*Corresponding author:
Dr Ankur Kumar Jindal,
Assistant Professor- Pediatric Allergy Immunology Unit, Advanced
Pediatrics Centre, Department of Pediatrics, Post Graduate Institute of
Medical Education and Research, Chandigarh, India- 160012
Email:
ankurjindal11@gmail.com
Ph: +91-95920-65559
Word Count: 1000 (approx.)
Table: 1
Figure: 1
Supplementary figure: 2
Sources of funding: Funded by Indian Council of Medical
Research (Id 2020-9482)
Conflicts of interest: All authors declare there are no
conflicts of interest
Informed consent: Written informed consent was obtained from
parents of children included in this study for publication as clinical
image
Consent for publication: All authors have given final approval
for publication
Competing interests: None
Author contributions: AS, SB, JD, PV, DS and AKJ were actively
involved in the diagnosis and management of this case. JD, AKJ and SS
were involved in the immunological tests and microbiological tests done
in this child and interpreted the results of those tests. AS and SB
wrote the manuscript. AKJ and AS edited the manuscript. AKJ supervised
the entire manuscript preparation.
Disseminated Mycobacterium fortuitum infection in a young
girl withIFN-γR1defect masquerading as histiocytosis
Archan Sil, Suprit Basu, Jhumki Das, Sunil Sethi, Debajyoti Chatterjee,
Vignesh P, Deepti Suri, Ankur Kumar Jindal*
To the Editor,
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare
inborn error of immunity (IEI) of interferon-γ (IFN- γ) and interleukin
12-23 (IL12-23) pathway with predisposition to weakly virulent
mycobacterial infections (Mycobacterium bovis and environmental
non-tuberculous mycobacteria) and intra-macrophagic organisms like
bacteria (typhoidal and non-typhoidal Salmonella, Listeria, Klebsiella
etc.), fungus (Histoplasmosis, coccidiomycosis, paracoccidiomycosis,
candida) and parasites (toxoplasma, leishmania) (1). While Bacille
Calmette-Guérin (BCG) vaccine related complications were initially
reported in 1951, first gene associated with MSMD
(IFNγR1 defect) was discovered in 1996 (2). Till date,
18 different gene defects and 250 mutations have been reported in
patients with MSMD (IL12Rβ1 defect is the most common) (2).
Clinical manifestations may vary from early onset, fatal, disseminated
mycobacterial disease to late onset, localized, less severe
mycobacterial infection that may remain clinically silent for long
duration (1,2). This variation in clinical presentation depends on the
specific gene involved and can be explained by incomplete penetrance.
Clinical spectrum of MSMD can be divided into two main classes- (1)
Isolated MSMD (mycobacterial infection as the predominant manifestation)
and (2) Syndromic MSMD (presence of mycobacterial as well as
non-mycobacterial infections) (2). In countries where tuberculosis is
endemic, suspicion and diagnosis of MSMD has far reaching effects (1).
Unrestrained infection at times can lead to atypical manifestations such
as macrophage activation syndrome or vasculitis (1). Although
uncontrolled mycobacterial infection and abnormal T cell function can
act as triggers for hemophagocytic lymphohistiocytosis, it is considered
as an uncommon presentation of MSMD (3). A predominant histiocytosis
like presentation because of chronic mycobacterium infection has rarely
been reported in children with MSMD (4). This may create a diagnostic
conundrum form the treating physician. Herein, we report one such case.
A 3-year-old girl presented with abdominal distension for 1-year along
with multiple neck swellings, intermittent fever and progressive pallor
for 3 months. She was given anti-tubercular treatment for 3 months prior
to coming to us. Her elder brother had died at the age of 3 months due
to pneumonia. However, his medical records could not be retrieved.
On examination, she had pallor, generalized lymphadenopathy, eczematous
skin rashes, tachypnea and spleno-hepatomegaly (spleen reaching nearly
up to umbilicus). Laboratory investigations showed anemia and
thrombocytopenia with elevated inflammatory markers[Table 1] . Infective
work up including tuberculosis, kala-azar, cytomegalovirus and HIV came
negative. Serum beta-D glucan was within normal limits [Table
1] . Contrast enhanced computed tomography showed patchy consolidation
with ground glass opacities in dependent region of both lungs. Fine
needle aspiration cytology from lymph node showed granulomatous
inflammation and acid-fast bacilli (AFB) stain was negative.
Immunological work up showed decreased proportion of naïve helper
(CD3+CD4+CD45RA+) and cytotoxic T lymphocytes (CD3+CD8+CD45RA+) and
increased proportion of memory helper T lymphocytes
(CD3+ CD4+CD45RO+). Lymph node
biopsy and bone marrow biopsy showed infiltration of mixed histiocytic
population without any evidence of malignancy suggesting a possibility
of a histiocytic disorder (Figure 1) . However, negative CD1a
and S-100 stain ruled out Langerhans cell histiocytosis (LCH).
She was initially treated with broad spectrum antimicrobials. However,
she continued to have eczematous skin lesions and frequent blood
transfusion requirements. Considering a clinical possibility of non-LCH
histiocytic disorder, she was initiated on oral prednisolone (2
mg/kg/day) and whole exome sequencing was sent. She showed a brisk
clinical response, her rashes subsided and her transfusion requirements
reduced.
Whole exome sequencing revealed a homozygous c.201-2A>G
splice variant in intron 2 of IFN-γR1 gene. This splice variant
skips from end of exon 2 to middle of exon 3 and omit bases 201–302.
The observed variation has previously been reported in patients with
nontuberculous mycobacterial infections with MSMD. Flow-cytometry showed
reduced expression of phospho STAT-1 (Supplementary Figure 1)and phospho STAT-4 on gated monocytes and decreased IFN-γ receptor 1
expression on activated granulocytes and monocytes(Supplementary Figure 2) in the index child compared to
control. She was diagnosed to have MSMD and was empirically initiated on
anti-tubercular treatment (isoniazid, rifampicin, levofloxacin and
ethambutol). Oral prednisolone was gradually tapered and discontinued.
Four months later, she had recurrence of fever, skin rash and size of
liver and spleen increased. A lymph node biopsy was repeated from the
axilla which grew Mycobacterium fortuitum . She was initiated on
meropenem, amikacin, cefixime, clofazimine and levoflocxacin as per drug
sensitivity pattern. Due to sub-optimal response, she was subsequently
initiated on 3 million units of subcutaneous interferon-α (IFN-α) thrice
weekly. On follow-up, regression of hepatosplenomegaly and improvement
in cytopenia were noted. She is presently being evaluated for
hematopoietic stem cell transplantation.
Uncontrolled activation of macrophages and natural killer (NK) cells
cause increased production of pro-inflammatory cytokines. This leads to
a state of immune dysregulation that affects multiple systems presenting
as sub-acute to chronic febrile illness, eczematous rashes, generalized
lymphadenopathy, hepatosplenomegaly, pulmonary infiltrations, and lytic
bony lesions. Pancytopenia, hyperferritinemia, hypertriglyceridemia and
hypofibrinogenemia reflect this hyperinflammatory state (3). Index child
had similar multisystemic involvement which made us consider
possibilities of histiocytic disorders and initiation of corticosteroids
was considered. However, whole exome sequencing suggested a diagnosis of
MSMD and subsequently M. fortuitum was also isolated form the
lymph node biopsy. Histiocytic presentation of MSMD has rarely been
reported in literature in patients with both IL-12Rβ1 andIFN-γR1 defects (3,4).
Environmental non-tuberculous mycobacteria are one of the signature
organisms associated with MSMD. Index child showed growth of M.
fortuitum from lymph node biopsy. M. fortuitum has been
previously reported on multiple occasions in patients with completeIFN-γR1 deficiency (5). Most reported patients of MSMD withM. fortuitum infection are from Turkey, Italy, Greece and Spain.
Some of them had associated co-infections with non-typhoidalSalmonella or M. tuberculosis . Three of them underwent
HSCT and 2 of them succumbed to the illness (5). Cephalosporine
(cefoxitin, cefixime), aminoglycosides (amikacin, gentamycin) and
fluroquinolones (ciprofloxacin, levofloxacin) are used as empiric
treatment for M. fortuitum . The index child was, however, treated
with meropenem, levofloxacin, amikacin, clofazimine and cefixime based
on sensitivity pattern.
Interferon alpha has been found to be useful in patients with MSMD who
have refractory mycobacterium infection as was also seen in the index
case (6). She is presently being evaluated for HSCT.
To conclude, MSMD should be considered in patients with unexplained
histiocytic disorders. All attempts should be made to identify
mycobacteria in these cases so that targeted therapy can be used.
Interferon alpha may be used in patients with IFN-γR1 defect to
control mycobacterium infection.