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\begin{document}

\title{Fatal visceral varicella in a child with newly diagnosed acute
lymphoblastic leukemia}



\author[1]{Paul Schnitzler}%
\author[2]{Julia Tabatabai}%
\author[3]{Neysan Rafat}%
\author[4]{Hendrik Witt}%
\author[5]{Andreas Sauerbrei}%
\author[5]{Roland Zell}%
\affil[1]{Universitatsklinikum Heidelberg Zentrum fur Infektiologie}%
\affil[2]{UniversitatsKlinikum Heidelberg Zentrum fur Kinder und Jugendmedizin}%
\affil[3]{Universitat Heidelberg Medizinische Fakultat Mannheim}%
\affil[4]{Praxis für Kinder- und Jugendmedizin}%
\affil[5]{Friedrich Schiller Universitat Jena Institut fur Mikrobiologie}%


\vspace{-1em}



  
  \date{March 14, 2025}


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\textbf{Fatal visceral varicella in a child with newly diagnosed acute
lymphoblastic leukemia}

Julia Tabatabai\textsuperscript{a,b}, Neysan Rafat\textsuperscript{c},
Hendrik Witt\textsuperscript{d}, Andreas Sauerbrei\textsuperscript{e},
Roland Zell\textsuperscript{e},

Paul Schnitzler\textsuperscript{b}

\textsuperscript{a}Center for Childhood and Adolescent Medicine,
University Hospital Heidelberg, Heidelberg,
Germany;\textsuperscript{b}Center for Infectious Diseases, Virology,
University Hospital Heidelberg, Heidelberg, Germany;
\textsuperscript{c}Department of Neonatology and Pediatric Critical
Care, University Children's Hospital, University of Heidelberg,
Mannheim, Germany;\textsuperscript{d}Praxis f\selectlanguage{ngerman}ür Kinder- und
Jugendmedizin, Weinheim, Germany; \textsuperscript{e}Section of
Experimental Virology, Institute for Medical Microbiology, Jena
University Hospital, Friedrich Schiller University of Jena, Jena,
Germany

\textbf{Corresponding author}

Dr. med. Julia Tabatabai

Tel.: +49-6221-56 39149

E-mail address: julia.tabatabai@med.uni-heidelberg.de

\subsubsection*{}

{\label{section}}

Word count: 850

Tables/Figures: 2

\textbf{Running title:} Fatal varicella in a child with ALL

\textbf{Keywords:} Varicella zoster virus, VZV, acute lymphoblastic
leukemia, ALL

To the editor:

We report a 15-year-old boy with a high suspicion of ALL with
leucocytosis, anaemia, thrombocytopenia and hyperuricaemia, see Table 1.
The routine blood draw was performed by the paediatrician prior to
discontinuation of testosterone injections in hypergonadotropic
hypogonadism in the context of Klinefelter's syndrome. The patient was
admitted to our paediatric intensive care unit on suspicion of tumour
lysis syndrome with leucocytosis, blasts \textgreater{}83\% and LDH of
1,600 U/l. Physical examination revealed hepatosplenomegaly and facial
acne. After bone marrow biopsy and lumbar puncture with intrathecal
administration of 12 mg methotrexate, treatment with prednisolone was
started. Initially, the total leucocytes dropped to approximately 60/nl,
while cell decay was controllable. On day 4, the leukocyte count rose,
continuing the next day to 180/nl despite increasing the prednisolone
dosage. LDH rose to 7,489 U/l and epigastric abdominal pain increased,
which we treated empirically with pantoprazole suspecting
corticosteroid-induced gastritis. There was also liver capsule pain and
generalised pruritus, which improved only slightly after administration
of an antihistamine. On day 5, the patient's condition worsened with
oxygen demand and dyspnoea. Cyclophosphamide was administered to improve
cell decay and prednisolone was administered full dose. We also decided
to start haemodialysis with increasing renal retention parameters and
LDH of 13,636 U/l)).

On day 6, we electively intubated and placed the boy on mechanical
ventilation. Ubiquitous fluid-filled vesicles with brownish-reddish
contents developed. The intravesicular fluid was tested positive for VZV
DNA with a high viral load of 1,3 x10\textsuperscript{9} copies/ml.
Retrospective analysis showed rising viral loads of VZV DNA with a peak
of 2.1 x 10\textsuperscript{8} copies/ml on day 6 in peripheral blood.
The causative pathogen was genotyped and revealed a variant of the VZV
clade 3, European genotype E2 (Fig. 1). Retrospectively, serum samples
from day 1 to day 6 were analysed for anti-VZV (IgG, IgM) antibodies,
all with negative result. The patient was immediately started on
acyclovir intravenously and blood exchange to reduce the leukostasis
syndrome. Uncontrollable haemorrhages with diffuse bleeding from
puncture sites and mucous membranes developed. Acute respiratory
distress syndrome occurred with extremely high ventilation parameters
and multiple cardiac arrests with ultimately unsuccessful resuscitation
attempts. The patient died due to multi-organ failure.

The parents reported that the patient joined a school trip to Italy the
week before he was hospitalised. Chickenpox cases had been observed in
the meantime among other students of the school trip. There was no prior
history of varicella or vaccination against varicella for the patient.
This case is a tragic course of an initially undiagnosable primary
varicella infection at the time of the manifestation of acute
lymphoblastic leukaemia with hyperleukocytosis. Due to immunosuppression
caused by the underlying disease in combination with the required
corticosteroid treatment, a fulminant VZV sepsis with multi-organ
failure occurred.

The standard treatment for organ VZV infection is acyclovir and should
be started immediately upon suspicion of the
diagnosis.\textsuperscript{1} Older age at ALL diagnosis, and VZV
diagnosis during or within three weeks of prednisone therapy are
independently associated with an increased risk for severe
infection.\textsuperscript{2} Despite the varicella vaccine and a
dropping incidence of primary infections, VZV remains a dangerous
pathogen for paediatric patients with ALL. Patients who are on ALL
therapy and are exposed to VZV should have steroid therapy delayed until
after the VZV incubation period.

Organ failure in disseminated VZV infections is caused primarily by
VZV-induced cell damage and cell lysis.\textsuperscript{3} Extensive
visceral dissemination can occur several days before the skin lesions
appear. Another fatal case of a child from Germany suffering from ALL
with a VZV viral load of 7 x 10\textsuperscript{6} copies/ml had been
reported previously.\textsuperscript{4} The VZV viral load of 2.1 x
10\textsuperscript{8} copies/ml in the peripheral blood of our case is
extremely high compared to healthy children with primary varicella,
ranging from 3 x 10\textsuperscript{2} to 6 x
10\textsuperscript{3}copies/ml.\textsuperscript{5} The clinical course
of this disease is often so rapid, that the initiation of antiviral
therapy may be too late. An unexplained liver dysfunction in
immunocompromised children needs prompt consideration of visceral VZV
infection, even in the absence of a history of VZV exposure and also in
patients without skin involvement. The detection of VZV DNA in
peripheral blood by PCR and prompt initiation of antiviral therapy are
therefore recommended in such a clinical setting.

Recommendations for vaccination include seronegative people at special
risk, such as children with leukaemia. These recommendations apply
certainly to the patient of this report with no history of chickenpox,
and vaccination against varicella prior to the immunosuppressive therapy
might have prevented the fatal outcome of this primary VZV infection. A
study of varicella vaccination in paediatric oncology patients without
interruption of chemotherapy (no steroids) had been presented, where
live-attenuated VZV vaccine was safely administered, and adaptive
immunity was induced despite incomplete
seroconversion.\textsuperscript{6}

In conclusion, immunocompromised patients without varicella history are
at special risk to develop life-threatening complications of varicella.
The most effective method to prevent severe varicella in
immunocompromised patients is active immunization prior to the
immunosuppressive therapy. However, severe VZV-related complications are
rare in children with ALL and cannot be prevented in all cases,
especially in newly diagnosed ALL.

ACKNOWLEDGEMENT

The authors would like to thank the technicians in the virology
diagnostic laboratory for excellent technical support. JT is grateful
for the support by a research scholarship from the Medical Faculty
Heidelberg, Germany in 2022 during the time the draft of this manuscript
was finalized.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
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\item
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\item
  Nikkels AF, Delvenne P, Sadzot-Delvaux C et al. Distribution of
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\item
  Schrauder A., Henke-Gendo C., Seidemann K. et al. (2007). Varicella
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\item
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\item
  van de Wetering M.D., Vossen M.T.M., Jansen M.H., Caron H.N., Kuijpers
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\item
  Zell R, Taudien S, Pfaff F, Wutzler P, Platzer M, Sauerbrei A.
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\item
  Sauerbrei A, Zell R, Philipps A, Wutzler P. Genotypes of
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\end{enumerate}

\textbf{Figure legend}

\textbf{Fig 1.} Genotyping of the clinical VZV strain 202-14 (in bold).
For the phylogenetic analysis, the ORF21-22 gene region (969 nt) of
strain 202-14 and 35 VZV reference sequences representing five VZV
clades were compiled and used for tree inference utilizing the
neighbor-joining method implemented in MEGA
X.\textsuperscript{7,8}Genetic distances were computed with the
p-distance method; the bar indicates substitutions per site. Grey boxes
indicate the five VZV clades.\selectlanguage{english}
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