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\title{Asthma 17q21 Polymorphism Associates with COVID-19 in Children}



\author[1]{Ioulia Gourari}%
\author[1]{Rika Gomi}%
\author[1]{Madeline Young}%
\author[1]{Geancarlo Jordan}%
\author[1]{Madeline  Liongson}%
\author[1]{Andrea Heras}%
\author[1]{Linda Gerber}%
\author[1]{Charlene  Thomas}%
\author[1]{Kalliope Tsirilakis}%
\author[1]{Jennie Ono}%
\author[2]{Pramod Narula}%
\author[1]{Thomas Ketas}%
\author[1]{John Moore}%
\author[1]{Stefan Worgall}%
\author[1]{Perdita Permaul}%
\affil[1]{Weill Cornell Medicine}%
\affil[2]{NewYork-Presbyterian Brooklyn Methodist Hospital}%


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  \date{May 16, 2024}


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\textbf{Asthma 17q21 Polymorphism Associates with COVID-19 in Children}

\textbf{TO THE EDITOR:}

Infection with Severe Acute Respiratory Syndrome Coronavirus-2
(SARS-CoV-2) in children rarely leads to severe disease. This has been
particularly surprising for children with asthma - the most common,
chronic inflammatory disease in childhood. We sought to determine
predictors for COVID-19 illness in children and adolescents, with and
without asthma, exposed to SARS-CoV-2 across the epicenter of the
ongoing pandemic in New York City (NYC).

Data collected from May 2020 through April 2021 during the early
pandemic and prior to vaccine roll-out as part of the ongoing
observational \textbf{S} ARS-CoV-2 and \textbf{P} ediatric \textbf{A}
sthma in \textbf{N} YC (SPAN) urban cohort study of children and
adolescents were analyzed. Study participants were recruited during
routine New York-Presbyterian/Weill Cornell Medicine outpatient clinic
visits across the epicenter of the COVID-19 pandemic including general
pediatrics, adolescent, pulmonary, and allergy clinics. The study
population included participants aged 2-21 years without asthma and
those with physician-diagnosed asthma for at least one year and at least
one of the following: current daily preventive asthma medication use,
wheezing in the past year, or an unscheduled healthcare visit for asthma
in the past year. Parents/legal guardians of enrolled participants gave
written informed consent. Written assent was obtained from participants
aged 7-17 years. This study was approved by Institutional Review Boards
at Weill Cornell Medicine, NewYork-Presbyterian Queens, and
NewYork-Presbyterian Brooklyn Methodist Hospital.

A comprehensive survey administered to the parent/legal guardian
included questions regarding demographics, clinical information and
exposures, specifically as it pertained to COVID-19 illness. Body mass
index (BMI) was calculated using the weight data(kg) and dividing it by
height(m) squared(kg/m2). Pediatric age and sex-adjusted BMI percentiles
were then calculated using the Centers for Disease Control
classification category: normal weight (5-84\textsuperscript{th} BMI
percentile), overweight ([?]85-94\textsuperscript{th} BMI percentile), and
obese ([?]95\textsuperscript{th} BMI percentile). Blood and nasal
biospecimens were collected during the participants' outpatient clinic
visits.

As variations at the asthma-risk 17q21 locus associated with ORMDL3
expression, in particular the minor allele of single nucleotide
polymorphism (SNP) rs7216389, are strongly linked to childhood asthma
and viral triggers for wheezing(1, 2), genotyping of this SNP was
performed on extracted DNA using QIAamp DNA blood micro/mini kits
(QIAGEN) according to manufacturer's instructions. COVID-19 infection
was ascertained by positive SARS-CoV-2 specific antibodies.~IgG
antibodies against SARS-CoV-2 were determined in plasma by ELISA using
the SARS-CoV-2 spike protein as antigen as previously described(3).

Descriptive statistics were calculated to characterize the SPAN cohort
(Table 1). Primary outcomes of interest included: 1) positive COVID-19
serology test, and 2) symptomatic COVID-19 illness defined as having a
positive COVID-19 test~\emph{AND} ~having at least one of the following
symptoms - fever, chills, sore throat, cough, body aches, nasal
congestion, rhinorrhea, loss of taste, anosmia, shortness of breath,
diarrhea, vomiting, rash, and/or COVID toes, or hospitalization.
Univariate logistic regression modeling calculated the unadjusted odds
ratio (OR) for each of the demographic and clinical factors of interest
on both outcomes, independently. A multivariate logistic regression
model evaluated the independent effect of ORMDL genotype on developing
COVID-19 while controlling for potential confounders such as age,
inhaled corticosteroid (ICS) use, race, borough of residence, household
SARS-CoV-2 exposure, and BMI. Collinearity between predictors in the
models was evaluated prior to the formulation of the final model.
Ninety-five percent confidence intervals for all parameters of interest
were calculated to assess the precision of the obtained estimates. All
p-values were two-sided with statistical significance evaluated at the
0.05 alpha level. All analyses were performed in R Version 4.0.5 (R
Foundation for Statistical Computing, Vienna, Austria).

Of 186 participants enrolled, 68 (37\%) were infected with SARS-CoV-2,
and of these, 38 (56\%) endorsed symptoms and two (2.9\%) were
hospitalized. Sixty-nine participants were obese (38\%) while 76 (42\%)
were healthy weight; 34 (50\%) of the obese subset were infected,
compared to 22(32\%) of healthy weight participants (\emph{p} =0.03)
(Table 1). Multivariable logistic regression analysis showed that
obesity (\emph{p} =0.049) and household SARS-CoV-2 exposure (\emph{p}
\textless{}0.001) were risk factors for acquiring SARS-CoV-2 infection
while the T/T genotype in asthma participants (\emph{p} =0.029) was
associated with decreased infection risk. Increasing age (\emph{p}
=0.029) was the only predictor associated with more symptomatic
infection (Table 2).

The primary objective of this analysis was to better understand the
demographic and clinical factors associated with COVID-19 illness in the
pediatric population during the early pandemic prior to vaccine
roll-out, particularly in those with asthma. Most COVID-19 pediatric
investigations have been retrospective analyses of hospitalized
children; thus, observational cohort studies in non-hospitalized and
healthy children are essential to assess prevalence and risk for
COVID-19. As such, the SPAN cohort offers unique data and exhibited a
high prevalence of SARS-CoV-2 infection in the outpatient setting;
almost half were asymptomatic and unaware they had contracted COVID-19.
As anticipated, home contact increased the risk for infection. Similar
to adult studies, obesity was associated with more symptomatic
illness(4) as was increasing age of the child.

Most notably, we identified a novel association of decreased risk for
COVID-19 illness to a common childhood asthma-associated 17q21 genotype.
Asthma has not been a distinct risk factor for severe(5) COVID-19
disease in children or adults, and the presence of asthma and allergies
may even be protective(6). Steroid use, thought to be a factor for this
protective effect(7), was not a confounder in our cohort. Thus, 17q21
asthma-risk genotypes may confer a protective effect against SARS-CoV-2
infection, particularly in children with asthma. It has been
demonstrated that children with 17q21 asthma-risk genotypes, such as
rs7216389, have lower sphingolipid synthesis(1, 8). Recent findings
suggest that sphingolipids may play a role in modulating cellular
SARS-CoV-2 entry(9). While a larger replication cohort is needed to
validate our findings, our study lays the initial groundwork to
uncovering a mechanism for why children with asthma are not as
vulnerable to the SARS-CoV-2 virus as originally expected. Moreover,
future mechanistic studies are needed to understand how
asthma-associated alterations in sphingolipid levels might be implicated
in COVID-19 pathology.

\emph{References:}

1. Ono JG, Kim BI, Zhao Y, Christos PJ, Tesfaigzi Y, Worgall TS, et al.
Decreased sphingolipid synthesis in children with 17q21 asthma-risk
genotypes. J Clin Invest. 2020;130(2):921-6.

2. Cal\selectlanguage{polish}ış\selectlanguage{english}kan M, Bochkov YA, Kreiner-M\selectlanguage{ngerman}øller E, Bønnelykke K, Stein MM, Du
G, et al. Rhinovirus wheezing illness and genetic risk of
childhood-onset asthma. N Engl J Med. 2013;368(15):1398-407.

3. Ketas TJ, Chaturbhuj D, Portillo VMC, Francomano E, Golden E,
Chandrasekhar S, et al. Antibody Responses to SARS-CoV-2 mRNA Vaccines
Are Detectable in Saliva. Pathog Immun. 2021;6(1):116-34.

4. Sattar N, Valabhji J. Obesity as a Risk Factor for Severe COVID-19:
Summary of the Best Evidence and Implications for Health Care. Curr Obes
Rep. 2021;10(3):282-9.

5. Lim ZJ, Subramaniam A, Ponnapa Reddy M, Blecher G, Kadam U, Afroz A,
et al. Case Fatality Rates for Patients with COVID-19 Requiring Invasive
Mechanical Ventilation. A Meta-analysis. Am J Respir Crit Care Med.
2021;203(1):54-66.

6. Green I, Merzon E, Vinker S, Golan-Cohen A, Magen E. COVID-19
Susceptibility in Bronchial Asthma. J Allergy Clin Immunol Pract.
2021;9(2):684-92.e1.

7. Ramakrishnan S, Nicolau DV, Langford B, Mahdi M, Jeffers H, Mwasuku
C, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC):
a phase 2, open-label, randomised controlled trial. Lancet Respir Med.
2021;9(7):763-72.

8. Rago D, Pedersen CT, Huang M, Kelly RS, Gürdeniz G, Brustad N, et al.
Characteristics and Mechanisms of a Sphingolipid-associated Childhood
Asthma Endotype. Am J Respir Crit Care Med. 2021;203(7):853-63.

9. Törnquist K, Asghar MY, Srinivasan V, Korhonen L, Lindholm D.
Sphingolipids as Modulators of SARS-CoV-2 Infection. Front Cell Dev
Biol. 2021;9:689854.

\textbf{Authors:}

Ioulia Gourari, MD\textsuperscript{1}, Rika Gomi, MD,
PhD\textsuperscript{1}, Madeline Young, BS\textsuperscript{1}, Geancarlo
Jordan, BS\textsuperscript{1}, Madeline Liongson,
MPH\textsuperscript{1}, Andrea Heras, MD\textsuperscript{1}, Linda M.
Gerber, PhD\textsuperscript{2}, Charlene Thomas, MS\textsuperscript{2},
Kalliope Tsirilakis, MD\textsuperscript{1}, Jennie Ono,
MD\textsuperscript{3}, Pramod Narula, MD\textsuperscript{4}, Thomas
Ketas, BA\textsuperscript{5}, John P. Moore, PhD\textsuperscript{5},
Stefan Worgall, MD\textsuperscript{1,6,7}, and Perdita Permaul,
MD\textsuperscript{1,6}

\textbf{Institutional Affiliations:}

\textsuperscript{1}Division of Pediatric Pulmonology, Allergy \&
Immunology, Weill Cornell Medicine, New York, NY

\textsuperscript{2}Department of Population Health Sciences, Weill
Cornell Medicine, New York, NY

\textsuperscript{3}Department of Pediatrics, Weill Cornell Medicine, New
York, NY

\textsuperscript{4}Department of Pediatrics, New York-Presbyterian
Brooklyn Methodist Hospital, Brooklyn, NY

\textsuperscript{5}Department of Microbiology and Immunology, Weill
Cornell Medicine, New York, NY

\textsuperscript{6}Drukier Institute for Children's Health, Weill
Cornell Medicine, New York, NY

\textsuperscript{7}Department of Genetic Medicine, Weill Cornell
Medicine, New York, NY

\textbf{Corresponding Author:} Perdita Permaul, MD, Division of
Pediatric Pulmonology, Allergy and Immunology, Weill Cornell Medicine,
505 East 70\textsuperscript{th} Street, Helmsley Tower \#3F, New York,
NY 10021 Telephone: 646-962-3410, Fax: 646-962-0246

Email: pep9004@med.cornell.edu

\textbf{Funding:} This research is supported by NIH K23 AI123517 (PP);
R01 AI36082 and P01 AI110657 (JPM); and KL2 TR0002385-05 (AH).

This study received support from NewYork-Presbyterian Hospital (NYPH)
and Weill Cornell Medical College (WCMC), including the Clinical and
Translational Science Center (CTSC) (UL1 TR000457) and Joint Clinical
Trials Office (JCTO).

\textbf{Conflict of Interests:} All the authors declare that there are
no conflicts of interest.

\textbf{Key Words:} asthma, children, COVID-19, SARS-CoV-2, SNP, body
mass index, BMI

\textbf{Word Count:} 965

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