Phagocyte disorders

Overview & Definition

Picture a three-year-old boy admitted for the third time in a year — once for a staphylococcal liver abscess that needed weeks of intravenous antibiotics, once for a necrotising pneumonia that turned out to be caused by Serratia marcescens, and now for a swollen, chronically inflamed gum that a biopsy calls granulomatous. His neutrophil count is normal, and each time the infection has produced abundant pus, yet the organisms keep recurring. The clue is the organism list itself — Staphylococcus, Serratia, and a granulomatous response — and it points straight to a phagocyte killing defect. This child has chronic granulomatous disease, and the single test that confirms it, the dihydrorhodamine flow cytometry assay, measures the oxidative burst his neutrophils cannot generate. [4] [5]

The phagocyte disorders are the primary immunodeficiencies in which neutrophils and monocytes — the innate effector cells that migrate into infected tissue, ingest microbes, and kill them with reactive oxygen species and granule enzymes — fail at one of these steps. The 2024 IUIS classification, led by Poli and colleagues, groups them under congenital defects of phagocyte number or function, and the field divides cleanly along three mechanistic axes: a failure of killing (CGD, the largest group), a failure of adhesion and migration (leukocyte adhesion deficiency), and a failure of production or granule packaging (severe congenital neutropenia, cyclic neutropenia, Chédiak-Higashi, specific granule deficiency). Each axis produces a recognisable clinical phenotype, and recognising the phenotype is how the diagnosis is made at the bedside. [1] [2]

What unifies these disorders, and what the examination tests, is that the recurrent infection they cause is driven by a predictable cluster of organisms and by a paradoxical tissue response. In CGD the catalase-positive bacteria and Aspergillus survive because the respiratory burst fails; the host responds with granulomatous inflammation that can obstruct the gut or urinary tract. In LAD the neutrophils cannot migrate, so infection smoulders without pus while the neutrophil count climbs. In congenital neutropenia the marrow simply cannot make enough neutrophils, and the child presents with overwhelming bacterial sepsis. Understanding why each disease produces its particular fingerprint is the key to recognising all of them. [3] [4]

The clinical task has two halves. The first is recognition and protection — suspect a phagocyte disorder from the organism list or the bedside paradox, confirm with the DHR assay or flow cytometry, and start prophylaxis and infection surveillance. The second is the curative decision — haematopoietic stem cell transplantation for the severe forms, particularly CGD and LAD, in which the transplant replaces the defective phagocyte lineage with healthy donor cells. The 712-patient multicentre cohort reported by Chiesa and colleagues established that transplant works across genotypes and ages, making the decision not whether to transplant but when and with what donor. A candidate who diagnoses CGD but does not know the organism cluster, the DHR assay, or the transplant evidence fails the question. [4] [7]