Skip to main content

Main menu

  • Home
  • Current issue
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions

Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis

Bohee Lee, Grace Lewis, Eldad Agyei-Manu, Nadege Atkins, Urmila Bhattacharyya, Marshall Dozier, Jasmin Rostron, Aziz Sheikh, Ruth McQuillan, Evropi Theodoratou for the Usher Network for COVID-19 Evidence Reviews (UNCOVER) group
European Respiratory Review 2022 31: 220066; DOI: 10.1183/16000617.0066-2022
Bohee Lee
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
2Asthma UK Centre for Applied Research, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Bohee Lee
Grace Lewis
2Asthma UK Centre for Applied Research, University of Edinburgh, Edinburgh, UK
3School of Healthcare, University of Leeds, Leeds, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Grace Lewis
Eldad Agyei-Manu
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eldad Agyei-Manu
Nadege Atkins
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nadege Atkins
Urmila Bhattacharyya
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Urmila Bhattacharyya
Marshall Dozier
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marshall Dozier
Jasmin Rostron
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jasmin Rostron
Aziz Sheikh
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
2Asthma UK Centre for Applied Research, University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Aziz Sheikh
Ruth McQuillan
1Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK
6R. McQuillan and E. Theodoratou contributed equally to this article as lead authors and supervised the work
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ruth McQuillan
  • For correspondence: Ruth.McQuillan@ed.ac.uk
Evropi Theodoratou
4Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
5Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
6R. McQuillan and E. Theodoratou contributed equally to this article as lead authors and supervised the work
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Evropi Theodoratou
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Background The Joint Committee on Vaccination and Immunisation in the United Kingdom requested an evidence synthesis to investigate the relationship between asthma and coronavirus disease 2019 (COVID-19) outcomes.

Objective We conducted a systematic review and meta-analysis to summarise evidence on the risk of severe COVID-19 outcomes in people with uncontrolled asthma or markers of asthma severity.

Methods High-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) were used as markers of asthma severity, following international or national asthma guidelines. Risk of bias was assessed using Joanna Briggs Institute tools. Adjusted point estimates were extracted for random-effects meta-analyses and subgroup analyses.

Results After screening, 12 studies (11 in adults and one in children) met the eligibility criteria. Adults using high-dose ICS or OCS had a pooled adjusted hazard ratio (aHR) of 1.33 (95% CI 1.06–1.67, I2=0%) for hospitalisation and an aHR of 1.22 (95% CI 0.90–1.65, I2=70%) for mortality for COVID-19. We found insufficient evidence for associations between markers on COVID-19 mortality in the subgroup analyses.

Conclusions Adults with severe asthma are at increased risk of COVID-19 hospitalisation compared to nonusers. Our analysis highlighted the dearth of studies in children with asthma investigating serious COVID-19 outcomes.

Abstract

This systematic review demonstrated that adults with severe asthma requiring high-dose inhaled corticosteroids or oral corticosteroids have a higher risk of hospitalisation from COVID-19 than those with mild asthma or no asthma. https://bit.ly/3zYiWaO

Introduction

Coronavirus disease 2019 (COVID-19) is a respiratory condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in a pandemic [1], affecting both adults and children [2]. Older people and people with comorbidities such as type 2 diabetes mellitus, hypertension, cancer and some other respiratory diseases are known to have an increased likelihood of developing severe COVID-19 outcomes such as hospitalisation, admission to intensive care unit (ICU), having to go on a ventilator, or death [3, 4].

According to the International Severe Acute Respiratory and Emerging Infection Consortium, 14% of COVID-19 patients in the United Kingdom (UK) had an underlying diagnosis of asthma, although asthma was not linked to a higher fatality rate [5]. To the contrary, current evidence shows that asthma may have potential protective effects due to the use of inhaled corticosteroids (ICS). In a recent systematic review and meta-analysis of 57 studies, people with asthma were at lower risk of acquiring COVID-19 or hospitalisation with COVID-19 than those without asthma [6]. In a recent randomised controlled trial in the UK, an ICS, inhaled budesonide (800 μg twice daily for 14 days) was protective in reducing the risk of hospital admissions or COVID-19 related deaths [7].

In the UK, the Joint Committee on Vaccination and Immunisation (JCVI) requested an evidence synthesis to inform national policy deliberations on COVID-19 vaccines and boosters in children and adults with asthma. One of the deliberations they had to advise on was whether people with severe asthma should receive vaccines or boosters for COVID-19 and how to identify those people using routinely collected health data. After further discussions with British Thoracic Society and JCVI, we considered reframing this using markers of severity/uncontrolled asthma. Hence, this review aimed to provide the best evidence of severe outcomes of COVID-19 in relation to markers of asthma severity.

Methods

This systematic review was guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-2020) protocols statement [8]. A study protocol was developed and registered on the International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/PROSPERO/ identifier number CRD42021270284).

Search strategy

We developed a search strategy by combining terms for two concepts: COVID-19 and asthma. The search strategy was designed to identify studies that reported the characteristics of severe asthma patients who required hospitalisation, ICU admission, mechanical ventilation or intubation, and death from SARS-CoV-2 infection. All results were screened, but to facilitate the identification of existing reviews, we also used the Scottish Intercollegiate Guidelines Network MEDLINE filter for systematic reviews (adapted for other databases) [9].

We searched Ovid MEDLINE, the World Health Organization COVID-19 literature database and medRxiv. Draft searches were piloted in each database, refined, run for this review on 19 July 2021 and updated 23 September 2021 and 18 January 2022 by M. Dozier. Detailed search strategies are provided in supplementary table E1.

Screening and selection of studies

Two independent reviewers from a group of six reviewers (B. Lee, E. Agyei-Manu, N. Atkins, U. Bhattacharyya, G. Lewis, J. Rostron) conducted title and abstract screening and full-text screening on www.Covidence.org. Additional duplicates were identified and removed manually during title and abstract screening. Eligible studies presented severe asthma definitions, included confirmed COVID-19 cases using reverse transcriptase (RT)-PCR and compared outcomes with relevant comparators (e.g. people with mild or no asthma). We selected studies that included both confirmed and clinically highly suspected COVID-19 cases due to limited access to RT-PCR in the early months of the COVID-19 pandemic.

The following criteria were used to screen records. We used European Respiratory Society and American Thoracic Society guidelines and Global Initiative for Asthma (GINA) to define severe asthma, either as 1) requiring high-dose ICS (e.g. inhaled budesonide: for adults and adolescents (aged ≥12 years) >800 μg·day−1; for children 6–11 years >400 μg·day−1) and a second controller; 2) use of oral corticosteroids (OCS); or 3) asthma that remained “uncontrolled” despite therapy [10, 11]. We also included studies using any other guideline definitions of asthma severity based on medication use [11, 12]. Severe outcomes for COVID-19 were defined as COVID-19 related hospitalisation, mortality, ICU admission or mechanical ventilation. Table 1 outlines the eligibility criteria. Disagreements were resolved by a third reviewer (E. Theodoratou or R. McQuillan).

View this table:
  • View inline
  • View popup
TABLE 1

Inclusion and exclusion criteria

Risk-of-bias assessment

We used Joanna Briggs Institute (JBI) critical appraisal tools to assess the quality of evidence of eligible studies [13]. Studies were assessed independently by two reviewers and the percentage of “yes” responses among all questions was calculated (ranging from 0% to 100%) to attain comparable quality scores among the selected studies. Studies with a score ≥80% were considered high quality, those with a score ≥50% but <80% were considered moderate quality, and those with a score <50% were considered low quality.

Data extraction and data analysis

Evidence was summarised by types of severe COVID-19 outcomes. Information on study settings such as population-based or hospital-based and asthma medication regimens were extracted. We did not extract data on vaccination status. For the associations, we extracted adjusted risk ratios, odds ratios (aOR) or hazard ratios (aHR) and 95% confidence intervals. We performed a general inverse variance method using random-effects meta-analysis, employing the restricted maximum-likelihood estimation and Hartung–Knapp–Sidik–Jonkman adjustment [14]. To explore the reasons for heterogeneity, we calculated τ2, I2 and Cochrane's Q. Subgroup analyses were conducted by study settings and asthma medication regimens. As all of the analyses included <10 studies, we did not assess publication bias using funnel plots, Begg correlation or Egger test. We presented all results in the form of forest plots using R software (version 4.1.2). The results were presented narratively when meta-analysis was not possible due to excessive heterogeneity between studies or a lack of research.

Results

Characteristics of included studies

Out of 2649 records identified after deduplication, 317 underwent full-text screening. Of these, 12 studies were retained for data extraction [15–26]. The screening process is summarised in a PRISMA flow chart (figure 1).

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses screening process.

Table 2 summarises the characteristics of the included studies. Seven studies were from the UK [15–19, 24, 25], two each were from South Korea [21, 23] and the United States (USA) [22, 26] and one study was from the Netherlands [20]. Nine studies were population-based [15, 18–21, 23–26] and three studies were hospital-based [16, 17, 22].

View this table:
  • View inline
  • View popup
TABLE 2

Characteristics of studies included in the review (n=12)

Markers of asthma severity

Supplementary table E3 summarises markers of asthma severity used in the included studies. Five studies classified asthma severity by high-dose ICS use [15, 16, 18, 20, 26] and four studies used OCS use [17, 19, 21, 22, 24, 25]. Three studies adopted broader markers, but did not provide outcomes of subgroups of either high-dose ICS or OCS use [17, 22, 23]. Studies where medication regimens were not clearly defined were categorised after contacting the authors [15] or after discussion with reviewers [16, 18]. For patients who were treated with three medications from different classes, ICS plus long-acting β-agonist plus another medication, we classified them as the high-dose ICS group, since such patients were more likely to use high-dose ICS [16]. Two studies by Shi and co-workers [24, 25] categorised asthma severity by the number of OCS used (from none to two courses) and hospitalisation within 1 or 2 years before March 2020. To reduce heterogeneity among the included studies, we utilised estimates of one course of OCS within 1 year as a minimum estimate for hospitalisation and mortality. Since an estimate of OCS use within 1 year for ICU admission includes COVID-19-related mortality, we used the estimate for OCS use within 2 years to obtain each estimate.

Risk of bias of included studies

Based on the JBI critical appraisal tool standards for cohort studies and the calculation of the quality score, 11 out of 12 studies in the review were assessed as high quality. One study was assessed to be of moderate quality, scoring 63% [20]. Details are available in supplementary table E4.

Severe COVID-19 outcomes in children

Out of 12 studies, three included children (aged <18 years) [16, 21, 24], but only one study provided point estimates of outcomes of interest [24]. In a Korean study, 22 children were categorised as GINA steps 4 (n=22) and 5 (n=0), but no estimates in children were available [21]. In a UK study of children (aged <16 years) with asthma (n=74), five used OCS and 11 used ICS and other controllers, and only a small number of children with asthma were admitted to ICU (n=10), none of whom died [16]. Another UK study of children aged 5–17 years demonstrated that two or more courses of OCS were associated with an increased risk of COVID-19 hospital admission compared with those without asthma (aHR 3.53, 95% CI 1.87–6.67), but not one course of OCS (aHR 1.52, 95% CI 0.90–2.57) [24]. However, the number of COVID-19 related deaths was very few (n<5) in this group [24].

Severe COVID-19 outcomes in adults

We conducted a meta-analysis with the aHRs which were adjusted for covariates, resulting in excluding three articles [20, 23, 26] presenting aORs, which are not interchangeable with aHRs. A separate meta-analysis was conducted with these three studies (supplementary figures E1–E3).

Figure 2 summarises the risks of severe COVID-19 outcomes for adults with severe asthma requiring high-dose ICS or OCS. The result of the meta-analysis showed that adults with severe asthma had a higher aHR of 1.33 (95% CI 1.06–1.67, I2=0%) for hospital admission than those without asthma or any respiratory diseases (figure 2a).

FIGURE 2
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 2

Adjusted hazard ratios (aHRs) for severe coronavirus disease 2019 (COVID-19) outcomes. a) Hospital admission; b) intensive care unit (ICU) admission; c) mortality for COVID-19.

Two population-based studies examined the association between severe asthma and ICU admission related to COVID-19 and the pooled aHR was 1.26 (95% CI 0.89–1.79, I2=0%) [15, 25] (figure 2b). Although both studies showed a higher risk for ICU admission in adults with severe asthma, they used different markers for severe asthma (three different asthma medications [15], versus one course of OCS within 2 years [25]).

For mechanical ventilation/intubation, only two studies investigated mechanical ventilation risk in relation to severe asthma [20, 22]. In a cohort study by Eger et al. [20], people in the Registry of Adult Patients with Severe Asthma for Optimal Disease Management (RAPSODI) requiring high-dose ICS showed a higher intubation prevalence than the general Dutch population (0.79% for RAPSODI versus 0.02% for the general Dutch population). In addition, in this group, severe asthma had an OR 40.8 for intubation (95% CI 16.9–98.5) compared with the general Dutch population. According to Robinson et al. [22], the rate of event per 1000 person-days of mechanical ventilation was 1.6 (95% CI 0.2–3.0) in the severe asthma group using OCS within 1 year. There was no significant difference between severe and nonsevere asthma after matching for age, sex and date of SARS-CoV-2 test (aHR 2.10, 95% CI 0.77–5.76) [22].

Lastly, 11 studies examined the association between severe asthma and COVID-19 mortality [15–23, 25, 26]. Of these studies, there were no COVID-19 deaths in two studies [21, 22]. Three studies presenting odds ratios were included in a separate meta-analysis, which showed OR 1.07 (95% CI 0.15–7.82, I2=30%) (supplementary figure E3) [20, 23, 26]. When six aHRs were included in the meta-analysis [15–19, 25], severe asthma in adults was not associated with a higher aHR (1.22, 95% CI 0.90–1.65; I2=70%) (figure 2c).

Figure 3a and b shows the risks of mortality for COVID-19 in subgroups by study setting and by asthma medication regimens.

FIGURE 3
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 3

Adjusted hazard ratios (aHRs) for coronavirus disease 2019 (COVID-19) mortality in subgroup analyses. a) Study setting; b) asthma medication regimens. df: degrees of freedom; OCS: oral corticosteroids; ICS: inhaled corticosteroids.

The pooled aHR derived from four population-based cohorts [15, 18, 19, 25] was 1.10 (95% CI 0.84–1.46), with moderately high heterogeneity (I2=66%) (figure 3a). Two hospital-based cohort studies also showed a higher aHR of 1.96 for death from COVID-19 (95% CI 0.12–31.28) compared to those with no asthma or no severe asthma, with low heterogeneity (I2=0%).

For OCS, two population-based studies showed that severe asthma patients on OCS had an aHR of 1.04 (95% CI 0.32–3.33; I2=72%) compared to patients with nonsevere or no asthma [19, 25] (figure 3b).

For high-dose ICS, four studies were included in the analysis (figure 3b). Use of high-dose ICS had an aHR of 1.42 in adults, compared to those with mild or no asthma (aHR 1.42, 95% CI 0.84–2.40; I2=75%) [15–18]. When dividing the studies by settings again, two population-based cohort studies [15] showed an aHR of 1.27 (95% CI 0.11–14.76, I2=78%) and two hospital-based studies [16, 17] showed an aHR for death from COVID-19 of 1.96 (95% CI 0.12–31.28, I2=0%) compared to those with nonsevere or no asthma.

Discussion

Our findings show that high-dose ICS or OCS use in adults with severe asthma was associated with a higher risk of hospitalisation for COVID-19, but not ICU admission and mortality. Our subgroup analyses demonstrated there was insufficient evidence supporting the association between high-dose ICS or OCS use in adults with severe asthma and an increased risk of COVID-19 mortality, compared to those with mild/moderate asthma or no asthma. However, we observed high heterogeneity between studies, and it may be due to different sample sizes, different comparators, the inclusion of suspected COVID-19 cases or different covariates used in their statistical analyses (supplementary tables E2 and E5).

It is noteworthy that severe asthma definitions used in some studies were too broad or unclear to classify asthma regimens binarily. Therefore, it may cause the potential misclassification of people with nonsevere asthma as severe asthma. Five studies [15, 16, 18, 21, 22] commented that some patients with severe asthma might have been misclassified as those with nonsevere or non-high-dose ICS users due to limited access to full medication information. For instance, in Aveyard et al. [15], participants had to use one of three asthma medications in a 1-year period. This would mean someone prescribed a single prescription of salbutamol and other medicines in different classes once a year would be classified as “severe asthma”. In Bloom et al. [16], participants reported their medication within 2 weeks of hospital admission. Participants in the OpenSAFELY research could be prescribed an ICS at any point in the 4 months leading up to their enrolment. Similarly, four studies using data in the early pandemic [15, 16, 18, 19] might have some clinically suspected patients being incorrectly identified as having COVID-19 due to inaccessibility of testing. Therefore, these definitions could have led to misclassification and may have limited findings.

The behavioural change due to governmental COVID-19 mitigations could have affected outcomes. Aveyard et al. [15] examined the impact of shielding or national lockdown in England on severe COVID-19 risks in people with severe asthma by comparing the pre-shielding period (31 March 2020) to the post-shielding period (1–30 April 2020). However, they did not find any effects of shielding. Regardless of shielding, severe asthma increased hospitalisation and ICU admission risks except for mortality. Williamson et al. [19] did not find any differences in the aHRs for mortality between early censoring in early April 2020 and patients who were more likely to comply with the shielding and physical distancing in England.

Our findings are in line with other studies. A case–control study in South Korea revealed no significant increase in COVID-19 related mortality in ICS adult users whose cumulative ICS dose was ≥15 000 μg in the past 12 months, compared to non-ICS users in asthma patients, after adjusting for baseline demographic characteristics and comorbidities [27]. In addition, a large cohort study using the Cleveland Clinic COVID-19 registry showed that ICS therapy did not increase the risk of COVID-19 related mortality in adults with COPD compared with those with COPD not taking ICS; however, the dose of ICS was not detailed in their report [28]. Some in vitro models showing inhibitory effects of ICS alone or in combination with β-agonists on coronavirus HCoV-229E replication and cytokine production could support protective effects of ICS treatment [29, 30]. Some studies hypothesised that a protective effect of type 2 T-helper (Th2) cell inflammation might explain the low risk of severe COVID-19 outcome in severe asthmatics. Type 2 inflammation, common with severe asthmatic symptoms, triggers reducing cellular receptors such as angiotensin-converting enzyme (ACE)2, a receptor for SARS-CoV-2 [31, 32]. Respiratory allergies or interleukin-13 are associated with a significant reduction in ACE2 expression, resulting in decreasing susceptibility to SARS-CoV-2 [33]. Therefore, future studies should consider asthma types concerning severe outcomes of COVID-19 [34].

We acknowledge some limitations to this review. Firstly, we might have missed some literature, as we excluded studies not having clear severe asthma definitions. In addition, there was a risk of overlapping cases using two OpenSAFELY cohort studies [18, 19]. Although they used different statistical approaches, high-dose ICS users in Schultze et al. [18] may have also been included in Williamson et al. [19], considering that both studies used the same cohort and overlapping data collection times. To address the risk of double counting, we only used hazard ratios adjusted for oral steroids for Schultze et al. [18]. Although our findings did not show positive associations between severe asthma and COVID-19 mortality, there was high heterogeneity in the comparator groups (nonsevere asthma, no asthma or mild asthma), participants’ characteristics (e.g. age, sex), sample size and statistical approach. To address other comorbidities that are known to be associated with poor COVID-19 outcomes, we used aHRs for all underlying diseases from the studies. However, types of other comorbidities were not consistently applied across the included studies.

We did not examine publication bias that can be caused by small studies, because evaluating publication bias is not reliable with <10 studies [35]. Thus, our meta-analyses could be limited not only by high heterogeneity but also by the small number of studies. We noticed that most of the studies included in the main meta-analyses were from the UK. Studies from the Netherlands [20], South Korea [23] and the USA [26] were analysed separately because of different types of estimates (odds ratios) (supplementary figures E1–E3), showing no associations between severe asthma and serious outcomes. We did not intend to conduct subgroup analyses by country, but this result could be considered as one of the limitations of this study.

Lastly, we did not consider biological drug treatment as a marker of asthma severity. However, a study using the Italian Registry of Severe Asthma network showed that biological drug users did not have higher risk of hospitalisation, ICU admission and mortality [36]. Another large cohort study of COVID-19 in the Severe Asthma Network in Italy (including 65% biologicals users) did not show a higher mortality (7.7%) than the general population (14.5% in Italy) [37].

As we did not further investigate risks by sex, sex-related differences in the severity of COVID-19 were not considered in this review. However, two included studies showed different risks for hospitalisation by sex. In the study by Aveyard et al. [15], women with severe asthma showed higher risks not only for hospitalisation (aHR 1.40, 95% CI 1.29–1.51), but also for ICU admission (aHR 1.80, 95% CI 1.37–2.37) than men. Robinson et al. [22] also observed higher hospitalisation rates in women with severe asthma (n=33, 75%) than in men. Such difference could be explained by hormonal changes that can modify the prevalence of the immunological asthma endotype, resulting in more frequent nonatopic asthma in women than in men. Therefore, it could cause different responses to SARS-CoV-2 infection, driven by greater Th1 activity in nonatopic asthma than in atopic asthma [38]. Further investigations are needed to clarify whether female sex with severe asthma could be a risk factor for COVID-19 hospitalisation.

This is the first systematic review to examine whether severe asthma is associated with severe COVID-19 outcomes. Despite our extensive searches, very few studies were identified for the paediatric population with asthma. One large population-based study demonstrated that previous recent hospital admission and two or more OCS use could be risk factors of COVID-19 related hospitalisation [24]. Still, as the authors noted, the small numbers of COVID-19 outcome cases were included in this study due to a lack of records for emergency room attendance. Thus, further research would be needed on the paediatric population with severe asthma. Furthermore, although positive effects of COVID-19 specific therapies reducing progression to serious COVID-19 outcomes are well evident and this could confound the associations, most studies were done before treatments became available. Future studies should consider this covariate in the analysis and confirm the associations of severe asthma with serious outcomes. Contrary to the findings from Sunjaya et al. [6] and Yu et al. [7] which suggest that people with mild or well-controlled asthma may have protective effects due to ICS use, the evidence from our review shows that adults with moderate-to-severe or poorly controlled asthma requiring high-dose ICS or OCS have a higher risk of hospitalisation than those with mild or no asthma. It is noteworthy that some of the primary studies included in this review used proxies to grade asthma severity (i.e. either number of high-dose ICS use or OCS use) rather than using actual ICS or OCS dosage levels to classify people according to disease severity. Due to the complexities in differentiating asthma control from asthma severity, the evidence from this review may suggest an association with asthma control. Thus, adults with poorly controlled asthma (i.e. severe asthma) may be at a higher risk of hospitalisation or death from COVID-19, hence the need for adequate control in severe asthma treatment and management.

In conclusion, there is limited evidence demonstrating that those with severe asthma are at increased risk of COVID-19 mortality compared to those with mild asthma or no asthma. However, high-quality evidence demonstrated that severe asthma requiring high-dose ICS or OCS was associated with a higher risk of COVID-19 hospitalisation compared to mild asthmatics and/or nonasthmatic controls. Therefore, it may be beneficial to reduce hospitalisation rates by accelerating COVID-19 boosters for people with severe asthma. Further research is urgently needed for the paediatric population with severe asthma and associated COVID-19 outcomes.

Points for clinical practice

High-quality evidence demonstrated that severe asthma in adults had a 33% higher hospitalisation risk (95% CI 1.06–1.67%) with COVID-19 than those with mild or no asthma. Therefore, it may be beneficial to reduce hospitalisation rates by accelerating COVID-19 boosters for people with severe asthma. Further research is urgently needed for the paediatric population with severe asthma and associated COVID-19 outcomes.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material ERR-0066-2022.SUPPLEMENT

Acknowledgements

UNCOVER (Usher Network for COVID-19 Evidence Reviews) advisors who contributed to this review are Gerry Fowkes (Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK) and Harry Campbell (Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK).

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information.

  • Conflict of interest: B. Lee has nothing to disclose.

  • Conflict of interest: G. Lewis has nothing to disclose.

  • Conflict of interest: E. Agyei-Manu has nothing to disclose.

  • Conflict of interest: N. Atkins has nothing to disclose.

  • Conflict of interest: U. Bhattacharyya has nothing to disclose.

  • Conflict of interest: M. Dozier has nothing to disclose.

  • Conflict of interest: J. Rostron has nothing to disclose.

  • Conflict of interest: A. Sheikh is a member of GINA and was a co-author of two of the studies included in this review; he was not involved in their assessment. A. Sheikh is a member of the UK Government's NERVTAG Risk Stratification Subgroup and the Scottish Government's Standing Committee on Pandemics. He was a member of AstraZeneca's Thrombotic Thrombocytopenic Task Force. All A. Sheikh's roles are unremunerated.

  • Conflict of interest: R. McQuillan has nothing to disclose.

  • Conflict of interest: E. Theodoratou has nothing to disclose.

  • Support statement: E. Theodoratou is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). B. Lee and G. Lewis are supported by Asthma UK Centre for Applied Research PhD Programme Fellowships. UNCOVER group is supported by Wellcome Trust's Institutional Strategic Support Fund (ISSF3), the Data-Driven Innovation and the Principal's Teaching Awards Scheme (PTAS). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received April 12, 2022.
  • Accepted July 31, 2022.
  • Copyright ©The authors 2022
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

References

  1. ↵
    1. Tabari P,
    2. Amini M,
    3. Moghadami M, et al.
    International public health responses to COVID-19 outbreak: a rapid review. Iran J Med Sci 2020; 45: 157–169. doi:10.30476/ijms.2020.85810.1537
    OpenUrlPubMed
  2. ↵
    1. Viner RM,
    2. Mytton OT,
    3. Bonell C, et al.
    Susceptibility to SARS-CoV-2 infection among children and adolescents compared with adults: a systematic review and meta-analysis. JAMA Pediatr 2021; 175: 143–156. doi:10.1001/jamapediatrics.2020.4573
    OpenUrlPubMed
  3. ↵
    1. Booth A,
    2. Reed AB,
    3. Ponzo S, et al.
    Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis. PLoS One 2021; 16: e0247461. doi:10.1371/journal.pone.0247461
    OpenUrlCrossRefPubMed
  4. ↵
    1. Zheng Z,
    2. Peng F,
    3. Xu B, et al.
    Risk factors of critical and mortal COVID-19 cases: a systematic literature review and meta-analysis. J Infect 2020; 81: e16–e25. doi:10.1016/j.jinf.2020.04.021
    OpenUrlCrossRefPubMed
  5. ↵
    1. Docherty AB,
    2. Harrison EM,
    3. Green CA, et al.
    Features of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020; 369: m1985. doi:10.1136/bmj.m1985
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Sunjaya AP,
    2. Allida SM,
    3. Di Tanna GL, et al.
    Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: systematic review and meta-analysis. J Asthma 2022; 59: 866–879. doi:10.1080/02770903.2021.1888116
    OpenUrl
  7. ↵
    1. Yu LM,
    2. Bafadhel M,
    3. Dorward J, et al.
    Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021; 398: 843–855. doi:10.1016/S0140-6736(21)01744-X
    OpenUrlCrossRefPubMed
  8. ↵
    1. Page MJ,
    2. McKenzie JE,
    3. Bossuyt PM, et al.
    The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. doi:10.1136/bmj.n71
    OpenUrlFREE Full Text
  9. ↵
    1. Scottish Intercollegiate Guidelines Network
    . Search Filters. www.sign.ac.uk/what-we-do/methodology/search-filters/. Date last accessed: 18 January 2022.
  10. ↵
    1. Global Initiative for Asthma (GINA)
    . Global Strategy for Asthma Management and Prevention. 2021. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf Date last updated: 2021. Date last accessed: 31 March 2022.
  11. ↵
    1. Chung KF,
    2. Wenzel SE,
    3. Brozek JL, et al.
    International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–373. doi:10.1183/09031936.00202013
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. National Institute for Health and Care Excellence (NICE)
    . COVID-19 Rapid Guideline: Severe Asthma. 2020. www.nice.org.uk/guidance/ng166/ Date last updated: 3 April 2020. Date last accessed: 31 March 2022.
  13. ↵
    1. Joanna Briggs Institute
    . Checklist for Qualitative Research. Available from: https://jbi.global/critical-appraisal-tools Date last accessed: 31 March 2022.
  14. ↵
    1. IntHout J,
    2. Ioannidis JPA,
    3. Borm GF
    . The Hartung–Knapp–Sidik–Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian–Laird method. BMC Med Res Methodol 2014; 14: 25. doi:10.1186/1471-2288-14-25
    OpenUrlCrossRefPubMed
  15. ↵
    1. Aveyard P,
    2. Gao M,
    3. Lindson N, et al.
    Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. Lancet Respir Med 2021; 9: 909–923. doi:10.1016/S2213-2600(21)00095-3
    OpenUrl
  16. ↵
    1. Bloom CI,
    2. Drake TM,
    3. Docherty AB, et al.
    Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Respir Med 2021; 9: 699–711. doi:10.1016/S2213-2600(21)00013-8
    OpenUrl
  17. ↵
    1. Fong WCG,
    2. Borca F,
    3. Phan H, et al.
    Asthma did not increase in-hospital COVID-19-related mortality in a tertiary UK hospital. Clin Exp Allergy 2021; 51: 939–941. doi:10.1111/cea.13855
    OpenUrl
  18. ↵
    1. Schultze A,
    2. Walker AJ,
    3. MacKenna B, et al.
    Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform. Lancet Respir Med 2020; 8: 1106–1120. doi:10.1016/S2213-2600(20)30415-X
    OpenUrl
  19. ↵
    1. Williamson EJ,
    2. Walker AJ,
    3. Bhaskaran K, et al.
    Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020; 584: 430–436. doi:10.1038/s41586-020-2521-4
    OpenUrlCrossRefPubMed
  20. ↵
    1. Eger K,
    2. Hashimoto S,
    3. Braunstahl GJ, et al.
    Poor outcome of SARS-CoV-2 infection in patients with severe asthma on biologic therapy. Respir Med 2020; 177: 106287. doi:10.1016/j.rmed.2020.106287
    OpenUrl
  21. ↵
    1. Choi YJ,
    2. Park J-Y,
    3. Lee HS, et al.
    Effect of asthma and asthma medication on the prognosis of patients with COVID-19. Eur Respir J 2021; 57: 2002226. doi:10.1183/13993003.02226-2020
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Robinson LB,
    2. Wang L,
    3. Fu X, et al.
    COVID-19 severity in asthma patients: a multi-center matched cohort study. J Asthma 2022: 59: 442–450. doi:10.1080/02770903.2020.1857396
    OpenUrl
  23. ↵
    1. Jung Y,
    2. Wee JH,
    3. Kim JH, et al.
    The effects of previous asthma and COPD on the susceptibility to and severity of COVID-19: a nationwide cohort study in South Korea. J Clin Med 2021; 10: 4626. doi:10.3390/jcm10204626
    OpenUrl
  24. ↵
    1. Shi T,
    2. Pan J,
    3. Katikireddi SV, et al.
    Risk of COVID-19 hospital admission among children aged 5–17 years with asthma in Scotland: a national incident cohort study. Lancet Respir Med 2022; 10: 191–198. doi:10.1016/S2213-2600(21)00491-4
    OpenUrl
  25. ↵
    1. Shi T,
    2. Pan J,
    3. Vasileiou E, et al.
    Risk of serious COVID-19 outcomes among adults with asthma in Scotland: a national incident cohort study. Lancet Respir Med 2022; 10: 347–345. doi:10.1016/S2213-2600(21)00543-9
    OpenUrl
  26. ↵
    1. Zein JG,
    2. Mitri J,
    3. Bell JM, et al.
    The relationship of asthma severity to COVID-19 outcomes. J Allergy Clin Immunol Pract 2022; 10: 318–321. doi:10.1016/j.jaip.2021.10.041
    OpenUrl
  27. ↵
    1. Choi JC,
    2. Jung SY,
    3. Yoon UA, et al.
    Inhaled corticosteroids and COVID-19 risk and mortality: a nationwide cohort study. J Clin Med 2020; 9: 3406. doi:10.3390/jcm9113406
    OpenUrl
  28. ↵
    1. Sen P,
    2. Majumdar U,
    3. Zein J, et al.
    Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: an analysis of Cleveland Clinic's COVID-19 registry. PLoS One 2021; 16: e0252576. doi:10.1371/journal.pone.0252576
    OpenUrl
  29. ↵
    1. Yamaya M,
    2. Nishimura H,
    3. Deng X, et al.
    Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells. Respir Investig 2020; 58: 155–168. doi:10.1016/j.resinv.2019.12.005
    OpenUrlCrossRefPubMed
  30. ↵
    1. Matsuyama S,
    2. Kawase M,
    3. Nao N, et al.
    The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting the viral replication-transcription complex in cultured cells. J Virol 2020; 95: e01648-20. doi:10.1128/JVI.01648-20
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Chung MK,
    2. Karnik S,
    3. Saef J, et al.
    SARS-CoV-2 and ACE2: the biology and clinical data settling the ARB and ACEI controversy. EBioMedicine 2020; 58: 102907. doi:10.1016/j.ebiom.2020.102907
    OpenUrl
  32. ↵
    1. Jackson DJ,
    2. Busse WW,
    3. Bacharier LB, et al.
    Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2. J Allergy Clin Immunol 2020; 146: 203–206. doi:10.1016/j.jaci.2020.04.009
    OpenUrlPubMed
  33. ↵
    1. Yao Y,
    2. Wang H,
    3. Liu Z
    . Expression of ACE2 in airways: implication for COVID-19 risk and disease management in patients with chronic inflammatory respiratory diseases. Clin Exp Allergy 2020; 50: 1313–1324. doi:10.1111/cea.13746
    OpenUrlPubMed
  34. ↵
    1. Kuruvilla ME,
    2. Lee FEH,
    3. Lee GB
    . Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 2019; 56: 219–233. doi:10.1007/s12016-018-8712-1
    OpenUrlPubMed
  35. ↵
    1. Dalton JE,
    2. Bolen SD,
    3. Mascha EJ
    . Publication bias: the elephant in the review. Anesth Analg 2016; 123: 812–813. doi:10.1213/ANE.0000000000001596
    OpenUrlPubMed
  36. ↵
    1. Antonicelli L,
    2. Tontini C,
    3. Manzotti G, et al.
    Severe asthma in adults does not significantly affect the outcome of COVID-19 disease: results from the Italian severe asthma registry. Allergy 2021; 76: 902–905. doi:10.1111/all.14558
    OpenUrl
  37. ↵
    1. Heffler E,
    2. Detoraki A,
    3. Contoli M, et al.
    COVID-19 in Severe Asthma Network in Italy (SANI) patients: clinical features, impact of comorbidities and treatments. Allergy 2021; 76: 887–892. doi:10.1111/all.14532
    OpenUrlCrossRef
  38. ↵
    1. Fernando M,
    2. Agusti A,
    3. Dharmage S, et al.
    Are women with asthma at increased risk for severe COVID-19? Lancet Respir Med 2021; 9: 125–126. doi:10.1016/S2213-2600(21)00007-2
    OpenUrl
PreviousNext
Back to top
View this article with LENS
Vol 31 Issue 166 Table of Contents
European Respiratory Review: 31 (166)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis
Bohee Lee, Grace Lewis, Eldad Agyei-Manu, Nadege Atkins, Urmila Bhattacharyya, Marshall Dozier, Jasmin Rostron, Aziz Sheikh, Ruth McQuillan, Evropi Theodoratou
European Respiratory Review Dec 2022, 31 (166) 220066; DOI: 10.1183/16000617.0066-2022

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis
Bohee Lee, Grace Lewis, Eldad Agyei-Manu, Nadege Atkins, Urmila Bhattacharyya, Marshall Dozier, Jasmin Rostron, Aziz Sheikh, Ruth McQuillan, Evropi Theodoratou
European Respiratory Review Dec 2022, 31 (166) 220066; DOI: 10.1183/16000617.0066-2022
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Supplementary material
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Asthma and allergy
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Severe COVID-19 versus multisystem inflammatory syndrome
  • PROMs for paediatric acute lower respiratory infection studies
  • Forbearance with endobronchial stenting: cognisance before conviction
Show more Reviews

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERR

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising
  • Sponsorship

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN: 0905-9180
Online ISSN: 1600-0617

Copyright © 2023 by the European Respiratory Society