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]

SAQ 2 (10 marks)

An eight-year-old girl is referred with a history of recurrent otitis media, sinusitis and pneumonia, with two hospital admissions in the past year and new crackles and wheeze suggesting early bronchiectasis. Serum immunoglobulins show low IgG and IgA, and her response to a pneumococcal vaccine challenge is poor. [7]

Question: (a) What is the likely diagnostic category, and what is the differential of recurrent sinopulmonary infection? (b) Outline the further workup and the definitive management. (10 marks) [5]

Model answer

(a) Diagnostic category and differential (3 marks). The likely category is a predominantly antibody deficiency — common variable immunodeficiency in an eight-year-old with low IgG and IgA and poor functional antibody response, although X-linked agammaglobulinaemia is considered in a younger boy with absent tonsils and absent B-cells. The differential of recurrent sinopulmonary infection in a child is broad: normal exposure-driven infection in a daycare-age child (but she is eight, has had admissions, and has emerging bronchiectasis, which breaks the reassuring rules); anatomical causes such as adenoidal obstruction and structural lung disease; atopic disease with allergic rhinitis; and secondary immunodeficiency, which must be excluded — HIV, protein loss (nephrotic syndrome, protein-losing enteropathy), immunosuppressive therapy, malnutrition and malignancy. [5] [7]

(b) Further workup and definitive management (7 marks). The further workup confirms the antibody deficiency and its subtype: lymphocyte-subset flow cytometry to quantify B-cells (absent in X-linked agammaglobulinaemia, present but functionally impaired in common variable immunodeficiency), a formal functional vaccine-antibody response measured before and after a protein and polysaccharide vaccine challenge, and genetic testing to define the molecular diagnosis. An HIV test and exclusion of protein loss complete the secondary-causes screen. [7]

The definitive management is immunoglobulin replacement therapy — intravenous or subcutaneous — titrated to maintain a protective trough IgG level, which prevents the recurrent infection and halts the progression to bronchiectasis. Antibiotic prophylaxis and aggressive treatment of acute breakthrough infection supplement the replacement. Structured respiratory surveillance with pulmonary-function testing and imaging monitors for bronchiectasis. The family receives genetic counselling, and the child transitions to long-term immunology-led care with a written action plan and planned transition to adult immunology. The disposition also includes ensuring killed and subunit vaccines are given while live vaccines are coordinated with immunology. [7] [5]