Phagocyte disorders — formative SAQs

SAQ 1 (10 marks)

A three-year-old boy is admitted with a two-week history of fever, right-upper-quadrant pain, and weight loss. Ultrasound shows a 4 cm liver abscess, drained at laparotomy, from which Staphylococcus aureus grows. Over the preceding year he has had a necrotising pneumonia caused by Serratia marcescens and a persistent, granulomatous, swollen gingivitis. His full blood count is normal with a neutrophil count of 6.8 × 10⁹/L. His maternal uncle died in childhood from "constant infections." [4]

Question: (a) What is the most likely diagnosis and what is the single most informative clinical clue? (b) Outline the confirmatory investigation and its expected result. (c) Describe the immediate and long-term medical management. (d) Discuss the curative option and the factors that determine its timing. (10 marks) [5]

Model answer

(a) Diagnosis and the clinical clue (2 marks). The diagnosis is chronic granulomatous disease (CGD). The single most informative clue is not the abscess itself but the organism list — Staphylococcus aureus and Serratia marcescens are members of the CGD cluster of catalase-positive organisms, which thrive when the phagocyte respiratory burst fails. The granulomatous gingivitis and the family history of an affected maternal uncle (consistent with X-linked inheritance) reinforce the diagnosis. The normal neutrophil count is expected, because in CGD the cells are made and they arrive at the infection in normal numbers — they simply cannot kill. [4]

(b) Confirmatory investigation (2 marks). The decisive test is the dihydrorhodamine (DHR) 123 flow cytometry assay, which quantifies the oxidative burst after stimulation with phorbol myristate acetate. In X-linked CGD (CYBB / gp91phox) the fluorescence is virtually absent — a flat histogram. In the autosomal recessive p47phox (NCF1) form it is reduced but present, a mosaic pattern reflecting residual oxidase activity. Genetic testing with a targeted panel covering CYBB, NCF1, NCF2, CYBA, and NCF4 then confirms the molecular diagnosis and, for an affected boy with a maternal family history, identifies the CYBB mutation and triggers maternal carrier testing. [4]

(c) Immediate and long-term medical management (4 marks). Control the active infection aggressively with prolonged, organism-targeted intravenous therapy (an anti-staphylococcal agent guided by susceptibility), because short courses fail and recurrence is the rule in CGD; surgical drainage of the liver abscess, already performed, was essential. Withhold the live BCG vaccine and any other live bacterial vaccine, because the attenuated mycobacterium persists in a defective phagocyte and can cause local or disseminated disease. Start lifelong antimicrobial prophylaxis immediately: co-trimoxazole (approximately 5 mg/kg/day of the trimethoprim component orally once daily) against the catalase-positive bacterial cluster, plus itraconazole or posaconazole for anti-mould prophylaxis against Aspergillus. Address the inflammatory complications — the granulomatous gingivitis and any colitis or obstruction may require anti-inflammatory therapy, often corticosteroids, alongside the antimicrobials, because CGD is a disease of both infection and inflammation. [5] [12]

(d) Curative option and the timing decision (2 marks). The curative therapy is haematopoietic stem cell transplantation, which replaces the defective phagocyte lineage with healthy donor cells; a normal DHR assay after transplant confirms cure. The 712-patient multicentre cohort reported by Chiesa and colleagues established overall survival of roughly 70 to 95 percent depending on age, genotype, infection status, and donor, with the best outcomes when transplant occurs before severe infection-driven organ damage and with a matched sibling donor. The decision of when to transplant is individualised: a child with good infection control on prophylaxis may defer, while a child with recurrent severe infection or intractable inflammatory complications benefits from earlier transplant. For this boy with recurrent abscess-forming infection and granulomatous complications, transplant evaluation is warranted, beginning with HLA typing and a sibling donor search. [7]

SAQ 2 (10 marks)

A three-week-old neonate is admitted with a five-day history of fever and a red, draining infection of the umbilical cord stump, which is still firmly attached. Swabs grow Staphylococcus aureus, yet the registrar notes there is almost no pus at the site. The full blood count shows a neutrophil count of 85 × 10⁹/L. The parents are first cousins. [8]

Question: (a) What is the diagnosis and how do the three features — delayed cord separation, absent pus, and the neutrophil count — fit the pathophysiology? (b) Outline the confirmatory investigation. (c) Describe the immediate management and the curative option. (d) What are the genetic implications for the family? (10 marks) [8]

Model answer

(a) Diagnosis and pathophysiology (3 marks). The diagnosis is leukocyte adhesion deficiency type 1 (LAD-1). The three features form a coherent pathophysiological story. The neutrophils are manufactured in normal numbers — indeed in vast numbers, 85 × 10⁹/L — because the bone marrow is normal. The oxidative burst is intact, so the cells can kill. The defect is in adhesion: the beta-2 integrin CD18 (encoded by ITGB2) is absent or dysfunctional, so the neutrophils cannot bind the vascular endothelium at the site of infection and cannot emigrate from the bloodstream into the tissue. Because they never reach the infection, no pus accumulates (pus is neutrophils in tissue), and the cells pile up in the circulation, producing the striking leukocytosis. The delayed cord separation is part of the same failure — leucocyte emigration is needed for the normal inflammatory separation of the umbilical cord. The consanguinity fits the autosomal recessive inheritance. [8]

(b) Confirmatory investigation (2 marks). Flow cytometry for the beta-2 integrin CD18 and its partner CD11b on the leucocyte surface shows absent or severely reduced expression in LAD-1. Genetic testing for the ITGB2 mutation confirms the molecular diagnosis. The DHR assay would be normal (the respiratory burst is intact in LAD), which is itself a useful distinguishing result from CGD, where the burst is absent but the cells can emigrate. [8]

(c) Immediate management and curative option (3 marks). Treat the active omphalitis aggressively with intravenous anti-staphylococcal therapy guided by the culture, because the neutrophils cannot localise the infection and a localised omphalitis can progress to systemic sepsis. Avoid the live BCG vaccine. Because medical management alone cannot overcome the adhesion defect, the curative therapy is haematopoietic stem cell transplantation, which replaces the defective leucocyte lineage with healthy donor cells that express normal CD18. HSCT is offered early in the severe phenotype, because the severe form of LAD-1 has a poor prognosis without transplant, with significant early-childhood mortality from intractable infection. The donor hierarchy is the same as for other immunodeficiencies — matched sibling, matched unrelated, haploidentical. [8] [12]

(d) Genetic implications (2 marks). LAD-1 is autosomal recessive, and the consanguinity in this family is directly relevant: each subsequent pregnancy carries a one-in-four risk of an affected child. Offer parental carrier testing (both parents are obligate carriers), sibling testing, and prenatal or preimplantation genetic diagnosis for future pregnancies. Because the severe phenotype benefits from early transplant, early diagnosis of an affected sibling — ideally before the first severe infection — is the difference between a good outcome and significant mortality, so the reproductive counselling is part of the management, not an afterthought. Culturally safe genetic counselling with trained interpreters is essential. [8]