Journal of Cancer Research and Practice 4 (2017) 109e110

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Journal of Cancer Research and Practice

journal homepage: http://www.journals.elsevier.com/journal-of-cancer-
research-and-practice

Case Report

Successful treatment of herpes simplex virus associated

hemophagocytic syndrome coexisting with ARDS with intravenous
immunoglobulin in acute myeloid leukemia patient
I-Hsuan Huang a, Wei-Chun Lin b, Ping-Ying Chang c, *
a
Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
b
Department of Surgery, Song Shan Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
c
Division of Hematology Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by excessive
Received 12 October 2016 macrophage function. The diagnosis of HLH in adults is challenging because initial signs and symptoms
Received in revised form of HLH mimic common infections. Herein is described a case of HSV infection causing virus-associated
16 February 2017
hemophagocytic syndrome (VAHS) with severe hemodynamic distress. This patient manifested acute
Accepted 23 February 2017
Available online 24 February 2017
respiratory distress syndrome (ARDS), which responded well to intravenous immunoglobulin. Patients
with herpes simplex virus-associated hemophagocytic syndrome coexisting with ARDS may be given a
trial of immune globulin. However, there are few reported cases of AML occurring with VAHS in the
Keywords:
Hemophagocytic syndrome
literature, which were successfully treated with IVIG; therefore, this finding requires further investiga-
Intravenous immunoglobulin tion in a similar setting.
Acute respiratory distress syndrome © 2017 Taiwan Oncology Society. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction immunoglobulin (IVIG).

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical

syndrome which is characterized by excessive macrophage func-
tion. The diagnosis of HLH in adults is challenging because initial
signs and symptoms of HLH seem like common infections or fever
of unknown origin. Infections (41.1%), malignancies (28.8%), auto-
immune disorders (6.8%), primary immunodeficiency (1.4%), or
post solid organ transplantation (2.7%) have been linked to this
syndrome.1
Herein is described a case of HSV infection causing virus-
associated hemophagocytic syndrome (VAHS) with severe he-
modynamic distress in an AML patient after high-dose Ara-C-
based consolidation chemotherapy. Standard therapy for VAHS
has not been defined due to the small number of cases, and the
clinical course is variable. This patient manifested acute respira-
tory distress syndrome, which responded well to intravenous
* Corresponding author. Division of Hematology Oncology, Department of In-
ternal Medicine, Tri-Service General Hospital, No. 325, Cheng-Kung Rd, Sec 2, Neihu
114, Taipei, Taiwan.
E-mail address: hicafetsgh@gmail.com (P.-Y. Chang).
Peer review under responsibility of Taiwan Oncology Society.
2. Case report
A 65-year-old male with diabetes mellitus was diagnosed 5
months earlier with acute myeloid leukemia, French-
eAmericaneBritish classification subtype M2. He received induc-
tion chemotherapy with high dose cytarabine in combination with
anthracycline and achieved a complete remission, followed by
three cycles of high-dose Ara-C-based consolidation chemotherapy.
He developed febrile neutropenia 8 days after the last chemo-
therapy and was admitted on the same day. Thereafter, parenteral
antibiotic therapy with Cefepime was started, and granulocyte
colony-stimulating factor (G-CSF) was initiated for persistent
neutropenia. Trimethoprim-sulfamethoxazole and micafungin
were added due to suspected pneumocystis carinii pneumonia
infection or candidiasis. The patient presented with dyspnea,
tachycardia, hypoxemia, and diffuse crackles. The chest radiograph
showed bilateral alveolar infiltrates, sparing costophrenic angles.
High concentrations of supplemental oxygen were required to
maintain adequate oxygenation. Computed tomography (CT) of the
chest showed widespread patchy consolidation. Cardiogenic pul-
monary edema was excluded after measurement of plasma brain

http://dx.doi.org/10.1016/j.jcrpr.2017.02.003
2311-3006/© 2017 Taiwan Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
110 I.-H. Huang et al. / Journal of Cancer Research and Practice 4 (2017) 109e110
natriuretic peptide levels and echocardiography. Thereafter, acute
respiratory distress syndrome was diagnosed. Blood culture and
sputum culture were collected to identify the cause of infection.
However, despite broad-spectrum antimicrobial therapy, the pa-
tient's fever persisted, reaching 39.7  C, and his general state
deteriorated rapidly. Follow-up laboratory examination showed
pancytopenia, with a white blood cell count of 3150/mL, with 12.5%
lymphocytes, 46.9% neutrophils, 4.7% monocytes, a hemoglobin
level of 8.7 g/dl, and a platelet count 8000/mL, liver function ab-
normalities (aspartate aminotransferase of 150 IU/L, and alanine
aminotransferase of 280 IU/L). The plasma levels of fibrinogen were
603.0 mg/dL. Triglycerides (121 mg/dL), Lactic dehydrogenase, PT
and, aPTT were within normal limits. Multiple cultures of blood,
urine, and stool were negative for bacterial, fungal, mycobacterial,
or parasitic organism infection. Secondary haemophagocytic syn-
drome was suspected since serum ferritin was significantly
elevated (16,500 ng/mL). The abdominal sonography showed
splenomegaly. A bone marrow smear obtained one day later dis-
played relatively normal cellularly for age, compatible with
leukemic remission, but showed macrophage infiltration with
active hemophagocytosis. He immediately received intravenous
immunoglobulin (IVIG, 1 g/kg for 2 days). The fever subsided and
the laboratory data improved 2 days later. In addition, serum
studies were negative for hepatitis B surface antigen, hepatitis C
virus, hepatitis A IgM antibody and IgM antibody to Mycoplasma
pneumonia. Epstein-Barr virus viral-capsid antigen IgG antibodies
were positive and EBV IgM antibodies were negative. CMV DNA was
not amplified from the patient's plasma by PCR. Antinuclear anti-
body and double stranded DNA antibody were negative. Herpes
simplex virus-1 PCR detection from sputum and blood both sub-
sequently showed positive result. We diagnosed a hemopagocytic
syndrome in an immunocompromised patient, with HSV infection.
This diagnosis was established as the patient met five out of the
eight criteria (HLH-2004): fever, hepatomegaly, cytopenia of two
cell lines, hemophagocytosis in bone marrow, and ferritin >500 mg/
L. Ultimately, the patient had been successfully weaned from me-
chanical ventilation after his respiratory failure improved.
3. Discussion
In HLH, macrophages become activated and secrete excessive
amounts of cytokines, ultimately causing severe tissue damage that
can lead to organ failure. Natural killer (NK) cells and/or cytotoxic T
lymphocytes fail to eliminate activated macrophages. This lack of
normal feedback regulation results in excessive macrophage ac-
tivity and highly elevated levels of interferon gamma plus other
cytokines.2 Immune activation is typically initiated by an infection.
The most common infectious trigger for HLH is viral infection,
particularly with Epstein-Barr virus (EBV).2 Patients with HLH
should receive appropriate transfusions, and prevention and
treatment of bleeding and opportunistic infections. Etoposide-
containing immunochemotherapy, including HLH-94 protocol or
HLH-2004 protocol, has become the recommended treatment for
HLH. However, corticosteroids, IVIG, or a combination of these
agents continues to be widely used. Hot et al. used only immuno-
globulin, with a very successful response in cytomegalovirus
associated HLH.3 Perhaps virus-associated HLH has a particularly
favorable result with immunoglobulin as evidenced in Eps-
teineBarr associated HLH seen in children.4 Intravenous immune
globulin (IVIG) contains the polyvalent IgG antibodies extracted
from a pool of at least 1000 individual donors. It is believed to have
multiple mechanisms of action, but the precise mechanism has not
been definitively established. It is believed to involve suppression
of inflammatory and immune-mediated processes. The donor
antibody may interact with Fc receptors on phagocytic cells,
reducing immune activity.5 Alternatively, the massive quantity of
antibody may accelerate the fractional rate of catabolism of IgG.6
IVIG also promotes solubilization and clearance of immune com-
plex deposits.5 IVIG can also alter the number of T cells and T cell
subsets.7 In 2014, Ezhilarasi Subbiah from India reported that IVIG
and HLH-2004 protocol may be equally effective in the manage-
ment of HLH in children.8 IVIG may be a preferable initial regimen,
to avoid the adverse events of etoposide such as myelosuppression,
mucositis, secondary leukemia, and myelodysplasic syndromes.
Despite the fact that data regarding IVIG in herpes simplex virus-
associated hemophagocytic syndrome was limited, few cases of
virus-associated hemophagocytic syndrome have been described
in the literature.
In previous reports, some HLH patients were diagnosed with
ARDS during their clinical course, as in our case. Nahum et al. re-
ported that respiratory failure including ARDS was noted in 7 of 11
HLH children, with multiple organ failure after a diagnosis of HLH
having been made in the pediatric population.9 The incidence of
hemophagocytic syndrome coexisting with ARDS in adult popula-
tion was unknown. The treatment of underlying causes of ARDS
might be of import because no drug has proven beneficial in the
prevention or management of ARDS.
In conclusion, this patient was successfully treated with 1 g/kg
intravenous immune globulin. Patients with herpes simplex virus-
associated hemophagocytic syndrome coexisting with ARDS may
be given a trial of immune globulin. New studies encompassing
larger patient populations are needed to analyze and determine the
efficacy of IVIG and the best dosage and timing of starting IVIG in
patients with hemophagocytic syndrome precipitated by HSV
reactivation.
Conflict of interest
The authors declare no conflicts of interest.
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