Disseminated Bacillus Calmette-Guerin Infection: The Harbinger of Severe Combined Immunodeficiency Disease

Sir,

A 7-month-old boy presented with recurrent fever and cough unresponsive to antibiotics, for 3 months and a generalized erythematous rash for 3 weeks. He was second-born to third-degree consanguineous parents, with a normal birth weight, and unremarkable family history. He was on exclusive breast feeds, attained age-appropriate milestones, and was fully vaccinated for age.

He appeared pale, febrile, and lethargic. His weight and height were more than 85% of the expected (no malnutrition). There were multiple, red-brown papules, some umbilicated or eroded, scattered all over the body [Figure 1a-d], sparing the oral mucosa, palms, and soles. A 1 × 1 cm superficial ulcer [Figure 1e] was seen over the Bacillus Calmette-Guerin (BCG) vaccination site. He had hepatomegaly and normal breath sounds on auscultation. Laboratory investigations revealed low haemoglobin – 8.3 g/dl (normal range 12-15), albumin – 2.8 g/dL (3.5–5.0), and elevated CRP – 94.1 mg/L (<6), leukocytes – 26,300/mm³ (6000-17,000) with neutrophilia. Blood tests, including serological testing for common infectious diseases, chest X-ray, and ultrasound abdomen failed to detect any infections.

Figure 1.

Multiple red-brown papules, scattered over (a) chest and abdomen (b) back (c) face, upper lips (d) groin, with few exhibiting umbilication (black arrow and inset) or surface erosion (blue arrow), with scattered postinflammatory hyperpigmented macules (e) a superficial ulcer of size 1 × 1 cm over the BCG vaccination site

Histology from a papule revealed dermal histiocytes and foamy macrophages containing acid-fast bacilli [Figure 2a and b], which were also detected by Ziehl-Neelsen staining of skin smears [Figure 2c]. Mycobacterial culture from the skin papule and gastric aspirate detected rifampicin-susceptible Mycobacterium tuberculosis complex (MTBC), which was identified as M. bovis BCG strain using real-time polymerase chain reaction (PCR).[1]

Figure 2.

(a) Pandermal dense infiltrate of spindle-shaped cells (CD68+, S100- and CD1a-) and foamy macrophages (haematoxylin and eosin, original magnification ×200) (b) foamy macrophages containing numerous acid-fast bacilli in globi (Ziehl-Neelsen stain, original magnification ×200) (c) Skin smears from papule showing numerous long and slender acid-fast bacilli in globi (Ziehl-Neelsen stain, oil immersion)

Based on low serum immunoglobulins, low absolute lymphocyte count (929/microlitre), lymphocyte subset analysis showing absent T-cells, reduced age-specific B-cell absolute counts, and molecular characterization of the MTBC detected on culture, the diagnosis of disseminated BCG infection (BCGiosis) in severe combined immunodeficiency disease (SCID) was made. Genetic studies using the primary immunodeficiency (PID) panel revealed a homozygous pathogenic variant c.2T>C (p.Met1?) in exon1 of the IL7R, confirming the diagnosis. His clinical condition improved after administering weight-based antimycobacterial treatment. He was initiated on 3-weekly intravenous immunoglobulin, prophylaxis against opportunistic infections, and advised bone marrow transplant.

BCGiosis is a rare, life-threatening complication of the BCG vaccine, largely encountered in cellular immunodeficiency.[2,3,4] They often present with persistent or prolonged, unexplained fever, weight loss, failure to thrive, chronic cough, anaemia, lymphadenopathy, hepatosplenomegaly, and skin rash.[2,4] Of the many morphologies of skin rash described in BCGiosis, maculo-papules, subcutaneous nodules, and ulcers are commonly encountered.[2,3] We found only two reports of BCGiosis presenting with umbilicated papules similar to our case.[3,5] BCGiosis may also involve the lymph nodes, lungs, liver, spleen, bone marrow, and bones.[2,4] Though the chest X-ray was normal, MTBC detected in gastric aspirate indicates lung involvement in our patient, thus fulfilling the European Society for Immunodeficiency diagnostic criteria for BCGiosis.[2]

Biopsy of skin lesions for histopathology and microbiological confirmation with cultures and PCR is imperative for accurate diagnosis.[3,4] Antimycobacterial treatment is administered, with later modifications based on the antimicrobial sensitivity and clinical response; pyrazinamide is excluded due to inherent resistance.[2]

In tuberculosis-endemic countries, with routine BCG vaccination, BCGiosis can be the presenting complaint of PID, including SCID. Therefore, BCGiosis should be considered in a vaccinated infant with persistent fever, generalized rash, and ulceration of the vaccination site, as delay in diagnosis may prove fatal.

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Conflicts of interest

There are no conflicts of interest.