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\begin{document}

\title{Silent RSV in infants with SARS-CoV-2 infection: a case series}



\author[1]{Antonietta Giannattasio}%
\author[1]{Marco Maglione}%
\author[1]{Carolina D'Anna}%
\author[1]{Stefania Muzzica}%
\author[1]{Francesca Angrisani}%
\author[1]{Sabrina Acierno}%
\author[2]{Alessandro Perrella}%
\author[1]{Vincenzo Tipo}%
\affil[1]{AORN Santobono Pausilipon}%
\affil[2]{AORN Cardarelli}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{Silent RSV in infants with SARS-CoV-2 infection: a case series}

Antonietta Giannattasio, MD, PhD\textsuperscript{1}, Marco Maglione, MD,
PhD\textsuperscript{1}, Carolina D'Anna, MD\textsuperscript{1}, Stefania
Muzzica, MD\textsuperscript{1}\textsubscript{,}Francesca Angrisani,
MD\textsuperscript{1}, Sabrina Acierno, MD\textsuperscript{1},
Alessandro Perrella\textsuperscript{2}, MD, PhD\textsuperscript{2},
Vincenzo Tipo, MD\textsuperscript{1}

\textsuperscript{1}Santobono-Pausilipon Children's Hospital, Pediatric
Emergency and Short Stay Unit, Naples, Italy

\textsuperscript{2}Cardarelli Hospital, Infectious Disease-Health Policy
Direction, Naples, Italy

\textbf{Correspondingauthor:}

Antonietta Giannattasio, MD, PhD

Pediatric Emergency and Short Stay Unit,

Santobono-Pausilipon Children's Hospital, Naples, Italy

+39 3392695959

\emph{antonella.giannattasio@virgilio.it}

\textbf{Keywords:} SARS-CoV-2; respiratory syncytial virus; infants;
outcome.

\textbf{Abbreviated title:} SARS-CoV-2 and VRS co-infection in infants

To the Editor,

We deeply commend Rotulo et al. in a recent issue of Pediatric
Pulmonology on their hypothesis regarding the possible role of an
undiagnosed severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)infection in determining a peak of severe cases of
bronchiolitis during early 2020, just before the pandemic outbreak in
Italy.\textsuperscript{1}

Given the limited prevalence of severe SARS-CoV-2 infection in children
compared to adults, the role of coexistent infection by other pathogens
is of particular interest, as its potential to worsen the clinical
expression of the disease is yet to be determined. During the SARS-CoV-2
pandemic, the number of accesses to emergency departments because of
viral infections other than SARS-CoV-2 has been significantly lower in
comparison to non-pandemic years.\textsuperscript{2} On the other hand,
respiratory syncytial virus(RSV), the main responsible of bronchiolitis,
representsa traditionally important cause of hospitalization in children
under 12 months of age.\textsuperscript{1} To date, clinical course of
SARS-CoV-2 and RSV co-infection has been poorly described and its impact
on patients' outcomes has not been clarified.We described clinical
features and outcome of 6 infants from the Coronavirus disease 2019
(COVID-19) Unit of a tertiary care pediatrichospital who were
co-infected with both SARS-CoV-2 and RSV.

A total of 97infants under 1 year of age with SARS-CoV-2 infection were
hospitalized at our Pediatric COVID Unit between December
1\textsuperscript{st}, 2020 and March 30\textsuperscript{th}, 2021.
Among them, 6 had SARS-CoV-2 and RSV co-infection at admission.
SARS-CoV-2 was searched by real-time PCR (RT-PCR) on nasopharyngeal
swab. RSV was searched by direct detection of viral antigens on
nasopharyngeal swab. Patients' characteristics are reported
in\textbf{Table} .

Patient 1 was admitted because of a 2-day-history of cough. Physical
examination was unremarkable, with no respiratory distress or
gastrointestinal symptoms and good oxygen saturation. Blood tests
revealed a slight increase of C-reactive protein (CRP) levels, normal
procalcitonin (PCT) and lymphomonocitosys. Chest X-ray upon admission
was normal.

Patient 2 was admitted for fever and cough occurred in the previous 24
hours. She had a previously diagnosed compensated interatrial defect.
Parents were already positive to SARS-CoV-2 before hospital admission.
At examination the infant had mild pharyngitis, coarse pulmonary
cracklesand mild subcostal retractions. Blood laboratory investigations
only showed lymphomonocytosis. During the hospital stay she presented no
significant dyspnea or other symptoms.

Patient 3 was admitted fordyspneathat occurred a fewhours ago. Mother
was positive for SARS-CoV-2. At admission the infant was alert with mild
subcostal retractions and good oxygen saturation. Blood tests revealed
elevated ferritin (1054 ng/ml, n.r. \textless{}320) and monocytosis.
Chest X-ray was unremarkable. During hospital stay she presented mild
diarrhea with no dehydration.

Patient 4 was admitted for fever, whooping cough and vomiting occurred
in the previous few hours. Both parents were already positive for
SARS-CoV-2. At examination the infant had pharyngitis and a mild
respiratory distress with an oxygen saturation of 95\%. Blood tests
revealed lymphocytosis. The clinical course was unremarkable and no
dyspnea or other symptoms occurred.

Patient 5 was admitted for fever occurred one day before. Parents
resulted positive for SARS-CoV-2 infection. Blood tests showed high
ferritin and lymphomonocytosis. Clinical course was unremarkable.

Patient 6 was admitted forrespiratory distress since the day before. She
had a history a perinatal pneumothorax and a neonatal sepsis. Physical
examination revealed sporadic rales. Chest X-ray showed small areas of
linear consolidation in the left lower lobe. She had an unremarkable
hospital stay.

No patient required oxygen supplementation or other treatments during
the hospital stay.

Patients with SARS-CoV-2 infection can be co-infected with other
respiratory viruses or bacterial pathogens.\textsuperscript{3}In adults,
no significant difference in patient outcomes was observed between the
simple SARS-CoV-2 and co-infected groups.\textsuperscript{3} However,
data on RSV-SARS-CoV-2 co-infected patients were not described
separately.\textsuperscript{3}Whether the combined RSV-SARS-CoV-2
infection in infants results in worse clinical expression compared to
the infection by the single viruses is still unclear. Jiang et al
reported a child infected with SARS-COV-2, RSV and human metapneumovirus
who developed severe respiratory symptoms requiring intensive care, with
ground glass opacities at chest computed
tomography.\textsuperscript{4}This finding, typical of COVID-19,
suggested that the main responsible of the severe clinical course in
this patient was SARS-CoV-2 rather than the other 2 viruses
detected.Similarly, Rotulo and coworkers hypothesized a role of
SARS-CoV2 in the more severe course of cases of bronchiolitis occurred
during the first 3 months of 2020.\textsuperscript{1} They reported
that, in comparison to previous years, during early 2020 a higher
proportion of infants with bronchiolitis required oxygen
supplementation.\textsuperscript{1}Nevertheless, their reasonable
speculations mostly rely on the assumption that SARS-CoV-2was likely to
circulate in Italy already since the end of 2019, but are not supported
by viral detection, as at the time RT-PCR for this pathogen was not
available yet.Our data do not support the hypothesis that the combined
RSV-SARS-CoV-2 infection leads to a more severe clinical picture, as our
patients only presented mild fever and respiratory symptoms with an
uncomplicated evolution.

These apparently conflicting data likely derive from the patients
included in the available studies. Indeed, RSV is known to be of scarce
clinical relevance in adults, but it may cause severe respiratory
disease in infants. Therefore, one could speculate that no worse
clinical expression was found in patients with combined RSV and
SARS-CoV-2 infection due to the fact that in adults RSV is generally not
responsible for significant symptoms. However, unexpectedly, our results
confirm that, also in infants, RSV coexistence does not worsen COVID-19
symptoms. A very recent study showed that pathways for over-expressed
genes are highly concordant between patients with SARS-CoV-2 and
non-SARS-CoV-2 viral infections.\textsuperscript{5} We can speculate
that, in co-infected patients, increased SARS-CoV-2 viral replication
may occur compared to concomitant other viruses, due to the
characteristics of infectivity and replication of SARS-CoV-2. As
COVID-19 in children is a mild disease in the majority of
cases,\textsuperscript{6} it is possible to hypothesize that, in
co-infected children, SARS-CoV-2 overbears RSV, inhibiting its
replication and thus its clinical expression. Further studies are
mandatory in order to investigate the clinical course of RSV in infants
with a concomitant SARS-CoV-2 infection.

\textbf{Competing interests:} Authors state no conflict of interest.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Rotulo GA, Casalini E, Brisca G, Piccotti E, Castagnola E. Unexpected
  peak of bronchiolitis requiring oxygen therapy in February 2020: Could
  an undetected SARS-CoV2-RSV co-infection be the
  cause?\emph{PediatrPulmonol} . 2021 Mar 3. (Online ahead of print).
\item
  Dopfer C, Wetzke M, ZychlinskyScharff A,Mueller F,Dressler F, Baumann
  U, Sasse M, Hansen G, Jablonka A, Happle C. COVID-19 related reduction
  in pediatric emergency healthcare utilization--a concerning
  trend.\emph{BMC Pediatr.} 20, 427 (2020).
\item
  Ma L, Wang W, Le Grange JM, Wang X, Du S, Li C, Wei J, Zhang JN.
  Coinfection of SARS-CoV-2 and Other Respiratory Pathogens.\emph{Infect
  Drug Resist} . 2020;13:3045-3053.
\item
  Jiang S,~ Liu P,~Xiong G,~Yang Z,~Wang M,~Li~Y, Yu X. Coinfection of
  SARS-CoV-2 and multiple respiratory pathogens in
  children.\emph{ClinChem Lab Med.}2020;58:1160--1161.
\item
  Thair SA, He YD, Hasin-Brumshtein Y, Sakaram S, Pandya R, Toh J,
  Rawling D, Remmel M, Coyle S, Dalekos GN, et al. Transcriptomic
  similarities and differences in host response between SARS-CoV-2 and
  other viral infections. \emph{iScience.} 2021;24:101947.
\item
  Garazzino S, Montagnani C, Don\selectlanguage{ngerman}à D, Meini A, Felici E, Vergine G,
  Bernardi S, Giacchero R, Lo Vecchio A, Marchisio P, et al.; Italian
  SITIP-SIP Pediatric Infection Study Group; et al. Italian SITIP-SIP
  SARS-CoV-2 paediatric infection study group. Multicentre Italian study
  of SARS-CoV-2 infection in children and adolescents, preliminary data
  as at 10 April 2020. \emph{Euro Surveill}. 2020;25:2000600.
\end{enumerate}

\textbf{Table. Characteristics of 6 infants with SARS-CoV-2 and RSV
co-infection}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 1\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 2\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 3\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 4\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 5\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Patient 6\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19 days\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 months\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18 days\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 months\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24 days\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 month\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Gender}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Gestational age (weeks)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
37\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Duration of hospital stay (days)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Peak temperature (°C)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
37.1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
36.5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
37.8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
36.8\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Lowest oxygen saturation (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
99\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
95\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
98\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
95\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
99\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Clinical findings:}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Systemic\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Fever\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Fever\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Respiratory\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cough\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cough, big bubble rales, slight subcostal retraction\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dyspnea, slight subcostal retraction\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mild respiratory distress\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Unremarkable\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Sporadic rales\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gastrointestinal\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Diarrhea\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Vomit\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Inflammatory index:}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CRP highest value\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7.39\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.53\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.57\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.01\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.32\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.27\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PCT highest value\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.06\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.08\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.22\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ferritin highest value\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
338\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
58.8\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1054\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
39.4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
671\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
36\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Blood count (x10\textsuperscript{9} cells/L):} Leukocytes
Neutrophils Lymphocytes Monocytes\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.76 1.88 11.38 2.33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13.50 3.73 7.15 2.52\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9.49 2.39 4.20 2.54\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23.19 7.94 12.24 2.85\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11.30 3.16 5.99 2.11\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9.58 2.18 6.06 1.23\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

CRP: C-reativeprotein (n.v.\textless{}5 mg/L); PCT: procalcitonin (n.v.
\textless{}0.5ng/ml); ferritin: n.v. \textless{}320ng/ml

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