key: cord-340583-kjrxrk50
authors: Castro‐Rodriguez, Jose A.; Forno, Erick
title: Asthma and COVID‐19 in children – a systematic review and call for data
date: 2020-06-18
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.24909
sha: 
doc_id: 340583
cord_uid: kjrxrk50

RATIONALE: Whether asthma constitutes a risk factor for COVID‐19 is unclear. Here we aimed to assess whether asthma, the most common chronic disease in children, is associated with higher COVID‐19 risk or severity in pediatric populations. METHODS: We performed a systematic literature search in three stages: First, we reviewed PubMed, EMBASE and CINAHL for systematic reviews of SARS‐CoV‐2 and COVID‐19 in pediatric populations, and reviewed their primary articles; second, we searched PubMed for studies on COVID‐19 or SARS‐CoV‐2 and asthma/wheeze, and evaluated whether the resulting studies included pediatric populations; third, we repeated the second search in BioRxiv.org and MedRxiv.org to find pre‐prints that may have information on pediatric asthma. RESULTS: In the first search, eight systematic reviews were found, of which five were done in pediatric populations; none of the 67 primary studies included data on pediatric asthma as a comorbidity for COVID‐19. In the second search, we found 34 results in PubMed, of which five reported asthma in adults, but none included data on children. In the third search, 25 pre‐prints in MedRxiv included data on asthma, but none on children. We found one report by the U.S. CDC stating that 40/345 (~11.5%) children with data on chronic conditions had “chronic lung diseases including asthma”, and one from a tertiary hospital in New York that reported asthma in 11/46 (~23.9%) children hospitalized for COVID‐19. CONCLUSION: There is scarcely any data on whether childhood asthma (or other pediatric respiratory diseases) constitute risk factors for SARS‐CoV‐2 infection or COVID‐19 severity. Studies are needed that go beyond counting the number of cases in the pediatric age range. This article is protected by copyright. All rights reserved.

The current outbreak of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), started in or around December, 2019, in Wuhan (1) . On January 30 th , 2020 the World Health Organization (WHO) declared COVID-19 a pandemic health emergency (2) . Since then, COVID-19 has continued to spread quickly and has now become the most dangerous pandemic in over 100 years.

An interactive real-time COVID-19 reporting system set up by the Center for Systemic Science and Engineering at Johns Hopkins University (3) shows, as of the time of this writing, more than 5.8 million confirmed cases and over 361,000 deaths worldwide (led by the U.S., with ~30% of all cases and ~28% of all deaths). Globally, this corresponds to a ~6% case fatality rate, although rates vary widely among countries and subpopulations and it is difficult to ascertain both the true numerator (active unresolved cases may eventually become deaths) and the true denominator (many true cases may go untested or undetected).

The first pediatric case in the literature was reported on January 2020 in 10-yearold boy from Shenzhen, China, whose family had visited Wuhan (4) . All epidemiological evidence to date suggests that SARS-CoV-2 infection is less severe in children than in adults. In the latest and largest study in the UK, including 16,749 patients hospitalized for COVID-19, only 239 (2%) were <18 years of age (including 139 who were <5 years This article is protected by copyright. All rights reserved.

Supplementary Table 1) .

None of the primary studies reviewed reported asthma or recurrent wheezing as a comorbidity or risk factor for COVID-19. Instead, some of those studies reported young age (especially children <1 year of age) as a group with more severe COVID-19. One large Chinese study (16) reported non-respiratory chronic conditions (hydronephrosis, leukemia receiving chemotherapy, and intussusception) among three children who required ICU support and mechanical ventilation. Among them, one death occurred in a10-month old child with intussusception. Another study reported a patient who developed shock with metabolic acidosis requiring ICU (17) . Yet another report from China (18) described one patient aged 10-19 years who died, without other clinical information; that death probably represents the same 14-year-old boy described by Dong and colleagues (19) . Unfortunately, the two larger studies in Chinese pediatric patients, Dong et al. (19) (2,413 children) and Wu and MacGoogan (20) (965 children) did not report enough clinical data to identify comorbidities or risk factors for COVID-19 severity. In the German survey of 33 hospitalized children, 4 out of 22 (18%) children with clinical information had "respiratory comorbidities" without further details (15) .

Our second search yielded 34 results in PubMed. Of those, five were primary studies that reported on asthma in adults (21) (22) (23) (24) (25) ; one other was a guidance statement (26) that referenced a primary report that also included information on asthma in adults (27) . No studies from that search included information on asthma in children, although one case series reported two young children (ages 2 and 3 years) with history of atopic dermatitis and allergic rhinitis, who were hospitalized with COVID-19; both patients recovered (28) . This article is protected by copyright. All rights reserved.

Our third search yielded 26 pre-prints in BioRxiv and 137 in MedRxiv. None of the BioRxiv posts were relevant to our topic. Of the 137 pre-prints in MedRxiv, 23 nonduplicate studies included information on asthma , but none of them included specific information in children.

Weekly Report (MMWR) (52) , published by the CDC, that included information from 2,572 U.S. children aged < 18 years. Of those cases, 345 had data on clinical and underlying conditions, and 80 of those children (23%) had at least one underlying condition. The most common underlying conditions were "chronic lung diseases (including asthma)" in 40 children, cardiovascular disease in 25, and immunosuppression in 10; separate information on asthma was not provided. Among the 295 cases for which data on both hospitalization status and underlying medical conditions was available, 28/37 (77%) hospitalized patients had one or more underlying medical condition (including all six patients admitted to an ICU); compared to 30/258 (12%) patients who were not hospitalized (52) . A recently published Italian study, including100 children seen in 17 emergency departments, reported that 27% had comorbidities without more specifications, and no deaths occurred (53) . And most recently, a study of 46 children 

This article is protected by copyright. All rights reserved.

In a systematic review of the literature, we only found two reports that described asthma or recurrent wheezing as potential risk factors for COVID-19 in children. Importantly, none of the largest epidemiological studies including children with COVID-19 reported clinical findings or underlying characteristics to help assess whether asthma -or other chronic lung diseases-constitutes a risk factor for SARS-CoV-2 infection or COVID-19 severity.

COVID-19 affects primarily the lungs, and accordingly several international guidelines have designated some respiratory conditions as a potential risk factor for severe disease. Chinese guidelines (54) state that "children with a history of contact with severe 2019-nCoV infected cases, or with underlying conditions (such as congenital heart disease, bronchial pulmonary hypoplasia, respiratory tract anomaly, with abnormal hemoglobin level, severe malnutrition), or with immune deficiency or immunocompromised status… may become severe cases". A recent statement from the EAACI Section on Pediatrics (26) declared that "patients with asthma (particularly severe or uncontrolled asthma) and immunodeficiency have also been classified to be at increased risk of developing severe COVID-19, based more on common sense rather than mounting evidence". The Global Initiative for Asthma (GINA) recommends avoiding the use of nebulizers due to the increased risk of disseminating COVID-19 to other patients and healthcare staff; they thus recommend the use of pressurized metered dose inhalers (pMDI) as the preferred delivery system during asthma attacks (55) . A recent randomized controlled trial (RCT) (56) showed that even in children with severe asthma exacerbations, administration of albuterol/salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by nasal cannula was more effective than This article is protected by copyright. All rights reserved. Accepted Article nebulized administration. GINA (55) and the British Thoracic Society (57) do not recommend stopping oral steroids in the patients already taking them for asthma management, and they do not recommend avoiding them for acute asthma attacks even if due to COVID-19. The U.S. CDC, the Canadian Pediatric Society, and other professional associations have issued guidance for patients with asthma and/or allergies (58) (59) (60) . Other professional organizations, such as the American Academy of Pediatrics and the American Thoracic Society, have published interim guidelines that do not specifically address asthma, likely given a paucity of evidence (61, 62) .

Rather than a risk factor, a recent review of data in adults reported that both asthma and COPD appear to be under-represented in the comorbidities reported for patients with COVID-19, compared with global estimates of prevalence for these conditions in the general population (63) . This is consistent with individual studies we found during our search, which have shown lower-than-expected prevalence of asthma among cases of COVID-19 (21) (22) (23) (24) 27) , and in contrast to the prevalence of other chronic diseases such as diabetes, which occurred with higher frequency among patients with COVID-19 than the estimated national prevalence (63) . If asthma is indeed "protective", this could be due to several factors, including changes in the immune response or decreased risk secondary to chronic medications such as inhaled corticosteroids (ICS). Invitro models have shown that ICS may suppress both coronavirus replication and cytokine production (64, 65) . Analysis of induced sputum samples in a well-characterized cohort of adults with severe asthma found reduced ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane protease serine 2) gene expression among patients taking ICS, and especially among those on higher doses (66) ; ACE2 and TMPRSS2 mediate This article is protected by copyright. All rights reserved.

patients with asthma and respiratory allergies had reduced ACE2 gene expression in airway cells, suggesting a potential mechanism of reduced COVID-19 risk (67) . This is particularly noteworthy considering that one of the potential explanations for children being generally less affected than adults is the hypothesis that children have lower ACE2 receptor expression in alveolar type 2 cells (68) . However, the lower prevalence of asthma among COVID-19 cases could also stem from bias due to underdiagnosis and underreporting, or because patients with chronic lung diseases may be especially cautious in practicing physical distancing and other measures to avoid infection. Finally, it is also conceivable that some milder cases of COVID-19 might be confused with exacerbations of respiratory disease, and/or that these patients may be reluctant to seek medical care even when sick and are thus never counted.

It is important to note that our understanding of the role of asthma -even in adults-is still incipient. In the largest and most recent analysis to date, UK investigators analyzed data from 17 million adults, including 5,683 deaths due to COVID-19, and reported that both asthma (adjusted hazard ratio, aHR: 1.11 [95% confidence interval:

1.02-1.20]) and severe asthma (aHR: 1.25 [1.08-1.44]) were risk factors for COVID-19 mortality (51) . This study compared COVID-19 deaths to the general population (regardless of being SARS-CoV-2 positive or not), so the estimates combine both risk of infection and risk of death once infected. These results highlight how incomplete our understanding still is. As with most other studies, this large analysis did not include a pediatric population.

This article is protected by copyright. All rights reserved.

After an extensive review of the current literature, only two reports included information on asthma as a potential risk factor for COVID-19 infection -but not severity or mortality-in children. However, the largest studies to date have been limited to a description of the number of cases by age group, and so it remains unclear whether childhood asthma -or other pediatric respiratory diseases-are associated with COVID-19 risk or severity.

We hereby ask the public health community to move beyond confirming what's already known -that the disease affects children and young adults less frequently and severely than older groups-and to study affected pediatric populations in more detail.

Does asthma constitute a risk factor for COVID-19 in children? Do asthma severity or control modify the course of the disease? Are asthma medications (particularly ICS and systemic steroids) or their doses protective or detrimental? Given the limited numbers of pediatric cases in any one given center/country, collaborative international efforts may be the only way to shed light on the topic. Initiatives such as the Pediatric Asthma in Real Life (PeARL) group (69) or a pediatric version of the International Severe Asthma Registry (70) , or efforts coordinated by large professional societies, may be best suited for the task. This will be true not just for childhood asthma but for pediatric diseases in general.

This article is protected by copyright. All rights reserved.

China Medical Treatment Expert Group for C. Clinical Characteristics of Coronavirus Disease 2019 in China

WHO Director-General's opening remarks at the media briefing on COVID-19

An interactive web-based dashboard to track COVID-19 in real time

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

Preferred reporting items for systematic review and metaanalysis protocols (PRISMA-P) 2015: elaboration and explanation

Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis

School closure and management practices during coronavirus outbreaks including COVID-19: a rapid systematic review

Systematic Review of Important Viral Diseases in Africa in Light of the 'One Health

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review

Epidemiology and clinical features of coronavirus disease 2019 in children

Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and meta-analysis

Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults

Epub 2020/04/23

Chinese Pediatric Novel Coronavirus Study T. SARS-CoV-2 Infection in Children

Novel Coronavirus Pneumonia Emergency Response Epidemiology T

Characteristics of and Important Lessons From the

COVID-19) Outbreak in China: Summary of a Report of 72314

Cases From the Chinese Center for Disease Control and Prevention

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

Distinct characteristics of COVID-19 patients with initial rRT-PCR-positive and rRT-PCRnegative results for SARS-CoV-2. Allergy. 2020

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Postmortem Lung Findings in an Asthmatic with Coronavirus Disease

Managing childhood allergies and immunodeficiencies during respiratory virus epidemics -the 2020 COVID-19 pandemic

Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 -COVID-NET, 14 States

Eleven faces of coronavirus disease 2019

COVID-19 in Iran, a comprehensive investigation from exposure to treatment outcomes

ICU and ventilator mortality among critically ill adults with COVID-19

Prevalence of SARS-CoV-2 infection in previously undiagnosed health care workers at the onset of the U.S. COVID-19 epidemic

Predicting mortality due to SARS-CoV-2: A mechanistic score relating and diabetes to COVID-19 outcomes in Mexico

An international characterisation of patients hospitalised with COVID-19 and a comparison with those previously hospitalised with influenza

How many are at increased risk of severe COVID-19 disease? Rapid global, regional and national estimates for 2020

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

Key predictors of attending hospital with COVID19: An association study from the COVID Symptom Tracker App in 2,618,948 individuals

Clinical Characteristics of Hospitalized Covid-19 Patients

Between-centre differences for COVID-19 ICU mortality from early data in England

Machine Learning to Predict Mortality and Critical Events in COVID-19 Positive

Test performance evaluation of SARS-CoV-2 serological assays

Potential Factors for Prediction of Disease Severity of COVID-19 Patients

Development and Validation of a Diagnostic Nomogram to Predict COVID-19 Pneumonia

Clinical characteristics associated with COVID-19 severity in California

Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City

Early Short Course Corticosteroids in Hospitalized Patients with

Pre-Existing Characteristics Associated with Covid-19 Illness Severity

Supplementing the National Early Warning Score (NEWS2) for anticipating early deterioration among patients with COVID-19 infection

SARS-COV-2 comorbidity network and outcome in hospitalized patients in

Updated estimates of comorbidities associated with risk for COVID-19 complications based on US data

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Coronavirus Infection in Pediatric Emergency Departments Research G. Children with Covid-19 in Pediatric Emergency Departments in Italy

Accepted Article China Medicine Education Association Committee on P, Chinese Research Hospital Association Committee on P, Chinese Non-government Medical Institutions Association Committee on P, China Association of Traditional Chinese Medicine CoCsH, Medicine R, China News of Drug Information Association CoCsSM, Global Pediatric Pulmonology A. Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement

Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial

People who are at higher risk -people with asthma 2020

Paediatric asthma and COVID-19 2020

COVID-19: Pandemic Contingency Planning for the Allergy and Immunology Clinic. The journal of allergy and clinical immunology In practice

COVID-19: Interim guidance on management pending empirical evidence. From an American Thoracic Society-led International Task Force

Accepted Article 62

Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? The lancet Respiratory medicine

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

National Heart L, Blood Institute Severe Asthma Research Program I. COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids

Association of Respiratory Allergy, Asthma and Expression of the SARS-CoV-2 Receptor, ACE2

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic

Accepted Article Papadopoulos NG. 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 journal of allergy and clinical immunology In practice

Development of the International Severe Asthma Registry (ISAR): A Modified Delphi Study. The journal of allergy and clinical immunology In practice