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\begin{document}

\title{A Case of Varicella due to Primary Varicella Zoster Virus Infection
Followed by Cytomegalovirus Reactivation on the Background of an
Immunocompromised Condition}



\author[1]{Hizuru Tomita}%
\author[2]{Yoshimasa Nobeyama}%
\author[1]{Miya Morishima}%
\author[1]{Akihiko  Asahina}%
\affil[1]{Jikei University School of Medicine}%
\affil[2]{The Jikei University School of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{A Case of Varicella due to Primary Varicella Zoster Virus
Infection Followed by Cytomegalovirus Reactivation on the Background of
an Immunocompromised Condition}

Hizuru Tomita, MD\textsuperscript{1}, Yoshimasa Nobeyama,
MD\textsuperscript{1}, Miya Morishima, MD\textsuperscript{1}, Akihiko
Asahina, MD\textsuperscript{1}

1. Department of Dermatology, The Jikei University School of Medicine,
Tokyo, Japan

Corresponding author:

Yoshimasa Nobeyama, MD

Department of Dermatology, The Jikei University School of Medicine,

3-25-8, Minato-ku, Tokyo, 105-8461, Japan

E-mail: \emph{nobederm@jikei.ac.jp}

The authors have no conflict of interest to declare.

The authors have no financial support in the case report.

977 words, 3 figures.

Key words: varicella zoster virus infection, varicella, Cytomegalovirus
activation, systemic lupus erythematosus, immunocompromised condition.

\textbf{Key Clinical Message}

We encountered an immunocompromised patient with cytomegalovirus (CMV)
reactivation immediately after varicella. Varicella appears to precede
CMV reactivation in cases of reactivation, reinfection, and primary
infection of varicella zoster virus.

\textbf{Introduction}

Cytomegalovirus (CMV) reactivation potentially leads to severe
conditions, including retinitis, hepatitis, gastrointestinal ulceration,
skin ulcers, and pneumonia \textsuperscript{1,2}. To prevent these
clinical conditions, the reactivation needs to be detected in the early
stage. Three cases of CMV reactivation combined with varicella due to
the reactivation or reinfection of varicella zoster virus (VZV) in
immunocompromised adults have been reported in the English literature in
the past 10 years \textsuperscript{3-5}. Varicella preceded CMV
reactivation in all three cases. Based on these findings, varicella is
strongly suggested to lead to CMV reactivation in immunocompromised
patients. The reactivation or reinfection of VZV was suggested as the
developmental mechanism of varicella in the cases reported by
Kasuya\emph{et al} . \textsuperscript{3} and Hioki \emph{et al}
.\textsuperscript{4}, although Qi \emph{et al} . did not definitively
indicate the developmental mechanism of varicella \textsuperscript{5}.
Therefore, it currently remains unclear whether primary infection of VZV
is followed by the reactivation of CMV. We encountered a compromised
patient with the onset of varicella as primary VZV infection immediately
followed by CMV reactivation.

\textbf{Case Report}

A 49-year-old female was referred to us with a 4-day history of
cutaneous manifestations on the trunk and extremities. The patient had
been diagnosed with systemic lupus erythematosus (SLE) 2 months earlier
according to the European League Against Rheumatism and the American
College of Rheumatology (2019) criteria \textsuperscript{6} and remained
hospitalized. SLE was controlled well by a treatment with prednisolone
at 0.7 mg/kg/day, mycophenolate mofetil at 2,000 mg/day, and
hydroxychloroquine at 200 and 400 mg on alternate days. Four days before
presentation, the patient developed red papules on the right lower jaw.
Two days before, dyspnea with pyrexia occurred and, thus, the
administration of oxygen was initiated. In the first visit, the
eruptions became vesicles, which spread over the body (\textbf{Figure 1}
). The Tzanck test and immunochromatography to detect VZV antigens
(DermaQuick VZV; Marho, Osaka, Japan) for vesicles were both positive.
In blood tests, VZV-specific IgM and VZV-specific IgG examined using
enzyme-linked immunosorbent assays (ELISA) were 0.38 (negative range,
\textless{}0.8) and \textless{}2.0 (negative range, \textless{}2.0),
respectively, while a CMV antigen-detecting test using the C7
horseradish peroxidase method was positive (4 positive cells per 50,000
white blood cells). Bilateral ground-glass opacities were observed on
chest computed tomography (CT) (\textbf{Figure 2} ).

A histopathological examination revealed intraepidermal blisters with
large multinucleated giant cells and intranuclear inclusion bodies
(\textbf{Figure 3a} ). There were no vascular changes in the dermis,
such as endothelial swelling suggestive of CMV infection, the so-called
owl's eye sign. An immunohistochemical examination of vesicle tissue
showed VZV antigens in keratinocytes on the adjacent side of blisters
(\textbf{Figure 3b} ), but failed to detect CMV antigens. Based on these
findings, we diagnosed the patient with adult varicella due to primary
VZV infection and CMV pneumonia. We administered acyclovir (ACV) at 10
mg/kg/day and added a dose of valganciclovir (VGCV) at 1,800 mg/day.

Eight days after the first visit, vesicles became crusted through the
administration of ACV and ELISA for VZV-specific IgM and IgG were 1.50
and 52.6, respectively. Fourteen days later, ELISA for VZV-specific IgM
and IgG were 1.25 and 1,080, respectively. Eighteen days later, the
attenuation of dyspnea was noted and, thus, oxygen inhalation and VGCV
were stopped.

\textbf{Discussion}

The immunocompromised patient was diagnosed with varicella caused by
primary VZV infection based on the results of physical, blood, and
histopathological examinations. The patient was also diagnosed with CMV
pneumonia based on the results of CMV antigen test in the blood and the
findings of chest CT; the previous studies reported that CMV pneumonia
on CT is mainly detected as ground-glass opacities
\textsuperscript{7}and varicella pneumonia mainly as nodular lesions
\textsuperscript{8}. The onset of varicella preceded that of CMV
pneumonia by a few days.

Three mechanisms have been proposed for the development of adult-onset
varicella: i) the reactivation of latent VZV, ii) reinfection by VZV of
a different genotype from that of latent VZV, and iii) primary VZV
infection. In the case of varicella caused by the reactivation of latent
VZV, VZV-specific IgG potentially increases commonly from a certain
level, whereas VZV-specific IgM does not. In the case of varicella due
to reinfection by VZV of a different genotype, VZV-specific IgM
potentially increases, whereas VZV-specific IgG appears to rapidly
increase commonly from a certain level at an early time point from the
onset \textsuperscript{9}. In the case of varicella caused by primary
VZV infection, VZV-specific IgM definitely increases, whereas
VZV-specific IgG gradually becomes elevated over 2-3 weeks from a
negative level. Increases in VZV-specific IgM were followed by a gradual
elevation in VZV-specific IgG over 2 weeks from a negative level in the
present case, which was compatible with primary VZV infection.

VZV-specific IgG levels in SLE patients previously infected by VZV were
previously reported to be significantly elevated regardless of total IgG
levels through the significant activation of B-cells to specific
antigens as the pathogenesis of SLE; however, total IgG and complement
factor 3 levels sometimes decrease with an increase in the disease
activity of SLE \textsuperscript{10}. In the present case, the level of
VZV-specific IgG in the early stage of varicella was low, which
indicated primary VZV infection in our patient.

Cases in which varicella due to the reactivation of or reinfection by
VZV preceded CMV reactivation have been reported. In an experiment on
monkeys, Ohtaki \emph{et al} . showed that CMV was reactivated after an
inoculation with VZV \textsuperscript{11}. However, primary VZV
infection followed by CMV reactivation has not been reported in humans.
This is the first human case of primary VZV infection leading to the
reactivation of CMV. Dermatologists need to consider CMV reactivation
with the appearance of varicella caused by any type of VZV infection,
including reactivation, reinfection, and primary infection.

\textbf{Acknowledgment:} None

\textbf{Statement of Ethics:} This study protocol was approved by The
Ethics Committee of The Jikei University School of Medicine and the
patient provided written informed consent.

\textbf{Consent statement:} Written informed consent was obtained from
the patient to publish this report in accordance with the journal's
patient consent policy.

\textbf{Data Availability Statement:} Additional data sharing is not
applicable to this article due to ethical restrictions.

\textbf{Author Contributions}

Hizuru Tomita: The author contributed to data curation, resources, and
drafting the original manuscript.

Yoshimasa Nobeyama: The author contributed to conceptualization and
project administration.

Miya Morishima: The author contributed to resources and preparation for
writing of the manuscript.

Akihiko Asahina: The author contributed to review and supervision.

\textbf{References}

1 Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the
immunocompromised host. \emph{Nat Rev Microbiol} 2021. \textbf{19} :
759-773.

2 Guo RF, Gebreab FH, Tang EH \emph{et al.} Cutaneous ulcer as leading
symptom of systemic cytomegalovirus infection. \emph{Case Rep Infect
Dis} 2015. \textbf{2015} : 723962.

3 Kasuya A, Kaneko Y, Enomoto N \emph{et al.} Simultaneous reactivation
of cytomegalovirus in an adult patient with varicella. \emph{J
Dermatol}2015. \textbf{42} : 658-659.

4 Hioki T, Takama H, Makita S \emph{et al.} Cytomegalovirus reactivation
accompanied by varicella zoster virus reactivation or reinfection in an
adult patient of multiple myeloma during bortezomib therapy. \emph{J
Dermatol} 2018. \textbf{45} : 108-109.

5 Qi Z, Sun Y, Li J \emph{et al.} Severe pulmonary co-infection with
varicella-zoster virus, Pneumocystis jirovecii and Cytomegalovirus: a
case report. \emph{J Int Med Res} 2022. \textbf{50} : 3000605211070759.

6 Aringer M, Costenbader K, Daikh D \emph{et al.} 2019 European League
Against Rheumatism/American College of Rheumatology Classification
Criteria for Systemic Lupus Erythematosus. \emph{Arthritis
Rheumatol}2019. \textbf{71} : 1400-1412.

7 Moon JH, Kim EA, Lee KS \emph{et al.} Cytomegalovirus pneumonia:
high-resolution CT findings in ten non-AIDS immunocompromised
patients.\emph{Korean J Radiol} 2000. \textbf{1} : 73-78.

8 Kim JS, Ryu CW, Lee SI \emph{et al.} High-resolution CT findings of
varicella-zoster pneumonia. \emph{AJR Am J Roentgenol} 1999.\textbf{172}
: 113-116.

9 Kimura N, Urabe K, Furue M. Recurrent Varicella in a Patient with
Systemic Lupus Erythematosus Treated with
Immunosuppressants.\emph{Nishinihon J Dermatol} 2018. \textbf{80} :
354-357.

10 Rondaan C, van Leer CC, van Assen S \emph{et al.} Longitudinal
analysis of varicella-zoster virus-specific antibodies in systemic lupus
erythematosus: No association with subclinical viral reactivations or
lupus disease activity. \emph{Lupus} 2018. \textbf{27} : 1271-1278.

11 Ohtaki S, Kodama H, Hondo R, Kurata T. Activation of cytomegalovirus
infection in immunosuppressed cynomolgus monkeys inoculated with
varicella-zoster virus. \emph{Acta Pathol Jpn} 1986. \textbf{36} :
1537-1552.

\textbf{Figure legends}

\textbf{Figure 1. Clinical manifestations in the first visit}

\textbf{a)} Papules, papular vesicles, crusted vesicles, and crusts are
mutually intermingled on the back. \textbf{b)} Vesicles \textless{}6 mm
in diameter are shown. Some vesicles have an umbilication representing
necrosis in the center.

\textbf{Figure 2. CT imaging of lungs}

Ground-glass opacities are observed in the bilateral lungs; however, no
nodules suggestive of varicella pneumonia are found.

\textbf{Figure 3. Histopathological findings of vesicles}

\textbf{a)} Hematoxylin-eosin stain, \selectlanguage{ngerman}× 400. Intraepidermal blisters with
large multinucleated giant cells and intranuclear inclusion bodies shown
as a pale amorphous substance are evident. \textbf{b)} Direct
immunofluorescence, × 1,000. The nuclei of cells in vesicles are
reactive to an anti-VZV antibody (Denka, Tokyo, Japan), as indicated by
white arrowheads.\selectlanguage{english}
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