Primary immunodeficiency: warning signs and diagnostic approach — branching viva

Branching structured-oral viva on primary immunodeficiency: the Jeffrey Modell warning signs and the pattern-not-frequency principle, the IUIS 2022 classification and the immune-arm infection signatures, the tiered diagnostic workup, the abnormal newborn TREC result and the urgent SCID pathway, and the management of the antibody-deficient child including immunoglobulin replacement and the live-vaccine contraindication.

branching clinical structured oral6 min readVerification in progress

Prompt

You are the general paediatric registrar in clinic. A seven-month-old boy is referred by the GP for failure to thrive, persistent oral thrush and two pneumonias, one needing intravenous antibiotics. His full blood count shows an absolute lymphocyte count of 1.8 × 10⁹/L, and there is a family history of a male cousin who died in infancy from an unexplained infection. The examiner asks you to take the candidate through the recognition, the diagnostic workup, the immediate management and the definitive pathway.

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]

References5Show

[1]Subbarayan A; Colarusso G; Hughes SM; Gennery AR; Slatter M; Cant AJ; Barge D; Flood T; Abinun M; Hambleton S Clinical features that identify children with primary immunodeficiency diseases. Pediatrics, 2011.PMID 21482601
[5]de Vries E; European Society for Immunodeficiencies (ESID) members Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol, 2012.PMID 22132890
[7]Fried AJ; Bonilla FA Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev, 2009.PMID 19597006
[6]Kwan A; Abraham RS; Currier R; Brower A; Andruszewski K; Fuller TM; et al Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA, 2014.PMID 25138334
[11]Thakar MS; Logan BR; Puck JM; Pai SY; Notarangelo LD; Satter LF; et al Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal data linkage study. Lancet, 2023.PMID 37352885