Immune dysregulation, lymphoproliferation and autoinflammatory disease — viva

Opening (must-hit)

"I hold this group of diseases on a three-mechanism framework. Immune dysregulation is failed tolerance (FOXP3, AIRE, CTLA4, LRBA); lymphoproliferation is failed apoptosis (the FAS pathway, in ALPS); autoinflammation is innate cytokine over-activation (NLRP3, MEFV, TNFRSF1A, MVK). The intersection is the cytokine storm, HLH or MAS. My first move in every case is to clear the HLH/MAS threat gate — fever plus splenomegaly plus cytopenias plus a very high ferritin — before anything else. Then I phenotype by the dominant mechanism, match therapy to the pathway, and reserve haematopoietic stem cell transplant for the severe immune-dysregulation and primary-HLH diseases." [1] [8]

Branch A — The infant with enteropathy, eczema and diabetes

Examiner: A six-month-old male infant has intractable bloody diarrhoea, severe eczema, and was diagnosed with type-1 diabetes last month. Candidate: This is the classic presentation of IPEX — immune dysregulation, polyendocrinopathy, enteropathy, X-linked — caused by FOXP3 loss and failure of regulatory T-cell function. It is X-linked, which fits a male infant. I would phenotype with organ-specific autoantibodies, immunoglobulins and immunophenotype, and confirm with a targeted gene panel including FOXP3. Management is immunosuppression and nutritional support to bridge, with haematopoietic stem cell transplant as the only curative option for severe disease, because the disease is life-threatening without it. [3]

Branch B — The four-year-old with big glands and a falling platelet count

Examiner: A four-year-old has chronic painless splenomegaly, large cervical lymph nodes, and a platelet count that keeps falling with a positive direct antiglobulin test. Candidate: This is autoimmune lymphoproliferative syndrome — ALPS. The picture of chronic, non-malignant organomegaly with autoimmune cytopenias in an otherwise well child, after I exclude lymphoma with a film and biopsy if needed, points to a defect in the Fas apoptotic pathway. I confirm with an immunophenotype looking for double-negative T cells — alpha-beta T-cell-receptor positive, CD4-negative, CD8-negative — alongside elevated vitamin B12 and soluble Fas ligand. The first-line definitive therapy is steroid-sparing sirolimus; I avoid splenectomy, which historically caused overwhelming sepsis without cure. [6] [7]

Branch C — Clockwork fevers every five weeks

Examiner: A two-year-old has had fevers every five weeks for a year, each with a red throat, mouth ulcers and tender cervical glands, and is entirely well between attacks. Candidate: This is PFAPA. The regularity — every three to eight weeks — with pharyngitis, aphthous stomatitis and cervical adenitis, and complete wellbeing between attacks, is the classic phenotype. The natural history is spontaneous resolution over years, so the prognosis is excellent. I manage with anticipatory corticosteroid at the very start of an attack, which aborts it in many children; tonsillectomy is reserved for severe, refractory cases. Stojanov showed PFAPA is a disorder of innate immunity and T-helper-1 activation responsive to interleukin-1 blockade, which is where I would turn for refractory disease. [13]

Branch D — The six-month-old with the ferritin of 10,000

Examiner: The six-month-old cousin has persistent fever, splenomegaly, a ferritin well above 10,000 and falling cell counts. Candidate: This is the HLH or MAS threat gate firing. Fever plus splenomegaly plus cytopenias plus a very high ferritin is haemophagocytic lymphohistiocytosis until proven otherwise, and it kills quickly through multi-organ failure. My immediate priorities are time-critical bloods — ferritin, triglycerides, fibrinogen, full blood count, liver function, lactate dehydrogenase and a soluble interleukin-2 receptor level where available — empiric broad-spectrum antibiotics because sepsis is indistinguishable, and treatment for suspected primary HLH on clinical grounds per HLH-2004 principles, moving to dexamethasone-based therapy with specialist-guided escalation. I escalate to tertiary immunology or rheumatology and paediatric intensive care without delay, and plan transplant for confirmed primary disease. [8] [9]

Branch E — The wrong first test

Examiner: A colleague plans to order a broad serum allergy and autoantibody panel in an unsettled infant being worked up for possible immune dysregulation. Candidate: I would redirect that. A non-specific allergy or autoantibody panel generates false positives, drives anxiety, and does not characterise the mechanism. The right approach is phenotype-driven, targeted testing: an immunophenotype, immunoglobulins and vaccine antibody responses, organ-specific autoantibodies directed by what the child actually has, and then a phenotype-guided gene panel. Whole-exome sequencing is reserved for atypical or undiagnosed cases. The principle is to confirm the dominant mechanism first and then seek its genetic cause. [1]

Branch F — Which diseases are transplant-curable?

Examiner: How do you decide between lifelong medical therapy and haematopoietic stem cell transplant in this group? Candidate: Transplant replaces the faulty immune system, so it is curative for the severe immune-dysregulation and primary-HLH diseases — primary HLH, severe IPEX, severe CTLA4 or LRBA deficiency, and refractory ALPS. By contrast, diseases driven by innate cytokine excess — familial Mediterranean fever, the cryopyrin-associated periodic syndromes, and most ALPS — are managed medically for life, because transplant does not reverse existing organ damage and carries real morbidity. The decision rests on the mechanism, the severity, and whether medical therapy has failed. [9]

Branch G — Matching therapy to the pathway

Examiner: A child with cryopyrin-associated periodic syndrome asks why a specific biologic was chosen. Candidate: The cryopyrin-associated periodic syndromes are driven by gain-of-function of the NLRP3 inflammasome, which over-activates interleukin-1. I choose interleukin-1 blockade — anakinra, the receptor antagonist, or canakinumab, the monoclonal antibody to interleukin-1 beta — because it blocks the final mediator of the disease, which is why the response is dramatic. The EULAR and American College of Rheumatology points to consider endorse this as first-line biological therapy for the interleukin-1-mediated autoinflammatory diseases. The same logic — match the drug to the pathway — governs colchicine for familial Mediterranean fever, sirolimus for ALPS, abatacept for CTLA4 deficiency, and JAK inhibitors for the interferonopathies. [12]