DISSEMINATED MYCOBACTERIUM PEREGRINUM INFECTION IN A CHILD... : The Pediatric Infectious Disease Journal (original) (raw)
We describe an infant who at the age of 1 year developed chronic disseminating infection caused by a fast growing, poorly pathogenic mycobacterial species, Mycobacterium peregrinum. The child was diagnosed with complete interferon-gamma receptor-1 deficiency resulting from a novel, recessive null mutation in IFNGR1. This is only the second reported case of interferon-gamma receptor-1 deficiency in which the primary infection was caused by a fast growing mycobacterial species.
A 14-month-old Italian boy presented with a 2-month history of generalized lymphadenopathy (cervical, axillary and inguinal), hepatosplenomegaly and bronchitis. He had a history of recurrent upper respiratory tract infections and fever, had not been vaccinated with Mycobacterium bovis Calmette-Guérin bacillus and was the youngest child of healthy parents. There was no known consanguinity in the family. His three siblings (13, 12 and 10 years of age) were healthy.
An abdominal ultrasound examination revealed mesenteric lymph node enlargement, and the chest radiograph showed perihilar infiltration but no lymphadenopathy. A biopsy of the cervical lymph node revealed preserved lymph node structure with nonspecific reactive changes, compatible with reactive lymphadenitis. Neither granulomas nor acid-fast bacilli were detectable. A second biopsy 2 months later revealed lymphocytic and epithelioid infiltration, proliferation of small vessels and a clonal rearrangement of the T cell receptor gamma-chain, leading to the tentative diagnosis of angioimmunoblastic lymphadenopathy with dysproteinemia. Lymph node tissue cultures from the first and second biopsy were positive for a mycobacterial species that was later identified as Mycobacterium peregrinum. M. peregrinum is a fast growing mycobacterial species that is rarely and poorly pathogenic, typically after iatrogenic or traumatic infections of subcutaneous tissues. 1, 2 It is not known to be an opportunistic pathogen in AIDS patients. The selection criteria for the differentiation of rapidly growing nonpigmented mycobacteria were: growth at 25°C, 31°C, 37°C, 40°C and 45°C; utilization of mannitol, sodium citrate and inositol; tolerance to 5% NaCl, coloring after iron uptake; nitrate reduction; inhibition by pipemidic acid, polymyxin B, ciprofloxacin and amikacin; and positivity for arylsulfatase. Both isolates were susceptible in vitro to imipenem and capreomycin. The mycobacterial 16S ribosomal RNA gene was amplified by PCR, with the use of sets of broad range eubacterial primers in combination with mycobacterial genus-specific primers. The species was subsequently characterized by direct cycle sequencing of the 16S ribosomal DNA amplicons. One year later a third biopsy was taken which again revealed atypical lymphocytic infiltration, without clearly detectable granuloma formation or influx of eosinophils or macrophages. The culture from this biopsy revealed again M. peregrinum.
Laboratory investigations on admission showed a microcytic anemia, hyperleukocytosis, elevated inflammatory markers, normal serum IgG concentrations (including IgG1 to IgG4 isotypes) and increased IgM and IgA. Specific IgG antibodies to poliovirus, diphtheria, tetanus toxoid, adenovirus and Epstein-Barr virus were present, whereas no specific IgG to cytomegalovirus (CMV), HIV, Coxsackie virus, hepatitis A virus, hepatitis B virus, hepatitis C virus or Toxoplasma was found. In the second biopsy human herpes virus type 6 DNA was found, whereas there was no detectable Epstein-Barr virus or Bartonella DNA. Absolute numbers of peripheral CD3, CD3/CD4, CD3/CD8 and CD19 (T and B) cells were normal, whereas numbers of CD16/CD56 cells were slightly decreased.
To seek a molecular diagnosis of this unusual syndrome, defects in the type 1 cytokine cascade were sought, because genetic deficiencies in interleukin 12 (IL-12) p40, interleukin 12 receptor beta-1, interferon-gamma receptor-1 (IFNγR1), IFNγR2 or signal transducer and activator of transcription-1 have been found in patients with unusually severe infections caused by mycobacteria of low virulence. 3–8 No defects in IL-12 receptor expression or function or IL-12 p40 production were detectable (data not shown), but there was a complete lack of IFNγR1 expression at the surface of the patient’s cells accompanied by a lack of cellular responsiveness to IFN-gamma (data not shown), whereas both parents were normal. Genomic IFNGR1 sequencing revealed a homozygous nucleotide deletion in exon 4 at position 523 (523delT) that resulted in a frame shift, causing a premature stop in the extracellular domain of the protein, thus explaining the observed cellular and clinical phenotype. Both parents were heterozygous for the mutation and expressed normal levels of IFNγR1 at their cell surface. The patient had a healthy brother who was homozygous for the wild-type sequence and a sister and brother who were heterozygous for the mutation.
Treatment with capreomycin and imipenem improved the child‘s condition. Therapy was given for 1 year during which antibiotics were discontinued for periods up to 3 to 4 weeks, but the patient’s condition deteriorated each time the therapy was interrupted.
Because the oldest sibling was HLA-identical, a bone marrow transplantation (BMT) with reduced conditioning was performed. The donor was CMV positive. The chimerism analysis 3 weeks post-BMT revealed a full donor engraftment but subsequently autologous bone marrow reconstituted. The child’s clinical condition improved during the first 10 months post-BMT, even after cessation of antibiotics. However, multifocal osteomyelitis developed 2 months later. Although no infectious agents could be found by PCR or culture in the biopsy specimen from the radiologically abnormal bone, the clinical and radiologic findings improved after treatment with imipenem and capreomycin. Because of the poor prognosis of children with IFNγR1 deficiency described in the literature, we decided to perform a second transplantation 20 months later, using a more intensive preparative regimen which was followed by the administration of peripheral hematopoietic stem cells. Unfortunately the patient reconstituted promptly with autologous cells. At the time of writing, 21 months after the second transplantation, the general condition of the child was good, except for episodes of recurrent obstructive bronchitis, which require therapy with bronchodilators, inhaled corticosteroids and beta-agonists. The patient continues to receive 2-week cycles of antibiotics (Cefaclor) with 2- to 3-week intervals between treatments. No mycobacterial DNA is detectable in the patients’ blood, and no signs of CMV reactivation have been seen. The long term prognosis is uncertain.
This is the first description of a disseminating M. peregrinum infection in a patient with genetic IFNγR1 deficiency. Infections with fast growing mycobacterial species are more often seen in patients with complete IFNγR1 or IFNγR2 deficiency, when compared with IL-12 receptor beta-1 deficiency or partial IFN-γ receptor deficiency. In previously described IFNγR1-deficient patients who had disseminating infections caused by fast growing mycobacterial species, Mycobacterium fortuitum, Mycobacterium smegmatis, M. abscessus and Mycobacterium chelonae were identified. 3, 4, 9 Our patient is the second reported case of IFNγR1 deficiency in which the primary infection is caused by a fast growing Mycobacterium (see Ref. 4, Footnote 3). The clinical phenotype of our patient was severe, comparable with the disseminating, treatment-resistant and often fatal syndromes seen in other patients with complete IFNγR1 deficiency. 5–7
Acknowledgment. This work was supported by the Netherlands Leprosy Foundation and the Netherlands Organization for Scientific Research.
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Keywords:
Interferon-gamma receptor-1 deficiency Mycobacterium peregrinum infection; disseminated mycobacterial disease; infection and interferon-gamma receptor-1 deficiency
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