Primary immunodeficiency: warning signs and diagnostic approach — formative SAQs

SAQ 1 (10 marks)

A seven-month-old boy presents with failure to thrive, persistent oral thrush, and two admissions for pneumonia — one requiring intravenous antibiotics. His full blood count shows an absolute lymphocyte count of 1.8 × 10⁹/L. He has a male cousin who died in infancy from an infection the family never understood. [1]

Question: Outline your recognition of this presentation, the tiered diagnostic workup, the immediate protective management, and the definitive pathway. (10 marks) [5]

Model answer

Recognition — the SCID alarm (2 marks). This infant breaks every reassuring rule: failure to thrive, persistent oral candidiasis beyond infancy, two pneumonias with one needing intravenous antibiotics, a lymphocyte count that — although it appears numerically normal at an adult threshold — is low for age because infants normally have high lymphocyte counts, and a family history of early childhood death from infection. These are multiple Jeffrey Modell warning signs, and the synthesis is severe combined immunodeficiency until proven otherwise. The response is a same-day immunology referral; this is a time-critical diagnosis. [1] [12]

Tiered diagnostic workup (3 marks). The first-line tests are already partly done: a full blood count with differential, read against age-specific ranges, and serum immunoglobulins IgG, IgA and IgM. The next step is lymphocyte-subset flow cytometry (CD3, CD4, CD8, CD19 and CD56) to quantify T, B and natural-killer cells, with naive and memory T-cell markers (CD45RA, CD45RO) and T-cell receptor excision circle (TREC) analysis. Functional assessment includes a vaccine-antibody response and an HIV test to exclude secondary immunodeficiency. Definitive confirmation is genetic — a targeted gene panel or whole-exome sequencing identifying IL2RG for the X-linked form, or RAG1/2, adenosine deaminase, JAK3 or Artemis. The European Society for Immunodeficiencies multi-stage protocol structures this ladder. [5]

Immediate protective management (2 marks). Pending confirmation, the child is managed to keep him infection-free until transplantation: isolation, prophylactic co-trimoxazole against Pneumocystis, antiviral and antifungal prophylaxis as guided, withholding of all live vaccines (bacille Calmette–Guérin, rotavirus, measles-mumps-rubella, varicella), and blood products given only irradiated and cytomegalovirus-safe. Breastfeeding continues only if the mother is cytomegalovirus-negative, because cytomegalovirus transmission can be devastating in SCID. [9]

Definitive pathway and prognosis (3 marks). The only curative therapy is haematopoietic stem cell transplantation, increasingly complemented by gene therapy for specific genotypes. Timing is the load-bearing variable: transplantation before three to four months of age and before the child has acquired serious infection is associated with markedly higher survival. The longitudinal linkage data demonstrate a clear, durable survival benefit for screen-detected, infection-free transplantation, which is the entire rationale for newborn TREC screening. The family requires genetic counselling for cascade testing of at-risk relatives. [11] [9]