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Indian Pediatr 2017;54:
145-146 |
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Disseminated Cryptococcosis in an
Immunocompetent Toddler
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Neeraj Gupta, Anil Sachdev, Dhiren Gupta and *Nita
Radhakrishnan
From the Departments of Pediatrics and *Pediatric
Hemato-oncology, Sir Ganga Ram Hospital,
Rajinder Nagar, New Delhi, India.
Correspondence to: Dr Neeraj Gupta, Consultant,
Department of Pediatrics, Sir Ganga Ram Hospital, Rajinder Nagar,
New Delhi 110 060, India.
Email: [email protected]
Received: May 13, 2016;
Initial review: August 11, 2016;
Accepted: December 22, 2016.
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Background: Immunodeficient children are more
prone for invasive cryptococcal infections. Case characteristics:
A 2-year-old boy with disseminated cryptococcosis was evaluated for
underlying immunodeficiency without success. Intervention/outcome:
Child was managed successfully. Message: Immunocompetent
children with disseminated cryptococcosis can present diagnostic or
therapeutic challenge in resource-limited settings.
Keywords: Cryptococcus, Immunodeficiency, Lymphocyte
proliferation defect.
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C
ryptococcosis is an uncommonly recognized and
often fatal disease in children [1]. Following invasion of respiratory
tract, the organism may become quiescent in immunocompetent host, until
an immune defect appears. Here we present an apparently immunocompetent
child with disseminated cryptococcal infection, who was managed
successfully with antifungal treatment.
Case Report
A 2-year-old 11.5 kg boy, presented with intermittent
high-grade fever and cough for 2 months and irritability for 15 days,
despite having received multiple antibiotics and four drug
anti-tubercular therapy for one month (due to prolonged illness).
Hospitalization for pneumonia at 6 months of age was the only
significant past history. There was no history of any direct contact
with pets/birds or other risk factors. He was well-nourished (height 85
cm, head-circumference 48.4 cm) with generalized lympha-denopathy and
massive hepatosplenomegaly (Liver 10 cm, spleen 3 cm below costal
margin). Diffuse crepitations were heard over chest. There were no
clinical features of meningeal irritation. Hematological investigations
revealed white-blood-cell count 39100/µL (N 57L23E16),
hemoglobin 6.3 g/dl (iron deficiency anemia) and ESR 113mm/1st
hour. C-reactive protein was 107 mg/l. Chest X-ray (Web Fig.
1a) showed military pattern with generalized lymphadenopathy.
Abdomino-thoracic computed tomogram (CT) suggested hyperdense nodular
areas in lungs and spleen (Web Fig. 1b).
Investigations for malaria, typhoid and tuberculosis were
non-contributory. Treatment with Meropenem and Teicoplanin was
empirically started, on which child showed no improvement. Microscopic
analysis of bone marrow aspirate and bronchoalveolar lavage were
inconclusive, with negative staining for acid-fast bacilli. After 5 days
of blood incubation in Sabouraud-dextrose-agar, Cryptococcus
neoformans was grown. CSF examination revealed 98 cells (100%
lymphocytes), 75 mg/dl protein and positive cryptococcal antigen test
with encapsulated yeast cells. MRI brain suggested prominent gyri and
sulci. Later, Cryptococcus was also identified in bronchoalveolar lavage
fluid analysis and bone-marrow biopsy. Stool examination was negative.
Antifungal agents (Amphotericin-B and Flucytosine) were started, as per
standard guidelines [2]. In view of the disseminated nature of disease,
he was evaluated for underlying immunodeficiency. HIV ELISA was
negative. Immuno-logical investigations suggested high IgE (1565.68 IU/mL),
with mildly elevated immunoglobulin G and A. Lymphocyte subset analysis
showed normal CD19, CD3, CD4, CD8 and CD56 positive cells. Chronic
granulomatous disease was also ruled out by nitroblue-tetrazolium (NBT)
dye test. T lymphocyte proliferation after stimulation with PHA was
significantly less for the patient sample when compared with the control
(17% vs. 86%). Targeted sequencing, done for STAT1, STAT3, CARD9,
IFNGR1 and IFNGR2 genes in view of the invasive fungal disease, were
normal. Whole exome sequencing was not performed.
After starting antifungal therapy, fever decreased in
five days with reduction in cough, irritability, hepatosplenomegaly,
lymphadenopathy and resolution of chest infiltrates in 2 weeks. CSF
cleared after 6 weeks of intravenous antifungals. Child has been
neurodevelop-mentally well without any recurrence.
Discussion
There are two varieties of Cryptococcus neoformans
with different virulence: var neoformans consisting of
serotype A and D, which cause disease in immunodeficient patients and
var gatti consisting of serotype B and C, which have the potential
to affect normal hosts. In the present case, we were unable to identify
the serotype.
The organism can lead to disseminated disease in
persons with severe cell-mediated immunodeficiency. In humans,
cryptococci may survive because of a polysaccharide capsule (CPS) that
allows them to evade phagocytotosis [3]. Disseminated cryptococcal
infection is uncommon in patients with intact immune system and almost
always occurs in HIV-infected patients [4]. The other risk factors
include: corticosteroid use, lymphomas, solid organ transplant
recipient, sarcoidosis and patients with immune-suppressive disease or
receiving such drugs. Clinical presentation of disseminated
cryptococcosis is variable. CNS involvement is the most common
manifestation of disseminated disease [5]. Classic meningeal signs, such
as nuchal rigidity, are absent in 75% of cases [6]. Our case presented
with fever and irritability although meningeal signs were absent. Lung
is the second most commonly affected organ, which was involved in
present case [3].
A recent study demonstrated that C. neoformans
can cause an allergic bronchopulmonary mycosis characterized by
production of Th2 cytokines, elevated levels of serum IgE, recruitment
of eosinophils and alternative activation of macrophages [7]. Another
study suggested that CPS-induced IL-10 production was an important
mechanism in the CPS-mediated suppression of lymphocyte proliferation
[8]. Recently there have been some reports about invasive cryptococcosis
in immunocompetent patients. Goldman described an adult male with
pulmonary and CNS lesions due to C. gattii [9]. Bothra and colleagues
identified the fungus in a 5-year immunocompetent child [10]. In our
case, we detected elevated IgE levels with reduced T-cell proliferation,
which may be secondary to cryptococcal infection per se rather
than primary cause, as the child was previously well and our
investigations did not yield any cause.
As per the Infectious Diseases Society of America
guidelines for management of Cryptococcal disease [2], non-HIV,
non-transplant patients should be treated with dual therapy (Amphotericin
B and Flucytosine during induction phase (up to 4 weeks after CSF
clearance) followed by Fluconazole in consolidation and maintenance
phase. Our patient required longer duration of intravenous antifungals
in view of prolonged CSF clearance.
To conclude, one should apply a cautious approach
towards diagnosis and treatment of unusual organisms such as
cryptococcosis due to changing resistance pattern and host-predilection.
This becomes more challenging in immunocompetent individuals; that too
with limited resources.
Acknowledgements: Dr Manisha Madkaikar, NIIH,
Mumbai for T lymphocyte proliferation assay and Prof. Hidenori Ohnishi,
Gifu University, Japan for the molecular work-up.
Contributors: NG: collected the clinical
details and managed the case; NR: helped in immunological work-up; AS,
DG: supervised case management. All were involved in drafting the
manuscript.
Funding: None; Competing interest: None
stated.
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