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\begin{document}

\title{Protracted Respiratory Findings in Children Post-COVID-19 Infection}



\author[1]{Shoshana Leftin Dobkin}%
\author[2]{Joseph Collaco}%
\author[3]{Sharon McGrath-Morrow}%
\affil[1]{The Children's Hospital of Philadelphia}%
\affil[2]{Johns Hopkins Medical Institutions}%
\affil[3]{Johns Hopkins Medical Insitutions}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction: Although prolonged respiratory symptoms following
SARS-CoV-2 infection have been reported in adults, there is a paucity of
literature describing post-acute symptoms in pediatric patients
following COVID-19. In this study we describe health data and
respiratory findings in pediatric patients presenting with complaints of
persistent respiratory symptoms following acute COVID-19 infection.
Methods: This study included patients referred to Pulmonary Clinic at
the Children's Hospital of Philadelphia between December 2020 and April
2021 (n=29). Inclusion criteria included a history of SARS-CoV-2 RNA
positivity or confirmed close household contact. A retrospective chart
review was performed and demographic, clinical, imaging, and functional
test data were collected. Results: The mean age at presentation to
clinic was 13.1 years (range: 4-19 years). Patients had persistent
respiratory symptoms ranging from 1.3 to 6.7 months post-acute
infection. Persistent dyspnea and/or exertional dyspnea were present in
nearly all (96.6\%) of the patients at the time of clinic presentation.
Other reported chronic symptoms included cough (51.7\%) and exercise
intolerance (48.3\%). Fatigue was reported in 13.7\% of subjects. Many
subjects were overweight or obese (62.1\%) and eleven subjects had a
prior history of asthma. Lung function was normal in most patients. The
six-minute walk test (6MWT) revealed exercise intolerance and
significant tachycardia in two-thirds of children tested. Conclusion:
Exertional dyspnea, cough and exercise intolerance were the most common
respiratory symptoms in children with post-acute COVID-19 respiratory
symptoms seen in an outpatient pulmonary clinic. Lung function, however,
was mostly normal, and exertional intolerance was frequently
demonstrated using the 6MWT.%
\end{abstract}%



\sloppy


\textbf{Protracted Respiratory Findings in Children Post-COVID-19
Infection}

Shoshana C. Leftin Dobkin\textsuperscript{1}, MD, Joseph M.
Collaco\textsuperscript{2}, MD, MS, PhD, Sharon A.
McGrath-Morrow\textsuperscript{3}, MD, MBA

\textsuperscript{1}Division of Pulmonary Medicine, Children's Hospital
of Philadelphia, Philadelphia, Pennsylvania, USA

\textsuperscript{2}Eudowood Division of Pediatric Respiratory Sciences,
Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore,
Maryland, USA

\textsuperscript{3}Division of Pulmonary Medicine, The Perelman School
of Medicine at the University of Pennsylvania, Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA

\textbf{Corresponding Author:}

Shoshana Leftin Dobkin, MD

Division of Pulmonary Medicine

Children's Hospital of Philadelphia

Colket Translational Research Building

3501 Civic Center Boulevard, Philadelphia, PA 19104

Phone: (267) 854-5403

E-mail: leftindobs@chop.edu

\textbf{Contributors:} Conceptualization: all authors; Design: all
authors; Data collection: SLD; Data analysis: SLD, JMC; Data
interpretation: SLD, JMC, SAM; Manuscript writing: SLD; Manuscript
review: all authors. SLD had full access to the study data and takes
responsibility for the integrity of the data and the accuracy of the
analysis.

\textbf{Funding:} The study was funded by The Children's Hospital of
Philadelphia

\textbf{Competing Interests:} None

\textbf{Keywords:} exercise, functional capacity, breathlessness,
pulmonary function, post-covid syndrome

\textbf{Running Title:} Long COVID in Children

\textbf{Word Count:} 1,754

\textbf{Abstract}

\textbf{Introduction:} Although prolonged respiratory symptoms following
SARS-CoV-2 infection have been reported in adults, there is a paucity of
literature describing post-acute symptoms in pediatric patients
following COVID-19. In this study we describe health data and
respiratory findings in pediatric patients presenting with complaints of
persistent respiratory symptoms following acute COVID-19 infection.

\textbf{Methods:} This study included patients referred to Pulmonary
Clinic at the Children's Hospital of Philadelphia between December 2020
and April 2021 (n=29). Inclusion criteria included a history of
SARS-CoV-2 RNA positivity or confirmed close household contact. A
retrospective chart review was performed and demographic, clinical,
imaging, and functional test data were collected.

\textbf{Results:} The mean age at presentation to clinic was 13.1 years
(range: 4-19 years). Patients had persistent respiratory symptoms
ranging from 1.3 to 6.7 months post-acute infection. Persistent dyspnea
and/or exertional dyspnea were present in nearly all (96.6\%) of the
patients at the time of clinic presentation. Other reported chronic
symptoms included cough (51.7\%) and exercise intolerance (48.3\%).
Fatigue was reported in 13.7\% of subjects. Many subjects were
overweight or obese (62.1\%) and eleven subjects had a prior history of
asthma. Lung function was normal in most patients. The six-minute walk
test (6MWT) revealed exercise intolerance and significant tachycardia in
two-thirds of children tested.

\textbf{Conclusion:} Exertional dyspnea, cough and exercise intolerance
were the most common respiratory symptoms in children with post-acute
COVID-19 respiratory symptoms seen in an outpatient pulmonary clinic.
Lung function, however, was mostly normal, and exertional intolerance
was frequently demonstrated using the 6MWT.



\textbf{Introduction}

The novel coronavirus (COVID-19) began spreading through the U.S. in
early 2020, and there have been over 30 million cases in the U.S. as of
June 2021, of which over 4 million have been reported in children
(14.2\% of all cases). The overall rate is 5,347 cases of COVID-19 per
100,000 children in the population \textsuperscript{1,2}. Although
severe illness due to COVID-19 is rare among
children\textsuperscript{3}, there is a lack of data on the longer-term
impacts of the pandemic on children, including the long-term physical
harm on the health of infected children \textsuperscript{4}. Although
there is little data in children, increasing reports have emerged that
adult patients frequently experience long-term adverse outcomes related
to COVID-19 following resolution of the acute
illness\textsuperscript{5-11}. In a recent study by JK Logue et al.,
persistent symptoms were reported by 32.7\% of adult outpatients
following mild acute COVID-19 infection \textsuperscript{8}. In a study
of 180 mild cases of COVID-19 from the Faroe Islands, 53\% of patients
were symptomatic at mean 4-month follow up with fatigue in 30\%, dyspnea
in 10\%, and chest tightness in 5\% \textsuperscript{9}. In a large
longitudinal study of hospitalized patients from Wuhan, among
individuals who did not require supplemental oxygen during acute
COVID-19, 81\% reported residual symptoms six months after acute
illness\textsuperscript{7}. Previous studies have reported that even
among young adults aged 18--34 years with no chronic medical conditions,
approximately one in five had not returned to their usual state of
health 14--21 days after acute infection \textsuperscript{10}. The
National Institute of Health and Care Excellence defines ``long COVID''
as symptoms that persistent beyond four weeks, and distinguishes between
ongoing symptomatic COVID-19 as signs and symptoms of COVID-19 from four
to twelve weeks and post-COVID-19 syndrome as signs and symptoms that
continue for more than twelve weeks \textsuperscript{12}. There is
currently a paucity of literature describing such post-acute symptoms in
pediatric patients with COVID-19. The aim of this study is to describe
baseline health data and respiratory findings in a cohort of pediatric
patients experiencing prolonged symptoms following acute COVID-19
infection.

\textbf{Methods}

Subjects were referred to Pulmonary Clinic at the Children's Hospital of
Philadelphia (CHOP) for evaluation of persistent respiratory symptoms
six weeks or more after acute COVID-19 infection between December 2020
and April 2021. Inclusion criteria included a history of SARS-CoV-2 RNA
positivity or confirmed close household contact. Demographic, clinical,
imaging, and functional test data were collected through retrospective
chart review. Pulmonary function and six-minute walk test (6MWT)
variables were referenced to predicted normal
values\textsuperscript{13-15}. The study was approved by the Children's
Hospital of Philadelphia Institutional Review Board for exempt research.

\textbf{Results}

\textbf{Study Population}

Over a five months period, 29 pediatric subjects presented to CHOP
Pulmonary Clinic for evaluation of persistent symptoms six weeks or more
after COVID-19 infection (\textbf{Table 1} ). Of subjects seen for
COVID- related complaints, 14\% had previously been followed in CHOP
Pulmonary Clinic for other concerns prior to their acute COVID-19
infection. The mean age at presentation was 13.1 years (range: 4-19
years). Females (58.6\%) and non-whites (55.25\%) made up the majority
of the patients seen. Many subjects were overweight or obese with a BMI
above the 85th percentile (62.1\%). Baseline atopy, defined as presence
of asthma, eczema and/or allergic rhinitis, was present in 65.5\% of
subjects. Of the eleven subjects with asthma, 55\% had mild asthma, 36\%
had moderate asthma, and 9\% had severe asthma. Eight subjects with
asthma were previously prescribed a daily inhaled corticosteroid. Most
subjects (96.6\%) reported engagement in regular physical activity prior
to acute COVID-19 infection.

\textbf{Acute COVID Illness Characteristics}

All subjects had positive SARS-CoV-2 PCR testing or confirmed close
household contacts with positive SARS-CoV-2 testing at the time of
initial illness. The most common reported acute COVID-19 symptoms were
fever (69\%), cough (55.2\%), dyspnea (48.3\%), ageusia/anosmia (41.4\%)
and myalgia (37.9\%) (\textbf{Table 2} ). Only four patients (13.8\%)
required hospitalization during initial illness. All four were treated
with systemic steroids and one received remdesivir. No patient required
intubation. One additional patient was hospitalized six weeks after
acute symptom onset owing to multisystem inflammatory syndrome in
children (MIS-C). Chest radiograph opacities were present in 3 of 13
patients (23\%) who had imaging performed at the time of acute illness.

\textbf{Post-COVID Characteristics}

Subjects presented to clinic a mean of 3.2 months after a SARS-CoV-2
positive PCR or confirmed close contact (range: 1.3 to 6.7 months)
(\textbf{Table 3} ). Persistent dyspnea and/or exertional dyspnea were
present in nearly all (96.6\%) of the patients at the time of clinic
presentation. Other commonly reported chronic symptoms were cough
(51.7\%) and exercise intolerance (48.3\%). Fatigue was reported in four
subjects (13.7\%). One subject had an ongoing supplemental oxygen
requirement. Oxyhemoglobin saturations ranged from 97\% to 100\%. Lung
auscultation findings were normal in 27 subjects. Two subjects (6.9\%)
had abnormal auscultatory findings including decreased breath sounds and
intermittent wheezing. Spirometry was performed in 28 patients. Mean
percent predicted spirometry results included an FEV\textsubscript{1} of
107\%, an FVC of 110\%, an FEV\textsubscript{1}/FVC of 86\%, and an
FEF25-75\% of 100\%. Improvement following bronchodilator administration
was observed in 47.6\% of the 21 subjects who underwent
post-bronchodilator testing. Broncho-responsiveness occurred in ten
patients, five of whom have known underlying asthma and five of whom do
not. Plethysmography and diffusion capacity testing were performed in 14
subjects. Average percent predicted plethysmography results include a
TLC of 108\%, a VC of 120\%, an FRC of 99\%, and a RV of 87\%. An
elevated RV/TLC above 30\% was observed in six patients ranging from
32\% to 89\%, suggestive of air trapping. Average percent predicted DLCO
was 95\% and DLCO/VA was 97\%. Exercise intolerance on a six-minute walk
test was observed in five out of nine patients (66.7\%). Notably, these
patients were found to have significant tachycardia for age (HR range:
120-213 bpm). Of the eight patients who had chest radiographs performed
at the time of follow-up, only one was abnormal (12.5\%). All of the 15
patients who had follow-up cardiac evaluations had normal EKG and/or
echocardiogram (\textbf{Table 3} ).

\textbf{Discussion}

This is a descriptive study of patients referred to pediatric pulmonary
for Post-Acute Sequelae of SARS-CoV-2 infection (PASC), as defined by
the National Institute of Health and Care Excellence
guidelines\textsuperscript{12}. Most patients seen for protracted
respiratory symptoms following COVID-19 infection were not hospitalized
and had mild acute-COVID-19 symptomatology. Protracted respiratory
symptoms post-COVID-19 occurred in children as young as 4-years-old. In
comparable studies that included adults who did not require
hospitalization during initial COVID-19 illness, the most common
complaints were dyspnea and fatigue \textsuperscript{5,8}. In contrast,
in our pediatric study population, fatigue was only reported by four
patients (13.8\%). Similar to our study in which we found that
exertional dyspnea was presented in almost all patients, Townsend et al.
reported that 62\% of adult survivors of COVID-19 reported persistent
dyspnea and exertional limitation 75 days after their acute illness.
Interestingly, persistent dyspnea and exertional limitation were not
associated with initial disease severity in their
study\textsuperscript{16}.

In our study, although patients reported persistent exertional dyspnea,
cough and exercise intolerance, lung function was normal in most
children. Although objective measures of pulmonary function were
generally normal, including pulse oximetry, imaging and pulmonary
function testing, the six-minute walk test revealed exercise intolerance
and significant tachycardia in two-thirds of children tested. This
finding suggests that the six-minute walk test may be a low-cost and
simple way to evaluate children after COVID-19 and provide a
quantitative result that can be trended over time to assess improvement
or progression of disability.

We found an increased prevalence of atopy and obesity in our study
population that presented with prolonged post-COVID-19 respiratory
symptoms. According to the CDC, the most recent national asthma data
from 2019 suggests an asthma prevalence of 7\% in children under 18
years \textsuperscript{17}. The asthma prevalence in our study
population was 37.9\%, which is nearly five times higher than the
general population, and two-thirds were atopic. This may suggest that
asthma and atopy are risk factors for developing long COVID respiratory
symptoms in children and will require larger studies to confirm this
association. Obesity, defined as a BMI above the
95\textsuperscript{th}percentile, may also be linked to persistent
symptoms after COVID-19. Our study population has a higher rate of child
obesity of 37.9\% compared to the local population rate of 20.3\%
\textsuperscript{18}; however, this again may reflect study sample bias.

More studies are needed regarding effective management of patients with
post-COVID syndrome. Existing guidelines and rehabilitation programs are
directed at adult survivors of COVID-19 and recommend multidisciplinary
treatment approaches including pulmonary rehabilitation and physical
therapy \textsuperscript{19}. There are limited studies that report
improvement in persistent symptoms following
vaccination\textsuperscript{20}, but so far there are no studies looking
at the impact of vaccination in pediatric patients. Pacing and gradual
return to exercise may lessen exertional symptoms \textsuperscript{19}.
Additionally, the high prevalence of asthma and improvement following
bronchodilator administration observed in 47.6\% of patients suggests
that there may be a role for bronchodilators and inhaled corticosteroids
in some pediatric patients.

Our population was recruited as a convenience sample and represents a
limitation to our study. Patients in this study were seen in a pediatric
pulmonary clinic and thus may be more motivated to seek out specialty
care or have fewer barriers to accessing care. It is likely that our
sample represents a small fraction of total cases of protracted COVID-19
symptoms in children within our catchment area, with the majority of
cases being seen by primary care physicians. The youngest subject in our
population was four years old, which may reflect the youngest age for
subjects to actively report symptoms, thus we cannot comment on whether
these protracted symptoms could be observed in even younger patients.

The burden of caring for COVID-19 survivors is expected to be
tremendous, and future medical and social interventions must consider
the late sequelae of SARS-CoV-2 infection. Even though children
experience less severe COVID-19 infections than adults, our study shows
that children can have significant long-term respiratory symptoms which
can impact quality of life in these children. Our study indicates that
ongoing respiratory morbidity can persist even in children with mild
acute-COVID-19 infection history and when impairments are not clearly
identified by available objective testing. This suggests that there will
be an increasing need to follow these children longitudinally to
determine the long-term consequences of COVID-19 infection on
respiratory health, as this information will have important implications
for public health surveillance, health resource allocation, clinical
research, and future treatments.

\textbf{Acknowledgements}

The authors wish to thank the patients and their families who
participated in this study.

\textbf{References}

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3. Zimmermann P, Curtis N. Coronavirus Infections in Children Including
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4. Yelin D, Wirtheim E, Vetter P, et al. Long-term consequences of
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5. Carf\selectlanguage{ngerman}ì A, Bernabei R, Landi F. Persistent Symptoms in Patients After
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9. Petersen MS, Kristiansen MF, Hanusson KD, et al. Long COVID in the
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18. Robbins JM, Mallya G, Wagner A, Buehler JW. Prevalence, Disparities,
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