or linguistic restrictions. We used the following free text search terms: (chronic obstructive pulmonary disease, COPD); and (COVID19, COVID-19, COVID 19, nCoV, 2019nCoV, 2019-nCoV, CoV-2, CoV 2, SARS-CoV-2, SARSCoV2) for this purpose. We also examined the bibliographies of selected articles and recent reviews and searched our files, for any relevant publications.
After removing duplicate citations, two reviewers (ANA and RA) screened all titles and abstracts identified from the literature search. We omitted publications not reporting on COPD or COVID-19. We also excluded experimental, radiological, or autopsy studies, case reports, letters-to-editor not describing original observations, conference abstracts, preprints, narrative and systematic reviews, guidelines, study protocols, and editorials. The full texts of citations considered potentially eligible by either reviewer were retrieved for a further independent assessment.
We included a study for data synthesis if it (a) included patients with COVID-19 confirmed by the detection of SARS-CoV2 RNA in respiratory specimens, or strongly suspected on clinical/radiological assessment if a confirmatory test was not available, (b) assessed one or more of the following patient outcomes – severe COVID-19, hospital admission, transfer to ICU, need for mechanical ventilation, mortality, or a combination of these, and (c) provided numerical data (or information from which such numerical data could be extracted) on the number of patients with and without COPD in the study population as well as number of patients experiencing outcome(s) of interest in either patient category. Severe COVID-19 was described as per the prevalent guidance from the World Health Organization or authors' institutional practice guidelines. If the same (or substantially overlapping) patient cohort was studied for any particular outcome in more than one publication, only the one describing the largest patient population was selected. In case of any disagreement, study inclusion was decided by consensus between the two reviewers.
Data extraction and study quality
We extracted the following data from the studies finally eligible for inclusion: lead author, study design, location and healthcare setting where the studies were carried out, inclusion and exclusion criteria for study subjects, the period of patient enrollment, source of patient information, method of ascertaining COPD diagnosis, outcomes reported, number of COVID-19 patients with and without COPD, and number of events of interest in COVID-19 patients with and without COPD. We also noted if any measures of association (such as odds ratio [OR] or hazard ratio [HR]) were reported for any outcomes after adjusting for potential covariates in multivariate models. We used the nine-item Newcastle–Ottawa scale (NOS) to assess the methodological quality of all the included studies. We considered any study with a score of 7 or more (out of a maximum possible score of nine) as being of a good quality.
We computed the relative risk (RR) and the corresponding 95% confidence interval (95% CI), for each of the predefined outcomes, from each study. RR was calculated as the proportion of COPD patients experiencing a particular outcome, divided by the proportion of other COVID-19 patients (i.e., those not having COPD) experiencing the same outcome. We used a continuity correction of 0.5 for studies with zero cell frequencies before all calculations.
We constructed forest plots to graphically evaluate the spectrum of RRs for every explored outcome of interest reported by individual studies. Wherever feasible, we pooled our data using the DerSimonian and Laird random-effects model to generate summary estimates for RR. Between-study heterogeneity was expressed using Higgins' inconsistency index (I2) and considered high for values exceeding 0.75. We used the statistical package Stata (Intercooled Edition 12.0, Stata Corp, Texas, USA) for data analysis.
| Results|| |
We identified 997 publications from our search of electronic databases and other sources and finally selected 110 articles for data synthesis [Figure 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, All studies were published in 2020. There were 31 publications from China, 17 from other countries in Asia, 33 from Europe, and 29 from North America [Table 1]. All studies reported data from retrospective patient cohorts, except for three (2.7%) that collected information prospectively.,, The patient information was retrieved mainly from medical records at participating healthcare facilities or from multicenter/regional/national registries on COVID-19 [Table 1]. Two investigators queried insurance claims databases., The period of data collection variably ranged between December 2019 and August 2020 [Table 1]. Five (4.5%) studies also included COVID-19 patients based on high clinical or radiological suspicion; all others only studied patients with disease confirmed by the detection of SARS-CoV2 RNA in respiratory specimens. Most investigators reviewed patient records or used COPD-related diagnostic (or medication) codes in databases to identify COPD patients. However, 25 (22.7%) studies did not explicitly specify the process for defining COPD [Table 1]. The NOS score for study quality was 5 or higher for all studies; however, only 27 (24.5%) studies were of high quality [Table 1].
Severe coronavirus disease
Twenty studies with 10,888 COVID-19 patients, of whom 333 (3.1%) had COPD, provided information on severe COVID-19. Of the 3168 patients with severe disease in the included cohorts, 194 (6.1%) had underlying COPD. All but three studies reported an RR for severe COVID-19 that exceeded 1.0, although confidence limits for most studies were wide [Figure 2]. There was considerable heterogeneity between the studies (I2 = 80.6%). The summary RR for severe disease was 2.44 (95% CI 1.93–3.09), indicating a statistically significant higher risk of severe COVID-19 among COPD patients.
|Figure 2: Relative risk, and corresponding 95% confidence interval, of severe disease among coronavirus disease patients with chronic obstructive pulmonary disease|
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Need for hospitalization
Eighteen studies with 491,503 COVID-19 patients, of whom 11,302 (2.3%) had COPD, provided information on hospitalization due to COVID-19. Overall, 31.0% of patients were hospitalized. Of the 152,568 patients who required hospitalization in the included cohorts, 6701 (4.4%) had underlying COPD. All except two studies reported an RR for hospitalization that statistically significantly exceeded 1.0, with the confidence limits for most studies being narrow [Figure 3]. There was considerable heterogeneity between the studies (I2 = 97.7%). The summary RR for hospitalization was 1.91 (95% CI 1.70–2.14), suggesting a statistically significant higher risk of hospitalization among COPD patients.
|Figure 3: Relative risk, and corresponding 95% confidence interval, of need for hospitalization among coronavirus disease patients with chronic obstructive pulmonary disease|
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Need for intensive care unit admission
Twenty-one studies with 28,022 COVID-19 patients, of whom 1277 (4.6%) had COPD, provided information on the need for admission to ICU due to COVID-19. Overall, 9.4% of patients required ICU care. Of the 2630 patients who were admitted to ICU in the included cohorts, 278 (10.6%) had underlying COPD. All except five studies reported an RR for admission to ICU that exceeded 1.0, although confidence limits for most studies were wide [Figure 4]. There was considerable heterogeneity between the studies (I2 = 84.9%). The summary RR for ICU admission was 1.81 (95% CI 1.35–2.43), denoting a statistically significant higher risk of the need for ICU care among COPD patients.
|Figure 4: Relative risk, and corresponding 95% confidence interval, of need for admission to intensive care unit among coronavirus disease patients with chronic obstructive pulmonary disease|
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Need for mechanical ventilation
Nine studies with 27,344 COVID-19 patients, of whom 3279 (12.0%) had COPD, provided information on the need for mechanical ventilation due to COVID-19. Overall, 8.0% of patients were mechanically ventilated. Of the 2194 patients who required mechanical ventilation in the included cohorts, 389 (17.7%) had underlying COPD. All except two studies reported an RR for the need for mechanical ventilation that statistically significantly exceeded 1.0, and confidence limits for most studies were wide [Figure 5]. There was considerable heterogeneity between the studies (I2 = 77.2%). The summary RR for need for mechanical ventilation was 1.75 (95% CI 1.35–2.28), indicative of a statistically significant higher risk of mechanical ventilation among COPD patients.
|Figure 5: Relative risk, and corresponding 95% confidence interval, of need for mechanical ventilation among coronavirus disease patients with chronic obstructive pulmonary disease|
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Sixty-seven studies with 512,318 COVID-19 patients, of whom 16,102 (3.1%) had COPD, provided information on mortality due to COVID-19. The overall mortality rate was 16.6%. Of the 85,057 patients who died in the included cohorts, 5247 (6.2%) had underlying COPD. All except four studies reported an RR for hospitalization that exceeded 1.0, although confidence limits for several studies were wide [Figure 6]. There was considerable heterogeneity between the studies (I2 = 95.5%). The summary RR for mortality was 2.20 (95% CI 1.93–2.51), pointing to a statistically significant higher risk of death among COPD patients.
|Figure 6: Relative risk, and corresponding 95% confidence interval, of mortality among coronavirus disease patients with chronic obstructive pulmonary disease|
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Composite adverse outcomes
Five studies with 2912 COVID-19 patients, of whom 66 (2.3%) had COPD, provided information on patients who died or required ICU admission or mechanical ventilation. Of the 477 patients for whom this composite adverse outcome was reported in the included cohorts, 66 (15.8%) had underlying COPD. All studies, except one, reported an RR for this composite adverse outcome that statistically significantly exceeded 1.0, although confidence limits for most studies were wide [Figure 7]. There was considerable heterogeneity between the studies (I2 = 90.1%). The summary RR was 3.31 (95% CI 1.62–6.07), implying a statistically significant higher risk of ICU admission, mechanical ventilation, or death among COPD patients.
|Figure 7: Relative risk, and corresponding 95% confidence interval, of composite adverse outcomes among coronavirus disease patients with chronic obstructive pulmonary disease|
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Further, eight studies with 93,034 COVID-19 patients, of whom 2152 (2.3%) had COPD, provided information on patients who died or required ICU admission. Of the 12,540 patients for whom this composite adverse outcome was reported in the included cohorts, 715 (5.7%) had underlying COPD. All studies reported an RR for this composite adverse outcome that exceeded 1.0, although confidence limits for most studies were wide [Figure 7]. There was considerable heterogeneity between the studies (I2 = 84.9%). The summary RR was 2.17 (95% CI 1.55–3.04), predictive of a statistically significant higher risk of ICU admission or death among COPD patients.
Patient outcomes in adjusted analyses
Eighteen studies performed multivariate logistic regression modeling to provide adjusted ORs for COVID-19 patients experiencing various adverse outcomes. Five studies reported adjusted ORs of COPD for patients with severe COVID-19. All values were greater than 1 (range 1.44–9.06), though only three studies showed statistically significant results [Figure 8]. Additional five studies looking at hospitalization due to COVID-19 reported ORs greater than 1 (range 1.36–2.27), and four of these were statistically significant [Figure 8]. Five studies provided adjusted ORs for patients requiring ICU admission, and all except one reported value greater than 1 (range 0.94–31.8). Four of these were statistically significant, with the highest adjusted OR being 31.8 [Figure 8]. Three studies reported higher odds of COPD among patients needing mechanical ventilation (range 1.13–3.20), and two of these results were statistically significant [Figure 8]. Finally, 11 studies reporting on mortality from COVID-19 reported ORs ranging from 0.61 to 3.21. Eight of these showed nonsignificant results, while three reported ORs significantly greater than one [Figure 8]. It was not possible to pool these figures to generate any summary estimates.
|Figure 8: Adjusted odds ratio, and corresponding 95% confidence interval, of severe disease and adverse outcomes among coronavirus disease patients with chronic obstructive pulmonary disease|
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Six studies performed multivariate Cox-proportional modeling to provide adjusted HRs for COVID-19 patients experiencing various adverse outcomes. Five studies reported higher hazards for mortality in COVID-19 patients with COPD (adjusted HRs ranging from 1.02 to 2.24), but only three of these estimates were statistically significant [Figure 9]. Two studies showed adjusted HRs of 1.20 and 3.20 for need for mechanical ventilation among COPD patients, but only the latter was statistically significant [Figure 9]. We did not pool these figures to generate any summary estimates.
|Figure 9: Adjusted hazards ratio, and corresponding 95% confidence interval, of (a) need for mechanical ventilation, and (b) mortality, among coronavirus disease patients with chronic obstructive pulmonary disease|
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| Discussion|| |
In this systematic review of 110 studies, we evaluated if underlying COPD was a significant risk factor contributing to severe COVID-19 and adverse COVID-19 outcomes. We found that among COVID-19 patients, those having COPD had an overall higher risk of severe disease (summary RR 2.44, 95% CI 1.93–3.09), hospitalization (summary RR 1.91, 95% CI 1.70–2.14), need for ICU care (summary RR 1.81, 95% CI 1.35–2.43), mechanical ventilation (summary RR 1.75, 95% CI 1.35–2.28), and mortality (summary RR 2.20, 95% CI 1.93–2.51). The current study implies that the risk of all major COVID-19 adverse outcomes is approximately doubled in patients with comorbid COPD.
A few earlier systematic reviews and meta-analyses have analyzed data regarding the influence of COPD on COVID-19 outcomes. Only some of these reported results exclusively for COPD patients, and all analyzed <30 studies.,,,, Others summarized information on COPD as one of the several comorbidities and risk factors studied.,,,,,,, We updated these results by summarizing data from 110 studies that included more recent publications, as well as those missed by previous reviews. Most of the previous reviews focused exclusively on COVID-19 severity or mortality, and other patient outcomes were not evaluated in detail.,,,,,,,,, We expanded the scope of our review to include other important outcomes, so as to provide a more inclusive and comprehensive picture of the impact of underlying COPD. Both the number of studies and the number of outcomes studied simultaneously are key strengths of our systematic review. Our summary estimates are likely to be more robust than earlier analyses, some of which reported equivocal results for some outcomes due to the small number of studies.
The prevalence of COPD among COVID-19 patients appears to be much less than other comorbid conditions such as diabetes or hypertension.,,,, Whether this is just related to underreporting or underrecognition of COPD among COVID-19 patients, or also to shielding strategies commonly advocated for people with respiratory impairment, is not clear. However, COPD patients seem to experience a higher risk of severe disease and adverse outcomes once they acquire SARS-CoV-2 infection. There could be several reasons for this apparent paradox. Many COPD patients have recurrent exacerbations related to viral and other respiratory infections due to impairment of local airway and lung defense mechanisms, and infections with SARS-CoV-2 may have precipitated the clinical worsening and respiratory failure. Recent studies have also shown elevated angiotensin-converting enzyme 2 (ACE2) protein and gene expression in the lung tissue and bronchial epithelium of smokers and patients having COPD.,,,, Increased pulmonary ACE2 expression could theoretically increase susceptibility to COVID-19 and greater viral load among COPD patients, since the SARS-CoV-2 virus uses ACE2 as a receptor for cellular attachment. In addition, the poor pulmonary reserve may increase the severity of disease and requirement for additional respiratory support. Besides, several patients with COPD are elderly and have associated comorbidities, which could be additive and independent risk factors for worse COVID-19 outcomes.
Our systematic review has several limitations. Due to dynamic nature of the pandemic, and the lag between data collection/analysis and publication of results, most of the included studies provide information from the first 6 months of 2020 and from areas that were severely afflicted earlier. This may not be truly representative of patient data from all geographic locations. Nearly all the included studies included in our review had a retrospective design and collated data from review of electronic health records that were likely completed in an overwhelmed health system. This may have resulted in both underreporting and misclassification of pre-existing comorbid diseases. Several studies reported only on inpatients (who even otherwise have a higher probability of adverse outcomes compared to other patients) rather than milder cases in the community, and outcome data were not available for all patients at the time of analysis in many instances. Only less than a quarter of the included studies were of sufficiently high quality (NOS score 7 or more). Several were not focused exclusively on COPD and measured estimates of association for many health conditions simultaneously. There was considerable heterogeneity in the studies reviewed, which resulted from several factors such as different definitions of severe COVID-19, variability in institutional healthcare strategies regarding SARS-CoV-2 testing and admission/transfer criteria, differences in the timing of investigations and other evaluations, and level and extent of medical intervention available to patients. Such heterogeneity can restrict the generalizability of our results. We cannot rule out an overestimation from lack of adjustment for potential confounders (such as age, gender, other comorbid health conditions, COPD severity and therapy, or other patient characteristics), as we focused on the univariate RR estimates for outcomes. Very few studies reported adjusted ORs [Figure 8]. Owing to the variability in nature and the number of covariates adjusted, and the lack of individual patient data, it was not possible to further summarize these data or compare it with our univariate RR estimates.
| Conclusion|| |
In this systematic review, we found that comorbid COPD among COVID-19 patients significantly increases the risk of severe COVID-19, hospitalization, ICU admission, mechanical ventilation, and mortality. However, most studies were of poor quality.
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Conflicts of interest
There are no conflicts of interest.
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