A 7-month-old male infant who had been unwell for 5 weeks prior to hospitalization presented with persistent fevers, cough, and fast breathing despite being on treatment for pneumonia with broad-spectrum antimicrobials comprising crystalline penicillin with gentamicin, ceftriaxone, and meropenem at a different health facility. Pertinent in family history, he was the only child of non-consanguineous parents. On examination, the child appeared sickly, was febrile, and had oral thrush and left axillary lymphadenopathy ipsilateral to the Calmette-Guerin bacillus (BCG) scar. He was tachypneic, had mild lower chest wall indrawing, and had normal oxygen saturation in room air. Good air entry was heard on auscultation bilaterally with few basal crepitations bilaterally. He was evaluated for the current illness and the possible underlying IEI. Details of investigations have been tabulated ( Table 1 ). Plain chest radiography at admission showed bilateral airspace opacities ( Figure 1A ). We commenced piperacillin-tazobactam, amikacin, high-dose cotrimoxazole, and fluconazole for the persistent pneumonia and candidiasis. Chest computed tomography (CT) revealed multiple bilateral large lung nodules ( Figure 1B ). Left axillary lymph node biopsy macroscopically revealed caseous material ( Figure 1C ). Lymph node tissue histology revealed granulomas suggestive of mycobacterial infection, but no acid-fast bacilli were seen. Periodic-acid Schiff stain for fungi was negative. The tuberculin skin test was positive, measuring 26 mm at 72 h ( Figure 1D ). First-line anti-tubercular therapy comprising isoniazid, rifampicin, pyrazinamide, and ethambutol was initiated.
BCG disease was a differential diagnosis based on axillary lymphadenopathy on the arm with the BCG scar. We were cognizant that BCG would be resistant to pyrazinamide. Fevers nonetheless subsided 72 h after beginning anti-tubercular therapy, and we chose a clinical approach pending further mycobacterial test results. We also considered CGD as a possible differential diagnosis because the infant was HIV negative and had recurrent fevers, probable BCG disease, and lung nodules on the CT chest that were not typical of tuberculosis (TB). Nitroblue tetrazolium (NBT) reduction and dihydrorhodamine reduction (DHR) tests to demonstrate an absent respiratory burst were not available in the country and could not be outsourced. Notably, lymphocyte subset testing is outsourced overseas for patients outside HIV programs.
On day 7 of admission, we sent blood via courier for genetic testing to rule out CGD or other IEI to INVITAE, a genetic laboratory in the USA. The targeted primary immunodeficiency panel employed next-generation sequencing and tested 407 genes including genes implicated in CGD. Permission was sought from this lab to use the genetic sequencing data for publication. On day 9 of admission, bronchoalveolar lavage (BAL) bacterial and fungal culture results returned negative. On day 10 of hospitalization, the Genotype MTBDRplus VER 2.0 (Hain) test result of lymph node tissue was received, detecting a Mycobacterium tuberculosis complex isolate susceptible to isoniazid and rifampicin. Following 10 days of empiric intravenous antimicrobials, the boy was discharged in a clinically stable condition. The plan was to complete 14 days of fluconazole and 21 days of therapeutic cotrimoxazole and continue anti-mycobacterial treatment as an outpatient.
Two weeks following hospital discharge, he developed new fevers. Prophylaxis with cotrimoxazole and itraconazole was started with clinical improvement. Anti-TB medication was continued. After 2 months of TB therapy, the follow-up CT chest showed complete resolution of the lung nodules; however, bilateral basal ground glass opacification was noted ( Figures 1E-H ). Notably during this time, itraconazole had run out, and the caregiver interchanged it with fluconazole. We educated the parents on the importance of compliance with the prescribed regimen. The mycobacterial culture was negative on bronchoalveolar lavage; results from lymph node biopsy were not found. The child completed 6 months of first-line TB treatment and was clinically well. Later, levofloxacin was added to cover for BCG disease.
We received the primary immunodeficiency genetic panel results 3 weeks post-discharge, which revealed a pathogenic hemizygous non-sense variant (c.736C>T, p.Gln246*) in exon 7 of CYBB gene in keeping with X-linked CGD. With these results, the team in Kenya consulted IEI experts in South Africa and India, who recommended hematopoietic stem cell transplantation (HSCT) to achieve a cure. We counseled his parents and extended family on his condition, all of whom were very receptive and keen on the HSCT. Both biological parents were screened for the CYBB mutation, and his mother was found to be a heterozygous carrier for the same variant.
He underwent a successful haplo-identical HSCT at the age of 1 year 2 months at an experienced center in India with his father as the donor (5/10 HLA match). The conditioning regimen consisted of anti-thymocyte globulin 7.5 mg/kg on day -11 to -9, fludarabine 180 mg/m2 on day -9 to -4, IV busulfan on day -7 to -4 (targeted AUC 86.4 mg/L), and thiotepa 10 mg/kg on day -3. The source of the stem cells was granulocyte colony-stimulating factor (G-CSF)-primed unmanipulated bone marrow. Post-transplant cyclophosphamide (50 mg/kg on days +3 and +4), tacrolimus, and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. The post-transplant neutrophil engraftment was achieved on day 15 and platelet engraftment on day +18. His last chimerism was 100% donor, and his immunosuppression was stopped on day +273. Major complications experienced were subclinical cytomegalovirus (CMV) reactivation and prolonged norovirus infection, which both resolved with treatment. The child is currently doing well more than 10 months post-transplant with no current infections or any evidence of graft-versus-host disease.
A timeline of events is illustrated in  Figure 2 .
Timeline of events. FBC, full blood count; PBF, peripheral blood film; CXR, chest radiograph; CRP, C reactive protein; PCT, procalcitonin; CT, computed tomography; BAL, bronchoalveolar lavage; TB, tuberculosis; RX, treatment; PID, primary immunodeficiency; +, positive.