key: cord-340486-wydlqq2z
authors: Grandbastien, Manon; Piotin, Anays; Godet, Julien; Abessolo-Amougou, Ines; Ederlé, Carole; Enache, Irina; Fraisse, Philippe; Tu Hoang, Thi Cam; Kassegne, Loic; Labani, Aissam; Leyendecker, Pierre; Manien, Louise; Marcot, Christophe; Pamart, Guillaume; Renaud-Picard, Benjamin; Riou, Marianne; Doyen, Virginie; Kessler, Romain; Fafi-Kremer, Samira; Metz-Favre, Carine; Khayath, Naji; de Blay, Frédéric
title: SARS-CoV-2 pneumonia in hospitalized asthmatic patients did not induce severe exacerbation
date: 2020-06-27
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.06.032
sha: 
doc_id: 340486
cord_uid: wydlqq2z

Abstract Background Viral infections are known to exacerbate asthma in adults. Previous studies have found few asthmatics among SARS-CoV-2 pneumonia cases. However, the relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known. Objective We assessed the frequency of asthma exacerbation in asthmatic patients hospitalized for SARS-CoV-2 pneumonia and compared symptoms laboratory and radiological findings in asthmatic and non-asthmatic patients with SARS-CoV-2 pneumonia. Methods We included 106 patients between March 4 and April 6, 2020, who were hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 were asthmatics. To assess the patients’ asthma status, three periods were defined: the last month before the onset of COVID-19 symptoms (p1), pre-hospitalization (p2) and during hospitalization (p3). Severe asthma exacerbations were defined according to GINA guidelines during p1 and p2. During p3, we defined severe asthma deterioration as the onset of breathlessness and wheezing requiring systemic corticosteroids and inhaled beta-2-agonist. Results We found no significant difference between asthmatics and non-asthmatics in terms of severity (length of stay, maximal oxygen flow needed, non-invasive ventilation requirement and ICU transfer). 52.2% of the asthmatic patients were Gina 1. One patient had a severe exacerbation during p1, two patients during p2, and five patients were treated with systemic corticosteroids and inhaled beta-2-agonist during p3. Conclusion Our results demonstrate that asthmatic patients appeared not to be at risk for severe SARS-CoV-2 pneumonia. Moreover, SARS-CoV-2 pneumonia did not induce severe asthma exacerbation.

Background: Viral infections are known to exacerbate asthma in adults. Previous studies 48 have found few asthmatics among SARS-CoV-2 pneumonia cases. However, the 49 relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known. 50 51 Objective: We assessed the frequency of asthma exacerbation in asthmatic patients 52 hospitalized for SARS-CoV-2 pneumonia and compared symptoms laboratory and 53 radiological findings in asthmatic and non-asthmatic patients with SARS-CoV-2 pneumonia. 54 55 Methods: We included 106 patients between March 4 and April 6, 2020, who were 56 hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 were 57 asthmatics. To assess the patients' asthma status, three periods were defined: the last 58 month before the onset of COVID-19 symptoms (p1), pre-hospitalization (p2) and during 59 hospitalization (p3). Severe asthma exacerbations were defined according to GINA guidelines 60 during p1 and p2. During p3, we defined severe asthma deterioration as the onset of 61 breathlessness and wheezing requiring systemic corticosteroids and inhaled beta-2-agonist. 62 63 Results: We found no significant difference between asthmatics and non-asthmatics in 64 terms of severity (length of stay, maximal oxygen flow needed, non-invasive ventilation 65 requirement and ICU transfer). 52.2% of the asthmatic patients were Gina 1. One patient 66 had a severe exacerbation during p1, two patients during p2, and five patients were 67 treated with systemic corticosteroids and inhaled beta-2-agonist during p3. abdominal pain, and recently anosmia, dysgeusia (4) and confusion (5) . Many patients also 106 develop lymphopenia and pneumonia with characteristic pulmonary ground glass opacity 107 changes on chest CT (6, 7) . 108

The pathophysiology mechanisms are not yet well characterized. After inhalation of SARS-110

CoV-2 through aerosolized uptake, the virus likely binds to epithelial cells from the nasal 111 cavity, starts replicating and reach the lower respiratory tract. The main receptor for the 112 SARS-CoV2 spike is the Angiotensin converting enzyme 2 (ACE2) that is expressed in several 113 organs such as the lung, heart, kidney, intestine and endothelial cells. For about 20% of the 114 infected patients, the disease will progress to a pneumoniae through propagation of SARS-115

CoV within type II cells through ACE2 and will compromise the alveolo-capilar space. It may 116 result in a diffuse alveolar damage and fibrosis. A hyperinflammatory syndrome called 117 "cytokine storm" consisting in fever, cytopenias, hyperferritinaemia, diffuse alveolar damage 118 and hypercytokinaemia, may occur during this phase. It may lead to multiorgan failure and 119 high rate of mortality. From an immunologic point of view it is characterized by an increased 120 interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 121 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and 122 tumour necrosis factor-α (8-11 To assess the patient's asthma status, we defined three periods. The first period was the 184 last month before the onset of COVID-19 symptoms (p1). The second period was the pre-185 hospitalization period between the beginning of the SARS-CoV-2 infection symptoms and 186 the first day of hospitalization (p2). The third period was during hospitalization (p3). 187

Severe asthma exacerbations were assessed during p1 and p2 periods, and defined as a 188 deterioration in asthma resulting in hospitalization or emergency room treatment or the 189 need for oral steroids for more than 3 consecutive days (19) 190

During the hospitalization (p3), we defined symptoms corresponding to asthma as We summarized continuous measures as medians and interquartile ranges (IQRs) and 236 categorical variables as frequencies and proportions. We tested comparisons between 237 asthmatic and non-asthmatic patients using Fisher's exact or chi-squared tests for 238 categorical variables and the Wilcoxon rank-sum test for numerical variables. Due to the 239 absence of randomization and to adjust for possible confusing factors, we performed 240 multivariable logistic regression analysis using a binomial generalized linear model to 241 determine the adjusted odds ratio (aOR). Variables with p < 0.1 in the univariate analysis 242

were selected as independent variables in the multivariate model. To evaluate whether 243 asthma is associated with and a risk factor for severe COVID-19 outcomes, we used 244 propensity scores to adjust for confounding variables. The propensity score allows analyzing 245 an observational nonrandomized study so that it mimics some of the particular 246 characteristics of a randomized controlled trial as it accounts for systematic differences in 247 baseline characteristics between asthmatic and non-asthmatic subjects when estimating the 248 effect of asthma on severe COVID-19 outcomes. Propensity scores were generated by 249 multiple logistic regression using known risk factors for COVID-19 (age, sex, hypertension, diabetes, BMI ≥ 30kg/m 2 and heart failure) as independent variables. Finally, we used a 251 generalized linear mixed-effect models with subjects as a random effect to evaluate change 252 in asthma exacerbation (logistic regression) and change in eosinophil counts (Gaussian 253 regression) during the three different time periods. Statistical analysis were performed using 254 R software version 3.6.3 (https ://cran.rproject.org). P < 0.05 was considered significant. Table I . The global severity of lung parenchyma involvement was similar in the two groups. In a 277

propensity score adjusted analysis, being asthmatic was not a risk factor for having more 278 The clinical characteristics of asthmatic patients are described in Table III . We found that 284 52.2% of the patients were Gina 1 and were not receiving any inhaled corticosteroid, and 285 39.1% were Gina 4 and 5. Only one patient was treated with biotherapy and oral 286 corticosteroids. Among asthmatic patients, 63.6% were well-controlled and 23.4% were 287 partially controlled. Eleven of the 23 asthmatic patients had at least one severe 288 exacerbation in the previous year, and 68.2% were considered allergic asthma according to In contrast to other respiratory viruses, SARS-CoV-2 may not be a risk factor for severe 344 asthma exacerbation. Several hypotheses can be raised. 345

Firstly, SARS-CoV-2 may be a disease mainly of the upper and lower respiratory tract, causing 346 ENT infection and pulmonary lesions. Angiotensin-converting enzyme 2 (ACE2) has been 347 shown to be the functional receptor of SARS-CoV-1 (28). This receptor is abundantly 348 expressed in type I and type II pneumocytes whereas bronchial epithelial cells exhibit only 349 weak staining (29,30). ACE2 has also been identified as the receptor of novel SARS-CoV-2 350 (31), indicating that alveolar pneumocytes in the lung could be a possible entry site for SARS-351

CoV-2. However, ACE expression is not limited to the lungs, and extrapulmonary spread of 352 SARS-CoV in ACE2 positive tissues has been observed. The same can be expected for SARS-353

CoV-2 (32). This is in accordance with the suggestion that COVID-19 seems to induce a 354 specific pathology of the alveolo-capillary space leading to severe altered gas exchanges and 355 pulmonary-specific vasculopathy (33,34). Very recently it has been suggested that ACE2 356 expression in nasal epithelium was inversely related to allergic sensitization (35). be an indicator of COVID-19 improvement. In their study, during the period of lower 363 eosinophil count, the SARS-CoV-2 RNA test remained positive, and after the eosinophil 364 count returned to normal, the SARS-CoV-2 RNA test was negative within 5 days. The 365 normalization of eosinophil count is also associated with improved symptoms and chest X-366 rays (36). However, that previous study included non-asthmatic patients. In our patients, 367

we did not find any significant difference in eosinophil counts between asthmatic and non-368 asthmatic patients. 369

The role of eosinophils in asthma exacerbation is widely published. Since the first paper on The third hypothesis is on the role of inhaled corticosteroids. In in vitro models, inhaled 378 corticoids alone or in association with bronchodilators inhibit human coronavirus (HCoV)-379 229E replication, partly by inhibiting receptor expression and/or endosomal function and 380 reducing cytokine production (IL-6, IL-8). This suggests that these drugs modulate infection-381 induced inflammation in the airways (42). 382 383 Roughly half of our asthmatic patients (52.2%) had GINA 1 asthma and did not use inhaled 384 corticosteroids on a regular basis. 63.6% of them were well-controlled. We did not find any 385 difference between the age of asthmatics and non-asthmatics. Moreover, the classical 386 factors associated with SARS-CoV-2 pneumonia (hypertension, obesity, diabetes) were found 387 in both groups. In contrast, the classical factors responsible for uncontrolled asthma, such as 388 tobacco smoke, obesity and obstructive sleep apnea, were not more frequent in the 389 asthmatic group. This suggests that the risk factors for hospitalization in our patients were 390 related more to the risk factors of SARS-CoV-2 pneumonia than to asthma. 

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Figure 1. Flow chart of patient inclusion 114 patients hospitalized for a suspicion of SARS-CoV-2 pneumonia from

Excluded (n=8): -Negative RT-PCR for SARS-CoV-2 (at least 2 tests; n=4) -Normal chest CT (n=1) -No chest