Phagocyte disorders — branching viva

Opening stem

A four-year-old boy presents with a staphylococcal liver abscess; in the past year he has had a Serratia pneumonia and a granulomatous gingivitis. His neutrophil count is normal, and his maternal uncle died in childhood from recurrent infection. The examiner asks: take me through how you reach the diagnosis, confirm it, and manage this child — and be prepared to branch. [4]

Branch 1 — The diagnosis and the organism cluster

Examiner: What is the single most informative clue, and why does the neutrophil count not reassure you? [4]

The organism list is the clue. Staphylococcus aureus and Serratia marcescens are members of the CGD cluster of catalase-positive organisms — alongside Burkholderia cepacia complex, Nocardia, and Aspergillus — which thrive when the phagocyte respiratory burst fails. The diagnosis is chronic granulomatous disease until proven otherwise. The neutrophil count is normal because in CGD the cells are made and they arrive at the infection in normal numbers; they simply cannot kill catalase-positive organisms. A normal neutrophil count never excludes CGD. The granulomatous gingivitis and the family history of an affected maternal uncle (X-linked inheritance) reinforce the diagnosis. [4] [5]

Branch 2 — The confirmatory test

Examiner: How do you confirm it, and what result do you expect? [4]

The decisive test is the dihydrorhodamine (DHR) 123 flow cytometry assay, which quantifies the oxidative burst after phorbol myristate acetate stimulation. Dihydrorhodamine fluoresces when oxidised, and the flow cytometer measures the fluorescence shift. 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 in a subpopulation. The DHR assay has replaced the older nitroblue tetrazolium slide test because it is faster, quantitative, and distinguishes the X-linked from the autosomal recessive pattern. Genetic testing with a targeted panel confirms the molecular diagnosis. [4]

Branch 3 — The mechanism (why catalase-positive?)

Examiner: Explain to me why these particular organisms trouble the CGD patient. [4]

The respiratory burst generates hydrogen peroxide via the NADPH oxidase, and myeloperoxidase uses that peroxide plus a halide to generate hypochlorous acid — bleach — the microbe-killing agent. Catalase-positive organisms carry the enzyme catalase, which destroys any peroxide the microbe itself makes. A normal neutrophil does not care, because it makes its own peroxide. A CGD neutrophil makes no peroxide, and the catalase-positive organism destroys the little it produces, so the microbe survives. Catalase-negative organisms such as the streptococci do not trouble the CGD patient, because they cannot destroy their own peroxide — that peroxide diffuses into the phagolysosome and fuels myeloperoxidase anyway. This is why CGD patients get staphylococcal and Aspergillus infection but not streptococcal infection. [4] [5]

Branch 4 — Medical management

Examiner: What is the immediate and long-term medical management? [5]

Control the active infection aggressively with prolonged, organism-targeted intravenous therapy, because short courses fail and recurrence is the rule; surgical drainage of the abscess is often required. Withhold the live BCG 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) against the catalase-positive bacterial cluster, plus itraconazole or posaconazole for anti-mould prophylaxis against Aspergillus. Address the inflammatory complications — the granulomatous gingivitis, colitis, or obstruction may require anti-inflammatory therapy, often corticosteroids, because CGD is a disease of both infection and inflammation and treating only the infection misses half the disease. [5] [12]

Branch 5 — The curative option and the transplant evidence

Examiner: Is there a cure, and when do you offer it? [7]

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 donor hierarchy is matched sibling, matched unrelated, haploidentical, and CGD transplant typically requires myeloablative or reduced-intensity conditioning because the bone marrow is cellular rather than empty. 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. Gene therapy is an emerging option for selected genotypes. [7]

Branch 6 — The wider differential (if time allows)

Examiner: How would the presentation differ if this were leukocyte adhesion deficiency, congenital neutropenia, or Chédiak-Higashi? [8]

In LAD-1 the presentation is neonatal: delayed cord separation beyond three weeks, omphalitis without pus, and a strikingly high neutrophil count — the cells are made and the burst is intact but they cannot emigrate from the vessel, so the site smoulders without pus while the count climbs. In severe congenital neutropenia the presentation is overwhelming bacterial sepsis in early infancy with a profound neutropenia (below 0.5 × 10⁹/L), and the long-term risk is myelodysplasia and leukaemia, which mandates serial bone-marrow cytogenetics. In Chédiak-Higashi syndrome the blood film shows giant granules, there is partial albinism and a bleeding tendency, and the chief cause of death is the accelerated (haemophagocytic) phase, which presents with fever and hepatosplenomegaly and demands emergency haematology involvement and the HLH protocol as a bridge to transplant. Each disease has its fingerprint, and recognising it is the examination skill. [8] [10] [11]