BCG-osis and tuberculosis in a child with chronic granulomatous disease

Article Outline

• Abstract
• Differential diagnosis
• Laboratory testing
• Diagnosis and discussion of pathogenesis
• Summary
• Acknowledgment
• References
• Copyright

A few known primary immunodeficiencies confer predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines (regional disease, known as BCG-itis, or disseminated disease, known as BCG-osis), or more virulent mycobacteria, such as Mycobacterium tuberculosis (pulmonary and disseminated tuberculosis). We investigated the clinical and genetic features of a 12-year-old boy with both recurrent BCG-osis and disseminated tuberculosis. The patient's phagocytic cells produced no O₂⁻. A hemizygous splice mutation was found in intron 5 of CYBB, leading to a diagnosis of X-linked chronic granulomatous disease. Chronic granulomatous disease should be suspected in all children with BCG-osis, even in the absence of nonmycobacterial infectious diseases, and in selected children with recurrent BCG-itis or severe tuberculosis.

Key words: BCG, tuberculosis, chronic granulomatous disease

Abbreviations used: CGD, Chronic granulomatous disease, EM, Environmental mycobacteria, MSMD, Mendelian susceptibility to mycobacterial diseases, NADPH, Nicotinamide dinucleotide phosphate, PMA, Phorbol 12-myristate 13-acetate, PMN, Polymorphonuclear neutrophil, TST, Tuberculin skin test

The patient was born in 1994 to a nonconsanguineous Turkish family living in Turkey. He was vaccinated with Mycobacterium bovis BCG at birth. Three months later, he developed progressive regional axillary lymphadenopathy. He was treated with antibiotics for 3 months with a favorable response. At the age of 13 months, the patient was admitted to the hospital with abdominal distension. Physical examination revealed ascites and hepatomegaly. A computerized tomography scan of the abdominal region was performed, which confirmed the clinical findings. Liver tissue biopsy revealed an infiltration of mononuclear cell into the portal spaces. Cultures of liver material obtained by needle biopsy, blood, and urine were negative for bacteria, fungi, and acid-fast organisms. BCG-osis was suspected, and the patient received antituberculous treatment with izoniazid, rifampin, and streptomycin for 4 months. The patient made a full clinical recovery.

At the age of 4 years, the patient presented with a high fever and cough. Gastric aspirates tested negative by culture for acid-fast bacilli, but PCR tests for Mycobacterium tuberculosis complex were positive. His chest x-ray showed no infiltrates in the lungs. A tuberculin skin test (TST) with purified protein derivative was strongly positive, producing a weal 23 mm × 24 mm. The medical history of the patient's family was analyzed, and no cases of tuberculosis were detected. It was not possible to discriminate between a recurrence of BCG-osis or a primary tuberculosis. The patient was prescribed izoniazid, rifampin, and pyrazinamide therapy for 9 months. He recovered fully.

At the age of 6 years, the patient underwent surgery for a hepatic cystic lesion. Liver histology showed hepatic abscess. No acid-fast bacilli were detected, and biopsy cultures for bacteria, mycobacteria, and fungi were negative. The patient received antituberculous medication (izoniazid, rifampin, and pyrazinamide), which was continued for 9 months, and then replaced with clarithromycin and ceftriaxone for 1 month. The patient's clinical status improved on antimycobacterial treatment.

At the age of 7 years, the patient was admitted to the hospital with respiratory symptoms and multiple submandibular lymphadenopathies. His weight and height were between the 10th and 25th percentiles for age. The liver remained 4 cm and the spleen 1.5 cm below the costal margin. Computed tomography of the chest revealed pneumonic infiltration of the upper and lower lobes of the left lung. Bronchoscopy was performed, and bronchoalveolar lavage sample cultures were negative. A TST with purified protein derivative produced a weal 23 mm × 25 mm. A cervical lymph node was excised, and histologic examination revealed a normal architecture, with a granulomatous lesion characterized by central caseous necrosis, little debris, and epithelioid and giant cells, with a lack of visible acid-fast rods (Fig 1). The caseous necrosis and the strong positivity of the TST strongly suggested (but did not formally prove) a diagnosis of tuberculosis as opposed to BCG-osis, and a 9-month course of treatment with izoniazid, rifampicin, and pyrazinamide was initiated. The patient recovered after antibiotic treatment.

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• Fig 1. 

  Cervical lymph node biopsy. Histologic section showing granuloma with epithelioid and giant cells with caseous necrosis. Hematoxylin and eosin staining (×40).

A tentative diagnosis of chronic granulomatous disease (CGD) led to the initiation of itraconazole and sulfamethoxazole-trimethoprime prophylaxis at the age of 10 years. This treatment has been maintained ever since, with no secondary effects. The patient is now 12 years old and has remained free of any major infection. The patient has 2 healthy brothers who were vaccinated with BCG with no adverse effect.

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Differential diagnosis 

Recurrent BCG-osis and probable tuberculosis in this case are suggestive of compromised immunity.¹, ² Differential diagnoses considered in this case included the syndrome of Mendelian susceptibility to mycobacterial diseases (MSMD) that affects otherwise healthy children.³ These patients are vulnerable to poorly virulent mycobacterial species, such as BCG vaccines, nontuberculous, environmental mycobacteria (EM), and more virulent M tuberculosis. The patients typically do not have other infections apart from salmonellosis, which affects less than half of the cases. Mutations in IFNGR1, IFNGR2, and signal transducer and activator of transcription 1 impair the cellular responses to IFN-γ, whereas mutations in IL12B, IL12RB1, and NF-κB essential modulator (NEMO) impair the IL-12/23–dependent production of IFN-γ.³ Allelic heterogeneity at these loci results in the definition of as many as 13 distinct inherited disorders involving IL-12/23–dependent, IFN-γ–mediated immunity. Other primary immunodeficiencies that may be considered in our patient typically confer a broader vulnerability to infections (including mycobacterial disease). They include CGD,⁴ anhidrotic ectodermal dysplasia with immunodeficiency, X-linked hyper IgM syndrome, CD40 deficiency, the hyperimmunoglobin E syndrome, and severe combined immunodeficiency.⁴ Most were excluded by simple clinical and laboratory findings. HIV infection had also been shown to predispose to BCG-osis and was excluded in our patient by serology.

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Laboratory testing 

Laboratory analyses revealed leukocyte counts of 15,300/mm³ (64% neutrophils and 36% lymphocytes). Hemoglobin levels reached 10.1 g/dL, and the patient's platelet count was 313,000 /mm³. C-reactive protein concentration was 6.53 mg/dL, and the patient had an erythrocyte sedimentation rate of 150 mm/h. Immunologic studies showed a normal leukocyte count including B cells and CD4 and CD8 T cells (T-cell receptors α–β and γ–δ). Serum IgG, IgA, and IgM levels were 1360 mg/dL, 268 mg/dL, and 823 mg/dL, respectively, and IgE levels reached 252 IU/L. Total hemolytic activity and complement C3 and C4 levels were within normal limits. The secretion of IL-12p40, IL-12p70, and IFN-γ (by ELISA) after stimulation the blood samples with BCG and BCG + IFN-γ or BCG + IL-12p70 was normal. Only 20% of control polymorphonuclear neutrophils (PMNs) activated by phorbol 12-myristate 13-acetate (PMA) in the peripheral blood were stained with nitroblue tetrazolium.

We assessed O₂⁻ production in neutrophils from the patient, his mother, another patient with X-linked CGD, and a healthy control, after activation with PMA. No respiratory burst function was detected in the neutrophils of the patient (0.3 nmol/10⁶ cells/30 min, 0.8% of the healthy control) or of the control CGD patient (0.2 nmol/10⁶ cells/30 min, 0.53% of the healthy control). Respiratory burst function was, however, recorded for the patient's mother's cells: 11.9 nmol/10⁶ cells/30 min (31.7% of control; Fig 2). Superoxide production by monocytes from the patient was absent (data not shown). Flow cytometry analysis of the formation of dihydrorhodamine oxidation products showed a complete deficiency in the patient's PMNs. His mother had 2 granulocyte populations, 1 strongly dihydrorhodamine-positive and the other dihydrorhodamine-negative (data not shown). These results strongly suggest that our patient had X-linked CGD.

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• Fig 2. 

  Investigation of NADPH pathway. Superoxide production in PMNs. Granulocytes from a normal control (C[+]), a patient with CGD (C[−]), the proband (P), and his mother (M) were activated with 40 ng/mL PMA for 30 minutes. NS, Not stimulated.

A cDNA analysis showed that CYBB mRNA from the patient had an abnormal structure. A product slightly larger than the wild-type product was observed (NM_000397 from National Center for Biotechnology Information [NCBI] databases), as previously described.⁵ We cloned the PCR product and discovered a heterogeneous splicing pattern: a product with a 110 bp insertion (form 1), another with a 61 bp insertion between exons 5 and 6 (form 2), a third product with a 110 bp insertion between exons 4 and 6 (skipping of exon 5; form 3), and a complete absence of the wild-type splicing pattern (Fig 3, A). The inserted fragments were identified within intron 5 (NT_079573 from NCBI databases; position 483+868 to position 483 + 976; position 483+917 to 483 + 976). The respective amounts of the splice products were as follows: 39% of form 1, 45% of form 2, and 16% of form 3 (Fig 3, A). The cryptic exons inserted into the CYBB cDNA disrupted the open reading frame, creating 3 different premature stop codons (Fig 3, B). Genomic sequencing of CYBB revealed a mutation in intron 5 at position 483 + 978: a G>T substitution (Fig 3, C) generating a 5′ splice site (ggaaga → gtaaga), as previously reported. No other mutation was found in the coding region or in introns 4 and 5. The patient's mother was heterozygous for this mutation, and both his brothers were wild-type (Fig 3, D).

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• Fig 3. 

  Intronic mutation in the CYBB gene. A, Schematic diagram of the relevant region in the CYBB gene. The crytic exons separating exons 4 and 5 and exons 4 and 6 are derived from intron 5 sequences. B, Predicted amino acid sequences showing the additional exons resulting in the premature termination of translation. C, Analysis of the genomic sequence of the CYBB gene. The patient carries a G>T mutation at position + 978 in intron 5. Genomic DNA was extracted from peripheral blood samples taken from a normal control (C) and the patient (P). D, Pedigree of the family. Each generation is designated by a Roman numeral (I, II), and each individual is represented as an Arabic numeral. The proband is represented by a black symbol and indicated by an arrow. The mother is an obligate carrier and is represented by the circle with a black arrow.

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Diagnosis and discussion of pathogenesis 

We report here an otherwise healthy patient who had BCG-osis and probably tuberculosis. His granulocytes displayed a defective nicotinamide dinucleotide phosphate (NADPH) oxidase function. The mutation in intron 5 of CYBB was transmitted from his mother, and it is loss-of-function as it alters the mRNA splicing and reading frame. This patient with CGD therefore presented with an unusual clinical picture, limited to mycobacterial diseases.

Chronic granulomatous disease is a primary immunodeficiency characterized by the total absence or low levels of reactive oxygen species production caused by a deficiency of the NADPH oxidase complex in phagocytes.⁶ The NADPH oxidase enzyme consists of cell membrane–bound gp91-phox and p22-phox and the cytoplasmic proteins p40-phox, p47-phox, p67-phox, and Ras-related C3 botulinum toxin substrate 2 (RAC2).⁷ GP91-phox and p22-phox form the membrane cytochrome b₅₅₈, which is associated with RAP1A, a member of the Ras family of guanosine triphosphate–binding proteins.⁸ P47-phox, p67-phox, p40-phox, and RAC2 are cytosolic oxidase components required for the activation of electron transport. They are translocated to the membrane on stimulation. Diverse mutations in 4 genes have been reported in patients with CGD.⁹ The most common form is caused by mutations in the CYBB gene,¹⁰, ¹¹, ¹² encoding the gp91-phox protein, leading to X-linked disease (Online Mendelian Inheritance in Man [OMIM] 306400). Defects in the genes encoding p22-phox (OMIM 608508), p47-phox (OMIM 233700), and p67-phox (OMIM 233710) lead to autosomal-recessive forms of CGD; a single missense mutation in the RAC2 gene has also been reported to cause a CGD-like disease.¹³

Patients with CGD are typically highly susceptible to multiple life-threatening bacterial and fungal infections, beginning early in childhood.⁹ These infections are often recurrent, despite aggressive antibiotic therapy, and patients often have pneumonia; lymphadenitis; and abscesses of the liver,¹⁴ subcutaneous tissues, and bones. The pathogens causing infection in patients with CGD include Staphylococcus aureus, Nocardia, and gram-negative bacteria, such as Salmonella, Klebsiella, Serratia, and Burkholderia.⁶ Aspergillus is the most frequently implicated fungus.¹⁵ Increasing numbers of cases of mycobacterial disease are being recognized in patients with CGD. A number of patients with BCG disease (BCG-itis or BCG-osis) and tuberculosis (pulmonary and disseminated) have been reported.⁴, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰

We reviewed the literature on CGD, paying specific attention to its association with mycobacterial diseases. We identified in PubMed 72 patients, including 38 patients with BCG disease, 4 with EM disease, 16 with tuberculosis, 7 with tuberculosis and BCG disease, and 7 with disease caused by Mycobacterium spp, who were reported from 1971 to December 2006 (Table I).¹, ², ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹ X-linked and autosomal recessive modes of inheritance were indicated in 34 and 9 patients, respectively. The mode of inheritance was not specified in the other patients. Most of the 72 CGD cases identified from previous studies had other infectious diseases. However, 9 patients were otherwise healthy and had isolated mycobacterial disease. Three patients had BCG disease only (2 BCG-osis and 1 BCG-itis), and 6 had tuberculosis (3 disseminated and 3 pulmonary diseases). Mycobacterial disease can thus occur in otherwise healthy patients with CGD.

Table I. Literature review of mycobacterial disease in CGD

AR, Autosomal recessive; NK, not known; XR, X-linked recessive; +, evidence of other infections; −, with no other infection.

In total, there were 45 cases of CGD with BCG disease including 29 cases of local or regional BCG lymphadenitis (BCG-itis) requiring surgery and/or antibiotic treatment and often recurrent.¹⁸, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴¹, ⁴², ⁴³, ⁴⁶, ⁴⁷, ⁴⁹, ⁵⁰, ⁵¹ BCG-itis was associated with other infections in 14 cases. Only 17 of the patients with BCG disease were reported to be healthy before vaccination. Sixteen patients presented with disseminated BCG disease (BCG-osis),², ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ⁴⁰ which proved fatal in 6 patients despite intensive antibiotic treatment. The mean age of these patients at the time of death was 2 years, 5 months (range, 4.30 months to 8 years).

By contrast, patients with CGD are much less susceptible to EM disease, despite exposure to these nearly ubiquitous microorganisms. One patient suffered from disseminated Mycobacterium flavescens infection at the age of 62 years,²² a second had Mycobacterium fortuitum pneumonitis and osteomyelitis at the age of 27 years,²¹ and 2 other patients were diagnosed with Mycobacterium avium disease at the ages of 9 and 10 years.²³, ²⁴ None of the patients with CGD with EM disease had been vaccinated with BCG, like IL-12Rβ1–deficient patients.⁵² The fact that BCG is the most widely distributed vaccine worldwide suggests BCG vaccination may prevent or delay the occurrence of EM disease in patients with CGD, as it does in IL-12Rβ1–deficient patients.

Among a total of 23 patients with tuberculosis, 18 had pulmonary disease.¹⁷, ¹⁸, ¹⁹, ²⁰, ⁵¹ One also had renal disease,¹⁷ another had splenic lesions,²⁰ 2 others presented with peripheral lymphadenitis,²⁰ and another had mediastinal adenopathy.⁵¹ In 7 cases, BCG infection at the site of vaccination (BCG-itis) did not prevent the subsequent development of tuberculosis, like in IL-12Rβ1–deficient patients.¹⁶, ¹⁸, ¹⁹, ²⁰, ⁵² No patient with CGD with BCG-osis or EM disease and tuberculosis was reported previously. Among the 23 patients with tuberculosis, 6 had only mycobacterial disease.²⁰ Age at time of tuberculosis infection was not known in all cases, but patients were diagnosed in the first 2 decades of life. The higher incidence of tuberculosis in patients with CGD from Iran, Hong Kong, and Argentina¹⁸, ¹⁹, ²⁰ probably reflects higher levels of exposure to M tuberculosis in endemic areas. Thus, CGD is clearly a primary immunodeficiency associated with an increase in susceptibility to tuberculosis.

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Summary 

A 12-year-old boy with X-linked CGD reported here presented with recurrent BCG-osis and probably tuberculosis. Clinically, this presentation resembles that of patients with the syndrome of MSMD, who develop mycobacterial disease caused by BCG, EM, and M tuberculosis and are typically resistant to other infectious agents, with the exception of Salmonella and a few other pathogens.⁵³, ⁵⁴ Genetic defects of the IL-12/23–IFN-γ circuit were found in patients with MSMD.³, ⁵⁵ The association of CGD with mycobacterial disease was well established in the literature. Our study emphasizes that patients with severe clinical disease caused by BCG and/or M tuberculosis should be investigated not only for defects in the IL-12/23–IFN-γ circuit, but also for CGD.⁵⁶ Our case report and literature review indicate that a defect of the phagocytic respiratory burst should be considered not only in all children with BCG-osis but also in selected patients with recurrent BCG-itis or severe tuberculosis, even in the absence of other infectious diseases.

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We thank Laurent Abel and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions and Serge Szulczewski for searching for references.

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