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New-onset asthma following COVID-19 in adults

2023; Elsevier BV; Volume: 11; Issue: 7 Linguagem: Inglês

10.1016/j.jaip.2023.03.050

2213-2201

Hyun Lee, Bo‐Guen Kim, Sung Jun Chung, Dong Won Park, Tai Sun Park, Ji‐Yong Moon, Tae‐Hyung Kim, Jang Won Sohn, Ho Joo Yoon, Sang‐Heon Kim,

Respiratory Support and Mechanisms

Clinical ImplicationsOur study suggests that a recent coronavirus disease 2019 (COVID-19) infection may rarely cause new-onset asthma, which could be linked to eosinophilic inflammation. Clinicians should consider asthma in the differential diagnosis of subacute or chronic respiratory symptoms following COVID-19 infection. Our study suggests that a recent coronavirus disease 2019 (COVID-19) infection may rarely cause new-onset asthma, which could be linked to eosinophilic inflammation. Clinicians should consider asthma in the differential diagnosis of subacute or chronic respiratory symptoms following COVID-19 infection. Viral infections, including respiratory syncytial virus, rhinovirus, and human metapneumovirus, have been suggested to elevate the risk for the development of incident asthma in children.1Sigurs N. Gustafsson P.M. Bjarnason R. Lundberg F. Schmidt S. Sigurbergsson F. et al.Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13.Am J Respir Crit Care Med. 2005; 171: 137-141Crossref PubMed Scopus (757) Google Scholar,2Coverstone A.M. Wilson B. Burgdorf D. Schechtman K.B. Storch G.A. Holtzman M.J. et al.Recurrent wheezing in children following human metapneumovirus infection.J Allergy Clin Immunol. 2018; 142: 297-301.e2Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Although the relationship between viral infection and new-onset asthma in adults has not been extensively investigated, there have been reports that lower respiratory infections are related to new adult-onset asthma.3Rantala A. Jaakkola J.J. Jaakkola M.S. Respiratory infections precede adult-onset asthma.PLoS One. 2011; 6e27912Crossref PubMed Scopus (43) Google Scholar The risk of new asthma onset was strongly increased in adult patients who had experienced lower respiratory infections in the preceding 12 months,3Rantala A. Jaakkola J.J. Jaakkola M.S. Respiratory infections precede adult-onset asthma.PLoS One. 2011; 6e27912Crossref PubMed Scopus (43) Google Scholar suggesting a causal relationship between viral infection and new adult-onset asthma. It is well known that some patients with coronavirus disease 2019 (COVID-19) have persistent respiratory symptoms (including coughing, dyspnea, or wheezing) even after the viral infection has subsided.4Jung Y.H. Ha E.-H. Choe K.W. Lee S. Jo D.H. Lee W.J. Persistent symptoms after acute COVID-19 infection in omicron era.J Korean Med Sci. 2022; 37: e213Crossref PubMed Scopus (7) Google Scholar However, the development of new-onset asthma after COVID-19 has not been evaluated, even though these respiratory symptoms are very common in asthma. Therefore, we aimed to evaluate whether prior COVID-19 infection was associated with the new development of asthma. Previous COVID-19 diagnosis was determined by the patient’s report of previous COVID-19 diagnosis based on the reverse-transcription polymerase chain reaction or antigen test. This study was approved by the institutional review board of our hospital (approval no.: HYUH-2022-11-056). Between April 1, 2022, and October 30, 2022, 394 patients who had recovered from the acute phase of COVID-19 (at least 7 days after initial diagnosis) visited the pulmonology and allergy outpatient clinic due to respiratory symptoms (eg, coughing, dyspnea, sputum, or wheezing). Of these, 36 patients (9.1%) were suspected of having asthma. After excluding 16 patients diagnosed with asthma before COVID-19 and 3 patients with symptoms suspicious of asthma (eg, wheezing episodes) before COVID-19 infection, we identified 17 people (4.3%) with possible new asthma diagnosis after COVID-19 infection. Of these, 6 patients (1.5%) were confirmed to have asthma using the current diagnostic criteria of asthma.5Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention (2022 update).https://ginasthma.org/gina-reports/Date accessed: December 15, 2022Google Scholar For comparison, we also evaluated the proportion and odds of developing new-onset asthma in patients with no prior COVID-19 infection who were seen in our clinics during the same time frame. Analysis of a matched 1:3 cohort (n = 1,182) by age and sex, showed that COVID-19 infection was associated with higher odds of developing new-onset asthma (odds ratio 4.55; 95% CI 1.29–17.89). Out of the 6 patients with newly diagnosed asthma after COVID-19, 3 were female and their ages ranged from 24 to 71 years. During the acute phase of COVID-19 infection, none of these patients required hospitalization for COVID-19 infection. The time between the COVID-19 and asthma diagnoses ranged from 27 to 271 days. All patients reported steadily worsening respiratory symptoms after COVID-19 infection. The most common symptoms were coughing (n = 6; 100%), followed by sputum production (n = 5; 83.3%), wheezing (n = 5; 83.3%), and dyspnea (n = 3; 50.0%) (Table I). Four patients were diagnosed with asthma based on methacholine provocation testing (MBPT) (a provocation concentration causing a 20% fall in the forced expiratory volume in 1 second [FEV1] from the normal range of 0.77–13.13 mg/mL), and 2 patients were diagnosed with asthma based on documented excessive variability of lung function (ie, a variation in the FEV1 > 12% and > 200 mL between visits in the absence of respiratory infection). Except for 1 patient who had airflow obstruction (postbronchodilator FEV1/forced vital capacity < 0.7 as well as lower limit of normal value), all patients had a normal range of spirometry results. Of 3 patients who had total immunoglobulin E results, 1 had a total immunoglobulin E level greater than 100 IU/mL. Of the 5 patients who underwent environmental skin prick testing or multiple allergen simultaneous testing (AdvanSureTMAlloScreen, LG Chem), 1 patient was sensitized to Dermatophagoides pteronyssinus and D. farinae. Blood eosinophil counts at the time of asthma diagnosis were elevated in all patients (range 297–1,219 cells/μL), and the fractional exhaled nitric oxide level was increased (>20 ppb) in 4 out of 5 patients (Table II). All patients were treated with a medium- or high-dose inhaled corticosteroid/long-acting beta-2 agonist either with or without systemic corticosteroids, and symptoms were substantially improved in all patients.Table IClinical characteristics and treatment of patients with new-onset asthma following COVID-19 infectionCase number1∗Patients 1 and 3 were diagnosed with asthma by a documented excessive variability in lung function variation in FEV1 > 12% and > 200 mL between visits, in the absence of respiratory infections.23∗Patients 1 and 3 were diagnosed with asthma by a documented excessive variability in lung function variation in FEV1 > 12% and > 200 mL between visits, in the absence of respiratory infections.456EthnicityAsianAsianAsianAsianAsianAsianAge, y713646245856SexMaleFemaleFemaleMaleFemaleMaleBody mass index, kg/m220.324.121.631.032.422.0Smoking historyNonsmokerNonsmokerNonsmokerSmokerNonsmokerNonsmokerDate of COVID-19 diagnosisAugust 15, 2021March5, 2022March 21, 2022April 1, 2022April 1, 2022May 15, 2022Date of asthma diagnosisMay 13, 2022April 7, 2022July 25, 2022-May 13, 2022April 28, 2022November 18, 2022Time from the COVID-19 diagnosis to the asthma diagnosis, d271331264227187Comorbidities COPDNoNoNoNoNoNo TuberculosisYesNoNoNoNoNo Previous allergic diseasesNoneNoneAllergic rhinitisAllergic rhinitisNoneAllergic rhinitisRespiratory symptoms CoughingYesYesYesYesYesYes WheezingYesNoYesYesYesYes DyspneaYesNoYesYesNoNo SputumYesYesYesYesNoYesTreatment InhalerHigh-dose ICS/LABAMedium-dose ICS/LABAMedium-doseICS/LABAMedium-dose ICS/LABAHigh-dose ICS/LABAMedium-doseICS/LABA Systemic CSYes, intravenous mPD 62.5 mg for 2 d and then oral PD 40 mg for 3 dNoNoYes,Oral PD 40 mg for 7 dNoNoCOPD, Chronic obstructive pulmonary disease; CS, corticosteroid; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; mPD, methylprednisolone; PD, prednisolone.∗ Patients 1 and 3 were diagnosed with asthma by a documented excessive variability in lung function variation in FEV1 > 12% and > 200 mL between visits, in the absence of respiratory infections. Open table in a new tab Table IIResult of laboratory tests in patients with new-onset asthma following COVID-19 infectionCase number123456LLN of FEV1/FVC∗The LLN for FEV1/FVC was calculated for each subject using the new reference equations by Korean population. These were based on the predicted value – 1.645 × the standard error of the estimate.61.776.073.478.370.666.5LLL of FEV1, L†The LLN for FEV1 was calculated for the mean – 1.645 × the SD by spirometry data of Korean population according to the age groups.1.572.292.063.561.642.32Spirometry during study period, n314432Baseline spirometry‡The first tests were performed at the time of the first visit to the outpatient clinic owing to symptoms after COVID-19 infection. FEV1/FVC %41.775.373.478.378.767.4 FEV1, L1.032.492.073.741.923.63 FEV1%pred31.979.268.583.884.493.9 Post-BD FEV1/FVC42.480.776.583.279.273.3 Post-BD FEV1, L1.082.552.274.111.993.94 Post-BD FEV1%pred33.781.175.191.987.1101.9Post-treatment spirometry FEV1/FVC69.5NA84.481.977.466.0 FEV1, L3.25NA2.654.131.793.55 FEV1%pred101.2NA86.792.678.591.9 Post-BD FEV1/FVC71.1NA87.083.380.372.4 Post-BD FEV1, L3.32NA2.644.331.863.80 Post-BD FEV1%pred103.6NA86.596.981.798.4BDRNegativeNegativeNegativeNegativeNegativeNegativeMBPT (PC20, mg/mL)§Positive MBPT was defined as PC20 < 16 mg/mL.NAPositive (7.17)NAPositive (10.08)Positive (0.77)Positive (13.13)Baseline FeNO, ppb‡The first tests were performed at the time of the first visit to the outpatient clinic owing to symptoms after COVID-19 infection.156NA853913119Posttreatment FeNO, ppb58NA775819105Baseline blood eosinophils, /uL1219597585297510393Total IgE, IU/mLNANANA44.5118.089.6Skin prick testNegativeNANegativeNANegativeNAMASTNANANAPositive for DP and DFNANegativeBD, Bronchodilator; BDR, bronchodilator response; DP, Dermatophagoides pteronyssinus; DF, Dermatophagoides farina; FeNO, fractional exhaled nitric oxide; FVC, forced vital capacity; IgE, immunoglobulin E; LLN, lower limit of normal; MAST, multiple allergen simultaneous test; NA, not available; PC20, provocation concentration causing a 20% fall in FEV1; %pred, % predicted value∗ The LLN for FEV1/FVC was calculated for each subject using the new reference equations by Korean population. These were based on the predicted value – 1.645 × the standard error of the estimate.† The LLN for FEV1 was calculated for the mean – 1.645 × the SD by spirometry data of Korean population according to the age groups.‡ The first tests were performed at the time of the first visit to the outpatient clinic owing to symptoms after COVID-19 infection.§ Positive MBPT was defined as PC20 < 16 mg/mL. Open table in a new tab COPD, Chronic obstructive pulmonary disease; CS, corticosteroid; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; mPD, methylprednisolone; PD, prednisolone. BD, Bronchodilator; BDR, bronchodilator response; DP, Dermatophagoides pteronyssinus; DF, Dermatophagoides farina; FeNO, fractional exhaled nitric oxide; FVC, forced vital capacity; IgE, immunoglobulin E; LLN, lower limit of normal; MAST, multiple allergen simultaneous test; NA, not available; PC20, provocation concentration causing a 20% fall in FEV1; %pred, % predicted value In the era of the COVID-19 pandemic, most studies have focused on the relationship between COVID-19 and the risk of severe COVID-19 in patients with asthma. However, although still struggling with COVID-19 infection, we are now entering the post-COVID-19 era, and many post-COVID-19 patients suffer from respiratory symptoms that mimic asthma. Accordingly, more information is needed on whether COVID-19 infection can trigger new-onset asthma. In our study, all patients reported coughing as their main complaint. Long COVID-19 syndrome involves a variety of new or ongoing symptoms that people experience more than 4 weeks after developing a COVID-19 infection.6Garg M. Maralakunte M. Garg S. Dhooria S. Sehgal I. Bhalla A.S. et al.The conundrum of “long-COVID-19”: a narrative review.Int J Gen Med. 2021; 14: 2491-2506Crossref PubMed Scopus (68) Google Scholar Considering that asthma usually presents as a chronic cough, it is interesting that our patients visited the clinic complaining of persistent coughing, which can be considered a symptom of long COVID-19. In our study, 5 patients with coughing also reported wheezing, so we easily suspected asthma. However, 1 had no wheezing, which made it difficult to appropriately diagnose asthma. Further testing showed a positive MBPT. Although the latter case does not indicate that tests for asthma are mandatory when evaluating coughing after COVID-19, it might be helpful for physicians to recognize that cough-variant asthma can present similarly to long COVID-19 syndrome. If persistent coughing is not improved with symptom-relieving treatment, then asthma may be considered as 1 of the etiologies. Interestingly, in our study, only 1 patient had airflow obstruction, which may suggest that the absence of airflow obstruction cannot rule out post-COVID-19 asthma and also may indicate the important role of MBPT in the diagnosis of post-COVID asthma. Our findings of elevated absolute eosinophil count and fractional exhaled nitric oxide in these patients with newly diagnosed asthma who responded well to inhaled corticosteroids with and without systemic steroids, along with minimal environmental allergens sensitization, indicate a T2-high nonallergic asthma phenotype. In line with our results, previous studies have shown that postviral inflammation in asthma is related to eosinophilic inflammation.7Kim S.R. Viral infection and airway epithelial immunity in asthma.Int J Mol Sci. 2022; 23: 9914Crossref PubMed Scopus (3) Google Scholar The exact mechanism that underlies how COVID-19 infection leads to asthma and which patients are susceptible to asthma is not well understood; however, 1 study reported that COVID-19 patients also could exhibit eosinophil-mediated inflammation.8Kim D.M. Seo J.W. Kim Y. Park U. Ha N.Y. Park H. et al.Eosinophil-mediated lung inflammation associated with elevated natural killer T cell response in COVID-19 patients.Korean J Intern Med. 2022; 37: 201-209Crossref PubMed Scopus (2) Google Scholar In conclusion, our study suggests that recent COVID-19 infection may rarely cause asthma, which might be linked to eosinophilic inflammation. Clinicians should consider asthma in the differential diagnosis of subacute or chronic respiratory symptoms following COVID-19 infection.