T-cell and combined immunodeficiencies — formative SAQs

SAQ 1 (10 marks)

A six-week-old boy is referred to the paediatric clinic because his newborn screening dried blood spot returned a low T-cell receptor excision circle (TREC) result. He was born at term, is feeding and growing well, and has had no infections. His maternal uncle died in infancy decades ago, "before they could find out what was wrong." His absolute lymphocyte count is 1.8 × 10⁹/L (low for age). [1]

Question: Outline the stepwise management of this infant, from confirmation of the newborn screen through to the curative decision and family counselling. (10 marks) [2]

Model answer

Confirmation and phenotyping (2 marks). A low TREC result on the newborn screen means the infant has few naive T cells leaving the thymus, and the differential includes SCID but also other causes of T-cell lymphopenia. The immediate next step is confirmatory flow cytometry for lymphocyte subsets — CD3, CD4, CD8, CD19/CD20 (B cells), and CD16/CD56 (NK cells) — to determine the immunophenotype. The family history of an affected maternal uncle and the low lymphocyte count make X-linked SCID the leading diagnosis, so the flow cytometry is likely to show a T⁻B⁺NK⁻ pattern. Genetic testing (a targeted SCID gene panel or whole-exome sequencing) then confirms the IL2RG mutation and triggers maternal carrier testing. [7]

Immediate protection — the non-negotiables (3 marks). While the diagnosis is being confirmed, the infant must be protected from iatrogenic harm. Stop all live vaccines — BCG, rotavirus, oral polio, and MMR are absolutely contraindicated because the attenuated organisms disseminate fatally in a child without T cells. Ensure that any blood product the child receives is irradiated, leucocyte-depleted, and CMV-negative, because non-irradiated blood causes transfusion-associated graft-versus-host disease, which is fatal in SCID. Start Pneumocystis prophylaxis with co-trimoxazole and antifungal prophylaxis with fluconazole. Begin immunoglobulin replacement (intravenous or subcutaneous, 400 to 600 mg per kilogram every three to four weeks) to provide passive humoral protection, because the child cannot mount antibody responses. [9] [10]

Urgent transplant referral (2 marks). Refer the infant urgently to a paediatric immunology and stem cell transplant centre. SCID is a medical emergency, and the timing of haematopoietic stem cell transplantation is the single most powerful determinant of survival. The donor search begins immediately — first a matched sibling donor (which gives the best outcomes), then a matched unrelated donor from a registry, then a haploidentical parent. Because this infant is only six weeks old and infection-free, the goal is transplant before 3.5 months of age and before any infection, a window in which survival exceeds 90 percent. [2] [10]

Family genetic counselling (2 marks). Confirming an IL2RG mutation identifies the mother as a carrier and has immediate implications for the wider family. Offer maternal carrier testing, sibling screening, and prenatal or preimplantation genetic diagnosis for future pregnancies. The power of early intervention on an affected sibling — transplant before infection — is the difference between near-normal survival and high mortality, so reproductive counselling is part of the management, not an afterthought. The family must understand that SCID is a genetic condition, that future pregnancies carry a one-in-four risk (for autosomal recessive forms) or a one-in-two risk of affected males (for X-linked forms), and that prenatal diagnosis is available. [6]

Disposition and long-term plan (1 mark). The infant is transferred to the transplant centre for haematopoietic stem cell transplantation. After transplant, long-term follow-up monitors immune reconstitution (T-cell subset recovery, thymic output by TREC), manages graft-versus-host disease, maintains malignancy surveillance, and plans transition to adult immunology care. The arc of the disease — from a near-uniformly fatal condition to one with over 90 percent survival when managed well — rests on the twin pillars of newborn screening and curative transplantation, and this infant, detected by TREC before symptoms, is the beneficiary of both. [1] [2]

SAQ 2 (10 marks)

A three-month-old girl whose family arrived as refugees six months ago presents with a two-month history of a non-healing ulcer at the site of her neonatal BCG vaccination, progressive axillary lymphadenitis, oral thrush that has not responded to topical therapy, and failure to thrive. Her absolute lymphocyte count is 1.2 × 10⁹/L (low for age). She received the neonatal BCG and the live rotavirus vaccine in her country of origin. [9]

Question: (a) What is the diagnosis and what does the presentation tell you? (b) Outline the immediate management and the protections you must put in place. (c) Explain the transplant decision and the factors that determine her outcome. (10 marks) [1]

Model answer

(a) Diagnosis and presentation (3 marks). The diagnosis is severe combined immunodeficiency (SCID), presenting with BCGosis — disseminated disease from the neonatal BCG vaccine — alongside refractory oral candidiasis, failure to thrive, and lymphopenia. The presentation is the fingerprint of SCID: severe, persistent, opportunistic infection that fails to respond to standard therapy, caused by organisms that should not trouble a normal infant. BCGosis is a sentinel presentation in countries that immunise with neonatal BCG, and it tells you that the infant's T-cell system cannot contain even the attenuated mycobacterium. The live rotavirus vaccine she also received is a risk for disseminated rotavirus disease, which may already be contributing to her failure to thrive. The low lymphocyte count is the bedside confirmation. [9]

(b) Immediate management and protections (4 marks). Confirm the diagnosis with flow cytometry for lymphocyte subsets to determine the immunophenotype, and send genetic testing (a SCID gene panel). While awaiting the results, institute immediate protection. Stop all live vaccines — she has already received BCG and rotavirus, so watch for and treat vaccine-derived disease, but ensure no further live vaccines (MMR, oral polio) are given. Ensure that every blood product she receives is irradiated, leucocyte-depleted, and CMV-negative, because non-irradiated blood causes transfusion-associated graft-versus-host disease, which is fatal in SCID. Start Pneumocystis prophylaxis with co-trimoxazole, antifungal prophylaxis, and immunoglobulin replacement (400 to 600 mg per kilogram every three to four weeks) for passive humoral protection. Treat the BCGosis with antimycobacterial therapy (the regimen directed by infectious diseases, typically a combination of anti-tuberculous agents active against the BCG strain) and treat the candidiasis with systemic antifungals. Refer urgently to a paediatric immunology and stem cell transplant centre, because the active infection and the older age (three months) both worsen the transplant outcome and compress the window for infection-free cure. [9] [10]

(c) Transplant decision and outcome factors (3 marks). The curative therapy is haematopoietic stem cell transplantation. The donor hierarchy begins with a matched sibling donor, then a matched unrelated donor, then a haploidentical parent. The decisive variable is timing: transplant before 3.5 months of age and before the onset of infection achieves survival above 90 to 94 percent, falling to roughly 70 to 80 percent when transplant occurs later or with active infection. This infant is three months old and already has active BCGosis, so she is in the higher-risk group, and the transplant must proceed as soon as the infection is controlled and a donor is identified. The conditioning regimen will depend on the donor and genotype — matched sibling transplants in young infants may use little or no chemotherapy, while unrelated or haploidentical transplants use reduced-intensity or myeloablative conditioning. The active infection is the leading threat to her transplant success, so aggressive, complete treatment of the BCGosis and any other infection before transplant is essential. [2] [10]

The key teaching point is that this infant's outcome is worse than the infant in SAQ 1 precisely because she was not detected by newborn screening — she presented after infection. This is why universal TREC screening is the most important advance in SCID management: it shifts diagnosis from the post-infection, high-mortality window to the pre-symptomatic, low-mortality window. For families from countries without screening, or from refugee and migrant backgrounds where screening access is uneven, the clinician must suspect SCID from the clinical picture and act urgently. [1]