Prognosis of COVID-19 in respiratory allergy: a systematic review and meta-analysis

Background Do underlying allergic respiratory diseases such as asthma and rhinitis predispose to a severe coronavirus (COVID-19) infection? We conducted this systematic review to map out and synthesize evidence of published literature. Main body of the abstract We searched five bibliographic databases for articles published between 1 January and 15 November 2020 using keywords: “COVID” AND “Allergic disease,” “Prognosis and COVID-19,” “SARS-CoV-2,” “Asthma,” “Allergic rhinitis.” We synthesized 32 eligible articles from a total of 11,376 articles retrieved from the search process. The profile of allergic respiratory conditions was identified, and only seven studies reported on the treatment administered. No significant difference was observed concerning the prevalence of COVID-19 in individuals with allergic asthma and those with non-allergic asthma (RR = 0.61, p = 0.08). The mortality rate significantly decreased in COVID-19-infected patients with asthma than patients without asthma (RR = 0.63, p = 0.04). Short conclusion There is little evidence available on the role of asthma medications and risk factors influencing the prognostic outcomes for COVID-19 individuals with respiratory allergies, which invites further research.


Background
Respiratory allergy, which infers that IgE-mediated allergic reaction is the major underlying pathophysiology in the upper and lower airways, includes allergic rhinitis and asthma [1][2][3]. In allergic individuals, airways exposure to an allergen will provoke allergic rhinitis and asthmatic reaction [4]. As is typical of most respiratory viruses, the main entry point in the human body by the on-going novel coronavirus disease (COVID- 19), announced a global pandemic, is through the nose and nasopharynx airway passage [5]. The main clinical features of COVID-19 are such that respiratory allergic diseases like allergic rhinitis and asthma mimic symptoms of COVID-19, runny nose and headache, are common symptoms of allergic rhinitis, while cough and dyspnea are shared with asthma [6]. Furthermore, one of the prevailing comorbidity conditions identified in individuals infected with COVID-19 is chronic respiratory diseases like respiratory allergies [3].
The chronic allergic disease is linked to the tissue remodeling process, and persistent inflammation with characteristic CD4 T helper 2 (Th2) polarization can impair the efficient antiviral immune response [7]. In that regard, Th2 cytokines have been implicated in the viral progression due to their suppressive effect on physical, humoral barriers against viruses [8]. Further findings have shown the role of Th2 cytokines in coronavirus recognition and infection through modulation of the
However, it is still unclear whether respiratory allergies such as asthma and rhinitis predispose one to rapid infection with COVID-19, or whether COVID-19 raises the risk of distressing respiratory allergies [11]. In addition to this research gap on the causal relationship between COVID-19 and respiratory allergies, there is currently no internationally approved therapies or vaccine for clinical trials that can be used to effectively manage COVID-19 infection particularly in adults and children with respiratory allergies [12]. Although informed severity of COVID-19 in children is minimal compared to adults, there is no evidence that allergic rhinitis and asthma medicines currently available, including inhaled corticosteroids (ICSs), antihistamines, and bronchodilators, increase the severity of COVID-19 infection in both adults and children with respiratory allergies [11].
Likewise, there is limited published evidence on the prognostic outcomes for COVID-19 in individuals with respiratory allergies [12]. One of the few available evidences is that from a nationwide cohort study from South Korea, which demonstrated that both allergic rhinitis and asthma were associated with worse clinical findings in individuals infected with COVID-19. Remarkably, patients with non-allergic asthma had a greater risk of testing positive for SARS-CoV-2 test and having a severe prognosis than patients with allergic asthma [13]. Given these uncertainties and limited evidence on clinical outcomes for COVID-19 in individuals with respiratory allergies, we conducted this systematic review to map out evidences and report findings from the synthesis of published literatures. Our review question and objective are outlined below.

Review questions
1. Does underlying respiratory allergic disease increase risk of COVID-19 infection? 2. What are the prognostic outcomes of COVID- 19 infection in individuals with respiratory allergic diseases? Does Allergy medication affect the prognostics?

Main objective
To determine risk factors for COVID-19 and the prognostic outcome in patients with respiratory allergic conditions.

Study design
This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [14] and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) [15] guidelines. The registration number for this review protocol in the International Prospective Register of Systematic Reviews (PROSPERO) is CRD42020198329.

Search sources and strategy
We carried out a comprehensive search on PubMed/ MEDLINE, Web of Science, Google Scholar, and EBSCO using a search strategy that was developed by two of our reviewers (AAES and BA). The search strategy contained medical subject headings (MeSH) and keywords that include "COVID" AND "Allergic disease, " "Prognosis and COVID-19, " "2019-nCoV, " "coronavirus, " "SARS-CoV-2, " "Asthma, " "Allergy, " "Allergic rhinitis, " and "COPD". The time frame for the search process was between 1 January 2019 and 15 November 2020.

Database screening
The database retrieved from the search process was reviewed for the removal of duplicates by AAES. The initial search process was conducted in June 2020 and thereafter, another search was conducted 15 November 2020. Two other authors (AS and AH) independently carried out the title and abstract screening of the articles in the first database while AAES and RA independently screened the newly retrieved database. To ensure that the methodological rigor is maintained during the screening process, NBHD independently reviewed the database after the title and abstract screening has been carried out. Lastly, full text of identified eligible studies from the title and abstract screening process were evaluated to determine articles were finally selected for data synthesis.

Study selection process
The titles and abstracts were screened and evaluated for selection into the study using our eligibility criteria which included the population (patients with respiratory allergic conditions infected with COVID-19), exposure (respiratory allergic diseases and their medication), comparison (if data available-compare outcome among COVID-19 infected individuals with or without respiratory allergy diseases), and outcomes (risk factors for COVID-19 and prognostic outcomes) (PECO) framework. To suit the context of our study, we replaced I (Intervention) in the usual PICO with E (exposures). In addition to the PECO inclusion criteria, only peer-reviewed published articles irrespective of language were included. Study designs of articles selected for further review and synthesis included case reports, case series, case-control, cross-sectional, cohort studies, and randomized control trials. Primary articles deemed eligible were also identified from the results section of systematic reviews in the database and selected for further review in our study. Articles were excluded if they involved other types of allergies (food allergy, drug allergy, skin allergy) and articles (reviews, book chapters, editorials, letters, and conference abstracts).

Quality assessment/critical appraisal
Two reviewers independently evaluated the quality of the eligible articles using the appropriate quality assessment tools for each study design of these articles. The NIH Quality Assessment Tool for observational studies [16] was used for the study that was case series, casecontrol, cross-sectional, and cohort. Furthermore, the Joanna Briggs Institute (JBI) checklist [17] was used to appraise the case reports. Other two reviewers (KEO and NBHD) reviewed the critically appraised articles for any discrepancies. There were no disagreements between the reviewers during the assessment process.

Data extraction
The data extraction process was done according to the list of items detailed in the design in a data extraction rubric. The data extracted include author, year of publication, geographical setting, study objectives, study design, study population such as respiratory allergic patients, sample size, treatment for COVID-19 and respiratory allergy, and treatment outcomes/useful statistical findings in the study. There were no scenarios of missing information or difficulty with the retrieval of full text for eligible articles. The PRISMA flow diagram ( Fig. 1) provides summaries of the methodological steps performed in this review.

Data synthesis
The data synthesis first involved a summary of findings synthesized from the data extracted from eligible articles and presented in a tabular form ( Tables 1 and 2). To further quantitatively determine the prognosis of COVID-19 in patients with respiratory diseases, we carried out a meta-analysis to report point estimates and the confidence interval. The meta-analysis was performed using a random effects model because of heterogeneity in the eligible studies that were synthesized. Heterogeneity of individual studies was evaluated using the I 2 statistics and was graphically presented using a forest plot.

Results
The literature search retrieved 11,376 articles and 4541 duplicate studies were removed. After screening of titles and abstracts of the total 6835 articles after duplicates have been removed, we excluded 6487 studies that were not relevant to our inclusion criteria. We further conducted a full-text screening of the remaining 348 articles and, this resulted in the identification of 32 studies as eligible for inclusion in our systematic review (Fig. 1).

Characteristics and quality of included studies
The summary and baseline characteristics of synthesized studies and the therapeutic management for respiratory allergic patients infected with COVID-19 are shown in Tables 1 and 2, respectively. According to the NIH Quality Assessment tool [16], the quality assessment of the included studies ranged between good and fair quality.

The prevalence of respiratory allergy in COVID-19 patients
The prevalence of asthma in COVID-19 patients more than 11 Fig. 4.

Principal findings
The present systematic review collects evidence from 32 studies that provide information about the prognostic outcome of COVID-19 in respiratory allergic patients (asthma & allergic rhinitis. The pooled results display no significant difference between the prevalence of COVID-19 with allergic asthma and non-allergic asthma. Asthma is characterized by chronic inflammation, hyper responsiveness of respiratory airways, mucus overproduction, and remodeling [49]. Allergy has been involved in 50-80% of asthma and the roughly 50% of severe asthma [50], though non-allergic asthma has been implicated in 10-33% of asthmatic individuals. The mechanism of allergic asthma has largely been associated with TH2 inflammation that is exemplified by high levels of eosinophils, IgE, and cytokines, such as IL-4, IL-5, IL-13, and IL-9 [51]. Compared with this allergic mechanism, TH1 response which involves the stimulation of neutrophils and mast cells has been characterized nonallergic asthma [52]. Together respiratory infections, failure in resolution of inflammation, and stimulation of IL-17 pathway attribute to neutrophilic inflammation [53]. In the included Korean nationwide cohort, allergic asthma patients were not diagnosed by their medical history, including laboratory data (e.g., IgE levels) but they were defined by International Classification of Disease codes, which may have miscaptured data, and allergic asthma was demarcated as asthma with at least one further allergic disorder (atopy or allergic rhinitis), while asthma without any atopic disorder was defined as nonallergic asthma [13].

Strengths and limitations
This review affords up-to-date results of the risk of respiratory allergic disease in patients with COVID-19. To the Allergic rhinitis, AR Atopic dermatitis, AD; HT hypertension, DM diabetes mellitus, CAD coronary artery disease, CHD chronic heart disease, COPD chronic obstructive pulmonary disease, CRD chronic renal disease, NR not reported

1.
Aghdam et al 2020 [18] In this case report of a 7-year-old boy who presented with 2 years history of allergic asthma, exposure to inhaled corticosteroids based on this history was reported but duration not specified. During his 8 day hospitalization for COVID-19, there was administration of fluticasone sprays along with intravenous hydrocortisone for at least 6 days.
Discharged and well. Initially, patient responded poorly to treatment until foreign body aspiration was identified.
Other underlying hidden causes other than COVID-19 must not be neglected in patients with concurrent COVID-19 and allergic respiratory conditions like allergic asthma 2.
Barroso et al 2020 [24] In this case series, LABA, SABA and ICS were administered to 11 asthmatic patients out of whom 6 had allergic asthma.
For all 11 asthmatic patients, six had intermittentasthma using short-acting-ß2-agonist and five with moderate-asthma on treatment with long-acting-ß2-agonist combined with inhaled glucocorticoid (LABA/GCI). Two of them with low-dose-LABA/GCI (one had prednisone 5mg/daily for rheumatoid arthritis) and the other three with medium-dose LABA/GCI (one had Antileukotrienes montelukast 10 mg/daily) Only one from the five patients with moderateasthma had good compliance with treatment.
Ten from the eleven had well controlled asthma, and one had partially controlled asthma (mediumdose-LABA/GCI and montelukast). Two (2) patients had an asthma exacerbation on admission for COVID-19. One of them died in ICU due to complication of orotracheal-intubation, a woman of 70 years with allergic moderate-asthma on treatment with medium-dose-LABA/GCI and montelukast, with bad compliance of inhaled treatment and other comorbidities (severe sleep-apneahypopnea-syndrome, obesity); she was treated with LABA-GCI and systemic GC during hospitalization.
The second patient with asthma exacerbation was a woman of 42 years with allergic moderate-asthma and obesity, active smoker, type 2 diabetes, and bad compliance with inhalation therapy; she received inhaled LABA-GCI during hospitalization but not systemic GC. The authors are of the opinion that the prognostic outcome earlier described can be attributed to underlying comorbid conditions these cases had.
They recommended for these findings to be confirmed by cohort studies with larger sample size of respiratory allergic patients with COVID-19.

3.
Barsoum 2020 [19] In this case report of a 12-year-old girl with history of asthma but phenotype not reported, oral corticosteroids was administered the first day she came to the accident and emergency department and later discontinued the next day once the diagnosis of COVID-19 was confirmed.
Case improved and was discharged after 2 days.
Underlying comorbidity such as asthma may increase risk of susceptibility to COVID-19. This is because the oral corticosteroids used to management of asthma prolonged the duration of COVID-19 clearance.
The authors therefore recommend that clinical presentations of COVID-19 in children be critically reviewed to improve treatment outcomes.

4.
Bhatraju et al., 2020 [25] In this case series of 24 critically ill cases, the 3 asthmatic cases received as an outpatient, systemic glucocorticoids for a presumed asthma exacerbation before becoming critically ill.
These 3 patients then presented to the hospital again, with severe respiratory failure requiring invasive mechanical ventilation.
The implications of this are uncertain and they recommend further research is necessary to determine the role of systemic glucocorticoids in patients with COVID-19 infection.

5.
Grandbastien et al., 2020 [35] 12 patients were not received any inhaled corticosteroid, and 11 patients were received inhaled corticosteroids combined with bronchodialators (only 1 patient was treated with biotherapy and oral corticosteroids).
Among patients with asthma, 14 patients were well controlled, 6 patients were partially controlled, and 2 patients were noncontrolled.
This suggests that the risk factors for hospitalization in their patients were related more to the risk factors of SARS-CoV-2 pneumonia (e.g., hypertension, obesity, diabetes, tobacco smoke, and obstructive sleep apnea) than to asthma. SARS-CoV-2 pneumonia did not induce the severe asthma symptoms. pollen allergy appeared not to be the reason for asthma exacerbation in our patients.     best of our knowledge, this is the first systematic review focused on the prevalence and outcome of COVID-19 infection in allergic asthma and allergic rhinitis patients. These studies were generated from several countries. However, this meta-analysis had some limitations. First, while only two studies described the phenotype of asthmatic patients, others offered no information. Also, there were no data on asthma control due to a lack of lung function tests which were not performed due to restrictions recommended during COVID-19. Second, data on allergic rhinitis was sourced only from three studies, other studies combined this data with other allergies (food allergy, eczema). Third, there is no detailed information on asthma severity, systemic antihistamines, leukotriene antagonists, and allergen immunotherapy displayed in the identified studies which keep us from further conclusions about their role in COVID-19 prognosis. Fourth, the pooled results of the prevalence of allergic rhinitis and asthma between COVID-19 patients were heterogenous. This might be related to methodological discrepancies in the sampling criteria and study design across the studies included in this part of the analysis.

Comparison with other studies
Regarding the outcome of COVID-19 infection in asthmatics patients, the pooled effect estimate showed that mortality rate was significantly reduced by 30% in COVID-19 patients with asthma than in patients without asthma (RR = 0. 63    were 15.5% and 9.5% respectively. The second explanation is that asthmatic patients were adherent to home isolation precaution during the COVID-19 epidemic as they were known as a high-risk group. Moreover, the hospitalized asthmatic patients were presented early to the hospital and were received an aggressive and timely management. The low prevalence of asthma may be attributed to the low risk of asthmatic patients to COVID-19 infection. Jackson et al. observed that allergic asthmatic patients have reduced expression of ACE2 in respiratory epithelial cells [56]. This can be attributed to the TH2 inflammatory pathway and asthmatic medications (ICS alone or with bronchodilators) which inhibit viral replication [57,58]. These observations may explain the low mortality risk in asthmatics patients with COVID-19 infection. The hospitalization time significantly increased with asthmatic patients more than non-asthmatic patient (MD = 0.88, 95% CI 0.21, 1.56, p = 0.01). Our finding could be clarified by the fact that the symptoms of asthma are exacerbated by respiratory viral infections and the management of asthma becomes more complicated during the COVID-19 pandemic [49]. The respiratory viruses penetrate the epithelium of the respiratory airway and elicit local inflammation, which disrupts the bronchial defense system [59]. There are several cytokines induced by a viral infection that play role in the exacerbation of asthma. Secretion of IL-25 and IL-33 in epithelial cells stimulates TH2 pathways to cause increased mucin production, eosinophilia, and secretion of proinflammatory cytokines (i.e., IL-4, IL-5, and IL-13) [60]. Interferons (IFNs) engage in a pivotal role in antiviral and allergic responses. Earlier studies have revealed that IFN secretion by respiratory epithelial cells and plasmacytoid dendritic cells (pDCs) is reduced in asthma [61]. Additionally, IgE cross-linking reduces antiviral responses through inhibition of pDC maturation, IFN-α response, and TLR-7 upregulation [62].
Concerning hospitalization and mortality in allergic rhinitis patients with COVID-19 infection, we could not do analysis as there is not enough data. Only included cohort studies assumed that allergic rhinitis showed a trend toward lower hospitalization, although not statistically significant (RR, 0.83;95%CI,0.64-1.07) [44]. There were seven synthesized articles that mentioned corticosteroids, bronchodilators, leukotriene antagonist therapy, and their outcome in asthmatic COVID-19 patients. They included 2 case reports and 1 case series that noted that prognostic outcome of COVID-19 infection can be attributed to underlying comorbid conditions and hidden causes other than COVID-19 in patients with concurrent COVID-19 and respiratory allergy [18,19,24]. In a French cohort study, they concluded that that the risk factors for hospitalization in their asthmatic patients were related more to the risk factors of SARS-CoV-2 pneumonia (e.g., hypertension, obesity, sleep apnea diabetes, smoking) than to asthma [63]. Bhatraju et al. could not draw a conclusion regarding the role of systemic glucocorticoids in patients with Covid-19 infection but recommended further research [25]. However, Chhiba et al., 2020, concluded that the use of ICS with or without systemic corticosteroids was not associated with COVID-19-related hospitalization [44].

Conclusions
Based on current findings, there was little evidence on therapeutic management of respiratory allergic patients infected with COVID-19 and the impact on prognostic outcomes. Consequently, it is critical that asthmatic patients should continue to administer medications prescribed to maintain asthma control regularly, in particular, ICS, long-acting bronchodilators, antileukotrienes drugs to avoid complications as increased hospitalization time. Further investigation is needed to determine the role of asthma medications and immunotherapy in the outcome of COVID-19 infection in asthmatic patients. In addition, the association of severe COVID-19 with other risk factors in asthmatic patients should be the topic of future studies.