key: cord-1028376-3ja88kek
authors: Papadopoulos, Nikolaos G.; Mathioudakis, Alexander G.; Custovic, Adnan; Deschildre, Antoine; Phipatanakul, Wanda; Wong, Gary; Xepapadaki, Paraskevi; Abou‐Taam, Rola; Agache, Ioana; Castro‐Rodriguez, Jose A.; Chen, Zhimin; Cros, Pierrick; Dubus, Jean‐Christophe; El‐Sayed, Zeinab Awad; El‐Owaidy, Rasha; Feleszko, Wojciech; Fierro, Vincenzo; Fiocchi, Alessandro; Garcia‐Marcos, Luis; Goh, Anne; Hossny, Elham M.; Huerta Villalobos, Yunuen R.; Jartti, Tuomas; Le Roux, Pascal; Levina, Julia; López García, Aida Inés; Ramos, Ángel Mazón; Morais‐Almeida, Mário; Murray, Clare; Nagaraju, Karthik; Nagaraju, Major K.; Navarrete Rodriguez, Elsy Maureen; Namazova‐Baranova, Leyla; Nieto Garcia, Antonio; Pozo Beltrán, Cesar Fireth; Ratchataswan, Thanaporn; Rivero Yeverino, Daniela; Rodríguez Zagal, Eréndira; Schweitzer, Cyril E.; Tulkki, Marleena; Wasilczuk, Katarzyna; Xu, Dan
title: Childhood asthma outcomes during the COVID‐19 pandemic: Findings from the PeARL multinational cohort
date: 2021-03-24
journal: Allergy
DOI: 10.1111/all.14787
sha: d7c39a9f94179004f1d6a7e05bba0406821acc62
doc_id: 1028376
cord_uid: 3ja88kek

BACKGROUND: The interplay between COVID‐19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID‐19 pandemic on childhood asthma outcomes. METHODS: The PeARL multinational cohort included 1,054 children with asthma and 505 non‐asthmatic children aged between 4 and 18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID‐19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. RESULTS: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks, and hospitalizations due to asthma, in comparison with the preceding year. Sixty‐six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre‐bronchodilatation FEV(1) and peak expiratory flow rate were improved during the pandemic. When compared to non‐asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits, or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. CONCLUSION: Childhood asthma outcomes, including control, were improved during the first wave of the COVID‐19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID‐19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.

A series of studies have demonstrated that the morbidity from Coronavirus Disease 2019 is lower in children compared to adults. [1] [2] [3] Risk factors for severe disease include older age, male sex, chronic respiratory diseases, diabetes, coronary artery disease, obesity, and ethnicity (black, Asian, and mixed). [4] [5] [6] Chronic respiratory diseases are among these high-risk pre-existing conditions, and asthma represents the majority of such patients. 4, 5, 7 Initial clinical reports did not identify asthma to be over-represented among COVID-19 patients, 8 but severe, uncontrolled asthma is included in most guidance documents among conditions which may increase the risk for severe Analysis in more than 17 million adults and ~11,000 COVID-19-related deaths identified severe asthma (defined as asthma with recent oral corticosteroid use) as a significant associate of COVID-19 death6. It is, however, unclear what is the impact of asthma on the risk of SARS-CoV-2 infection and severeCOVID-19 in children, and what is the impact of COVID-19 pandemic on asthmarelated outcomes in children. Survey data among pediatric asthma specialists suggest that there is no apparent increase in asthmarelated morbidity in children with asthma 10 ; it is even possible that due to increased adherence and reduced exposures due to confinement, such children may have improved outcomes. 10 Furthermore, it is also possible that allergic sensitization can have some protective effect against COVID- 19. 11 However, this needs to be further explored. 12, 13 For the above reasons, Pediatric Asthma in Real Life (PeARL), a think tank initiated by the Respiratory Effectiveness Group (REG), comprising of pediatric asthma experts globally, 14 opted to evaluate the interplay between childhood asthma and the pandemic due to COVID-19 infection in a multinational cohort of children with asthma and non-asthmatic controls. We aimed at assessing asthma activity (asthma control, respiratory infections, asthma attacks, and lung function) during the first months of the COVID-19 pandemic and exploring whether children with asthma had excess morbidity during this period, in comparison with prerecorded historical data.

The primary study objective was to assess differences in the impact of the pandemic on the frequency of upper (URTIs), lower respiratory tract infections (LRTIs), episodes of fever, emergency visits, and hospital admissions between asthmatic and non-asthmatic children. Secondary objectives to evaluate were as follows: (i) the impact of the pandemic on the frequency of asthma attacks, as well as the previously mentioned events among asthmatic children, compared to the baseline frequency of these events, during the preceding year (2019); (ii) the impact of the pandemic on disease control, evaluated using validated asthma clinical questionnaires, among children with asthma, compared to the baseline asthma control, during the preceding year (2019).

The impact of the COVID-19 pandemic on disease activity in children with asthma was evaluated in data collected as part of a multinational audit. Ethics review was not required for this audit, in most participating countries. When required, an ethics approval was acquired.

The cross-sectional case-control study was designed and managed by

This study evaluates the frequency of acute respiratory and febrile presentations furing the first wave of COVID-19 pandemic in childhood asthma. Data from the multinational PeARL cohort reveal improved health and asthma activity during the first wave of the COVID-19 pandemic, probably attributed to decreased exposure to asthma triggers and increased treatment adherence. During that period, children with asthma experienced fewer URTIs, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year.

the PeARL Steering Committee, was conducted in accordance with the Good Clinical Practice Guidelines and reported following the Strengthening the reporting of observational studies in epidemiology (STROBE) statement. 15 Participating centers were identified among members and collaborators of the PeARL think tank.

Eligible subjects were children aged between 4 and 18 years, diagnosed with asthma and monitored in one of the participating asthma clinics. Non-asthmatic controls included children of the same age range, monitored at the same healthcare setting for a non-respiratory condition, who did not clinically suffer from asthma.

Children with other chronic respiratory conditions, diabetes, hypertension, immunodeficiency, or any other chronic disease deemed by the responsible clinician that could impact the main outcomes of this study, were excluded. Each participating center was asked to contribute data from at least 45 participants, including twice as many children with asthma, compared to controls.

For the purposes of this study, the onset of the pandemic in each participating center was defined as the date of the first fatality due to COVID-19 in the respective country. For each participant, the duration of the pandemic period was defined as the period between the onset of the pandemic and the captured clinical visit. Historical data (before the pandemic) were captured during 2019 and the duration of observation before the onset of the pandemic was 1 year, for all participants.

We collected basic demographic data for all participants and data on the main outcomes of interest. The frequency of acute events (URTIs, LRTIs, asthma attacks, episodes of fever, emergency visits, for any reason, and hospital admissions, for any reason) during and before the pandemic was reported as recalled by the participants or their parents. URTIs included episodes of sore throat, pharyngitis, or rhino/sinusitis. LRTIs included episodes associated acute bronchitis or pneumonia and were differentiated from URTIs on the basis of the clinical presentation. Asthma attacks were defined as the need for systemic glucocorticoids administration for at least 48 h or an emergency visit or a hospitalization for asthma. Need for additional treatment was defined as any treatment escalation, including increased use of short-acting bronchodilators, increased dose of inhaled corticosteroids, or the administration of systemic corticosteroid courses. Asthma activity during and before the pandemic was measured using validated disease control questionnaires (asthma control test: ACT, 16 childhood asthma control test: C-ACT, 17 asthma control questionnaire: ACQ, 18 or composite asthma severity index: CASI 19 ). For each participant with asthma, at least one questionnaire was administered at least 2 months after the onset of the pandemic in their country and at least once during 2019 (the same questionnaire in both occasions). Physiological measurements, including forced expiratory value in 1 second (FEV 1 ), before or after bronchodilation and the peak expiratory flow rate (PFR), during and before the pandemic, were also captured when available.

Statistical analyses were performed using R statistical software (ver- In addition, we present the number of participants who had at least one event during the pandemic and during the preceding year.

Wilcoxon signed-rank test was also used to assess the impact of the pandemic on asthma control. As previously described, different standardized measures of asthma control were used in each center, depending on the measures that were evaluated during 2019, to facilitate comparisons. Firstly, we compared asthma control during versus before the pandemic in subgroups of participants, depending on the available asthma control tools. Next, we used Z-scores to estimate standardized differences by dividing the differences in the values during versus before the pandemic, with the standard deviation of all differences, for every test. In a sensitivity analysis, we only included subjects with a previous asthma control assessment between March and June 2019, during the same period as the pandemic, to account for seasonal variation.

Paired t test was used to compare pulmonary function measurements during versus before the pandemic. As previously, we conducted a sensitivity analysis only including subjects with a previous pulmonary function test, between March and June, 2019.

Finally, in a subgroup analysis, we repeated all previously described analyses only including data from participating centers that are in countries that were more severely hit by the pandemic (>200 deaths per million of inhabitants by 13/07/2020).

The study included 1,054 children with asthma and 505 control subjects, from 25 pediatric departments from 15 countries globally (Table S1 ). The baseline characteristics of the participants were generally balanced between the groups with a few, anticipated exceptions (Tables 1 and 2). A higher proportion of males (62.8% versus 51.9%) was observed in the asthma group compared to the controls, which is consistent with epidemiological characteristics of the disease in this age group. Allergic diseases such as allergic rhinitis (79.4% vs 39.4%) and food allergy (22.8% vs 15.6%) were also more prevalent in the asthma group. A higher proportion of children with asthma had a confirmed IgE sensitization and was vaccinated for the flu in the preceding year. Finally, children with asthma suffered a higher number of episodes of URTIs, LRTIs, emergency visits, or hospital admissions during 2019, compared to the control group (Tables 3 and 4) .

National lockdowns were imposed in all participating countries apart from Finland and Hong Kong Lockdown measures were in place for a median of 54.5% (quantiles 27.8%-76.7%) of the study period days. Moreover, schools were closed for the duration of the study period in over half of the participating centers (median 100%, quantiles: 57.7%-100%).

3.2.1 | Acute events frequency among asthmatic versus non-asthmatic controls during the pandemic Using generalized linear regression analysis, we evaluated betweengroup differences in the frequency of acute events during COVID-19 pandemic (Tables 3 and 4 ). Children with asthma were not found to be at increased risk of LRTIs, episodes of pyrexia, emergency visits, or hospitalizations during the pandemic. However, our analyses revealed an increased risk of URTI among children with asthma, compared to the control group, during the pandemic (p = 0.005). On the other hand, the pandemic did not appear to impact the frequency of emergency visits or hospital admissions of non-asthmatic controls. In this group, we observed a decreased frequency of URTIs and episodes of pyrexia, but also a significantly increased risk of LRTIs during the pandemic.

We then compared asthma control during versus before the pandemic ( Importantly, one in three children with asthma (33.2%) reported an improvement in control that exceeded the minimal clinically important difference of the test used.

Given the seasonal differences in asthma control, we conducted a sensitivity analysis where we only included historical asthma control measurements conducted during the same months with the first months of the pandemic (March-June 2019), with consistent findings (Table 5 ).

Pulmonary function during the pandemic compared to 2019 was evaluated in a subgroup of asthma children with available data ( 

In this subgroup analysis, all previously described analyses were repeated, including data from participating centers from countries that were more severely hit by the pandemic (>200 deaths per million of inhabitants by 13/07/2020). More specifically, we included data from France, Italy, Mexico, Spain, UK, and the USA. This subgroup analyses, which involved 597 children with asthma and 298 non-asthmatic controls, yielded consistent results with the main analyses (Tables S2-S6) . 

In the multinational PeARL childhood asthma cohort, we evaluated lergens, viral infections, physical exercise, and air pollution, due to social distancing, home sheltering, and reduced school days. 1, 12, [20] [21] [22] [23] Increased treatment adherence during the pandemic 24 could have also contributed. While our compliance data were self-reported and not objectively observed, we did find high adherence levels during the pandemic in our cohort. However, along with these "protective" effects of the pandemic, children were also more exposed to indoor allergens and pollutants and possibly adverse psychological factors and there is a chance this could have precipitated worse asthma control, nevertheless, in a minority of children (1/10 children in our cohort). Finally, during the pandemic we observed an increase in the frequency of URTIs among asthmatic children, compared to controls. While this could be considered consistent with previous findings suggesting COVID-19 infection may only be associated with limited upper respiratory symptoms in children, 25 it is more likely to reflect an increased attention given to minor symptoms or heightened awareness due to the COVID-19 pandemic.

The interplay between asthma and COVID-19 infection is being ex- In contrast, most outcomes were improved. These findings strongly reinforce the need and potential of compliance to treatment, 29,30 as well as the prospect of improved outcomes with environmental control in asthma, an area of some discrepancy. 31 The role of different viruses as asthma attack triggers has been investigated extensively. While rhinoviruses represent the main viral trigger of attacks, coronaviruses also trigger asthma attacks, albeit less frequently. 32 However, and in line with our findings, the outbreak of SARS in Singapore and Hong Kong was not associated with increased asthma attacks in children. 33, 34 On the contrary, and in line with our results, the incidence of acute respiratory tract infections and acute asthma attacks declined dramatically, likely due to the closure of schools for a period of time, stepped-up public hygiene measures and the use of facemasks. 33, 34 Despite that we did not have access to serology or exposure data, the improved outcomes among asthmatic children during 

This study was based on an audit and, therefore, we did not have access to COVID-19 serology or details on the exposure history of the children or their parents, which would have been informative.

Evaluation of the frequency of acute events during the pandemic is challenging, but we believe our methodology was rigorous. Firstly, the accuracy of parent-reported frequency of acute events has been previously validated. 38 We assumed a potential under-reporting of acute events during 2019, due to recall bias; however, we do not anticipate between-group differences in this bias. In addition, potential under-reporting of acute events prior to the pandemic would have led to an overestimation of the relative risk during the pandemic.

Since we did not find an increased risk, we suggest the impact of recall bias was minimal.

During the first wave of the pandemic, many patients hesitated to attend face-to-face follow-up visits, suggesting that potential participants may have been missed. 10 However, all participating centers offered alternative follow-up options, including phone call or teleconference facilities. Moreover, we would anticipate that patients with less controlled asthma, or those experiencing acute events are more likely to adhere to their follow-up visits or phone calls. However, study participants in the PeARL cohort reported in general better asthma control and less acute events during the pandemic. Therefore, it is unlikely that potential bias from missing wellcontrolled patients had a significant impact in our findings.

For estimating the duration of the pandemic, we considered the onset of the pandemic to coincide with the first fatality in each respective country. This usually followed a few days to weeks after the identification of the first case. We chose this time point as an objective marker that could better identify the onset of the impact of the pandemic in each community. Since we were inquiring for acute episodes during the epidemic, we wanted to avoid a potential underestimation of the frequency of the events that could have been caused by accounting for a wider time period of the epidemic.

Extrapolating an annualized asthma attack rate based on the events that were observed during the pandemic is complicated by the seasonal variability of asthma attacks. 39, 40 However, numerous high-quality studies demonstrate a peak in childhood asthma attack during autumn and schools reopening, which is counterbalanced by a low frequency during summer. 32, 41 Interestingly, these studies consistently show that the frequency of asthma attacks and asthma hospitalizations during spring and early summer levels with the median frequency of asthma attacks throughout the

year. 19, 20 The study period coincided with these months, suggesting that the frequency of acute events equals to their frequency throughout the year. This observation enhances our confidence on the accuracy of our annualized estimates and our findings, however, the limited observation period during the pandemic remains a limitation of this study.

The over-representation of atopic diseases in the control group shall be mentioned as a potential limitation, but it has been accounted for in our analyses. Finally, different validated questionnaires were used for assessing asthma control across the study centers, depending on the availability of historic measurements, to allow for paired comparisons. While the results of different tools are not directly comparable, our study revealed consistent results in the subgroups evaluated with different tools. On the other hand, the extensive, multinational study population with a good geographic balance across 4 continents, was a major strength of our study, increasing our confidence in our findings.

Overall, this analysis of the PeARL childhood asthma cohort revealed improved health and asthma activity during the COVID-19

pandemic, probably associated with decreased exposure to asthma triggers and increased treatment adherence. It also demonstrated that during the pandemic, children with predominantly mild to moderate atopic asthma did not suffer from an increase in the frequency of acute episodes that could represent COVID-19 infection. Kritikou for excellent administrative support of the study. 

Clinical and immune features of hospitalized pediatric patients with coronavirus disease

Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian Pediatric Intensive Care Units

Susceptibility to SARS-CoV-2 infection among children and adolescents compared with adults: a systematic review and meta-analysis

Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection

Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy

Factors associated with COVID-19-related death using OpenSAFELY

CDC COVID-19 Response Team. Coronavirus disease 2019 in children-United States

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

COVID-19 rapid guideline: severe asthma. 2020. NICE guideline

Impact of COVID-19 on pediatric asthma: Practice adjustments and disease burden

Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2

COVID-19 lockdown dropped the rate of paediatric asthma admissions

Pediatric asthma health care utilization, viral testing, and air pollution changes during the COVID-19 pandemic

Research Priorities in Pediatric Asthma: Results of a Global Survey of Multiple Stakeholder Groups by the Pediatric Asthma in Real Life (PeARL) Think Tank

The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies

Development of the asthma control test: a survey for assessing asthma control

Development and crosssectional validation of the childhood asthma control test

Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire

Development and validation of the Composite Asthma Severity Index-an outcome measure for use in children and adolescents

Toward personalization of asthma treatment according to trigger factors

The need for clean air: the way air pollution and climate change affect allergic rhinitis and asthma

Pediatric asthma healthcare utilization, viral testing, and air pollution changes during the COVID-19 Pandemic

The indirect impact of COVID-19 on children with asthma

ARIA-EAACI statement on asthma and COVID-19

Chrystopherson Gengyny Caballero López

SARS-CoV-2 infection in children

The association between COVID-19 and asthma: a systematic review and meta-analysis

Asthma and COVID-19: review of evidence on risks and management considerations

Does asthma increase the mortality of patients with COVID-19? A systematic review and meta-analysis

The relationship between real-world inhaled corticosteroid adherence and asthma outcomes: a multilevel approach

Acute asthma management during SARS-CoV2-pandemic 2020

Preventing severe asthma exacerbations in children. A randomized trial of mite-impermeable bedcovers

Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients

Childhood severe acute respiratory syndrome, coronavirus infections and asthma

Clinical presentations and outcome of severe acute respiratory syndrome in children

Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15

COVID-19-related genes in sputum cells in asthma. Relationship to demographic features and corticosteroids

Rhinovirus speciesspecific antibodies differentially reflect clinical outcomes in health and asthma

The September epidemic of asthma hospitalization: school children as disease vectors

Understanding the seasonal pattern of childhood asthma: Results from the national cooperative innercity asthma study (NCICAS)

Seasonal risk factors for asthma exacerbations among inner-city children