Disseminated Mycobacterium avium Complex Infection in a Child with Partial Dominant Interferon Gamma Receptor 1 Deficiency in India Varun K. Sharma, Gautham Pai, Caroline Deswarte, Rakesh Lodha, Sarman Singh, Liew Woei Kang, Chong Chia Yin, Jean-Laurent Casanova, et al. Journal of Clinical Immunology ISSN 0271-9142 J Clin Immunol DOI 10.1007/s10875-015-0173-1
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Author's personal copy J Clin Immunol DOI 10.1007/s10875-015-0173-1
ASTUTE CLINICIAN REPORT
Disseminated Mycobacterium avium Complex Infection in a Child with Partial Dominant Interferon Gamma Receptor 1 Deficiency in India Varun K. Sharma 1 & Gautham Pai 1 & Caroline Deswarte 2,3 & Rakesh Lodha 1 & Sarman Singh 4 & Liew Woei Kang 5 & Chong Chia Yin 5 & Jean-Laurent Casanova 2,3,6,7,8 & Jacinta Bustamante 2,3,9 & Sushil K. Kabra 1
Received: 8 April 2015 / Accepted: 29 May 2015 # Springer Science+Business Media New York 2015
Abstract Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by clinical disease caused by weakly virulent mycobacteria. All genes mutated in MSMD patients are involved in IFN-γ immunity. Autosomal partial dominant (PD) interferon-γ receptor 1 (IFN-γR1) deficiency is the most frequent abnormality affecting the group of MSMD patients leading to impaired response of IFN-γ. We describe here a patient from India with disseminated infection due to Mycobacterium avium intracellulare (MAC) including
multifocal osteomyelitis and BCG disease. A heterozygous mutation in exon 6 of IFNGR1 gene was identified, conferring an autosomal PD IFN-γR1 deficiency. Patient had recurrence of mycobacterial disease during antibiotic therapy for which subcutaneous IFN-γ was added as a modality of treatment for resistant MAC infection.
* Varun K. Sharma
[email protected]
Introduction
1
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U1163, Paris, France
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Imagine Institute, Paris Descartes University, Paris, FranceEU
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Department of Laboratory medicine, All India Institute of Medical Sciences, New Delhi, India
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Department of Pediatrics, KK Women and Children Hospital, Singapore, Singapore
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St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
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Howard Hughes Medical Institute, New York, USA
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Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
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Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, FranceEU
Keywords Interferon γ . mycobacteria . MSMD . IFN-γR1 deficiency
Disseminated disease due to Nontuberculous Mycobacterium (NTM) is mainly seen in patients with acquired immunodeficiency syndrome (AIDS) and other forms of severe immune-suppression. The incidence of NTM infections is increasing in the pediatric age group in otherwise immunocompetent hosts. In depth analysis of these patients has recently led to identification of a primary immunodeficiency termed as Mendelian susceptibility to Mycobacterial diseases (MSMD) [1]. Mutations lead to defects in interferon gamma (INF-γ) axis predisposing to infections with BCG and NTM [2–4]. We report a 6 years old child of Indian origin with partial dominant IFNGR1 mutation presenting with disseminated Mycobacterium avium complex (MAC) infection and recurrent multifocal osteomyelitis. This is one of the rare pediatric cases where IFN-γ was used adjuvant to antibiotic therapy for the treatment of recurrent mycobacterial infection after failure of antimycobacterial antibiotic therapy alone. This is the first patient with genetic etiology of MSMD identified in India.
Author's personal copy J Clin Immunol
Case Report The patient (Proband, P1) was born in August 2009 to a nonconsanguineous parents originating from India and living in Singapore. The parents gave a history of the child developing an abscess at the BCG injection site along with left sided axillary lymphadenitis at the age of 1 month. The biopsy of the node showed granulomatous lymphadenitis for which the child received isoniazid therapy for 3 months with good clinical response. At age of 2 years, he presented with multiple swelling over the scalp for 6 months, hoarseness of voice for 4 months and fever for 2 months. The lumps over the scalp were progressively increasing in size and number. Fever was low grade with an evening rise in temperature. There was no history of ear discharge, body rash, progressive pallor, abdominal distension or bleeding from any site. There was no history of similar illness in family and no contact with tuberculosis cases. On examination there were multiple nodular swellings over the scalp about 2 cm X 2 cm in size, firm to hard in consistency. X-ray revealed multiple lytic bony lesions in the ribs on either sides (Fig. 1a) and in left tibia (Fig. 1b). Computed tomography (CT) scan was suggestive of mediastinal enlargement with collapse of the left upper and lingular lobe (Fig. 1c, d). He also had hepatosplenomegaly with multiple focal hypoechoic lesions in the spleen, associated with peri-pancreatic lymphadenopathies (Fig. 1e). MRI of skull
Fig. 1 a X-ray showing multiple lytic bony lesions in the ribs on either sides of the chest; b; lytic lesion in left tibia; c, d: CT scan of chest showing enhancing mass in the superior and anterior mediastinum with collapse of the left upper and lingular lobe and hyperinflation in other areas; Fig. 1e:CT abdomen showing hepatosplenomegaly with multiple
showed multiple enhancing calvarial lesions in bilateral frontal bones and right parietal bone with a solitary lesion in the right half of mandible (Fig. 1f). Bone scan showed uptake in bilateral parietal bones, left frontal bone and multiple ribs suggestive of multifocal osteomyelitis. Bone marrow aspirate and biopsy was normal. Mantoux test with 5TU purified protein derivative from M. tuberculosis (PPD) was negative. Gastric aspirates for acid-fast bacillus (AFB) and MGITTM culture were negative for Mycobacterium tuberculosis. Blood for M. tuberculosis PCR and QuantiFERON-TB Gold were negative. Blood and urine cultures were negative for bacteria and fungus. The child underwent a scalp biopsy. The histopathology of the scalp biopsy showed granuloma with occasional AFB (Fig. 2). Culture of the scalp biopsy specimen grew atypical mycobacteria identified as Mycobacterium avium intracellulare (MAC) species. A diagnosis of disseminated MAC infection was made and child was started on rifampicin, ethambutol, ofloxacin and clarithromycin to which he responded well. On follow up after 6 months he showed clinical resolution. His appetite improved and he demonstrated weight gain of 3.5 kg with resolution of the scalp swelling. Workup for immune deficiency including HIV ELISA, immunoglobulin profile (serum IgA, IgG, IgM), CD4/CD8 counts, CD11 and CD18 counts were within normal limits. Nitrobluetetrazolium (NBT) test was positive, the staining being similar to the healthy control and not suggestive of chronic
focal hypoechoeic lesions in the spleen with peri-pancreatic lymphadenopathy; f: MRI of skull showed multiple enhancing calvarial lesions in bilateral frontal bones and right parietal bone with a solitary lesion in the right half of mandible
Author's personal copy J Clin Immunol Fig. 2 The histopathology of scalp biopsy showing granuloma with occasional AFB
granulomatous disease. BCG infection and disseminated MAC infection led to the hypothesis of an immunodeficiency of the IFN-γ circuit. Genetic sequencing of the IFNGR1 gene showed a heterozygous mutation in exon 6, 818delT conferring an autosomal PD IFN-γR1 deficiency. At 1 ½year of treatment with antimycobacterial drugs, patient developed another mandibular swelling, biopsy of which showed a recurrence of MAC infection. In view of recurrent disease, patient was started on IFN-γ 50 μg/m2 subcutaneously thrice a week. Patient received IFN-γ for 9 months with no adverse effects except occasional fever. Within 2 weeks of treatment, mandibular swelling and pain started subsiding. After 9 months as the patient was asymptomatic all the treatment was stopped. For next 3 months child remained asymptomatic, however subsequently he developed a cervical node swelling for which chemotherapy was restarted with same drugs. IFN-γ was not used during this relapse. Treatment was given for a total duration of 6 months. Patient improved subsequently leading to full recovery. For the last 1 year child is asymptomatic and is on azithromycin prophylaxis. The patient is clinically well at 6 years of age. Both parents are asymptomatic. The younger sibling who is just 4 months old has not being vaccinated with BCG and is asymptomatic. Unfortunately, parents reject the future genetic investigation in him.
Discussion MSMD should be considered as a differential diagnosis in all patients with primary immunodeficiency (PID). Evaluation of such patients is a difficult task in a developing country like India. Very few studies have been
published from India on primary immunodeficiency [5]. Major efforts are necessary to create a registry and to determine the incidence of PID in India. We report here a patient who suffered from disseminated BCG disease including multifocal osteomyelitis due to MAC infection. A heterozygous mutation, 818delT in exon 6 of IFNGR1 gene has been identified in this patient. This rare mutation confers the most frequent form of IFN-γR1deficiency leading to PD defect. Mutations in IFNGR1 have been increasingly recognised since 1996 [1, 2]. Newport et al. and Jouanguy et al. described the first bi-allelic mutations of IFNGR1 conferring complete IFN-γR1 deficiency [3, 4, 6]. Three different forms of IFN-γR1 deficiency have been described: complete, partial recessive (PR) and partial dominant (PD) [2]. Patients with complete IFN-γ R1 deficiency are sick in childhood with a syndrome characterized by chronic fever, weight loss, lymphadenopathy, hepatosplenomegaly and evidence of disseminated infection which may involve bone, skin, soft tissues, lung and meninges. Patients with autosomal PR form of IFN-γ R1 deficiency have less severe clinical phenotype and they suffer from mycobacterial infections [7]. Patients with autosomal PD IFN-γR1 deficiency are susceptible to mycobacterial diseases and frequent involvement of bone is observed, as seen in the case reported here [8]. The patient reported here had 818delT mutation. The treatment of MAC infection in the setting of IFN-γR1 deficiency is difficult and a topic of research. Reported cases have been treated with combination of antimycobacterial drugs like macrolides, ethambutol, rifabutin/rifampicin and quinolones/aminoglycoside. Despite a complete course of chemotherapy which is 18–24 months long, there are cases which are either resistant or they relapse
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once the drugs are stopped. IFN-γ is a promising biological agent of therapeutic potential in recurrent MAC infection in patients with partial IFN-γR1 deficiency. A significant clinical response was noted in our patients within 8 weeks of starting treatment. But there are very few case reports till date to support this modality of treatment [9–11]. Treatment with IFN-γ could be proposed to prevent or cure infection. Acknowledgments We acknowledge Dr Surjit Singh, Professor, Pediatric Allergy and Immunology Unit, Advanced Pediatric Centre, PGIM ER, Chandigarh, India for his valuable inputs in the initial diagnosis of this case. This research was funded in part by a grant of the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970, the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health grant number 8UL1TR000043, The Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID) and the French National Research Agency. (ANR) under the BInvestments for the future^ (grant number ANR-10IAHU-01).
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Conflict of interest None
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