Effect of Preexisting Asthma on the Risk of ICU Admission, Intubation, and Death from COVID-19: A Systematic Review and Meta-Analysis

Background The Centers for Disease Control and Prevention (CDC) identifies asthma as a comorbidity in COVID-19 that increases the risk of severity and death. However, research has shown that asthma is not associated with increased severity and death, thus making the consequences of asthma in COVID-19 unclear. Methods We searched the electronic databases PubMed, WHO COVID-19 database, and Taylor and Francis Online for studies that compared the medical outcomes of COVID-19 between patients with and without asthma, from the emergence of SARS-CoV-2 in December 2019 to the 3rd of September 2021, excluded duplicates, reviews, editorials, and case reports, and screened the titles, abstracts, and full texts. The quality of the included studies was assessed using the Newcastle–Ottawa Scale (NOS) for nonrandomized studies. Rates of intensive care unit (ICU) admission, intubation, and death among patients with and without asthma were compiled and meta-analysis was conducted using a random-effects model. Results Nineteen studies with a total of 289,449 participants met the inclusion criteria. COVID-19 patients with asthma had no significant association with increased risk of ICU admission, intubation, and death as compared with those without asthma ((odds ratio (OR) = 1.25, confidence interval (CI) = 0.90–1.74, I2 = 82%, X2 = 55.13, p < 0.01), (OR = 0.89, CI = 0.59–1.34, I2 = 91%, X2 = 110.82, p < 0.01), and (OR = 0.90, 95% CI = 0.63–1.27, I2 = 88%, X2 = 146.96, p < 0.01)), respectively. Conclusion Preexisting asthma did not significantly increase the risk of poorer prognosis and death from COVID-19.


Introduction
e first case of the coronavirus disease-2019 (COVID- 19) was reported from Wuhan, China, in December 2019. And as of now, 3 rd December 2021, which is 2 years from the emergence of SARS-CoV-2, over 230,000,000 cases have been diagnosed and over 4,750,000 deaths have been reported in over 200 countries [1]. A variety of risk factors are linked to having poorer medical prognosis and outcomes in COVID- 19, some of which are old age, obesity, male sex, and comorbidities such as hypertension, chronic kidney disease, diabetes, asthma, chronic obstructive pulmonary disease (COPD), immunodeficiency, malignancies, and cardiovascular diseases [2].
Asthma is one of the most common chronic respiratory diseases in the world. e Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) point out asthma as a comorbidity, and subjects with asthma are more likely to develop and die from severe complications in COVID-19 [2,3]. However, from recent research, findings suggest poorer COVID-19 outcomes in patients with asthma as well as no association of asthma with poor prognosis and outcomes making the true consequences of asthma in COVID-19 susceptibility unclear. e possible poor outcome might exist due to an interplay between the pathobiology of SARS-CoV-2 and asthma. Like other respiratory viruses, SARS-CoV-2 has a potential role in asthma exacerbation, making the infection even worse [4]. SARS-CoV-2's entry into the lung tissue, facilitated by the angiotensin converting enzyme-2 (ACE-2), creates exaggerated inflammatory response and widespread dissemination of the virus throughout the lung parenchyma, producing pneumonia [5]. In people with asthma, whose airways are already narrowed and mucus-filled, pneumonia may lead to worse outcomes [6]. To circumvent this, the pulmonary production of protective interferons (IFNs), usually IFN-α, IFN-β, and IFN-λ, are required [7]. Different studies report that the interferon production is significantly compromised in these patients which could further impede the immunity in seizing the viral spread, therefore worsening the outcomes of COVID-19 [8][9][10]. Contrary to this, poorer outcomes may be avoided by asthma due to the downregulation of ACE-2, the gateway of SARS-CoV-2 entry into lung tissue [11].
During this time of the COVID-19 pandemic where the virus is affecting the respiratory system, asthma patients are more concerned for their safety and recovery if infected [12]. Most of the systematic reviews to date have reported risks without specification to confounding factors, interventions, or specific outcomes which have made the true risk and implications more difficult to conceptualize. According to the statistics, the risk of asthmatics being admitted to the ICU, if hospitalized due to COVID-19, is statistically insignificant as compared to individuals who do not have asthma. erefore, we conducted a systematic review and meta-analysis of the studies that reported the medical prognosis and outcomes of COVID-19 patients in three specific variables, intensive care unit (ICU) admission, intubation, and mortality, which can aid in assuring the people and healthcare systems the true risks of poorer outcomes in COVID-19.

Search Strategy and Study Selection
e systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13] and registered in PROSPERO (CRD42021281934).
A comprehensive search was performed on online databases PubMed, WHO COVID-19 database, and Taylor and Francis Online for all relevant articles published from the emergence of COVID-19 in December 2019 to the 3 rd of September 2021. e search terms used were "COVID-19," "coronavirus," "SARS-CoV-2," "severity," "mortality," "severity," "risk," "asthma," and "asthmatic" connected by "OR" and "AND" Boolean operators. e full search string is (COVID-19 OR coronavirus OR SARS-CoV-2) AND (severe * OR risk OR factor OR mortality OR critical) AND (asthma OR asthmatic). us, retrieved articles were then exported on an Excel ® sheet, and duplicates were removed. e studies were subjected to screening by title and abstract, later followed by full-text screening by two investigators (AB and GD). Any discrepancies between the authors in the study selection process were solved through discussion and consensus from the supervisors (SS and SKM).

Eligibility Criteria.
Studies were included if they fulfilled the following criteria: (1) e study population size was greater than 100 (2) Participants were diagnosed with COVID-19 by a positive SARS-CoV-2 RT-PCR (severe acute respiratory syndrome coronavirus-2 reverse transcriptase polymerase chain reaction) (3) e population was categorized into asthmatic and nonasthmatic or at least specified asthma in the study (4) Data were provided on the medical outcomes of COVID-19 hospitalized patients including ICU admission, intubation, and death e following criteria were the exclusion criteria of our study: (1) Studies that did not show the prevalence or did not specify asthma in hospitalized COVID-19 patients (2) Articles whose full text was not accessible in English (3) Studies that only included the pediatric population, geriatric population, or pregnant women (4) Other articles such as case reports, editorials, review articles, case series, and perspectives

Data Extraction and Quality Assessment.
Two investigators AB and GD manually extracted the data into a prespecified data collection form consisting of the following variables: author, study design, the country where the study was conducted, sample size, age, sex, events of ICU admission, events of intubation, and events of death. e extracted data were tabulated in Microsoft Excel ® 2019 version (Microsoft Corporation).
For assessing the quality of the studies, the Newcastle-Ottawa Scale (NOS) for nonrandomized studies was used. e NOS is a scoring system of studies based on the fulfillment of a researcher's aim in 3 specific domains, selection, comparability, and outcome, in which stars are assigned as points [14]. e scoring was performed by two investigators (AB and GD). e total score was then assessed where 7-9 was considered a high-quality study with a low risk of bias, 4-6 as high risk of bias, and 0-3 as very high risk of bias. Any discrepancies during the risk of bias assessment were solved by the consensus of supervisor SS.

Outcomes of Interest.
e primary outcome of interest was to assess whether asthmatic patients with COVID-19 had an increased risk of ICU admission, intubation, and mortality when compared to nonasthmatic patients with COVID-19.

Statistical Analysis.
Meta-analysis of the extracted data was carried out by two investigators (AB and AS) using software R version 4.1.3. Effect sizes on events of ICU admission, intubation, and death were reported as odds ratio (OR) and were compared between the two populations: asthmatic and nonasthmatic under the following headings: (1) Risk of ICU admission (2) Risk of intubation (3) Risk of mortality Heterogeneity was assessed with Cochrane's Q test and I 2 statistic where values < 25%, 25%-50%, and >50% represented low, moderate, and high heterogeneity, respectively. Considering the high heterogeneity between the studies, a random-effects model was adopted to estimate the pooled OR under 95% confidence interval (CI), and forest plots were created for interpretation. "tau" was estimated using the DerSimonian and Laird method. In addition, sensitivity analysis was conducted to evaluate the stability of the outcome and was performed by excluding one study at a time. p < 0.05 was considered statistically significant.

Study Selection.
e literature search retrieved 3,208 articles. After the duplicates were removed, the remaining articles were screened by title and abstract followed by fulltext screening, and finally, 19 studies that fulfilled the inclusion criteria were included for qualitative as well as quantitative synthesis. e full study selection is displayed in Figure 1.

Study Characteristics.
e descriptive characteristics of the included studies are displayed in Table 1. ere were a total of 289,449 participants in the included studies, and almost all of them were older than 15 years. COVID-19

Quality Assessment.
e result of the quality assessment among the studies is shown in Table 2. All the studies were high-quality ones ranging from 7 to 9. e mean score was 8.10. Figure 2 summarizes the quality assessment of the studies. Sensitivity analyses that excluding each study one at a time had no significant effect on the overall estimates.

Clinical Outcomes of Included Studies.
e outcomes of ICU admission, intubation, and death in each study are shown in Table 3. e rates in each study varied but correlated.

Risk of ICU Admission.
e number of studies that reported the ICU admission rates was 11. e pooled odds ratio (OR) was 1.25 (I 2 � 82%, X 2 � 55.13, p < 0.01, and CI � 0.90-1.74) (Figure 3). According to the statistics, the risk of being admitted to the ICU if hospitalized due to COVID-19 is statistically insignificant compared to individuals who do not have asthma.

Risk of Intubation.
e number of studies that reported the intubation rates was 11. e pooled odds ratio (OR) was    (Figure 4). e statistics showed that although the p value is less than 0.01, asthma did not significantly increase the risk of being intubated due to COVID-19 due to lower odds ratio.

Risk of Mortality.
e number of studies that reported the mortality rates was 18. e pooled odds ratio (OR) was 0.90 (I 2 � 88%, X 2 � 146.96, p < 0.01, and CI � 0.63-1.27) ( Figure 5). e statistics showed that asthma in hospitalized patients was not statistically associated with an increased risk of mortality due to COVID-19 due to lower odds ratio.

Discussion
Our study aimed at evaluating the risk of poor prognosis in COVID-19 in patients with preexisting asthma. Few studies reported in favor of poor prognosis of COVID-19 in asthmatic patients [18,22,26,28,31]. However, other scientific observations have reported conflicting results [15-17, 19-21, 23-25, 27, 29, 30, 32, 33]. Our meta-analysis did not identify asthma as a significant risk factor in producing high severity and mortality from SARS-CoV-2. Asthma is a disease that has been shown to be acutely exacerbated by respiratory viral infections [34], but it is unclear on which viruses are involved and how severe the exacerbation is.
Branco et al. [35] have explained the possible role of angiotensin-converting enzyme-2 (ACE-2) receptor expression behind the lowered risk of severity in asthma. SARS-CoV-2 gets access to the host cell when its spike protein binds to the ACE-2. ACE-2 is largely expressed in the lungs and less in other organs such as the heart and the kidneys [36], and this can explain the respiratory involvement in SARS-CoV-2 infection. eoretically, it seems that the susceptibility of COVID-19 also depends on ACE-2 expression, and the susceptibility can be altered by either upregulation or downregulation of the receptor. Type I and Type II interferons (IFNs) are known to upregulate ACE-2 Bloom   Interdisciplinary Perspectives on Infectious Diseases expression. However, the damaged IFN responses in the asthmatic status confer to downregulation of the receptor, hence limiting the invasion of SARS-CoV-2 into the host cell [37], and this could probably explain the lowered risk. In contrast to this fact, Kaur et al. [38] showed that ACE-2 possesses a protective effect in lung pathology and its downregulation might compromise its protective effect. is suggests that ACE-2 downregulation in asthmatics is not the sole cause behind the protective mechanism, and in contradiction, it can worsen any lung pathology. According to Jeon et al. [39], the inhaled corticosteroid (ICS) therapy given to asthmatics might have beneficial effects on COVID-19, thus reducing the susceptibility. e nature of asthma either allergic or nonallergic is also found to be involved in minimizing the risks, and the allergic nature seemed to be in favor of minimal risk [40]. e phenotype of asthma may have significantly different COVID-19 prognosis as shown by Bloom et al. [41]. People with moderate to severe forms of asthma are more likely to have a poorer prognosis than people with mild forms [42]. Although vaccination programs have been going on, COVID-19 cases are still rising all across the globe and also is the prevalence of asthma due to increased air pollution. erefore, the actual mechanism is essential to be established from more observations, studies, and analyses so that COVID-19 and asthma can be made to discontinue going side by side in causing more fatalities.
e main strength of our study is that a large population is included from follow-up cohort studies to cross-sectional studies, and the pooled outcome can apply to the general population. ere are a few limitations of our study: First is that the type of asthma, allergic or nonallergic, and status could not be accessed. Secondly, the asthma severity status of the patient was not taken into consideration. irdly, we could not access the ICS therapy status of the population.
Fourthly, the publication bias of the studies was not accessed, and lastly, insufficiency in the analysis might be created due to the potential omission of studies that might have valuable data.

Conclusion
Asthma was not significantly associated with a higher risk of ICU admission, intubation, and risk of mortality. However, the focus on COVID-19 and asthma should not be withdrawn unless more studies are conducted which provide stronger evidence that asthma is not a significant risk factor in the case of COVID-19. Individuals with asthma, to an extent, can be assured towards their well-being during the pandemic but should never compromise on safety and preventive measures.

Data Availability
All the required information is included within the article.

Conflicts of Interest
e authors declare no conflicts of interest.

Authors' Contributions
AB, GD, and SS wrote the original manuscript, reviewed, and edited the manuscript. SKS, SKM, and AS reviewed the manuscript and reviewed for publication.