Controller therapy attenuates asthma exacerbations associated with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children.

Nearly 80% of asthma exacerbations are associated with viral respiratory infections.1Johnston SL Pattemore PK Sanderson G Smith S Lampe F Josephs L et al.Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.BMJ. 1995; 310: 1225-1229Crossref PubMed Google Scholar The first cases of coronavirus disease 2019 (COVID-19) because of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in late December 2019 in Wuhan, People's Republic of China, and was first reported in the United States in January 2020.2Holshue ML DeBolt C Lindquist S Lofy KH Wiesman J Bruce H et al.First case of 2019 novel coronavirus in the United States.N Engl J Med. 2020; 382: 929-936Crossref PubMed Scopus (4109) Google Scholar There were initial concerns that SARS-CoV-2 infection would increase the risk of asthma exacerbations, although earlier studies reported that the SARS-CoV-1 virus did not cause airway hyperresponsiveness or asthma exacerbations.3Van Bever HP Chng SY Goh DY. Childhood severe acute respiratory syndrome, coronavirus infections and asthma.Pediatr Allergy Immunol. 2004; 15: 206-209Crossref PubMed Scopus (46) Google Scholar In addition, studies suggested that there was no increased risk of asthma exacerbations triggered by SARS-CoV-2 infection, but were small in sample size, lacked adequate controls, or were not polymerase chain reaction (PCR) confirmed.4Amat F Delaisi B Labbé JP Leonardi J Houdouin V. Asthma may not be a risk factor for severe COVID-19 in children.J Allergy Clin Immunol Pract. 2021; 9: 2478-2479Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,5Ruano FJ Somoza Álvarez ML Haroun-Díaz E Vázquez de la Torre M López González P Prieto-Moreno A et al.Impact of the COVID-19 pandemic in children with allergic asthma.J Allergy Clin Immunol Pract. 2020; 8 (e1): 3172-3174Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar However, we recently found, using a large nationwide database, that prior SARS-CoV-2 infection, confirmed by PCR, significantly increases the risk of exacerbation rates in children with asthma.6Chou CC Morphew T Ehwerhemuepha L Galant SP. COVID-19 infection may trigger poor asthma control in children.J Allergy Clin Immunol Pract. 2022; 10: 1913-1915Abstract Full Text Full Text PDF PubMed Google Scholar Because respiratory viral-induced asthma exacerbations are attenuated by controller therapy,7Prazma CM Kral KM Gul N Yancey SW Stempel DA. Controller medications and their effects on asthma exacerbations temporally associated with upper respiratory infections.Respir Med. 2010; 104: 780-787Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar it was reasonable to assume, but not previously found, that controller therapy could be effective in attenuating SARS-CoV-2–associated asthma exacerbations. Furthermore, inhaled corticosteroids (ICSs) reduce 2 known binding factors critical in the pathogenesis of SARS-CoV-2 infection: the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2).8Adir Y Saliba W Beurnier A Humbert M. Asthma and COVID-19: an update.Eur Respir Rev. 2021; 30210152Crossref Scopus (41) Google Scholar Nonetheless, a recent study evaluating children with asthma infected with PCR-confirmed SARS-CoV-2 did not find that mono or combination controller therapy attenuated asthma exacerbations, but the study lacked adequate controls.9Chiang CY Ellwood P Ellwood E García-Marcos L Masekela R Asher I et al.Infection with SARS-CoV-2 among children with asthma: evidence from Global Asthma Network.Pediatr Allergy Immunol. 2022; 33: e13709Crossref PubMed Scopus (7) Google Scholar The aim of this study was to establish whether controller therapy could attenuate SARS-CoV-2–associated asthma exacerbations in children with asthma. Data for the retrospective study were retrieved from the Cerner Real-World Data, encompassing 108 health systems across the United States, which identified 61,916 children with asthma aged 2 to 17 years diagnosed by a physician who received a SARS-CoV-2 PCR test from March 2020 to February 2021.10Ehwerhemuepha L Gasperino G Bischoff N Taraman S Chang A Feaster W. HealtheDataLab—a cloud computing solution for data science and advanced analytics in healthcare with application to predicting multi-center pediatric readmissions.BMC Med Inform Decis Mak. 2020; 20: 115Crossref PubMed Scopus (43) Google Scholar The International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, codes used for asthma were 493 and J45, respectively. Baseline demographics, including age, sex, race, body mass index, high-risk asthma (≥2 emergency department [ED] visits, ≥2 oral corticosteroid [OCS] fills, ≥1 hospitalization, any in prior year), and asthma controller therapy, were determined. The study was approved by the Children's Hospital Orange County's Institutional Review Board (IRB #210445). Controller therapy was determined by medications prescribed at least 3 months before SARS-CoV-2 PCR testing, which included ICS, combination ICS andlong-acting β-agonist, leukotriene receptor antagonist, or other therapy (eg, cromolyn sodium, salmeterol xinafoate, theophylline). Patients were divided into 1 of the following 3 groups: no controller therapy, controller monotherapy, or controller combination therapy. Monotherapy included patients on only ICS or leukotriene receptor antagonist. The pre-PCR period was defined as the 6 months prior and the post-PCR period as the 6 months after the month of PCR testing. Asthma exacerbations were assessed by short-acting β-agonist (SABA) fill (≥3 canisters/6 months) rates, number of OCS fills, number of ED visit rates, and number of inpatient hospitalization rates per 1000 patients every 6 months. Rate ratios (RRs) were compared using Poisson regression through generalized estimating equation analyses and specification of exchangeable correlation structure. Analyses were adjusted for age, sex, race, obesity, and high-risk asthma status. All analyses were performed using IBM SPSS Statistics for Windows, Version 29.0 (IBM Corp., Armonk, New York). The children who were COVID positive (COVID+) not receiving controller therapy were significantly more likely to have asthma exacerbations (RR > 1) based on OCS fills (RR = 1.42, P < .05), ED visits (RR = 1.25, P < .05), hospitalizations (RR = 1.42, P < .05), and SABA use (RR = 1.48, P < .05) in the post– vs pre–6-month PCR test period (Table 1). In contrast, children with asthma on controller monotherapy who were COVID+ had decreased asthma exacerbations (RR < 1) with a significant decrease in OCS fills (RR = 0.74, P < .05). Combination therapy resulted in significant decreases in ED visits (RR = 0.38, P < .05), OCS fills (RR = 0.72, P < .05), SABA fills (RR = 0.48, P < .05), and borderline significant reduced hospitalizations (RR = 0.47, P = .06).Table 1Influence of Controller Therapy on Change in Exacerbation Rates Every 6 Months (Post vs Pre) in Children Who Tested COVID+/−, Adjusted for Age, Sex, Race, Obesity, and High-Risk AsthmaaCategorization of potential confounding factors in adjusted model: age (2-4, 5-11, 12-17), sex (male, female), race (African American/Black, Hispanic, White, mixed race, other, unknown), BMI percentile (normal, overweight, obese, unknown), and high-risk asthma (no, yes).COVID+ (N = 7746)COVID− (N = 54,170)Exacerbation MeasureExacerbation rate post- vs pre-COVID testRR (95% CI), P valuebEstimates and test of significance based on Poisson regression using GEE analyses for repeat measures and exchangeable correlation structure.Exacerbation rate post- vs pre-COVID testRR (95% CI), P valuebEstimates and test of significance based on Poisson regression using GEE analyses for repeat measures and exchangeable correlation structure.Hospitalization rate No controller therapycP < .05 (RR significantly differed between COVID+/− groups).1.42 (1.03-1.94)dP < .05 (RR significantly differed within group).0.25 (0.21-0.30)dP < .05 (RR significantly differed within group). MonotherapycP < .05 (RR significantly differed between COVID+/− groups).0.93 (0.56-1.55)0.17 (0.12-0.25)dP < .05 (RR significantly differed within group). Combo therapy0.47 (0.22-1.04)0.13 (0.07-0.24)dP < .05 (RR significantly differed within group).ED visit rate No controller therapycP < .05 (RR significantly differed between COVID+/− groups).1.25 (1.09-1.42)dP < .05 (RR significantly differed within group).0.69 (0.65-0.73)dP < .05 (RR significantly differed within group). MonotherapycP < .05 (RR significantly differed between COVID+/− groups).0.82 (0.54-1.24)0.37 (0.31-0.45)dP < .05 (RR significantly differed within group). Combo therapy0.38 (0.18-0.83)dP < .05 (RR significantly differed within group).0.47 (0.33-0.66)dP < .05 (RR significantly differed within group).OCS fill rate No controller therapycP < .05 (RR significantly differed between COVID+/− groups).1.42 (1.26-1.59)dP < .05 (RR significantly differed within group).0.82 (0.79-0.86)dP < .05 (RR significantly differed within group). MonotherapycP < .05 (RR significantly differed between COVID+/− groups).0.74 (0.56-0.97)dP < .05 (RR significantly differed within group).0.43 (0.38-0.48)dP < .05 (RR significantly differed within group). Combo therapycP < .05 (RR significantly differed between COVID+/− groups).0.72 (0.49-1.07)0.34 (0.27-0.42)dP < .05 (RR significantly differed within group).SABA (≥3 fills) rate No controller therapycP < .05 (RR significantly differed between COVID+/− groups).1.48 (1.11-1.97)dP < .05 (RR significantly differed within group).0.87 (0.78-0.98)dP < .05 (RR significantly differed within group). MonotherapycP < .05 (RR significantly differed between COVID+/− groups).0.70 (0.48-1.03)0.35 (0.29-0.42)dP < .05 (RR significantly differed within group). Combo therapy0.48 (0.25-0.91)dP < .05 (RR significantly differed within group).0.32 (0.23-0.43)dP < .05 (RR significantly differed within group).Abbreviations: BMI, body mass index; CI, confidence interval; combo, combination; COVID, coronavirus disease; COVID−, COVID negative; COVID+, COVID positive; ED, emergency department; GEE, generalized estimating equation; OCS, oral corticosteroid; RR, rate ratio; SABA, short-acting β-agonist.NOTE. Number of patients in each controller medication group (no controller therapy, monotherapy, combo therapy): COVID+ (n = 7151, n = 483, n = 112); COVID− (n = 49,811, n = 3617, n = 742).a Categorization of potential confounding factors in adjusted model: age (2-4, 5-11, 12-17), sex (male, female), race (African American/Black, Hispanic, White, mixed race, other, unknown), BMI percentile (normal, overweight, obese, unknown), and high-risk asthma (no, yes).b Estimates and test of significance based on Poisson regression using GEE analyses for repeat measures and exchangeable correlation structure.c P < .05 (RR significantly differed between COVID+/− groups).d P < .05 (RR significantly differed within group). Open table in a new tab Abbreviations: BMI, body mass index; CI, confidence interval; combo, combination; COVID, coronavirus disease; COVID−, COVID negative; COVID+, COVID positive; ED, emergency department; GEE, generalized estimating equation; OCS, oral corticosteroid; RR, rate ratio; SABA, short-acting β-agonist. NOTE. Number of patients in each controller medication group (no controller therapy, monotherapy, combo therapy): COVID+ (n = 7151, n = 483, n = 112); COVID− (n = 49,811, n = 3617, n = 742). Children with asthma who were COVID negative (COVID−) had a RR less than 1 without controller therapy but seemed to benefit from controller therapy, where RRs were almost half for those on any type of controller therapy vs no controller therapy (Table 1). The COVID− group has a post-/pre-PCR IRR less than 1 presumably because of the stay-at-home and mask mandates because of avoiding common viral asthma triggers.6Chou CC Morphew T Ehwerhemuepha L Galant SP. COVID-19 infection may trigger poor asthma control in children.J Allergy Clin Immunol Pract. 2022; 10: 1913-1915Abstract Full Text Full Text PDF PubMed Google Scholar We found that prior SARS-CoV-2 infection (COVID+) is associated with asthma exacerbations and that controller therapy is associated with decreased exacerbations in a treatment step-dependent manner. The effect of SARS-CoV-2 was best revealed by comparing the exacerbation rate for the 6-month post- vs pre-PCR testing for patients in the COVID+ group not receiving controller therapy, where the post- vs pre-PCR RR was more than 1 for all exacerbation metrics. The possible benefits of controller therapy were most evident by our observation that once children were on controller therapy, the RR was less than 1 for both the mono and combination therapies, becoming statistically significant for those on combination therapy. ICS therapy is considered first-line therapy for children with persistent asthma, and it was strongly recommended during the COVID-19 pandemic to prevent exacerbations. However, the potential immunosuppressive effect of ICS, which could promote viral replication and increase the risk of secondary infection, initially raised concerns during the pandemic. Therefore, it was most reassuring that our study revealed that controller therapy was associated with reduced asthma exacerbations in those COVID+ similar to those COVID−. Whereas, without controller therapy, increased exacerbation rates were observed in those COVID+ compared with a decreased rate in those COVID−. Limitations include the EMR retrospective data analysis, which limited the proof of causation of the attenuating effect of controller medication on COVID-19–induced exacerbations. The 6-month post–COVID-19 PCR testing period could also be a limitation, as other causes could have resulted in an asthma exacerbation; although, this limitation would apply to all 3 treatment groups. The strength of our study is the large sample representing diverse ethnic populations across the United States in multiple health care systems. Comparing patients with asthma who were COVID+ with those who were COVID−, we found that prior SARS-CoV-2 infection is associated with asthma exacerbations and that controller therapy attenuates this effect on the exacerbation rate in children with asthma. We thank the CSO Small Grants Program of the CHOC Children's Research Institute at the CHOC Children's Hospital of Orange County for their support of this study. The authors have no conflicts of interest to report. This work was supported by the CHOC Research Institute at CHOC Children's Hospital of Orange County (grant 16993001).