m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 7 8 ( 2 0 2 2 ) 9 9 e1 0 2

Available online at www.sciencedirect.com

ScienceDirect

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m j a fi

Case Report

Hemophagocytic lymphohistiocytosis in a child

with chronic granulomatous disease: A rare
complication of a rare disorder

Gitanjali Jain a,*, Suprita Kalra b, Saurabh Sharma c,

Gautam Kumar Vasnik d, Rakesh Gupta e
a
Graded Specialist, Department of Pediatrics, Armed Forces Medical College, Pune 411040, India
b
Classified Specialist (Pediatrics) & Trained in Pediatric Nephrology, Command Hospital (Southern Command), Pune
411040, India
c
Resident, Department of Pediatrics, Armed Forces Medical College, Pune 411040, India
d
Graded Specialist (Pathology), Military Hospital Nasirabad, Rajasthan, India
e
Director, Government Institute of Medical Sciences, Gautam Budh Nagar, Greater Noida, UP 201310, India

article info abstract

Article history: Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder (PID) of
Received 8 July 2018 phagocytic cells resulting in failure to eradicate catalase positive microorganisms like
Accepted 30 November 2018 Staphylococci and fungal infections; due to deficiency or malfunction of nicotinamide
Available online 15 April 2019 adenine dinucleotide phosphate (NADPH)-oxidase subunits in phagocytic leucocytes. We
illustrate here one such case; a six year old girl who was admitted in our hospital with
Keywords: history of prolonged fever, non resolving bilateral otitis media and recurrent pneumonia.
Chronic granulomatous disease She was evaluated for an underlying PID and was found to have CGD based on Nitro blue
Hemophagocytic Tetrazolium (NBT) Slide Test and flow cytometric Dihydrorhodamine (DHR) assay. The
lymphohistiocytosis child was symptomatic despite initial treatment with first-line followed by second-line
Immunodeficiency disorder antibiotics. During the course of current systemic infection, she also developed infection-
Infection associated secondary Hemophagocytic Lympho Histiocytosis (HLH) as suggested by her
Bone marrow clinical and laboratory parameters. Despite a thorough search, no microorganism could be
isolated and so she was treated with empircal antibiotic therapy comprising of mer-
openem, linezolid and an antifungal. Fever resolved with gradual improvement of labo-
ratory parameters and finally spontaneous resolution of HLH. We conclude that a high
index of suspicion for PID is required in a child with recurrent infections. Identification of
underlying infectious agent should be attempted to start targeted antimicrobial therapy;
both to prevent as well as cure infection associated secondary HLH.
© 2019, Armed Forces Medical Services (AFMS). All rights reserved.

* Corresponding author.
E-mail address: gitanjali_jain@yahoo.co.in (G. Jain).
https://doi.org/10.1016/j.mjafi.2018.11.012
0377-1237/© 2019, Armed Forces Medical Services (AFMS). All rights reserved.
100 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 7 8 ( 2 0 2 2 ) 9 9 e1 0 2
Fig. 1 e Chest radiograph on the day of admission shows
consolidation in the right upper zone.
Introduction
Chronic granulomatous disease (CGD) is a rare primary im-
munodeficiency disorder (PID) with an incidence of 4e5 per 1
million individuals.1 It is an inherited disorder caused by
functional impairment of the nicotinamide adenine dinucle-
otide phosphate (NADPH) oxidase complex in leucocytes such
as neutrophilis and monocytes. CGD is characterized by
recurrent infections, dysregulated inflammation and auto-
immunity.2 CGD patients are at increased risk for developing
hemophagocytic lymphohistiocytosis (HLH). HLH is a poten-
tially life-threatening condition because of the excess
amounts of cytokines being released by the activated
Fig. 2 e Contrast enhanced computed tomography (CECT) chest shows necrotizing pneumonia (cavitation and
consolidation) in the apical lobe of the right lung.
macrophages which is secondary to a dysregulated inflam-
mation. Remission of HLH is generally achieved after man-
agement with antimicrobials, steroids and/or intravenous
immunoglobulin.3,4 There are some case reports which show
that even immune-enhancing therapies may assist in the
control and the clearance of the infection.5
We report a female child patient who was previously
managed for two separate episodes of pneumonia (within a
span of six months) and this time presented with prolonged
fever, bilateral non-resolving otitis media and a new lobar
pneumonia, subsequently diagnosed to have CGD compli-
cated by secondary HLH.
Case report
A six-year-old female child patient was admitted in our hos-
pital with history of prolonged fever, bilateral ear discharge
and recurrent pneumonia (two episodes within a span of six
months). On general examination, her weight was 14 Kg (be-
tween 2 and 3 WHO Z score), height was 104 cms (between
2 and 3 WHO Z score) and pallor was noted. Bilateral ear
examination revealed a small central perforation with pulsa-
tile discharge on the right side and a moderate central perfo-
ration with mucopurulent discharge on the left side.
Respiratory examination revealed crackles in the right
suprascapular, interscapular and mammary regions. On
palpation of the abdomen, there was hepatomegaly with liver
span of 12 cm; however, spleen was not palpable.
Investigations at the time of admission showed haemo-
globin (Hb) of 8.2 gm%, total leucocyte count (TLC) of 39,500/
cmm with neutophilic leucocytosis and platelets were
3,20,000/cumm. Erythrocyte sedimentation rate (ESR) was
80 mm Hg fall in the first hour. Radiograph chest showed
homogenous consolidation of the upper lobe of the right lung
[Fig. 1]. Contrast enhanced computed tomography (CECT)
chest showed findings suggestive of necrotizing pneumonia
(cavitation and consolidation) in the apical lobe of the right
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 7 8 ( 2 0 2 2 ) 9 9 e1 0 2
Fig. 3 e A bone marrow aspirate smear shows histiocyte
with features of hemophagocytosis.
lung [Fig. 2]. Mantoux test was non-reactive; no acid fast bacilli
were seen on Ziehl Neelsen staining in gastric aspirate, and
Gene x-pert for Mycobacterium Tuberculosis (MTB) was
negative. No growth was noted in blood culture and ear
discharge culture.
The child was started on injection ceftriaxone and injec-
tion vancomycin initially; later, ceftriaxone was replaced with
piperacillin-tazobactum on the fifth day of admission because
of poor response to first-line antimicrobials.
In view of unremitting fever, recurrent pneumonia and
persistent otitis media, a workup for PID was carried out. The
Nitroblue Tetrazolium (NBT) slide test showed 0% NBT posi-
tive neutrophils, and a flow cytometric Dihydrorhodamine
(DHR) assay also revealed 0% DHR positive neutrophils. Based
on these reports, she was diagnosed as CGD on the sixth day of
hospital admission.
In view of incessant symptoms in a child with CGD, in-
jection fluconazole, injection metronidazole and oral
trimethoprim/sulfamethoxazole were added. Follow-up ESR
Fig. 4 e Chest radiograph at the end of four weeks of
antimicrobial therapy shows resolution of consolidation.
101
remained elevated in the range of 60e80 mm fall of mercury in
the first hour.
The child still continued to have high grade fever through
the third week of hospitalization, even though ears were dry
by then. The child also developed progressive hep-
atosplenomegaly with liver span increasing up to 15 cm and
the spleen being palpable up to 5 cm below the left subcostal
margin in the left midclavicular line. Repeat counts at this
juncture revealed Hb of 5.8 gm%, TLC of 2100/cmm and
platelets of 80,000/cmm. In view of persistent fever, pancyto-
penia and progressive hepatosplenomehaly, a possibility of
infection-associated secondary HLH was considered and she
was investigated for the same. Bone marrow study showed
histiocyte with features of hemophagocytosis [Fig. 3]. The
serum ferritin was 11 77 mcg/L (>500 mcg/L), fasting tri-
glycerides were 291 mg/dL (>265 mg/dL) and fibrinogen levels
were 0.8 g/L (<1.5 g/L). HLH-2004 diagnostic criteria were met
but without an identified infecting microorganism. Antibiotics
were upgraded to injection meropenem and injection line-
zolid. Child responded well to this change in antimicrobial
therapy and was completely afebrile after 72 h when a decline
in ESR was also noted. Hepatosplenomegaly regressed over a
week. The total leucocyte counts and platelet counts also
normalized. Radiological resolution of pneumonia was
noticed by the end of the fourth week [Fig. 4].
Discussion
In this case report, diagnosis of CGD was established. The
NADPH oxidase (which is defective in CGD) is a multicompo-
nent system. Defects in the genes that encode any of the
NADPH oxidase components may hamper the electron
transport and impair pathogen killing. Approximately 60% of
CGD cases are due to mutations in the gene encoding
gp91phox present at Xp21.1. Although 30% are autosomal
recessive,6 genetic evaluation was not performed in our
patient.
Later, diagnostic criteria for secondary HLH (six of eight of
HLH-2004 diagnostic criteria) were met.7 The patient had
developed secondary HLH because of untreated underlying
infection. The mechanism of infection-induced secondary
HLH is still not well understood and is hypothesized to be due
to defective degradation of inflammatory cytokines as a
result of inability to produce reactive oxygen species (ROS).
Deficient ROS also results in defective antiinflammatory
signalling which leads to persistent cell activation of CGD
macrophages.8
Around 72 h after upgrading the antibiotic to injection
meropenem, fever spikes reduced with fall in ESR and
improvement in cell counts. Even though we could not isolate
the organism on blood culture or ear discharge in our patient,
Burkholderia cepaciaecausing septic pulmonary embolisms
complicated with HLH and responding dramatically to mer-
openem have been reported in literature.8 In addition, Bur-
kholderia cepacia has been found to be the commonest
organism in CGD complicated with secondary HLH.9
Our patient responded to antimicrobials alone and did not
require immunosuppressant therapy for HLH. Kardas et al.
also reported a similar case of infection-associated HLH in a
102 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 7 8 ( 2 0 2 2 ) 9 9 e1 0 2
four-month-old infant with biotidinase deficiency where HLH
therapy was not administered as laboratory values were only
mildly within pathological limits for the diagnosis of HLH. The
infant responded to intravenous meropenem, amikacin and
teicoplanin for pneumonia. However, they had given intra-
venous immunoglobulin therapy in addition to antimicro-
bials.10 Intravenous immunoglobulin has also been used and
found to be safe and effective in patients of CGD with infec-
tion-triggered HLH.11 Nevertheless, early initiation of HLH
therapy should be considered in all cases, especially those
with severe disease.
This case represents a known but an uncommon
complication of a rare disease that is CGD and the thera-
peutic dilemma which we faced in its management. It re-
iterates the importance of comprehensive history taking and
corelating clinical examination with laboratory parameters,
without which diagnosis of CGD and later secondary HLH
would not have been possible. Extensive search should be
carried out for the underlying infectious agents, and
aggressive targeted antimicrobial therapy should be initiated
without delay.
Conflicts of interest
10. Kardas F, Patiroglu T, Unal E, Chiang SC, Bryceson YT,
The authors have none to declare.
references
11. Alvarez-Cardona
1. Kliegman, Nelson Robert, Waldo E. Nelson Textbook of
Pediatrics. 1st ed. Elsevier e Health Sciences Division;
2015:1045e1047.
2. Arnold Danielle E, Heimall Jennifer R. A review of chronic
granulomatous disease. Adv Ther. 2017;34:2543e2557.
3. Parekh C, Hofstra T, Church J, Coates T. Hemophagocytic
lymphohistiocytosis in children with chronic granulomatous
disease. Pediatr Blood Cancer. 2010;56:460e462.
4. Ramachandran S, Zaidi F, Aggarwal A, Gera R. Recent
advances in diagnostic and therapeutic guidelines for
primary and secondary hemophagocytic
lymphohistiocytosis. Blood Cells Mol Dis. 2017;64:53e57.
5. Valentine G, Thomas T, Nguyen T, Lai Y. Chronic
granulomatous disease presenting as hemophagocytic
lymphohistiocytosis: a case report. Pediatrics.
2014;134:1727e1730.
6. Seger RA. Modern management of chronic granulomatous
disease. Br J Haematol. 2008;140:255e266.
7. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and
therapeutic guidelines for hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124e131.
8. Hisano M, Sugawara K, Tatsuzawa O, KitagawabM,
Murashima A, Yamaguchi K. Bacteria associated
haemophagocytic syndrome and septic pulmonary embolism
caused by Burkholderia cepacia complex in a woman with
chronic granulomatous disease. J Med Microbiol.
2007;56:702e705.
9. Bode SF, Ammann S, Al-Herz W, et al. The syndrome of
hemophagocytic lymphohistiocytosis in primary
immunodeficiencies: implications for differential diagnosis
and pathogenesis. Haematologica. 2015;100:978e988.
Kendirci M. Hemophagocytic Syndrome in a 4 - month old
infant with biotidinase deficiency. Pediatr Blood Cancer. 2012
15;59:191e193.

A, Rodrı́guez-Lozano AL, Blancas-Galicia L,
Rivas-Larrauri FE, Yamazaki-Nakashimada MA. Intravenous
immunoglobulin treatment for macrophage activation.
syndrome complicating chronic granulomatous disease. J Clin
Immunol. 2012;32:207e211.