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\begin{document}

\title{A 7-year-old Boy with Orchitis after COVID-19 Infection}



\author[1]{Hossein Ali  Ghaffaripour}%
\author[1]{Elham Sadati}%
\author[2]{Sara Haseli}%
\author[1]{Seyed Alireza  Mahdaviani}%
\author[1]{Zahra Daneshmandi}%
\author[1]{Ali Akbar Velayati}%
\author[1]{Parisa Honarpisheh}%
\affil[1]{Masih Daneshvari Hospital}%
\affil[2]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Although most manifestations of coronavirus infection in children are
mainly related to the respiratory and gastrointestinal organs,
involvement of other organs has also been seen with less prevalence.
Because of the expression of virus receptors in male genitalia, this
system is regarded as a potential target for this virus.%
\end{abstract}%



\sloppy


\textbf{A 7-year-old Boy with Orchitis after COVID-19 Infection}

\textbf{Hossein Ali Ghaffaripour\textsuperscript{1}, Elham
Sadati\textsuperscript{2}, Sara Haseli\textsuperscript{3}, Seyed Alireza
Mahdaviani\textsuperscript{4}, Zahra Daneshmandi\textsuperscript{5}, Ali
Akbar Velayati\textsuperscript{6}, Parisa
Honarpisheh\textsuperscript{7*}}

1. Assistant professor, Pediatric Respiratory Diseases Research Center,
National Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Department of Pediatrics, Masih Daneshvari Hospital, Tehran, Iran.
Email:

\emph{Ho\_ghaffaripour@yahoo.com}

2. Clinical pulmonologist, Pediatric Respiratory Diseases Research
Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Department of Pediatrics, Masih Daneshvari Hospital, Tehran,
Iran. Email:\emph{sadati.dr@gmail.com}

3. Assistant professor, Pediatric Respiratory Diseases Research Center,
National Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Department of Radiology, Masih Daneshvari Hospital, Tehran, Iran.
Email:\emph{sarahaseli@gmail.com}

4. Professor, Pediatric Respiratory Diseases Research Center, National
Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Department of allergy and immunology, Masih Daneshvari Hospital, Tehran,
Iran. Email:\emph{mahdavini@yahoo.com}

5. Clinical immunologist, Pediatric Respiratory Diseases Research
Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Department of allergy and immunology, Masih Daneshvari
Hospital, Tehran, Iran. Email:

\emph{daneshmandiz@yahoo.com}

6. Professor, Pediatric Respiratory Diseases Research Center, National
Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Department of Pediatrics, Tehran, Iran. Email:
\emph{velayati@theaasm.org}

7. Clinical nephrologist, Pediatric Respiratory Diseases Research
Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Department of Pediatrics, Masih Daneshvari Hospital, Tehran,
Iran. Email:\emph{parisa30m@yahoo.com}

\textsuperscript{\textbf{*}}\textbf{Corresponding author:}Parisa
Honarpisheh, Pediatric Respiratory Diseases Research Center, National
Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Department of Pediatrics, Tehran, Iran. Email: parisa30m@yahoo.com,
ORCID: 0000-0001-5889-9475\textbf{Address:} Masih Daneshvari Hospital,
Darabad Avenue, Niavaran st., Tehran, Iran. ZIP: 1956944413\textbf{Phone
number:} +9821-27123000, +989133619890\textbf{Fax number:}
26109680-26109484

\textbf{Abstract} : Although most manifestations of coronavirus
infection in children are mainly related to the respiratory and
gastrointestinal organs, involvement of other organs has also been seen
with less prevalence.~Although little is known about its impact on male
genitalia, because of the expression of virus receptors in male
genitalia, the genital system is regarded as at risk for this virus and
may be a potential target for this virus. In this case, we reported
orchitis following COVID-19 infection in a 7-year-old boy who developed
orchitis in the third week of the disease. Orchitis was diagnosed based
on clinical and radiological investigations and recovered spontaneously
with supportive care. This case highlights this virus can enter testes
and cause virus-induced orchitis and orchitis should be considered one
of the rare complications of COVID-19.

\textbf{Keywords} : COVID-19, orchitis, scrotal discomfort

\textbf{Introduction}

Coronavirus disease 2019 (COVID-19) is still spreading worldwide and
infects all age groups. Initially, fewer children were affected;
therefore, many features of this disease, especially atypical
manifestations, have not yet been identified in this population, and
further time is needed to clarify it. Developed symptoms have changed
over time, and the emergence of new strains and virus mutations
contribute to these changes (1). In symptomatic children, the most
common reported symptoms were fever, upper and lower airway infection,
and gastrointestinal symptoms. Genitalia complaints seem to be rare in
COVID-19 patients, especially in children and there are few reports of
scrotal discomfort (2).

\textbf{Case presentation}

A 7-year-old boy was admitted to our outpatient clinic with a history of
fever, myalgia, diarrhea, nausea, vomiting, and severe and nonproductive
coughs. Fever ceased after 4 days, but the cough continued, especially
at night. Oxygen saturation was 96\%, and the respiratory rate was 17
per minute. The only finding in the examination was expiratory wheezing.
He had a previous history of asthma that was well-controlled. Regarding
the mentioned symptoms, COVID-19 was suspected, and a nasopharyngeal
swab polymerase chain reaction (PCR) test for COVID-19 was performed.
COVID-19 PCR was positive. Biochemical and hematologic tests showed
lymphopenia (WBC: 3400, lymph: 26\%) and a mild increase in aspartate
aminotransferase (AST), lactate dehydrogenase (LDH), and D-dimer {[}AST:
65 (NL: \textless{} 40 IU/L), LDH: 540 (NL: \textless{} 170 Units/lit),
D-dimer: 800 (NL: \textless{}500 ng/ml){]}. The child underwent
outpatient treatment with montelukast 5 mg daily, one puff Symbicort
inhaler 160 mcg twice a day, and acetaminophen. At the follow-up visit,
the patient's symptoms resolved after 5 days, but erythematous itchy
lesions on the palmar and plantar surfaces appeared, which resolved
spontaneously. In the 3rd week of the disease, the child was admitted to
the emergency department with swelling, pain, and erythema in one of the
testicles (Figure 1).

The pain had a gradual onset and became more intense in the next days,
woke up the child, and made him uncomfortable while seated. The patient
had no history of recent trauma. The right testis was erythematous and
tender and was located in the normal position on physical examination.
There was no groin lymphadenopathy, and bilateral cremasteric reflexes
were intact. Regarding severe scrotal pain to rule out torsion of the
testis or testicular appendage, a color Doppler ultrasound (DUS) was
performed which shows edematous scrotal wall thickening and extensive
hyperemia of the right testicle that all are indicative of orchitis
(Figure 2).

The patient was diagnosed with orchitis associated with COVID-19 and
underwent conservative treatment. In the periodic follow-up, the pain
was reduced, and it was completely resolved approximately two weeks
later.

\textbf{Discussion}

Although coronavirus mainly affects the lungs, many other organs are
involved in the disease (3). Several factors have been involved in the
development of COVID-19 infection. Entry of SARS-COV-2 into target cells
is a significant determinant of coronavirus infection. Coronavirus first
binds to ACE2 (angiotensin-converting enzyme 2) as a cell surface
receptor, and after viral attachment, cell surface protease activators
such as TMPRSS2 (transmembrane serine protease SS2) activate coronavirus
entry (4). ACE2 and TMPRSS2 are expressed in various tissues, including
the male urogenital, making it vulnerable to SARS-COV-2 infection (5).
ACE2 is present in almost all testis cells, especially Sertoli cells.
Xixi Liu et al. through single-cell transcriptome analysis of male germ
cells reported ACE2 expression in male testis (6)which reflects that the
genital system is regarded as at risk for this virus and may be a
potential target for this virus. To date, there are few reports about
male genitalia involvement in the setting of COVID-19. The first case of
orchiepididymitis associated with COVID-19 was reported in a 14-year-old
boy in Italy (7). After that, M.Haydar et al reported a case of
epididymitis in the setting of MIS-C (multisystem inflammatory syndrome
in children) in a 7- year-old boy from Syria (8). In a systematic review
conducted on 575 patients, including 538 males, scrotal discomfort,
swelling, pain, and erythema were described in 39 patients, among whom
acute orchitis was found in 10 patients and acute orchiepididymitis in
10(3). Other reported cases of genitourinary complications of SARS-COV-2
were mainly adults (9)(10)(11)(12) (Table 1). Scrotal pain is a
diagnostic challenge in children that necessitates accurate evaluation.
The most common causes of acute scrotal pain in children include
testicular torsion, appendix testis torsion, orchitis, and epididymitis.
The most important reason for scrotal discomfort is testicular torsion,
a surgical emergency that requires immediate diagnosis and treatment
(13). DUS is the choice modality for ruling out scrotal torsion from
other causes of scrotal discomfort and determining the presence of blood
flow (14). Orchitis is a local inflammation associated with abrupt onset
of testicular pain and swollen and tender testicles in examination
findings and hypoechoic and hypervascular areas in ultrasound. The
cremasteric reflex is intact, and the testis is in its normal anatomic
location. Orchitis in children usually occurs secondary to viral
infections, most commonly mumps virus. Less commonly, it is caused by
bacterial organisms, and in these conditions, orchitis occurs as a
result of the spreading of infection from epididymitis. Treatment of
orchitis depends on the underlying cause, and in viral cases, supportive
treatments such as analgesics, bed rest, hot or ice pack, and scrotal
elevation are used, and symptoms will go away on their own (15).

\textbf{Conclusion} : This case highlights the importance of follow-up
of COVID-19 patients and the consideration of orchitis as a consequence
of COVID-19.

\textbf{Abbreviations:}

COVID-19: coronavirus disease 2019

ACE2: Angiotensin-converting enzyme 2

TMPRSS2: Transmembrane serine protease SS2

DUS: Doppler ultrasound

PCR: polymerase chain reaction

\textbf{Acknowledgment:} The authors of this article would like to
express special thanks to the patient for consent to the publication of
her images and clinical history.

\textbf{Conflict of Interest:} The authors declare that they have no
conflict of interest.

\textbf{consent:} Informed consent was obtained from the patient.

\textbf{Funding:} No funding to declare.

\textbf{Author contributions:}

H.A Ghaffaripour and P. Honarpisheh: Writing the original draft

E. Sadati and S.A. Mahdaviani: Editing the manuscript

S.Haseli: Radiologic evaluation of patient

Z. daneshmandi: Gathering data

A.A. Velayati: Conceptualization

\textbf{References:}

1. Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: a new chapter in the
COVID-19 pandemic. Lancet. 2021;398(10317):2126--8.

2. Creta M, Sagnelli C, Celentano G, Napolitano L, La Rocca R, Capece M,
et al. SARS-CoV-2 infection affects the lower urinary tract and male
genital system: A systematic review. J Med Virol. 2021;93(5):3133--42.

3. da Rosa Mesquita R, Francelino Silva Junior LC, Santos Santana FM,
Farias de Oliveira T, Campos Alc\selectlanguage{ngerman}ântara R, Monteiro Arnozo G, et al.
Clinical manifestations of COVID-19 in the general population:
systematic review. Wien Klin Wochenschr {[}Internet{]}. 2020/11/26. 2021
Apr;133(7--8):377--82. Available from:
https://pubmed.ncbi.nlm.nih.gov/33242148

4. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry
mechanisms of SARS-CoV-2. Proc Natl Acad Sci. 2020;117(21):11727--34.

5. Sheikhzadeh Hesari F, Hosseinzadeh SS, Asl Monadi Sardroud MA. Review
of COVID\selectlanguage{english}-19 and male genital tract. Andrologia. 2021;53(1):e13914.

6. Liu X, Chen Y, Tang W, Zhang L, Chen W, Yan Z, et al. Single-cell
transcriptome analysis of the novel coronavirus (SARS-CoV-2) associated
gene ACE2 expression in normal and non-obstructive azoospermia (NOA)
human male testes. Sci China Life Sci. 2020;63(7):1006--15.

7. Gagliardi L, Bertacca C, Centenari C, Merusi I, Parolo E, Ragazzo V,
et al. Orchiepididymitis in a boy with COVID-19. Pediatr Infect Dis J.
2020;39(8):e200--2.

8. Haydar M, Baghdadi S, Taleb M, Al-Dali B, Badr H, Ghanem Y.
Orchiepididymitis in the context of multisystem inflammatory syndrome in
a child with Covid-19 from Syria: a very rare presentation for
SARS-Cov-19 in children. Oxford Med Case Reports. 2021;2021(7):omab052.

9. Whiteley MS, Abu-Bakr O, Holdstock JM. Testicular vein thrombosis
mimicking epididymo-orchitis after suspected Covid-19 infection. SAGE
Open Med Case Reports. 2021;9:2050313X211022425.

10. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a
complication of severe acute respiratory syndrome (SARS). Biol Reprod.
2006;74(2):410--6.

11. Duarte SAC, Pereira JG, Iscaife A, Leite KRM, Antunes AA. Is
prostate infarction and acute urinary retention a possible complication
of severe COVID-19 infection? Pathology. 2020;52(7):818--21.

12. Bridwell RE, Merrill DR, Griffith SA, Wray J, Oliver JJ. A
coronavirus disease 2019 (COVID-19) patient with bilateral orchitis. Am
J Emerg Med. 2021;42:260-e3.

13. Schalamon J, Ainoedhofer H, Schleef J, Singer G, Haxhija EQ,
Hollwarth ME. Management of acute scrotum in children---the impact of
Doppler ultrasound. J Pediatr Surg. 2006;41(8):1377--80.

14. Lev M, Ramon J, Mor Y, Jacobson JM, Soudack M. Sonographic
appearances of torsion of the appendix testis and appendix epididymis in
children. J Clin Ultrasound. 2015;43(8):485--9.

15. Khanna K, Liu DR. Epididymitis and orchitis. Fleisher Ludwig's
5-Minute Pediatr Emerg Med Consult. 2012;79(7):583--7.

\textbf{Table 1- Genitourinary Complications of SARS-COV-2}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Author & Number of patients & Age of patients(year) & Effects on
testis\tabularnewline
\midrule
\endhead
Whiteley MS, et al.\textsuperscript{9} & 1 & 70 & Left testicular vein
thrombosis\tabularnewline
Xu J, et al. \textsuperscript{10} & 5 & 20-58 & Apoptosis in
spermatogenetic cells and in a few of leydig cells\tabularnewline
Duarte SAC, et al. \textsuperscript{11} & 1 & 71 & Ischemic prostatic
infraction and acute urinary retention\tabularnewline
Bridwell RE, et al.\textsuperscript{12} & 1 & 37 & Bilateral
orchitis\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig 1.} \textbf{Testicle involvement after coronavirus
infection} : erythema and mild swelling in the right testis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig 2.} \textbf{Color Doppler of the testis:} Longitudinal
ultrasound of the right scrotum shows edematous scrotal wall thickening
as well as extensive hyperemia of the right testicle on color doppler
which all are indicative of orchitis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig-1/fig-1}

\end{center}
\end{figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig-2/fig-2}

\end{center}
\end{figure}

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