Primary immunodeficiency: warning signs and diagnostic approach — branching viva

Opening question

Examiner: Take me through this infant. What is your reading of the presentation, and what is your frame? [1]

Candidate: This infant has the signature of a combined immunodeficiency. He has failure to thrive, persistent oral candidiasis beyond infancy, two pneumonias with one needing intravenous antibiotics, and a lymphocyte count that — although it appears normal at an adult threshold — is low for age, because infants normally have high lymphocyte counts. He also has the family-history warning sign: a male cousin who died in infancy from an unexplained infection. My frame is that this is severe combined immunodeficiency until proven otherwise, which is a time-critical diagnosis, and my response is a same-day immunology referral with flow cytometry and a pathway to transplantation. [1]

Examiner: Why is a lymphocyte count of 1.8 × 10⁹/L abnormal in a seven-month-old when it would be normal in an adult? [5]

Candidate: Because lymphocyte counts are age-specific. Infants normally have an absolute lymphocyte count of five to seven × 10⁹/L or higher, so a count of 1.8 is in fact lymphopenic for age. This is one of the commonest reasons SCID is missed — the count is read against an adult threshold rather than an age-appropriate one, and the warning is lost. [5]

Branch 1 — warning signs and classification

Examiner: The examiner asks you to summarise the warning signs that should prompt a primary immunodeficiency workup. [1]

Candidate: The Jeffrey Modell Foundation ten warning signs are the bedside tool. They are: four or more new ear infections in a year; two or more serious sinus or lung infections in a year; two or more months on antibiotics with little effect; two or more deep-seated skin or organ infections; failure to thrive in an infant; recurrent deep abscesses; persistent oral thrush or cutaneous candidiasis beyond infancy; the need for intravenous antibiotics to clear infections; two or more deep-seated infections; and a family history of primary immunodeficiency. The UK prospective study confirmed that the number of signs correlates with the likelihood of a confirmed diagnosis, though no single sign is perfectly sensitive or specific — so any one sign is a prompt to investigate, not a rule. [1]

Examiner: How are inborn errors of immunity classified, and where does this child fit? [1]

Candidate: The IUIS 2022 classification groups them into ten categories: combined cellular-humoral, combined syndromic, predominantly antibody, immune dysregulation, congenital phagocyte, innate immunity, autoinflammatory, complement, bone-marrow-failure and cytopenias, and phenocopies of PID. This child, with failure to thrive and lymphopenia and opportunistic infection, fits the first category — combined immunodeficiency — with SCID the prototype until flow cytometry and genetics tell us otherwise. [1]

Branch 2 — tiered diagnostic workup

Examiner: Walk me through your diagnostic workup, tier by tier. [5]

Candidate: I present the investigations as the European Society for Immunodeficiencies multi-stage ladder. Tier one — the primary-care stage — is the full blood count with differential read against age-specific ranges, and serum immunoglobulins IgG, IgA and IgM; those are already partly done. Tier two — the general-paediatric or immunology stage — adds lymphocyte-subset flow cytometry to quantify CD3, CD4, CD8, CD19 and CD56, a formal functional vaccine-antibody response, naive and memory T-cell markers and T-cell receptor excision circle analysis, and an HIV test to exclude secondary immunodeficiency. Tier three — the specialist immunology stage — adds neutrophil-function testing, complement assays, KREC analysis, and genetic testing by targeted gene panel or whole-exome sequencing to confirm the molecular diagnosis and enable family counselling. [5]

Examiner: What does a TREC assay measure, and why does it matter? [6]

Candidate: T-cell receptor excision circles are by-products of T-cell development in the thymus — small circles of DNA excised during T-cell receptor rearrangement. A low or absent TREC level flags T-cell lymphopenia, including SCID, before the child becomes symptomatic. That is why the TREC assay is the population-level newborn screening test: it identifies SCID in the first days of life, before infection, which is exactly the window in which transplantation is life-saving. The eleven-programme United States cohort established its diagnostic yield. [6]

Branch 3 — immediate management and the urgent pathway

Examiner: While you await confirmation, how do you manage this child? [5]

Candidate: My aim is to keep him infection-free until transplantation. I admit or closely monitor him, start prophylactic co-trimoxazole against Pneumocystis, add antiviral and antifungal prophylaxis as the immunology team advises, withhold all live vaccines — bacille Calmette–Guérin, rotavirus, measles-mumps-rubella and varicella — because they can disseminate in SCID, and ensure any blood products are irradiated and cytomegalovirus-safe. Breastfeeding continues only if the mother is cytomegalovirus-negative, because cytomegalovirus transmission is devastating in SCID. [5]

Examiner: The newborn screening laboratory calls you about a different infant with an absent TREC result. What is your pathway? [6]

Candidate: A low or absent TREC result demands urgent recall. I bring the infant in, confirm with flow cytometry, start the same prophylactic measures — co-trimoxazole, withholding of live vaccines, irradiated and cytomegalovirus-safe blood products — and arrange the defined pathway to transplantation. I communicate carefully with the family: the result indicates T-cell lymphopenia, which has a differential beyond SCID including prematurity, transient lymphopenia and some syndromes, and the confirmatory testing will define the diagnosis. The principle is to act on the screen the same day, not to wait for the child to become symptomatic. [6]

Branch 4 — definitive management by immune arm

Examiner: The candidate is now asked about a different child — an eight-year-old with recurrent sinopulmonary infection, low IgG and IgA, and poor vaccine response. How do you manage her? [7]

Candidate: She has a predominantly antibody deficiency, most likely common variable immunodeficiency. The definitive management is immunoglobulin replacement therapy — intravenous or subcutaneous — titrated to maintain a protective trough IgG, which prevents the recurrent infection and halts the progression to bronchiectasis. Antibiotic prophylaxis and aggressive treatment of acute breakthrough infection supplement the replacement, and structured respiratory surveillance monitors for bronchiectasis. For the contrast, the phagocyte defects are managed with co-trimoxazole and an agent such as itraconazole, the complement deficiencies with meningococcal vaccination and standby antibiotics, and the combined immunodeficiencies with haematopoietic stem cell transplantation. [7]

Examiner: Why must live vaccines be withheld in a child under investigation for significant immunodeficiency? [7]

Candidate: Because a live vaccine is a controlled infection, and in a child who cannot mount the immune response to control it, that infection can disseminate. Bacille Calmette–Guérin can cause disseminated disease in SCID or chronic granulomatous disease; rotavirus causes persistent diarrhoea in SCID; measles-mumps-rubella and varicella cause severe disease in profoundly immunodeficient hosts. The rule is that any child under investigation for a significant immunodeficiency does not receive live vaccines until immunology has formally cleared the immune function. [7]

Branch 5 — prognosis and disposition

Examiner: Return to the original infant. What is his prognosis, and what determines it? [11]

Candidate: His prognosis is determined almost entirely by the timing of intervention. Untreated SCID is universally fatal within the first one to two years of life from opportunistic infection. Haematopoietic stem cell transplantation before three to four months of age, before the child has acquired serious infection, is associated with markedly higher survival, and the longitudinal linkage data demonstrate a clear, durable survival benefit for screen-detected, infection-free transplantation. His disposition is immunology-led multidisciplinary care — a written care plan, a named immunologist, family and school infection-prevention education, and genetic counselling for the parents and extended family, including cascade testing of at-risk relatives. Because he presented symptomatically rather than through screening, his window is narrow, which is why I made the same-day referral. [11]

Wrap

Examiner: Summarise the primary immunodeficiency stance in one sentence. [1]

Candidate: Recognise primary immunodeficiency from the pattern of infection — not the frequency — using the Jeffrey Modell ten warning signs; work it up through the tiered ladder of full blood count and immunoglobulins, lymphocyte subsets and vaccine response, then neutrophil function, complement, TREC/KREC and genetics; treat any infant with lymphopenia and failure to thrive as SCID until proven otherwise, with same-day immunology referral, prophylaxis, withholding of live vaccines, and a pathway to haematopoietic stem cell transplantation before infection; manage each immune arm specifically — immunoglobulin for antibody deficiency, co-trimoxazole and itraconazole for phagocyte defects, meningococcal vaccination and standby antibiotics for complement deficiency; and always exclude secondary causes, especially HIV, before settling on a primary diagnosis. [1] [11]