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\begin{document}

\title{``To the Editor'' COVID19-associated unilateral transient phrenic nerve
palsy in a young child with respiratory failure}



\author[1]{Pierre Goussard}%
\author[1]{Regan Solomons}%
\author[1]{Magriet van Niekerk}%
\author[1]{Noor Parker}%
\author[1]{Carien Bekker}%
\author[1]{Andre Gie}%
\author[1]{M Van der Zalm}%
\author[2]{Savvas Andronikou}%
\author[1]{Helena Rabie}%
\author[1]{Ronald van Toorn}%
\affil[1]{Stellenbosch University Faculty of Medicine and Health Sciences}%
\affil[2]{Department of Pediatric Radiology The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
We describe a case of unilateral phrenic nerve palsy due to SARS-COV-2
in a young child, which led to prolonged and complicated ventilation.
The child was treated with methylprednisolone and IVIG, which led to a
complete recovery of phrenic function. Temporary involvement of the
phrenic nerve should be considered in children infected with SARS-COV-2
requiring prolonged ventilation. The phrenic nerve palsy is postulated
to be due to peripheral nerve involvement by SARS-CoV-2. In South
Africa, children under 12 years of age are not prioritized for
SARS-CoV-2 vaccination. This case re-iterates that even though
SARS-CoV-2 disease is mild in the vast majority of children there are
more severe presentations which, in low- or middle-income countries,
might even go unrecognized.%
\end{abstract}%



\sloppy


\textbf{``To the Editor''}

\textbf{COVID19-associated unilateral transient phrenic nerve palsy in a
young child with respiratory failure}

Pierre Goussard PhD\textsuperscript{1}, Regan Solomons
PhD\textsuperscript{1}, Magriet van Niekerk FC Paed
(SA)\textsuperscript{1}, Noor Parker FC Paed (SA)\textsuperscript{1},
Carien Bekker FC Paed (SA)\textsuperscript{1} Andre Gie
PhD\textsuperscript{1}, Marieke M. van der Zalm PhD\textsuperscript{1},
Savvas Andronikou PhD\textsuperscript{2,3}, Helena Rabie
PhD\textsuperscript{1}, Ronald van Toorn PhD\textsuperscript{1}

\textsuperscript{1}Department of Paediatrics and Child Health, Faculty
of Medicine and Health Sciences, Stellenbosch University and Tygerberg
Hospital, Cape Town, South Africa.

\textsuperscript{2}Department of Pediatric Radiology, The Children's
Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

\textsuperscript{3}Department of Radiology, Perelman School, of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

\textbf{Address for correspondence}

Prof Pierre Goussard, Department of Paediatrics and Child Health,
Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box
241, Cape Town 8000, South Africa. Tel +27-21-938-9506; Fax
+27-21-938-9138; Email pgouss@sun.ac.za

\textbf{Keywords} : SARS-COV-2, unilateral phrenic nerve paralysis,
brachial plexopathy, lung collapse

We describe the case of a 4-year 11-month-old boy who presented to the
emergency department with right-sided focal motor status epilepticus.
The caregivers reported a normal birth and developmental history, no
family history of epilepsy, no exposure to trauma and no household
tuberculosis or COVID contacts. Examination revealed that he was
febrile; hypoxic and comatose (Glasgow Coma scale of 7/15) which
necessitated transfer to the pediatric intensive care unit (PICU) for
intermittent positive pressure ventilation. A low blood glucose level
(1.3 mmol/L) required correction with intravenous dextrose infusion.
There were no focal neurological signs, signs of raised intracranial
pressure or meningism. Respiratory examination revealed reduced
ventilation in the right middle and lower lobes. Examination of the
cardiovascular and abdominal systems proved unremarkable.

Blood investigations revealed normal full blood count and electrolytes,
and slightly elevated C-reactive protein (27 mg/L). Cerebrospinal fluid
(CSF) analysis revealed a clear and colorless macroscopic appearance
with 20 lymphocytes/\selectlanguage{greek}μ\selectlanguage{english}L, no polymorphs and normal biochemistry. CSF viral
panel (including Herpes simplex PCR) and CSF NMDA receptor antibodies
proved negative. Chest radiography demonstrated atelectasis of the right
lower and middle lobes. (Figure 1a) Tracheal aspirate microbiological
confirmation of \emph{Mycobacterium tuberculosis} proved negative by
Xpert MTB/RIF Ultra, microscopy and culture. The SARS-CoV-2 polymerase
chain reaction (PCR) was indeterminate twice, but the SARS-CoV-2 IgG was
positive. Contrasted cerebral computed tomography (CT) and subsequent
magnetic resonance imaging (MRI) proved normal.

Patient was empirically started on ceftriaxone (100 mg/kg/day),
acyclovir (30 mg/kg/day) and anti-tuberculous meningitis medication
which included rifampicin (20 mg/kg/day), isoniazid (20 mg/kg/day),
pyrazinamide (40 mg/kg/day) and ethionamide (20 mg/kg/day).
Methylprednisolone (pulse therapy 30mg/kg /day for 3 days) and
intravenous immune globulin (IVIG) (2g/kg over 2 days) were given to
cover the possibility of an autoimmune encephalitis.

On day 3, the patient was extubated to high-flow nasal cannula (HFNC)
oxygen but within hours required re-intubation due to worsening of
respiratory distress and persistence of depressed consciousness.
Bronchoscopy was performed with a 3.5 mm video bronchoscope due to
complete collapse of the right lung. (Figure 1b and 2a) The right main
bronchus was completely obstructed with mucus, which was cleared. On day
4 of ventilation, it was noted on the chest radiograph and subsequent
lung ultrasound that the patient had a right upper lobe collapse
consolidation and a very high right hemi-diaphragm. (Figure 1c)

The patient required ventilator support for 9 days followed by 2 further
days of supplementary nasal cannula oxygen. With normalization of
consciousness, it became apparent that the child also exhibited right
upper arm and shoulder weakness (grade 3/5) of a lower motor neuron
nature. Grasp was preserved. The right arm weakness responded favorably
to physiotherapy and full recovery of power was noted after 17 days in
hospital. Phrenic nerve conduction studies were planned but cancelled
after the complete recovery. Repeat chest radiography and ultrasound
prior to discharge on day 20 revealed persistence of the right sided
hemi-diaphragm paralysis. (Figure 1e and 2b) Clinical and radiological
review 56 days after presentation revealed complete resolution of the
right hemi-diaphragm. (Figure 1f)

The parents gave consent for the publication of this case report. The
study was approved by the Stellenbosch University Health Research Ethics
Committee (N20/04/013\_COVID-019).

Case reports and case series exist that report phrenic palsy-related
diaphragmatic weakness in adults with acute COVID-19 infection related
pneumonia. {[}1,2{]} Adbeldayem et al. reported incidental unilateral
diaphragmatic paralysis in 1.5\% (23 out of 1527) on CT scans in adult
patients with COVID-19 pneumonia. Twenty-one patients had shown complete
recovery of the associated diaphragmatic paralysis at follow-up chest
CT. {[}2{]}

Phrenic nerve palsy should also be excluded in adults with long COVID-19
suffering from prolonged dyspnea.{[}2{]} The case reported is unique as
it involves a child with unilateral phrenic nerve paralysis without any
cardiac, pleural, parenchymal or vascular pulmonary abnormalities. In
addition to the phrenic nerve palsy, the child also exhibited other
COVID-19 related neurological symptoms which included encephalitis with
seizures and ipsilateral shoulder and upper limb weakness secondary to
an associated brachial plexopathy.

The neurological features of the SARS-CoV-2 virus are highly variable,
involving the central and peripheral nervous system, both through acute
infection or post-infectious inflammation pathways. Neurological
manifestations described in children include
meningitis/encephalitis/encephalopathy; seizures, stroke, and loss of
smell and taste (anosmia and ageusia). Peripheral nerve manifestations
include Guillain-Barr\selectlanguage{ngerman}é syndrome, cranial nerve palsies (facial and
abducens), optic neuritis and unilateral vocal cord paralysis. {[}3,4{]}
It is likely that the diaphragmatic paralysis and ipsilateral shoulder
and upper limb weakness in this patient can be attributed to a brachial
plexopathy. The phrenic nerve originates mainly from the
4\textsuperscript{th} cervical nerve, but also receives contributions
from the 3\textsuperscript{rd} and 5\textsuperscript{th} cervical
nerves. The fever, seizures, depressed level of consciousness,
inflammatory CSF response and normal neuroimaging suggests the presence
of a concomitant encephalitis.

Multiple mechanisms of neurological involvement by the virus have been
postulated, including direct neuro-invasion (attachment to the neuronal
ACE-2 receptors, via the olfactory nerve) or immune-mediated
pathogenesis (impairment of function by pro-inflammatory
cytokines).{[}5{]} We postulate that the neurological manifestations of
COVID-19 in our patient is likely a consequence of an immune-mediated
phenomena. This is supported by the favorable response and full recovery
following administration of high dose corticosteroids and intravenous
immunoglobulins and the presence of SARS-CoV-s IgG. The absence of
anosmia and dysgeusia also argues against direct viral invasion. CSF
SARS-CoV-2 and CSF cytokine analysis was not performed in this patient.
The majority of adults with COVID-19 related phrenic nerve palsy
spontaneously recover.

We describe a case of unilateral phrenic nerve palsy due to SARS-COV-2
in a young child, which led to prolonged and complicated ventilation.
The child was treated with methylprednisolone and IVIG, which led to a
complete recovery of phrenic function. Temporary involvement of the
phrenic nerve should be considered in children infected with SARS-COV-2
requiring prolonged ventilation. The phrenic nerve palsy is postulated
to be due to peripheral nerve involvement by SARS-CoV-2. In South
Africa, children under 12 years of age are not prioritized for
SARS-CoV-2 vaccination. This case re-iterates that even though
SARS-CoV-2 disease is mild in the vast majority of children there are
more severe presentations which, in low- or middle-income countries,
might even go unrecognized.

\textbf{CONSENT FOR PUBLICATION}

The parents gave consent for the publication of this case report. The
study was approved by the Stellenbosch University Health Research Ethics
Committee (N20/04/013\_COVID\selectlanguage{english}-019).

\textbf{CONFLICT OF INTEREST}

The authors declare that they have no conflict of interest.

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Abdeldayem, E.H., Abdelrahman, A.S. \& Mansour, M.G. Recognition of
  phrenic paralysis as atypical presentation during CT chest examination
  of COVID-19 infection and its correlation with CT severity scoring: a
  local experience during pandemic era.~\emph{Egypt J Radiol Nucl
  Med.}2021;52:156.
\item
  Maurier F, Godbert B, Perrin J. Respiratory Distress in SARS-CoV-2
  without Lung Damage: Phrenic Paralysis Should Be Considered in
  COVID-19 Infection. \emph{Eur J Case Rep Intern Med} .
  2020;7(6):001728.
\item
  Paliwal VK, Garg RK, Gupta A, Tejan N. Neuromuscular presentations in
  patients with COVID-19. \emph{Neurol Sci.} 2020;41(11):3039-56.
\item
  Korkmaz MO, Guven M. Unilateral Vocal Cord Paralysis Case Related to
  COVID-19. \emph{SN Compr Clin Med.} 2021;3(11):2319-21.
\item
  Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased
  patients with coronavirus disease 2019: retrospective study.\emph{BMJ}
  . 2020;368:m1091.
\end{enumerate}

\textbf{LEGENDS}

\textbf{Figure 1 a-f}

Chest radiograph series in a 4 year 11-month-old boy COVID-19
encephalitis who was admitted to ICU with depressed conscious and
requiring ventilation.

Frontal chest radiographs from \textbf{day 1 of} presentation
to\textbf{day 6} of presentation demonstrate, in sequence, atelectasis
of the right lower and middle lobes, atelectasis of the whole right lung
and then atelectasis of the right upper lobe and right lower lobe, all
while the patient was intubated with appropriate positioning of the tip
of the endotracheal tube, above the level of the carina. The right
hemidiaphragm is not visible on these radiographs.

Frontal and lateral chest radiographs on day 18 demonstrate an
`apparently' elevated right hemidiaphragm, in keeping with phrenic nerve
palsy, while follow-up chest radiograph at day 56 demonstrates a normal
position of the right hemidiaphragm, indicating resolution.

\textbf{Figure 2 a-b}

Bronchoscopic image at the opening of the right main bronchus
demonstrating complete obstruction with mucus

Ultrasound image demonstrating right sided hemi-diaphragm paralysis\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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

\end{center}
\end{figure}

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