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\begin{document}

\title{Pulmonary Function Tests in Infants Following SARS-CoV-2 Infection}



\author[1]{Talia Benenson-Weinberg}%
\author[1]{Avigdor Hevroni}%
\author[1]{Laurice S. Boursheh}%
\author[1]{Oded Breuer}%
\affil[1]{Hadassah University Medical Center}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction}: The clinical spectrum of SARS-CoV-2 infection is
well-established. However, understanding its long-term implications,
especially in infants, remains limited. We aimed to evaluate pulmonary
function tests in infants (iPFT) several months after a documented
SARS-CoV-2 infection. \textbf{Methods}: An observational case-control
study was performed. iPFT results in infants with persistent respiratory
complaints several months after a SARS-CoV-2 infection were compared to
a registry of patients assessed at our center between 2008 and 2019
using the Mann--Whitney U and Fisher's exact tests. Excluded from the
study were infants with chronic diseases and extreme prematurity.
\textbf{Results}: iPFT data from sixteen infants with respiratory
complaints and a history of SARS-CoV-2 infection and 475 controls were
evaluated in the study. The median time between the SARS-CoV-2 infection
and iPFT evaluation was 5.5 months (IQR=2.8-8.0). There were no
differences between cases and controls in clinical characteristics and
reason for iPFT evaluation. iPFT results showed no significant
differences between cases and controls in lung volumes, compliance, or
resistance. Expiratory airflow limitation was observed in both groups,
with better low lung volume flows in the SARS-CoV-2 group.
Categorization according to iPFT physiologic alteration and
bronchodilator responsiveness were similar in the two groups.
\textbf{Conclusion}: This study provides the first comprehensive iPFT
data in infants following a SARS-CoV-2 infection. The findings suggest
that SARS-CoV-2 infection does not cause unique long-term effects on
pulmonary function in infants with chronic respiratory symptoms. Further
studies in larger cohorts, particularly in infants with severe acute
SARS-CoV-2 infection, are warranted to validate these findings.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Since emerging in November 2019, the severe acute respiratory syndrome
coronavirus 2 (SARS-Cov-2) has rapidly spread worldwide, causing
coronavirus disease 2019 (COVID-19). Although patients of all ages are
affected, the illness among children and adolescents is generally milder
compared to adults, with up to 66\% being asymptomatic
\textsuperscript{1}. Unlike children and adolescents, the majority of
infants have been reported to be symptomatic, with fever, upper
respiratory symptoms, and decreased oral intake being the most common
clinical features \textsuperscript{2}.

While the acute-phase illness of SARS-CoV-2 is well established,
understanding its long-term consequence and its effect on chronic lung
morbidity is still evolving. Previous studies have evaluated pulmonary
function tests (PFT) in patients post SARS-Cov-2 infection to
objectively assess the long-term respiratory influence of the virus. In
adults, a reduction in diffusion capacity was the main finding,
significantly correlated to the severity of the acute
illness\textsuperscript{3--5}. Only a limited number of studies
evaluated PFT in pediatric patients following a SARS-Cov-2 infection.
Unlike in adults, these studies did not identify any abnormality in
expiratory flows, lung volumes or diffusion capacity
\textsuperscript{6--9}.

To our knowledge, despite significant respiratory COVID-19-symptoms
reported in infants, no study has explored PFT in this age group,
following an infection. The aim of this study was to assess whether
SARS-Cov-2 infection has long term effects on pulmonary functions in
infants.

\textbf{METHODS}

\textbf{Study population}

After institutional review board approval (0204-23-HMO), an
observational case-control study was conducted. Given the retrospective
nature of the study involving existing data, informed consent was
exempted. Cases included infants who were referred for iPFT by a
pediatric pulmonologist due to persistent respiratory complaints with a
documented SARS-CoV-2 infection during their course of illness.

Controls included all infants who underwent iPFT at our medical center
prior to the COVID-19 era (between 2008 and 2019). Demographic and
clinical parameters of these patients were retrieved from computerized
database. Excluded from the study were subjects with any diagnosis of
chronic or congenital disease, including; extreme prematurity, chronic
lung disease, congenital heart disease, pulmonary hypertension, Down's
syndrome, congenital diaphragmatic hernia, and infants who underwent
iPFT testing prior to bone marrow transplant. We further excluded from
the study infants in which the primary respiratory complaint for which
they underwent a respiratory evaluation, was not documented in their
medical file.

\textbf{Infant Pulmonary Function Testing (iPFT)}

All measurements were performed according to the ATS-ERS
guidelines\textsuperscript{10--12}. Infants were clinically stable for
at least 4 weeks prior to testing. Prior to testing, parental written
consent was obtained. Infants were sedated using 100--150mg/kg triclofos
sodium syrup or the equivalent 50-75mg/kg chloral hydrate syrup.

Prior to 2019, flows and volumes were measured via a custom made iPFT
device using a heated pneumotachograph (series 3700A, Hans Rudolph Inc.,
USA) connected via a low-dead-space Rendell Baker face mask to a
differential pressure transducer and signal conditioner set to 100 Hz
(SCIREQ TD-05 \& SC-24), as previously
described\textsuperscript{13--16}. Subsequent to 2019, flows and volumes
were measured using a commercial device MasterScreen BabyBody
(JAEGER/Vyaire). Differences in flow and volume measurements between the
two testing devices were normalized for all infants tested, regardless
of inclusion in current study.

iPFT measurements were uniform and included: Tidal breathing analysis
with measurements of respiratory rate (RR), tidal volume (Vt), and
Minute ventilation (MV); Baby-body plethysmograph for the measurement of
functional residual capacity (FRCpleth) and airway resistance (Raw);
Measurement of respiratory system compliance (Crs) with the multiple
breaths occlusion technique prior to 2019 (for the control group) and
with the single breath occlusion technique after 2019 (for the
SARS-CoV-2 group); and Tidal and raised rapid thoraco-abdominal
compression techniques for the measurements of forced expiratory airway
flows. Forced expiratory flow at FRC (V\selectlanguage{english}maxFRC) was obtained from the
tidal forced expiratory flow-volume curve, and the forced vital capacity
(FVC), forced expiratory volume after 0.5 sec (FEV\textsubscript{0.5})
and forced expiratory flows at 50\%, 75\% and 85\% of vital capacity
(FEF\textsubscript{50\%}, FEF\textsubscript{75\%} and
FEF\textsubscript{85\%}) from the raised-volume expiratory flow-volume
curve. Residual volume (RV) and total lung capacity (TLC) were
calculated from the results of the plethysmography measurements and of
maximal expiratory flow-volume curves.

Bronchodilator responsiveness (BDR) was defined positive if an
improvement of 20\% in the V\selectlanguage{english}maxFRC was documented twenty minutes after
an inhalation of nebulized salbutamol as previously
described\textsuperscript{17} or 4-5 puffs of Salbutamol inhaler
(100mccg/puff) via valve holding chamber.

Pulmonary function results of all infants included in the study were
categorized according to the physiological pattern
diagnosed\textsuperscript{18}: normal lung function pattern - V\selectlanguage{english}maxFRC
(\%pred)\textgreater{} 80\%, and FRC(\%pred) 80\% -110\%, and FVC(\%
pred)\textgreater{}80\%; Obstructive pattern - VmaxFRC(\% pred)
\textless{}80\% and FRC(\% pred)\textgreater{} 80\%; Restrictive pattern
- VmaxFRC(\%pred)\textless{}80\% and FRC(\% pred)\textless{}80\%; Mixed
pattern (obstructive and restrictive) - infants who do not meet any of
the previous criteria.

\textbf{Statistical Analysis}

Results were summarized by standard descriptive statistics and shown as
medians and interquartile range (IQR) for continuous variables, and
percentages for nominal variables. Differences between groups were
evaluated using the Mann--Whitney U test for continuous variables and
chi-square tests for categorical variables, as appropriate. Tests were
conducted using Stata, version 17 (StataCorp) with p-values of less than
0.05 considered significant.

\textbf{RESULTS}

\textbf{Study population}

Eighteen infants were referred to perform iPFT at our institution due to
persistent respiratory complaints with a documented SARS-CoV-2
infection. After exclusion of two infants (one infant due to Down's
syndrome and a congenital heart defect, and the other due to extreme
prematurity) sixteen infants were included as cases in the study (81\%
male), see figure 1 for patient selection and table 1 for additional
patient characteristics.

The most common respiratory complaints for which these 16 infants were
referred for further evaluation with iPFT were chronic or recurrent
cough (56\%), recurrent wheezing (19\%), and noisy breathing and
tachypnea (13\% each). Of these sixteen infants, twelve (75\%)
experienced a symptomatic acute COVID-19 illness, most commonly fever
(6/12 (50\%)), cough (5/12 (42\%)) and dyspnea (4/12 (33\%)). In 11
infants, the symptoms were mild. One late-preterm infant suffered a
severe neonatal COVID-19 disease with acute respiratory distress
syndrome (ARDS), following vertical transmission. Four infants
experienced an asymptomatic SARS-CoV-2 infection and were diagnosed
following an exposure to a symptomatic individual. The median age at the
time of the documented SARS-CoV-2 infection was 4.0 months,
interquartile range (IQR)=1.1-7.3 months.

The median age of cases at the time of the iPFT was 10.5 months (IQR =
7.0-13.5), with a median time of 5.5 months (IQR=2.8-8.0) between the
documentation of a SARS-CoV-2 infection and the respiratory evaluation
with iPFT.

Four hundred and seventy-five subjects were included as controls in the
study (65\% male, median age at the time of iPFT = 9.4 months,
IQR=7.0-13.1) (see figure 1 for patient selection). No statistically
significant differences were found between cases and controls in
baseline clinical characteristics and the reason for referral to perform
iPFT (table 1).

\textbf{iPFT performance}

Included in the study were iPFT measurements that met the American
Thoracic Society/European Respiratory Society
criteria\textsuperscript{11,12,19}. In all SARS-CoV-2 cases included in
the study, all iPFT performed were acceptable. Tidal breathing
measurements and tidal forced expiratory flow-volume curves for V\selectlanguage{english}maxFRC
measurements were acceptable in 471 (99\%) of control subjects.
Raised-volume rapid thoracoabdominal compression allowing measurements
of maximal expiratory flow-volume loops (FVC, FEV\textsubscript{0.5}
FEF\textsubscript{75\%}and FEF\textsubscript{85\%}) were acceptable in
455 (96\%) of control subjects and calculation of RV and TLC were
acceptable in 428 (90\%) of control subjects.

\textbf{iPFT results}

As a group, iPFT results in the SARS-CoV-2 group showed normal lung
volumes, normal lung compliance (Crs) and normal airway resistance (Raw)
(table 2). Expiratory flows in the SARS-CoV-2 group were mildly
decreased, mainly when assessing flows from the tidal expiratory
flow-volume curve (median (IQR) V\selectlanguage{english}maxFRC=60 (37-80) \%predicted).

When comparing the SARS-CoV-2 group to controls, no differences in tidal
breathing measurements, lung volumes, compliance nor resistance were
found. The SARS-CoV-2 group demonstrated slightly better expiratory
flows when compared to the control, mainly for low lung volumes (median
(IQR) FEF\textsubscript{85\%}=75 (48-98) in the SARS-CoV-2 group Vs.
FEF\textsubscript{85\%}=58 (43-77) in controls, p=0.035) (table 2).

Categorization according to iPFT pattern and bronchodilator
responsiveness, showed no significant difference between the SARS-CoV-2
group and the controls, neither in the occurrence of different iPFT
patterns, nor in the iPFT results (table 3). The majority of infants
tested in both groups demonstrated an obstructive iPFT pattern (63\% of
the SARS-CoV-2 group and 66\% of the controls, p=0.776) and only a
minority showed normal iPFT results (31\% of the SARS-CoV-2 group and
15\% of the controls, p=0.074). Infants in the SARS-CoV-2 group with an
obstructive lung disease pattern had similar iPFT results to controls.

Assessment of bronchodilator responsiveness (BDR) was available in 335
infants from our cohort (7 from the SARS-CoV-2 group and 328 controls).
A positive BDR was present in 21\% of the SARS-CoV-2 group and 22\% of
controls (p=0.904), see table 3.

In the SARS-CoV-2 group, abnormal pulmonary function tests were not
associated with a personal or familial history of atopy nor with
exposure to second-hand smoke. Data regarding atopy and second-hand
smoke exposure were not sufficiently available for the control group.

\textbf{The association between iPFT results and acute COVID-19
respiratory symptoms}

Of the sixteen included cases, 7 infants (44\%) experienced respiratory
symptoms (cough and/or dyspnea) during their COVID-19 illness. There was
no association between the presence of respiratory symptoms during the
acute COVID-19 illness and iPFT results (p\textgreater{}0.05 for all
evaluated indices). The one infant who had postnatal acute COVID-19
related ARDS had normal iPFT results at 2.7 months of age
(V\selectlanguage{english}maxFRC=119\%predicted, FEV\textsubscript{0.5}=98\%predicted,
FVC=93\%predicted and TLC=105\% predicted).

\textbf{DISCUSSION}

In this case control study, we present iPFT data in infants with
persistent respiratory complaints and a history of SARS-CoV-2 infection.
Our results show that when compared to a large control group of infants
who were evaluated at our center prior to the COVID-19 era, infants who
suffered an acute SARS-CoV-2 infection have very similar iPFT results.
This suggests that a SARS-CoV-2 infection does not have lasting impact
on pulmonary function in infants. Results from this study add data in
infants to the already present data in children regarding the minimal
long-term effect of SARS-CoV-2 infection on pulmonary function.

No prior study has evaluated pulmonary function tests in infants
recovering from a SARS-CoV-2 infection. Most studies that have evaluated
pulmonary function tests in children and adolescents with respiratory
symptoms following a SARS-CoV-2 infection, found no significant
differences in spirometry, body plethysmography, impulse oscillometry,
lung clearance index and diffusion lung capacity for carbon monoxide
(DLCO) results between the study groups and healthy children and
adolescents \textsuperscript{6--9}. One study found evidence of a mild
obstructive pattern, in 45\% of school age children with ongoing
cardiorespiratory symptoms following a SARS-CoV-2
infection\textsuperscript{20}. We evaluated children with persistent
respiratory complaints several months after a SARS-CoV-2 infection and
found evidence of mild expiratory airflow limitation present in 63\% of
cases. However, in some of the included cases the respiratory complaints
were present also prior to the SARS-CoV-2 infection, thus not
necessarily a result of the SARS-CoV-2 infection itself.

When comparing iPFT results of cases included in the study, to a large
group of infants evaluated at our center by iPFT prior to the COVID-19
pandemic, our study did not find any significant differences between the
two groups. Cases and controls had similar demographic features and
underwent a respiratory evaluation for similar persistent respiratory
complaints. Cases showed a similar distribution in the pattern of
pulmonary function tests results as the controls, with similar rates of
obstructive, restrictive, and normal iPFT results. A mild but
statistically significant difference in expiratory flow limitation was
observed, with greater prominence in the control group. However, this
difference lost significance when comparing only infants with an
obstructive pattern. Thus, our results do not show evidence of a
long-lasting effect of SARS-CoV-2 infection on iPFT. These findings are
clinically relevant in view of the limited available evidence regarding
the long-term sequela of SARS-CoV-2 infection in children and due to the
ongoing reports of chronic residual symptoms following a SARS-CoV-2
infection, collectively termed Long-COVID.

Long-COVID is an ill-defined sequela of SARS-CoV-2 infection. It
includes a wide range of ongoing, new or recurring symptom and there is
currently little agreement worldwide in its definition and
categorization \textsuperscript{21}. Only a few studies have
investigated persistent symptoms in young children and infants following
a SARS-CoV-2 infection, making the categorization and diagnosis of
long-COVID in young children difficult. Data that is available show that
preschool aged children take longer to recover from a SARS-CoV-2
infection when compared to older children and that the ongoing
respiratory conditions may persist up to six months among children aged
1-5 years \textsuperscript{22}. Epidemiological studies further report
an increase in the prevalence of respiratory symptoms, mainly cough and
difficulty breathing, in young children recovering from SARS-CoV-2
infection\textsuperscript{6--9,23--26}.

We evaluated infants with persistent respiratory complaints and a
history of SARS-CoV-2 infection. Some of the included cases presented
with respiratory symptoms prior to the SARS-CoV-2 infection, while
others only following the infection. However, the occurrence of a
SARS-CoV-2 infection in infants suffering from persistent respiratory
complaints, present for months, calls for consideration that these
ongoing symptoms are a manifestation of long-COVID. Furthermore, the
anxiety surrounding a SARS-CoV-2 infection and its unknown long-term
outcomes in children and infants \textsuperscript{27}, further augments
the attention for an association between the persistent respiratory
complaints and the SARS-CoV-2 infection. We did not find any distinct
clinical or physiological features in cases included in our study which
may characterize them as a group and differentiate them from infants
with persistent respiratory complaints never infected by SARS-CoV-2.
This suggests that the SARS-CoV-2 infection did not uniquely influence
the disease course in included cases. This is further supported by the
finding that no association was present between the severity of the
acute SARS-CoV-2 infection and the iPFT results. Indeed, many
controversies exist regarding the diagnosis of long-COVID and it is not
currently established whether the long-term effects of COVID-19 are
specific to a SARS-CoV-2 infection or are similar to other post-viral
syndromes frequent in infancy \textsuperscript{27}.

A main strength of our study is the comprehensive data of PFT in infants
following documented SARS-CoV-2 infection, which, to the best of our
knowledge, has not been previously reported in the literature. However,
our study has several limitations. The primary concern is that the iPFT
were conducted in infants with pre-existing respiratory complaints,
which in some were present before their SARS-CoV-2 infection. This means
that the assessment was not focused on testing previously healthy
infants with symptoms following a SARS-CoV-2 infection. To address this
bias, we did not compare our cases to controls with normal iPFT results
but to a large control group of infants who underwent iPFT due to
respiratory complains prior to the COVID-19 era, speculating that the
SARS-CoV-2 infection may cause characteristic clinical and physiological
abnormalities if associated with the ongoing symptoms. Other limitations
include the retrospective design with missing clinical information
regarding the control group and the inclusion of a small number of
cases.

In conclusion, we present iPFT results in infants following a SARS-CoV-2
infection. Our study demonstrates that pulmonary function tests (PFT) in
infants evaluated for various respiratory complaints, a few months after
a SARS-CoV-2 infection, are comparable to infants who underwent iPFT
prior to the COVID-19 era. These findings suggest that SARS-CoV-2
infection may not have a lasting impact on lung function in infants.
However, further studies are required, particularly in infants who
suffered a severe respiratory COVID-19 illness, to validate and
strengthen these findings.

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adolescents. BMJ 2022;376:o143.

\textbf{FIGURE LEGENDS}

\textbf{Figure 1:} study population selection from the Hadassah infant
pulmonary function tests (iPFT) database\textbf{.}\selectlanguage{english}
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\textbf{Hosted file}

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