Introduction

Asthma is the most common chronic adversity of the lungs, and its prevalence was globally estimated to be in up to 350 million people.^1–4 Asthma, which has no complete cure, leads to several fatalities and involves significant expenses for its prevention and control.^2,3 The new coronavirus disease 2019 (COVID-19) pandemic had an impact on one and all, and it spread rapidly across the globe with millions of deaths. Individuals with asthma may be more affected with this virus and were at an increased risk of acquiring the disease or experiencing poor outcomes.^4,5

The cohort studies and individual case series were reported with conflicting results in subjects with asthma on the vulnerability to and risk of COVID-19 mortality. There are different reports on the vulnerability of asthma patients to COVID-19 based on various national- or local-level case series and analyses, and the conclusions reached were constrained by the inclusion of cases of COVID-19 and their related analyses that confer significant selection bias of asthma.^6,7 The maximum focus was on mortality and not on other important parameters such as admission to an intensive care unit (ICU), risk of being infected, hospitalization, and most importantly ventilator use when admitted.^8–10 A comprehensive understanding of the risk of COVID-19 among subjects with asthma is crucial globally as countries lift lockdown. The relationship between COVID-19 and asthma and also the impact of this virus on symptoms of asthma needs to be analyzed. The risk of SARS-Cov-2 (severe acute respiratory syndrome coronavirus 2) infection affecting people with asthma, hospitalization, ICU admission, and ventilator use should be recognized.^4,5,11,12

In this study, detailed searches with new analyses were done and therefore, the research question is that are subjects with asthma at a higher risk of being infected or hospitalized or vulnerable to weaker clinical outcomes from COVID-19? And, what is COVID-19’s impact on asthma outcomes? Consequently, the objective was to conduct a comprehensive systematic review and meta-analysis of the morbidity and mortality of COVID-19 among subjects with asthma.

Methods

Search strategy and also selection criteria

The systematic review and meta-analysis touch upon the risk of asthma in people with COVID-19. Also, it includes publications on the pandemic’s early stages, and the protocol used was from published studies, systematic reviews, and meta-analyses; the preferred reporting items were employed in the reporting of this study.¹³ A comprehensive search of electronic databases, including the Cochrane Database of Systematic Reviews, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, the World Health Organization COVID-19 Database, Embase, CINAHL, and PEDro, were conducted between 1 December 2019 and 31 July 2023. Also, a hand search of relevant systematic review references was conducted. All studies (primary controlled) reporting on adults with confirmed COVID-19 were included, with a pre-existing asthma diagnosis that was published in the English language, and the screenings were checked and confirmed by three independent reviewers.

Data collection

Three reviewers screened abstracts and titles, and excluded irrelevant studies using Rayyan QCRI.¹⁴ Independently, full-text publications were subsequently reviewed and disagreement resolved via consensus and also referral to a fourth reviewer. At the full-text review stage, potential overlaps between studies were identified in order to prevent double counting of individual patients. The data were extracted using a standard electronic form, and the quality of the included studies was rated using the Newcastle–Ottawa Scale.¹⁵

Outcomes

The outcomes were: (1) the risk of asthma, expressed as the proportion of confirmed asthmatic patients with a diagnosis of COVID-19; (2) risk of hospitalization from asthma with confirmed COVID-19; (3) risk of ICU admission (confirmed COVID-19 patients with asthma); (4) risk of being ventilated (asthmatic individuals with confirmed COVID-19); and (5) risk of death (asthmatic individuals with confirmed COVID-19).

Data analysis

In Table 1, descriptive statistics were utilized to summarize the details of the included studies. It was mentioned that the Newcastle–Ottawa Scale was applied to assess the quality of methodology of the included studies based on the relevant study designs, case–control or cohort. The main sets (two) of meta-analyses were performed. To estimate the prevalence of asthma among individuals with COVID-19, a binomial distribution was employed to model within-study variability. The Wilson score was used to calculate 95% confidence intervals for all the binary outcomes, and a Sidik–Jonkman random-effects meta-analysis was conducted. The degree of quantitative heterogeneity was evaluated through the implementation of a formal test of homogeneity and the estimation of the proportion of variability attributable to heterogeneity. In addition, prespecified subgroup analyses were conducted on the studies’ quality and content, and univariate meta-regression using proportions of current smokers, age, and former smokers as covariates were performed. All pooled results were presented in the results section, and statistical analyses were performed using Stata 16.

Results

The searches resulted in 41,392 citations. After removing of duplications, 17,831 abstracts and titles were screened, and 17,027 publications were excluded. From the remaining 804 manuscripts, 756 were excluded after reviewing the full text and a total of 48 studies were included in the review (Figure 1). Studies involving overlapping patient populations were excluded from the analysis if they reported identical outcomes.

Figure 1 Summary of the results of the screening and evaluation of the publications and citations searched.

Descriptive characteristics

This review is based on a pooled sample of patients diagnosed with COVID-19 who reported information related to asthma. Most of these hospital-based studies were from 27 countries spread across Europe, South America, Asia, North America, Africa, and Australia (Table 1).

The mean ± SD age of COVID-19 patients was 49.2 ± 13.6 years; 43.9% were male and 56.1% were female; and 6.6% were current smokers and 7.9% were former smokers. The asthma prevalence among those infected with the novel coronavirus (COVID-19) was 7.9%, and 2.8% also had COPD.

Risk of results’ bias

According to the Newcastle–Ottawa scores, all of the studies had scores of more than 7 and were of high quality.

Meta-analysis of the risk of acquiring COVID-19

The pooled analysis of studies demonstrated a 16.5% reduction in the risk ratio for acquiring COVID-19 among individuals with asthma compared to those without asthma. There was considerable heterogeneity across the studies and meta-regression by age revealed that the older ages was associated with enhanced risk of COVID-19 in individuals with asthma. However, the current smoker group did not demonstrate a statistically significant association.

Meta-analysis of the risk of hospitalization

There was no statistically significant difference with regard to the risk of hospitalization for COVID-19 individuals with and without asthma, and there was considerable heterogeneity observed across the studies. A meta-regression by age and current smoking status revealed no significant association between asthma and the risk of hospitalization due to COVID-19.

Meta-analysis of the risk of ICU admission

There was a no statistically significant difference in the ICU admission risk for subjects with asthma compared to those without asthma in a pooled analysis, and substantial heterogeneity was observed across the studies. A meta-regression analysis, with age and current smoking status as moderators, did not yield statistically significant results.

Meta-analysis of the risk of ventilator use when admitted in the ICU

In relation to the probability of mechanical ventilation, a statistically significant difference was not observed in the likelihood of being treated with a ventilator once admitted to the ICU for asthma compared to those with no asthma. Considerable heterogeneity was observed across the studies and a meta-regression analysis was conducted to determine the relationship between age and current smoking status. However, the results were not statistically significant.

Meta-analysis of the risk of death

The analysis revealed no statistically significant difference in the risk of death from COVID-19 between individuals with and without asthma, and considerable heterogeneity was observed across the studies. Including age as a moderator in the meta-regression analysis yielded no significant reduction in the risk of death, nor did it reveal any significant association with the current smoking status.

Analyses of the subgroup

Subgroup analyses by continent revealed substantial differences in the risk of acquisition of COVID-19 between the continents. The lowest risk was observed in Asia, while no major differences in hospitalization were found between continents. Nevertheless, significant discrepancies were observed in ICU admission rates across continents, and the maximum risk was found to be in Asia and the lowest in South America. In addition, the risk of ventilator use had significant differences across the continents, and the maximum risk was found in Europe. Similarly, the risk of death was found to vary considerably across the continents. The maximum risk was observed in Asia.

Discussion

The objective of this meta-analysis was to assess the vulnerability of patients with asthma who are infected with COVID-19. This discrepancy can be attributed to the more rigorous inclusion criteria employed, which excluded case series and single-arm cohort studies. The focus was on including only studies published by the nonasthma control group. Moreover, the prevalence rate was found to be lower than the global prevalence of self-reported symptoms of asthma. In this meta-analysis, the proportion estimated was less than in the recent UK studies which reported prevalence in those who were infected with the variant of B.1.1.7; lower prevalence rates were reported in other studies in Turkey and in Italy.^16–18 The current study found a significant decrease in the risk of acquiring COVID-19.

The study reported lower rates of positivity for COVID-19 test in asthma patients compared to those without asthma.¹⁹ Moreover, a community study demonstrated a lower prevalence of asthma in individuals who tested positive for the COVID-19 test compared to those who had negative COVID-19 test results.^20,21 Several mechanisms may contribute to the lower risk of acquiring COVID-19 in subjects with asthma compared to individuals with no asthma. A retrospective study demonstrated that asthma is associated with poor outcomes and lower risk, and that both in those with and without asthma, the presence of eosinophilia is associated with reduced risk of mortality. Although not statistically significant, a greater proportion of individuals with asthma exhibited eosinophilia compared to those without asthma.²² Subgroup analyses by continent revealed statistically significant differences in the risk of contracting the novel coronavirus (COVID-19) between the continents. The lowest risk was observed in Asia, followed by America and Europe. In addition, it was observed that there was consistent risk reduction in three out of the four regions, and all countries with a large testing regime may account for this variance between regions. Furthermore, it is crucial to acknowledge that the outcome may not be representative of other countries where testing protocols have been less comprehensive.

Furthermore, the lower risk of acquiring COVID-19 may be attributed to the angiotensin-converting enzyme 2 receptor expression that is significantly lower in asthmatic patients compared to healthy controls,²³ which supports the result of the current study analysis. The data demonstrated a clear correlation between increasing age and elevated risk of contracting the novel coronavirus. In a final directive, health authorities advised asthmatic patients to practice social distancing and to take particular care to avoid contracting the novel coronavirus. Furthermore, the pooled point estimate indicates a potential enhanced risk of hospitalization for COVID-19 for subjects with asthma, with a considerable degree of uncertainty. Similarly, the pooled point estimate indicates a potential increased risk of ICU admission due to COVID-19 for subjects with asthma, although this is not statistically significant.

It was reported that inhaled budesonide administration in early stage reduced the likelihood of urgent medical care and also time to recovery from COVID-19. The study demonstrated that the budesonide group exhibited a more rapid recovery compared to the usual care group.^24,25 A main finding of the current study was the similar risk of death between nonasthmatics and asthmatics from COVID-19. The information provided was limited on smoking that limits our ability to assess the impact of smoking.

Furthermore, reported were details of both nonasthma and asthma patients wherein COVID-19 infection status was used, and there was no access to information to determine if individuals with asthma were disproportionately represented among cases of mild or asymptomatic illness that did not undergo testing. This would suggest that there may be a need for further investigation into the potential underdiagnosis of asthma in this population. The findings from this analysis indicated that individuals with allergic asthma may be at a lower risk of COVID-19 infection compared to those without asthma but have a similar risk of ICU admission, ventilator use, hospitalization, and mortality. In light of the rapid evolution of the COVID-19 virus and the emergence of variants globally, it is imperative to exercise caution for individuals with asthma. Moreover, further research is necessary to ascertain the precise risk profile.