ASTHMA MIGHT PROTECT AGAINST MORTALITY IN CHILDREN HOSPITALIZED
WITH COVID-19
To the Editor,
The COVID-19 pandemic has been the greatest health challenge of the
century, claiming the lives of over five million people so far.
Fortunately, children and adolescents have been relatively spared, with
most of the deaths being among the eldest and those with preexisting
medical conditions. However, pediatric COVID-19 morbidity and mortality
are possible, especially among clinically and/or socioeconomically
vulnerable patients. Multiple studies have reported the risk associated
with specific previous comorbidities that might increase the odds of
adverse outcomes.1 Asthma is one of the most common
chronic diseases of childhood. The role played by the condition on the
outcomes of pediatric COVID-19 patients is still up for discussion. To
add to the debate, we have performed a large retrospective analysis of
pediatric COVID-19 patients hospitalized in Brazil, up to September
2021.
We have extracted data from the SIVEP-Gripe database, a national
surveillance databank that records data from all hospitalized patients
with severe acute respiratory infections, including COVID-19. The
notification is mandatory, and each observation contains over 160 fields
with information including demographic characteristics (like age, sex,
self or parent-reported race, municipality of residence), clinical
presentation, self or parent-reported comorbidities, etiological
investigation, and outcomes. We have included all patients with ages
ranging from 5 to 20 years, hospitalized, with COVID-19 infection
confirmed either by a positive PCR, positive antigen test, or positive
IgM test. Patients without a defined final outcome (discharge or death)
by September 6th, 2021 were excluded. After describing
the sociodemographic characteristics and clinical outcomes of asthmatic
and non-asthmatic patients, we studied the association of asthma with
three possible outcomes: pediatric intensive care unit (PICU) admission,
use of invasive ventilatory support (IVS), and in-hospital mortality. We
used multilevel mixed-effects generalized linear models (GLM) to
calculate de odds ratio (OR) between exposure and outcomes, assuming
municipality and health unit of hospitalization as random effects.
The analysis included 9,807 patients, 858 (8.7%) of whom had a self or
parent-reported diagnosis of asthma. Table 1 compares the
sociodemographic characteristics and outcomes of asthmatic and
non-asthmatic patients. When compared to asthmatic patients, a higher
proportion of non-asthmatic children lived in the northern half of the
country and were female. They also had more comorbidities and were
older. As for the outcomes, there was no difference among the groups in
PICU admission and IVS. Ten percent of non-asthmatic children died,
while for asthmatics this number was only 6.4% (p=0.001).
Table 2 shows the risk of adverse outcomes for asthmatic patients taking
non-asthmatic children as reference, and stratifying for age. For
children from 5 to 10 years, asthma lowers the risk of death by 56%
(95%CI 0.20-0.97) on the adjusted model. For all other outcomes and age
groups, the condition does not significantly affect the outcomes,
although there is a tendency to offer a higher risk of PICU admission
among adolescents on the adjusted model (OR 1.28 95%CI 0.98-1.67).
This analysis is one of the largest performed in Brazil to study the
role of asthma in COVID-19 pediatric patients. We have found that for
children aged 5 to 10 years, a previous diagnosis of asthma might be a
protective factor for mortality, reducing the odds of death by 60%. For
adolescents, and for other outcomes like PICU admission and use of IVS,
there seems to be no association between exposure and outcome.
Asthma is one of the most important risk factors for morbidity in
respiratory infectious diseases.2 Therefore, it is odd
to find the condition not associated with poor outcomes in COVID-19
patients. However, these results are not unique in the literature. In a
metanalysis by Sunjaya et al., including more than 965,000 COVID-19
patients of all ages, asthma was not a risk factor for ICU admission,
ventilator use, and mortality.3 Harwood et al.
included 21,412 children in a metanalysis that found asthma to reduce
the odds of admission to critical care and mortality.4The study is published as a preprint, pending peer-review. Putting our
results together with previous findings, it is coming clear that indeed
asthma is not a risk factor for poor outcomes in COVID-19 children and
adolescents, and might protect against some of them.
The main paths by which asthma and other allergic diseases might confer
protection against COVID-19 morbidity and mortality are still up for
discussion, but the role of the type of asthma phenotype is among the
main hypotheses. Current knowledge classifies the pathogenesis of asthma
into type 2 (T2) high and T2-low, with a predominance of eosinophilic
inflammation in the former, and a predominance of neutrophils in the
latter.5 The predominance of T2-high allergic asthma
among children is well known, reaching up to 80% of the cases and being
more responsive to corticosteroids, while in adults with obesity and
without allergic sensitization, T2-low asthma predominates with little
action of corticosteroids.6 Recently the cytokines
IL-4 and IL-13, more expressed in T2-high phenotype, were demonstrated
to reduce the expression of the angiotensin 2 receptor (ACE2) in the
airway epithelial cells, the gateway for the SARS-COV-2 virus. On the
other hand, the cytokines IL-12, IL-17, and TNF can increase the
expression of ACE2 in T2-low asthmatics and in chronic obstructive
pulmonary disease patients.7,8
Another finding that has intrigued researchers is the role of
eosinophils in COVID-19 patients with an allergic T2-high profile.
Previously recognized only in responses to helminths and allergic
diseases, eosinophils are currently known to have effector functions,
especially in the digestive tract and airways, releasing cytokines and
mediators that promote immunoregulation and antiviral
activity.9 Furthermore, many reports have shown the
potential effects of eosinophils during the COVID-19 pandemic: absence
of eosinophils on the first day of hospitalization in non-asthmatic
patients is associated with worse prognosis10,
patients with a low number of eosinophils require longer
hospitalizations and an increase in eosinophils is associated with
COVID-19 improvement and hospital discharge.11
The main limitations of this study are related to its reliance on
secondary data. Case ascertainment bias is a possibility, as is
underreporting. There is also a considerable rate of missingness for
some characteristics, especially ethnicity. Notably, the asthma
diagnosis is self or parent-reported, without objective parameters like
spirometry or an in-depth clinical evaluation. This leads to a
considerable degree of subjectivity, as a previous history of recurrent
wheezing might be reported as asthma, for instance. This also justified
the age group chosen for analysis, since before 5 years of age, wheezing
episodes could be more related to viral conditions. On the other hand, a
fair amount of underdiagnosis is expected, especially in regions with a
higher socioeconomic vulnerability and lower health care access. It is
also important to note that among all the comorbidities reported in the
database, asthma is the only one that confers protection against
mortality, with all of the others tending to confer risk, as previously
showed by our group.
In conclusion, we have described the role of asthma on the outcomes of
hospitalized children and adolescents with COVID-19 in Brazil. In this
population, the disease is not a risk factor for PICU admission and use
of IVS, and protects against mortality among children. Considering that
asthma is one of the most common chronic diseases of childhood, these
findings are important for public health measures concerning school
reopening and vaccination.
Braian Lucas Aguiar Sousa, MD
University of São Paulo School of Medicine – Department of Pediatrics.
Sao Paulo, Brazil.
Paulo Victor Ferreira Mai, MD
University of São Paulo School of Medicine – Department of Pediatrics.
Sao Paulo, Brazil.
Sandra Elisabete Vieira, MD, PhD
University of São Paulo School of Medicine – Department of Pediatrics.
Sao Paulo, Brazil.
Antonio Carlos Pastorino, MD, PhD
University of São Paulo School of Medicine – Department of Pediatrics.
Sao Paulo, Brazil.
Alexandre Archanjo Ferraro, MD, PhD
University of São Paulo School of Medicine – Department of Pediatrics.
Sao Paulo, Brazil.