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\begin{document}

\title{COVID-19 symptoms are attenuated in atopic dermatitis patients treated
with dupilumab Short running title: Reduced COVID-19 symptoms in
dupilumab-treated AD}



\author[1]{Benjamin Ungar}%
\author[1]{Jacob W. Glickman}%
\author[1]{Alexandra Golant}%
\author[1]{Celina Dubin}%
\author[1]{Olga Marushchak}%
\author[1]{Alyssa Gontzes}%
\author[1]{Daniela Mikhaylov}%
\author[1]{Giselle Singer}%
\author[1]{Danielle Baum}%
\author[1]{Nancy Wei}%
\author[1]{Diana Gruenstein}%
\author[1]{Mark Lebwohl}%
\author[1]{Ana Brandusa Pavel}%
\author[1]{Emma Guttman-Yassky}%
\affil[1]{Icahn School of Medicine at Mount Sinai}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} In the SARS-CoV-2/COVID-19 pandemic, we need to
understand the impact of immunomodulatory medications on COVID-19
symptom severity in patients with inflammatory diseases, including the
Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Since it is
believed that Type 1/Th1immunity controls viral infections, and that
there is a Th1/Th2 counter-regulation, we hypothesized that Th2
targeting with the IL-4R\selectlanguage{greek}α-\selectlanguage{english}antagonist, dupilumab, in patients with
moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to
attenuated COVID-19 symptoms. \textbf{Methods:} 1,237 moderate-to-severe
AD patients in the Icahn School of Medicine at Mount Sinai Department of
Dermatology were enrolled in a registry. Patients were screened for
COVID-19-related symptoms and assigned a severity score
(asymptomatic{[}0{]}-fatal{[}5{]}). Scores were compared among 3
treatment groups: dupilumab (n=632), other systemic treatments (n=107),
and limited/no treatment (n=498). Demographic and comorbid covariates
were adjusted by multivariate logistic regression models.
\textbf{Results:} The dupilumab-treated group showed reduced incidence
and severity of COVID-19 symptoms versus other treatment groups.
Dupilumab-treated patients were less likely to experience
moderate-to-severe symptoms versus patients on other systemics (p=0.01)
and on limited/no treatment (p=0.04), and less likely to experience any
symptoms versus patients on other systemics (p=0.01). This effect was
seen in our entire cohort and in the subgroup of patients with verified
COVID-19 or high-risk exposure. \textbf{Conclusions:} Patients on
dupilumab experienced less severe COVID-19 manifestations and lesser
symptoms compared to patients on other systemics and on limited/no
treatment. These results suggest that Th2 modulation with dupilumab may
have a protective effect on anti-viral immune response in AD patients.%
\end{abstract}%



\sloppy


Original Article

\textbf{Title:} COVID-19 symptoms are attenuated in atopic dermatitis
patients treated with dupilumab

\textbf{Short running title:} Reduced COVID-19 symptoms in
dupilumab-treated AD

\textbf{Authors:} Benjamin Ungar, MD\textsuperscript{1}; Jacob W.
Glickman, MD\textsuperscript{1*}; Alexandra Golant,
MD\textsuperscript{1*}; Celina Dubin, BA\textsuperscript{1}; Olga
Marushchak, MA\textsuperscript{1,2}; Alyssa Gontzes,
BS\textsuperscript{1}; Daniela Mikhaylov, BA\textsuperscript{1}; Giselle
K. Singer, BS\textsuperscript{1}; Danielle Baum, RN\textsuperscript{1};
Nancy Wei, BA\textsuperscript{1}; Diana Gruenstein,
BA\textsuperscript{1}; Mark G. Lebwohl, MD\textsuperscript{1}; Ana B.
Pavel, PhD\textsuperscript{1,3}; Emma Guttman-Yassky, MD,
PhD\textsuperscript{1}

\begin{enumerate}
\tightlist
\item
  Department of Dermatology and Laboratory of Inflammatory Skin
  Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
\item
  Touro College of Osteopathic Medicine, New York, NY, USA
\item
  Department of Biomedical Engineering, The University of Mississippi,
  University, MS, USA
\end{enumerate}

*Authors contributed equally

\textbf{Corresponding author:}

Emma Guttman-Yassky MD, PhD

Department of Dermatology and Laboratory of Inflammatory Skin Diseases

Icahn School of Medicine at Mount Sinai

5 E. 98\textsuperscript{th} Street, New York, NY 10029

Email: emma.guttman@mountsinai.org

Telephone: 212-241-9728/3288; Fax: 212-876-8961

\textbf{Word count:} 2,488

\textbf{Tables:} 4

\textbf{Figures:} 2

\textbf{IRB approval status:} Reviewed and approved by the Department of
Dermatology at the Icahn School of Medicine; approval protocols
STUDY-20-00410 and STUDY 20-00682

\textbf{Acknowledgements:} Study funding sources include~the Department
of Dermatology at the Icahn School of Medicine at Mount Sinai and a
grant from Regeneron and Sanofi. Patients were recruited from within the
Department of Dermatology at the Icahn School of Medicine. All funding
sources reviewed and accepted the study design and the manuscript, with
minimal input from Regeneron and Sanofi.

\textbf{ABSTRACT}

\textbf{Background:} In the SARS-CoV-2/COVID-19 pandemic, we need to
understand the impact of immunomodulatory medications on COVID-19
symptom severity in patients with inflammatory diseases, including the
Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Since it is
believed that Type 1/Th1immunity controls viral infections, and that
there is a Th1/Th2 counter-regulation, we hypothesized that Th2
targeting with the IL-4R\selectlanguage{greek}α-\selectlanguage{english}antagonist, dupilumab, in patients with
moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to
attenuated COVID-19 symptoms.

\textbf{Methods:} 1,237 moderate-to-severe AD patients in the Icahn
School of Medicine at Mount Sinai Department of Dermatology were
enrolled in a registry. Patients were screened for COVID-19-related
symptoms and assigned a severity score
(asymptomatic{[}0{]}-fatal{[}5{]}). Scores were compared among 3
treatment groups: dupilumab (n=632), other systemic treatments (n=107),
and limited/no treatment (n=498). Demographic and comorbid covariates
were adjusted by multivariate logistic regression models.

\textbf{Results:} The dupilumab-treated group showed reduced incidence
and severity of COVID-19 symptoms versus other treatment groups.
Dupilumab-treated patients were less likely to experience
moderate-to-severe symptoms versus patients on other systemics (p=0.01)
and on limited/no treatment (p=0.04), and less likely to experience any
symptoms versus patients on other systemics (p=0.01). This effect was
seen in our entire cohort and in the subgroup of patients with verified
COVID-19 or high-risk exposure.

\textbf{Conclusions:} Patients on dupilumab experienced less severe
COVID-19 manifestations and lesser symptoms compared to patients on
other systemics and on limited/no treatment. These results suggest that
Th2 modulation with dupilumab may have a protective effect on anti-viral
immune response in AD patients.

\textbf{Key words:} Atopic dermatitis; dupilumab; COVID-19; SARS-CoV-2;
Th2

\textbf{Abbreviations:}

AD: Atopic dermatitis

EUA: Emergency Use Authorization

BMI: Body mass index

IFN: Interferon

IL\textbf{:} Interleukin

TNF\textbf{:} Tumor necrosis factor



\textbf{INTRODUCTION}

As of July, 2021, there have been more than 182 million cases of
COVID-19 caused by the novel SARS-CoV-2 reported worldwide, leading to
nearly 4 million deaths.\textsuperscript{1-3} Recently, due to
extraordinary vaccine development efforts, the American Food and Drug
Administration issued Emergency Use Authorizations (EUA) for three
vaccines.\textsuperscript{4-6} Despite the advent of these vaccines,
effective treatments are still a target for research and development
efforts, with several therapies having been granted
EUA.\textsuperscript{7} Furthermore, the risk of patients with
inflammatory skin diseases to develop more symptomatic COVID-19
infection is unknown, particularly in context of immunomodulatory
medications.

Previous research has shown that abnormally elevated Th2 cytokines may
inhibit appropriate Th1 immune responses in the setting of viral
exposure, impeding the reliance on Th1 signaling in initial responses to
viral infections.\textsuperscript{8-11} This is especially relevant for
atopic dermatitis (AD), a disease characterized primarily by Th2
skewing,\textsuperscript{12} with an increased susceptibility to viral
infections.\textsuperscript{10} Moreover, elevated expression of Th2
cytokines in serum (e.g., IL-4, IL-10, and IL-13) was reported in
patients with COVID-19, especially during the cytokine
storm.\textsuperscript{2,13-15}

Despite the greater risk for viral infections and the baseline Th2
polarization in AD, the risk for COVID-19 incidence and symptom severity
in this common disease (\textasciitilde{}7\% of the adult US
population),\textsuperscript{16} is still unknown. Determining COVID-19
risk profiles is particularly important in patients with
moderate-to-severe AD on immunomodulatory medications. While some
society guidelines recommend continuing these medications, there remains
a dearth of evidence.\textsuperscript{17,18} Recent case series and
studies on some inflammatory conditions suggest that immunomodulatory
medications may not change the risk of infection or
symptomatology.\textsuperscript{19-21} However, most of these reports
were small-scale-studies or did not include AD. Furthermore, direct
comparisons of COVID-19 outcomes between specific immunomodulatory drugs
are lacking, making it difficult to draw conclusions about the
comparative effects of different immunomodulatory medications.

Dupilumab, which inhibits the key Th2 cytokines IL-4 and IL-13, is the
first FDA-approved treatment for moderate-to-severe AD, and is also
approved for asthma and chronic rhinosinusitis with nasal
polyps.\textsuperscript{22-24} While dupilumab has been shown to
robustly modulate the Th2 pathway, it does not affect Th1
signaling.\textsuperscript{23,25} Preliminary reports have not shown
increased SARS-CoV-2 infection rates among patients treated with
dupilumab.\textsuperscript{26-31} However, these limited studies did not
compare dupilumab-treated patients with those on other treatments or not
receiving systemic treatments. To date, no study has evaluated the
effects of SARS-CoV-2 exposure and infection in AD patients on dupilumab
compared to other therapeutics.

The present study is the first large-scale, prospective evaluation of
1,237 patients with moderate-to-severe AD treated with dupilumab, broad
immunosuppressants, or those not receiving systemic treatments. This
registry study aims to investigate whether targeting type 2 inflammation
with dupilumab may protect against symptomatic SARS-CoV-2 infections in
patients with AD. Our data show that patients on dupilumab were less
likely to develop symptomatic COVID-19 infection compared to patients on
other systemic treatments for AD.

\textbf{METHODS}

\textbf{Patients}

We performed a cross-sectional analysis of reported demographics,
medical history, and medications from 1,237 moderate-to-severe AD
patients enrolled from April 2\textsuperscript{nd} 2020 through January
31\textsuperscript{st}, 2021 in a prospective registry related to
COVID-19 in the Department of Dermatology at the Icahn School of
Medicine at Mount Sinai. Patients were enrolled under institutional
review board-approved consent, and the study was conducted according to
the Declaration of Helsinki. The electronic medical record was queried
for all related ICD10 codes and each patient chart was reviewed to
ensure inclusion criteria were met. Patients were enrolled at the time
of clinical visit, when applicable, or enrolled over the phone.
Inclusion criteria included being older than 9 years of age with a
diagnosis of moderate-to-severe atopic dermatitis, defined as currently
or previously being on systemic therapy (including dupilumab,
phototherapy, or oral immunomodulatory medications), or as candidates
for systemic therapy.

Patients were asked about past medical history, medications,
demographics (i.e., age, gender, and self-reported race), as well as the
presence and duration of individual COVID-19-related symptoms, including
objective or subjective fever, sore throat, cough, congestion, headache,
fatigue, anosmia, dysgeusia, dyspnea, nausea, vomiting, diarrhea,
anorexia, and skin changes. Based on the symptoms described, each
patient was given a COVID-19 symptom severity score from 0-5: 0:
``asymptomatic''; 1: ``mild disease'' (no fever, no dyspnea, resolving
in \textless{}7 days, resembling a common cold); 2: ``moderate disease''
(some fever and/or cough, or other lower respiratory symptoms, resolving
at home in 7-14 days); 3: ``severe disease'' (pneumonia, required
hospitalization, but resolved without intubation); 4: ``very severe
disease'' (required hospitalization, intubation, and other supportive
measures); 5: ``fatal.''

One thousand two-hundred and thirty-seven patients were included in the
final analysis, out of 1,357 patients enrolled. In the final analysis,
we excluded patients treated concomitantly with dupilumab and other
systemic therapies (due to the hypothesis that dupilumab would reduce
symptom severity compared to other systemic treatments), patients on
dupilumab for \textless{}2 months (in order to allow for the proposed
effects of dupilumab to manifest), and patients on additional
immunomodulating therapies for other skin or extracutaneous indications
besides AD (including TNF\selectlanguage{greek}α \selectlanguage{english}and IL-23/IL-17 antagonists).

\textbf{Statistical analysis}

Demographic characteristics between groups were assessed using a
two-sided Fisher exact test or ANOVA for categorical and continuous
variables, respectively. The primary outcome for this report was the
presence of moderate-to-severe COVID-19 symptoms in each treatment
group, with the secondary outcome being the incidence of any symptoms.
Because of the potential for multiple confounders, we associated the
presence of COVID-19-related symptoms with dupilumab treatment compared
to other systemic treatments and with dupilumab treatment compared to
limited/no treatments using multivariate logistic regression models. We
adjusted for known or suspected COVID-19-related comorbidities (age,
gender, race, hypertension, diabetes, body mass index {[}BMI{]}, asthma,
ACE-inhibitor usage). Using a similar approach, we also associated the
presence of COVID-19-related symptoms with AD treatments by stratifying
our cohort into a set of higher COVID-19-related risk patients with
confirmed positive SARS-CoV-2 polymerase chain reaction (PCR) or
COVID-19 serological tests, exposure to COVID-19-positive patients
(diagnosed via PCR or serology) or to a person with COVID-19-related
symptoms.

\textbf{RESULTS}

\textbf{Patients grouped by AD treatment}

Twelve-hundred, thirty-seven patients with moderate-to-severe AD were
included in the analysis (age range 9-95 years). Patients were initially
grouped based on their AD treatment: 632 patients on dupilumab, 107
patients on other systemic treatments, and 498 patients on limited or no
treatment. The 107 patients on other systemics included 52 on
phototherapy, 29 on oral JAK inhibitors, 14 on prednisone, 6 on
methotrexate, 4 on cyclosporine, and 2 on mycophenolate mofetil. Among
patients on limited or no treatment, 354 were on topicals and 153 had no
treatment. Demographics, medication history, and comorbidities are
listed in Table 1A. No significant differences were found between groups
in terms of age and race.

\textbf{COVID-19 symptom severity}

We calculated the distribution of COVID-19 symptom severity across
groups in six categories: 0/``asymptomatic,'' 1/``mild,''
2/``moderate,'' 3/``severe,'' 4/``very severe,'' and 5/``fatal'' (Table
1B). Our initial analysis focused on the entire cohort of patients,
agnostic to laboratory evidence of COVID-19 infection. Treatment groups
were compared to determine the proportions of patients in each symptom
category (Figure 1). Given the potential for multiple confounders and
risk factors for symptomatic infection (Table 1A),\textsuperscript{32}we
adjusted for known risk factors for increased COVID-19 morbidity (e.g.,
obesity, hypertension, etc.) using logistic regression models. We found
that patients on dupilumab were less likely to experience
moderate-to-severe symptoms compared to patients on other systemic
treatments (OR=3.89; p=0.008, Table 2A). Furthermore, they were less
likely to experience moderate-to-severe symptoms compared to those on
limited/no treatments (OR=1.96; p=0.04; Table 2B). Additionally, BMI was
significantly associated with moderate-to-severe symptoms across
COVID-19 related patients treated with biologic and systemic therapies
(p\textless{}0.001, Table 2A).

When evaluating the effects of various clinical variables on the
presence of COVID-19-related symptoms, we found that non-biologic
systemic treatment was significantly associated with symptomatology
relative to treatment with dupilumab (OR=1.87; p=0.01, Table 2C).
However, there were no differences in predicting symptomatology among
patients on dupilumab relative to the limited/no treatment group (Table
2D).

\textbf{Symptom severity in patients with confirmed COVID-19 diagnosis
or exposure}

Next, we compared the subgroup of patients comprised of those with a
laboratory confirmed COVID-19 infection history based on PCR testing, or
other antibody testing performed in a clinical context, or those with
high-risk COVID-19 exposures, including to individuals with documented
COVID-19 infection or with symptoms highly suspicious for COVID-19
infection (n=164 for dupilumab, n=26 for other systemics, n=116 for
limited/no treatment; Table 3; Figure 2). Similar to the previous
logistic regression model results, non-dupilumab systemic treatment was
significantly associated with moderate-to-severe symptoms relative to
treatment with dupilumab (OR=13.79; p=0.002; Table 4A). Additionally,
being on limited/no treatment was also significantly associated with
moderate-to-severe symptoms relative to dupilumab (OR=2.44; p=0.05;
Table 4B). BMI was a significant covariate of moderate-to-severe
symptoms across all systemic treatment groups in this known
infection/high-risk exposure group (p=0.005; Table 4A).

In patients with known COVID-19 infection or high-risk exposure, being
on non-dupilumab, systemic therapies was significantly associated with
symptomatology relative to being on dupilumab (OR=2.97; p=0.03, Table
4C). Similar to the entire cohort, there were also no differences in
predicting symptoms among high-risk exposure patients on dupilumab
relative to the limited/no treatment group (Table 4D).

\textbf{DISCUSSION}

The present study is the first large-scale evaluation of COVID-19
symptomatology in patients with moderate-to-severe AD, aiming to
understand the effect of specific Th2 modulation with dupilumab compared
with other systemic immunomodulators and to topical or no treatment.
Understanding COVID-19 symptomatology in patients with
moderate-to-severe AD in the context of immunomodulatory treatment is
crucial, due to the long-term health consequences of SARS-CoV-2
infection, which are more substantial with moderate-to-severe
symptomatology,\textsuperscript{33} as well as the massive economic
burden on the United States hospital system from treating COVID-19
patients.\textsuperscript{34} Patients with moderate-to-severe AD are
also particularly important to study in this context due to their
increased susceptibility to viral infections and their robust Type 2/Th2
activation.\textsuperscript{10,35} Since Type 1/Th1immunity is
considered to control viral responses, and there is a Th1/Th2
counter-regulation, we hypothesized that specific Th2 antagonism in
patients with moderate-to-severe AD with the anti-IL-4R\selectlanguage{greek}α, \selectlanguage{english}dupilumab, may
rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19
symptomatology.

Our study found that dupilumab reduces both the incidence and severity
of COVID-19 symptoms among AD patients, compared to both other systemic
treatments and to no systemic treatments. We found that patients treated
with dupilumab were less likely to experience moderate-to-severe
symptoms compared to patients on other systemics (p=0.01) as well as to
patients on limited/no treatment (p=0.04). Patients treated with
dupilumab were also less likely to experience any symptoms at all
compared to patients on other systemics (p=0.01). This effect holds true
for patients with suspected COVID-19, as well as for patients with a
confirmed COVID-19 diagnosis or a confirmed high-risk exposure. Those
treated with dupilumab were less likely to experience moderate-to-severe
symptoms compared to those on other systemics (p=0.002) as well as on
limited/no treatment (p=0.05) and were less likely to experience
symptoms at all compared to patients on other systemics (p=0.03).

The robust effect of dupilumab on COVID-19 symptomatology may be due to
primary modulation of Th2 pathway, without downregulation of Th1
immunity. This relationship between Th2 modulation and Th1/innate immune
responses has been demonstrated in other atopic disease states, such as
asthma.\textsuperscript{36} In one study, asthma patients treated with
the Th2 modulator omalizumab (anti-IgE) had a lower incidence of
respiratory virus-induced asthma exacerbations and a more robust IFN\selectlanguage{greek}α
\selectlanguage{english}response in vitro to rhinovirus
stimulation.\textsuperscript{36}Similarly, our study found that COVID-19
symptoms and severity were reduced in dupilumab even when compared to
limited/no treatment, suggesting that Th2 suppression may normalize the
Th1/Th2 imbalance Unlike dupilumab, broad acting immunosuppressants
downregulate Th1 and other immune axes in addition to the pathogenic Th2
axis,\textsuperscript{23,37-39} which may account for the significant
differences in clinical outcomes as compared to dupilumab, which reduces
incidence and severity of symptoms in COVID-19. These results hold even
when adjusting for a number of clinical and demographic variables that
may affect COVID-19 severity, including race, age, and
BMI.\textsuperscript{32} Older age and higher BMI were significantly
associated with more frequent and more severe symptoms, consistent with
prior knowledge.\textsuperscript{32}

The main analysis in our study included all patients with a likely
COVID-19 diagnosis, regardless of a laboratory-confirmed COVID-19
diagnosis. Thus, we acknowledge that some patients who reported probable
COVID-19 symptoms may have had other infections (e.g. respiratory or
gastrointestinal). However, we believe that this approach is crucial for
several reasons: primarily, because there are likely many COVID-19 cases
undiagnosed by formal testing in our cohort; testing was unreliable
early on, and even now laboratory screening for asymptomatic cases is
not routinely performed. Further, including all subjects may contribute
to eliminating biases in testing behavior, since symptomatic patients
are more likely to get tested. Additionally, although the impetus for
this study was to evaluate the impact of immunomodulatory drugs
specifically on COVID-19 symptomatology, these data showing that Th2
modulation potentially ameliorates COVID-19 symptoms extends beyond the
current era. Our findings may thus have implications for other common
viral infections, such as influenza, and for possible future pandemics.

In the setting of the current COVID-19 pandemic, despite the advent of
vaccination and increasing efforts to widely distribute vaccines to the
population, it remains crucial to understand the impact of
immunomodulatory medications in patients with chronic inflammatory
diseases; many people may be unable or unwilling to get vaccines, the
long-term protection offered by vaccines is still unknown, and the
efficacy and duration of immune response to vaccination in the setting
of immunomodulatory medications remains unknown. Because of this, we
also performed an analysis focused on outcomes in patients with
confirmed laboratory evidence of COVID-19 infection or with significant
known COVID-19 exposures, and the results in this subset were even more
significant than those found in the entire cohort.

We acknowledge some limitations in this study. Primarily, there are
inherent limitations to a registry-based study, including sampling bias,
recall bias, and patients being enrolled at a single timepoint. Our
study was also limited by the fact that we could not obtain laboratory
confirmation (via serology testing) of COVID-19 infection in many
patients. Additional testing will provide even more evidence for the
relevance of these findings to confirmed COVID-19 infection.

Future studies are needed to understand the implications of our findings
for other specific viral conditions. Furthermore, biomarker-based
studies may provide added support for the proposed mechanism by which
Th2 blockade might produce the results seen in this study. Additionally,
understanding the immune response to COVID-19 vaccination in patients on
immunomodulatory medications will be crucial as vaccination becomes
increasingly widespread. Lastly, further studies in other inflammatory
conditions commonly treated with immunomodulatory medications will be
needed as well. The present study is the first to demonstrate the
significant protection potentially offered by Th2-targeting with
dupilumab in reducing symptom incidence and severity compared to other
treatments for AD in the context of COVID-19 infection. These findings
have important implications, not only for the millions of
moderate-to-severe AD patients in this country exposed to COVID-19 and
other viral infections, but potentially for patients with chronic atopic
and other conditions on immunomodulatory medications.

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21. Neurath MF. Covid-19 and immunomodulation in IBD. Gut
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22. Corren J, Castro M, O'Riordan T, et al. Dupilumab Efficacy in
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24. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of
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parallel-group phase 3 trials. Lancet 2019;394:1638-50.

25. He H, Olesen CM, Pavel AB, et al. Tape-strip proteomic profiling of
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26. Patruno C, Stingeni L, Fabbrocini G, Hansel K, Napolitano M.
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27. Ferrucci S, Romagnuolo M, Angileri L, Berti E, Tavecchio S. Safety
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Dermatol Venereol 2020.

29. Rossi M, Rovati C, Arisi M, Soglia S, Calzavara-Pinton P. Management
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31. Carugno A, Raponi F, Locatelli A, et al. No evidence of increased
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2016;138:169-78.

\textbf{Table 1. Demographics and symptom severity for all patients and
treatment groups.}

\textbf{1A.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& \textbf{All patients} & \textbf{Dupilumab} & \textbf{Other systemics}
& \textbf{Limited/no treatment} & \textbf{P-value}\tabularnewline
\midrule
\endhead
\textbf{Sample size (n)} & 1237 & 632 & 107 & 498 &\tabularnewline
\textbf{Age (mean, SD)} & & 41.2 (19.1) & 42.0 (19.4) & 39.9 (18.9) &
0.39\tabularnewline
\textbf{Gender} & & & & & 0.001\tabularnewline
Male (n,\%) & 521 (42\%) & 296 (47\%) & 44 (41\%) & 181 (36\%)
&\tabularnewline
Female (n,\%) & 716 (58\%) & 336 (53\%) & 63 (59\%) & 317 (64\%)
&\tabularnewline
\textbf{Race} & & & & & ~0.46\tabularnewline
American Indian/Alaska Native (n,\%) & 5 (0.4\%) & 1 (0.0001\%) & 0
(0\%) & 4 (1\%) &\tabularnewline
Asian (n,\%) & 216 (17\%) & 126 (20\%) & 21 (20\%) & 69 (14\%)
&\tabularnewline
Black or African American (n,\%) & 205 (17\%) & 102 (16\%) & 18 (17\%) &
85 (17\%) &\tabularnewline
Mixed race (n,\%) & 40 (3\%) & 21 (3\%) & 3 (3\%) & 16 (3\%)
&\tabularnewline
Native Hawaiian/Other Pacific Islander (n,\%) & 4 (0.3\%) & 2 (0.0001\%)
& 0 (0\%) & 2 (0.0001\%) &\tabularnewline
Unknown (n,\%) & 95 (8\%) & 44 (7\%) & 7 (7\%) & 44 (9\%)
&\tabularnewline
White (n,\%) & 672 (54\%) & 336 (53\%) & 58 (54\%) & 278 (56\%)
&\tabularnewline
\textbf{Comorbidities} & & & & &\tabularnewline
Hypertension & & 115 (18\%) & 20 (19\%) & 72 (14\%) &
0.21\tabularnewline
Diabetes & & 37 (6\%) & 7 (7\%) & 26 (5\%) & 0.78\tabularnewline
Asthma & & 250 (40\%) & 38 (36\%) & 169 (34\%) & 0.16\tabularnewline
Obesity (BMI\textgreater{}30) & & 112 (20\%) & 14 (16\%) & 85 (19\%) &
0.61\tabularnewline
\textbf{Other medications} & & & & &\tabularnewline
ACEi & & 20 (3\%) & 4 (4\%) & 8 (2\%) & 0.16\tabularnewline
\textbf{COVID-19 infection} & & & & &\tabularnewline
Laboratory confirmed COVID-19 infection & 87 (7\%) & 39 (6\%) & 11
(10\%) & 37 (7\%) & 0.26\tabularnewline
\bottomrule
\end{longtable}

\textbf{1B.} Percentage of patients by COVID-19 symptom severity score
in each treatment group. COVID-19 symptom severity defined as a 5-level
score: 0 ``asymptomatic''; 1: ``mild disease'' (no fever, no dyspnea,
resolving in \textless{}7 days, resembling a common cold); 2: ``moderate
disease'' (some fever and/or cough, or other lower respiratory symptoms,
resolving at home in 7-14 days); 3: ``severe disease'' (pneumonia,
required hospitalization, but resolved without intubation); 4-5: ``very
severe disease'' (required hospitalization, intubation, and other
supportive measures) or ``fatal.''\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{All patients} \textbf{n=1233} & \textbf{Dupilumab}
\textbf{n=631} & \textbf{Other systemics} \textbf{n=107} &
\textbf{Limited/no treatment} \textbf{n=495}\tabularnewline
\midrule
\endhead
\textbf{Severity} & & & &\tabularnewline
0 (n, \%) & 947 (77\%) & 492 (78\%) & 73 (68\%) & 382
(77\%)\tabularnewline
1 (n, \%) & 204 (16\%) & 110 (17\%) & 18 (17\%) & 76
(15\%)\tabularnewline
2 (n,\%) & 78 (6\%) & 29 (5\%) & 15 (14\%) & 34 (7\%)\tabularnewline
3 (n,\%) & 4 (0.3\%) & 0 (0\%) & 1 (1\%) & 3 (1\%)\tabularnewline
4/5 (n, \%) & 0 (0\%) & 0 (0\%) & 0 (0\%) & 0 (0\%)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Logistic Regression Models Comparing Symptom Severity
Among All Patients in Different Treatment Groups.}

\textbf{A.} Logistic regression model predicting asymptomatic/mild
versus moderate-to-severe symptoms using treatment: Systemics vs
Dupilumab as a predictor variable and adjusting for other clinical
variables; \textbf{B} . Logistic regression model predicting
asymptomatic/mild versus moderate-to-severe symptoms using treatment:
Limited/No-treatment vs Dupilumab as a predictor variable and adjusting
for other clinical variables; \textbf{C} . Logistic regression model
predicting asymptomatic versus symptomatic using treatment: Systemics vs
Dupilumab as a predictor variable and adjusting for other clinical
variables; \textbf{D} . Logistic regression model predicting
asymptomatic versus symptomatic using treatment: Limited/No-treatment vs
Dupilumab as a predictor variable and adjusting for other clinical
variables. Log Odds Ratio is reported as the natural log of the odds
ratio in the logistic regression model.

\textbf{A}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -3.86 & 2.36 & -1.64 & 0.10\tabularnewline
Systemics & 1.36 & 0.51 & 2.66 & 0.008\tabularnewline
Age & 0.01 & 0.01 & 0.87 & 0.39\tabularnewline
Asthma & -0.61 & 0.45 & -1.36 & 0.17\tabularnewline
Gender & -0.35 & 0.45 & -0.78 & 0.43\tabularnewline
Hypertension & -1.15 & 0.75 & -1.53 & 0.12\tabularnewline
Diabetes & 0.75 & 0.90 & 0.83 & 0.41\tabularnewline
BMI & 0.13 & 0.04 & 3.41 & 0.001\tabularnewline
ACEi & 0.55 & 1.91 & 0.29 & 0.77\tabularnewline
Race & 0.07 & 0.10 & 0.63 & 0.53\tabularnewline
\bottomrule
\end{longtable}

\textbf{B}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -3.59 & 1.58 & -2.28 & 0.02\tabularnewline
Limited/no treatment & 0.67 & 0.33 & 2.04 & 0.04\tabularnewline
Age & 0.03 & 0.01 & 2.46 & 0.01\tabularnewline
Asthma & 0.26 & 0.33 & 0.79 & 0.43\tabularnewline
Gender & -0.03 & 0.34 & -0.08 & 0.94\tabularnewline
Hypertension & -0.96 & 0.58 & -1.67 & 0.09\tabularnewline
Diabetes & -0.09 & 0.72 & -0.13 & 0.90\tabularnewline
BMI & 0.04 & 0.03 & 1.55 & 0.12\tabularnewline
ACEi & 0.83 & 1.09 & 0.76 & 0.45\tabularnewline
Race & -0.07 & 0.08 & -0.85 & 0.39\tabularnewline
\bottomrule
\end{longtable}

\textbf{C}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic versus symptomatic} &
\textbf{Asymptomatic versus symptomatic} & \textbf{Asymptomatic versus
symptomatic} & \textbf{Asymptomatic versus symptomatic}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -0.59 & 0.97 & -0.60 & 0.55\tabularnewline
Systemics & 0.63 & 0.25 & 2.46 & 0.01\tabularnewline
Age & -0.001 & 0.01 & -0.28 & 0.78\tabularnewline
Asthma & 0.15 & 0.19 & 0.77 & 0.44\tabularnewline
Gender & -0.05 & 0.19 & -0.25 & 0.80\tabularnewline
Hypertension & -0.24 & 0.30 & -0.80 & 0.42\tabularnewline
Diabetes & 0.16 & 0.44 & 0.35 & 0.72\tabularnewline
BMI & 0.02 & 0.02 & 1.19 & 0.23\tabularnewline
ACEi & -0.74 & 0.68 & -1.08 & 0.28\tabularnewline
Race & -0.11 & 0.04 & -2.50 & 0.01\tabularnewline
\bottomrule
\end{longtable}

\textbf{D}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic versus symptomatic} &
\textbf{Asymptomatic versus symptomatic} & \textbf{Asymptomatic versus
symptomatic} & \textbf{Asymptomatic versus symptomatic}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -1.32 & 0.78 & -1.70 & 0.09\tabularnewline
Limited/no treatment & 0.10 & 0.15 & 0.64 & 0.52\tabularnewline
Age & 0.001 & 0.00 & 0.15 & 0.88\tabularnewline
Asthma & 0.27 & 0.16 & 1.75 & 0.08\tabularnewline
Gender & -0.09 & 0.16 & -0.56 & 0.58\tabularnewline
Hypertension & -0.38 & 0.26 & -1.46 & 0.15\tabularnewline
Diabetes & 0.15 & 0.36 & 0.41 & 0.68\tabularnewline
BMI & 0.01 & 0.01 & 0.67 & 0.51\tabularnewline
ACEi & -0.03 & 0.54 & -0.06 & 0.95\tabularnewline
Race & -0.08 & 0.04 & -2.20 & 0.03\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. Patient demographics in patients with confirmed
diagnosis or COVID-19 exposure.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{Dupilumab} & \textbf{Other systemics} & \textbf{Limited/no
treatment} & \textbf{P-value}\tabularnewline
\midrule
\endhead
\textbf{Sample size (n)} & 164 & 26 & 116 &\tabularnewline
\textbf{Age (mean, SD)} & 37.1 (16.7) & 42.8 (16.5) & 37.6 (15.9) &
\textless{}0.001\tabularnewline
\textbf{Gender} & & & & 0.04\tabularnewline
Male (n,\%) & 70 (43\%) & 9 (35\%) & 33 (28\%) &\tabularnewline
Female (n,\%) & 94 (57\%) & 17 (65\%) & 83 (72\%) &\tabularnewline
\textbf{Race} & & & & 0.51\tabularnewline
American Indian/Alaska Native (n,\%) & 0 (0\%) & 0 (0\%) & 3 (3\%)
&\tabularnewline
Asian (n,\%) & 28 (17\%) & 5 (19\%) & 13 (11\%) &\tabularnewline
Black or African American (n,\%) & 30 (18\%) & 5 (19\%) & 19 (16\%)
&\tabularnewline
Mixed race (n,\%) & 5 (3\%) & 1 (4\%) & 5 (4\%) &\tabularnewline
Native Hawaiian or Other Pacific Islander (n,\%) & 2 (1\%) & 0 (0\%) & 0
(0\%) &\tabularnewline
Unknown (n,\%) & 6 (4\%) & 1 (4\%) & 9 (8\%) &\tabularnewline
White (n,\%) & 93 (57\%) & 14 (54\%) & 67 (58\%) &\tabularnewline
\textbf{Comorbidities} & & & &\tabularnewline
Hypertension & 21 (13\%) & 6 (23\%) & 15 (13\%) & 0.35\tabularnewline
Diabetes & 9 (5\%) & 1 (4\%) & 5 (4\%) & 0.91\tabularnewline
Asthma & 61 (37\%) & 11 (42\%) & 44 (38\%) & 0.89\tabularnewline
Obesity (BMI\textgreater{}30) & 27 (19\%) & 7 (30\%) & 19 (18\%) &
0.38\tabularnewline
\textbf{Other medications} & & & &\tabularnewline
ACEi & 5 (3\%) & 0 (0\%) & 2 (2\%) & ~0.84\tabularnewline
\textbf{COVID exposure and testing} & & & &\tabularnewline
Tested positive for COVID 19 (n,\%) & 39 (24\%) & 11 (42\%) & 37 (32\%)
& 0.09\tabularnewline
Exposure to positive COVID 19 (n,\%) & 76 (46\%) & 6 (23\%) & 46 (40\%)
& 0.06\tabularnewline
Exposure to COVID 19-like symptoms (n,\%) & 49 (30\%) & 9 (35\%) & 33
(28\%) & 0.84\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4. Logistic Regression Models Comparing Symptom Severity
Among Patients with Confirmed Diagnosis or COVID-19 Exposure in
Different Treatment Groups.}

Within the population of patients with confirmed diagnosis or COVID-19
exposure: \textbf{A} . Logistic regression model predicting
asymptomatic/mild versus moderate-to-severe symptoms using treatment:
Systemics vs Dupilumab as a predictor variable and adjusting for other
clinical variables; \textbf{B} . Logistic regression model predicting
asymptomatic/mild versus moderate-to-severe symptoms using treatment:
Limited/No-treatment vs Dupilumab as a predictor variable and adjusting
for other clinical variables; \textbf{C.} Logistic regression model
predicting asymptomatic versus symptomatic using treatment: Systemics vs
Dupilumab as a predictor variable and adjusting for other clinical
variables; \textbf{D.} Logistic regression model predicting asymptomatic
versus symptomatic using treatment: Limited/No-treatment vs Dupilumab as
a predictor variable and adjusting for other clinical variables. Log
Odds Ratio is reported as the natural log of the odds ratio in the
logistic regression model.

\textbf{A}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -16.59 & 1455.40 & -0.01 & 0.99\tabularnewline
Systemics & 2.62 & 0.86 & 3.05 & 0.002\tabularnewline
Age & 0.04 & 0.02 & 1.55 & 0.12\tabularnewline
Asthma & -1.25 & 0.77 & -1.62 & 0.11\tabularnewline
Gender & -0.26 & 0.66 & -0.40 & 0.69\tabularnewline
Hypertension & -2.06 & 1.15 & -1.80 & 0.07\tabularnewline
Diabetes & 1.91 & 1.32 & 1.44 & 0.15\tabularnewline
BMI & 0.22 & 0.08 & 2.84 & 0.005\tabularnewline
ACEi & 12.09 & 1455.40 & 0.01 & 0.99\tabularnewline
Race & -0.11 & 0.16 & -0.70 & 0.48\tabularnewline
\bottomrule
\end{longtable}

\textbf{B}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms} & \textbf{Asymptomatic/mild versus moderate-to-severe
symptoms}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -19.95 & 1606.87 & -0.01 & 0.99\tabularnewline
Limited/no treatment & 0.89 & 0.46 & 1.94 & 0.05\tabularnewline
Age & 0.04 & 0.02 & 2.73 & 0.006\tabularnewline
Asthma & 0.10 & 0.46 & 0.22 & 0.83\tabularnewline
Gender & 0.11 & 0.49 & 0.23 & 0.82\tabularnewline
Hypertension & -0.97 & 0.79 & -1.22 & 0.22\tabularnewline
Diabetes & -0.87 & 1.14 & -0.76 & 0.45\tabularnewline
BMI & 0.08 & 0.04 & 1.91 & 0.06\tabularnewline
ACEi & 16.70 & 1606.87 & 0.01 & 0.99\tabularnewline
Race & -0.05 & 0.11 & -0.43 & 0.67\tabularnewline
\bottomrule
\end{longtable}

\textbf{C}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic versus symptomatic} &
\textbf{Asymptomatic versus symptomatic} & \textbf{Asymptomatic versus
symptomatic} & \textbf{Asymptomatic versus symptomatic}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & 0.86 & 1.86 & 0.46 & 0.64\tabularnewline
Systemics & 1.09 & 0.51 & 2.12 & 0.03\tabularnewline
Age & -0.001 & 0.01 & -0.05 & 0.96\tabularnewline
Asthma & 0.12 & 0.34 & 0.34 & 0.73\tabularnewline
Gender & 0.23 & 0.34 & 0.68 & 0.50\tabularnewline
Hypertension & 0.02 & 0.54 & 0.03 & 0.98\tabularnewline
Diabetes & 1.00 & 0.93 & 1.07 & 0.28\tabularnewline
BMI & -0.03 & 0.03 & -1.06 & 0.29\tabularnewline
ACEi & -1.40 & 1.44 & -0.97 & 0.33\tabularnewline
Race & -0.09 & 0.08 & -1.22 & 0.22\tabularnewline
\bottomrule
\end{longtable}

\textbf{D}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Outcome} & \textbf{Asymptomatic versus symptomatic} &
\textbf{Asymptomatic versus symptomatic} & \textbf{Asymptomatic versus
symptomatic} & \textbf{Asymptomatic versus symptomatic}\tabularnewline
\midrule
\endhead
& \textbf{Log Odds Ratio} & \textbf{Standard Error} & \textbf{Z-score} &
\textbf{P-value}\tabularnewline
Intercept & -0.54 & 1.41 & -0.38 & 0.70\tabularnewline
Limited/no treatment & 0.31 & 0.27 & 1.18 & 0.24\tabularnewline
Age & 0.01 & 0.01 & 1.13 & 0.26\tabularnewline
Asthma & 0.44 & 0.27 & 1.60 & 0.11\tabularnewline
Gender & 0.09 & 0.28 & 0.32 & 0.75\tabularnewline
Hypertension & -0.41 & 0.45 & -0.92 & 0.36\tabularnewline
Diabetes & 0.72 & 0.66 & 1.08 & 0.28\tabularnewline
BMI & -0.03 & 0.02 & -1.14 & 0.25\tabularnewline
ACEi & -0.58 & 0.98 & -0.58 & 0.56\tabularnewline
Race & -0.05 & 0.06 & -0.75 & 0.46\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure Legends}

\textbf{Figure 1A.} Whole patient cohort separated into treatment
groups, dupilumab (n=631), other systemics (n=107), and limited/no
treatment (n=495), grouping symptom severity in each treatment group by
scores of 0-1 (asymptomatic or mild symptoms) and 2-5 (moderately
symptomatic to fatal). *P\textless{}0.05.
**P\textless{}0.01.\textbf{1B.} Whole patient cohort separated into
treatment groups, dupilumab (n=631), other systemics (n=107), and
limited/no treatment (n=495), grouping presence of symptoms in each
treatment group by a score of 0 (asymptomatic) or 1-5 (symptomatic).
*P\textless{}0.05. **P\textless{}0.01.

\textbf{Figure 2A.} Cohort of patients with known infection or high risk
COVID-19 exposures, separated into treatment groups, dupilumab (n=164),
other systemics (n=26), and limited/no treatment (n=116), grouping
symptom severity in each treatment group by scores of 0-1 (asymptomatic
or mild symptoms) and 2-5 (moderately symptomatic to fatal).
*P\textless{}0.05. **P\textless{}0.01. \textbf{2B.} Cohort of patients
with known infection or high risk COVID-19 exposures, separated into
treatment groups, dupilumab (n=164), other systemics (n=26), and
limited/no treatment (n=116), grouping presence of symptoms in each
treatment group by a score of 0 (asymptomatic) or 1-5 (symptomatic).
*P\textless{}0.05. **P\textless{}0.01.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
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