1. E Walker, E McCarty, C Donnelly, C Emerson, S Quah GUM Clinic, Royal Victoria Hospital, Belfast

2. Patient 1 AD, 52 year old male HIV positive after Ix for sore throat, night sweats, weight loss Ulcer left tonsil, initial biopsy - ? T cell lymphoma Whole tonsil removed – reactive lymphoid hyperplasia CD4 90 at diagnosis – commenced Raltegravir/Truvada

3. Other history MSM, long term partner – no SI 3 partners total, all male PMH colitis, no regular meds Penicillin allergy

4. Admission to hospital 1/12 post HIV diagnosis Diarrhoea, pyrexia >39 o C, night sweats Investigated for PUO: blood/urine/stool cultures, atypical pneumonia screen EBV/CMV/toxo/CRAG negative Echo: TTE x2 negative CT CAP – mild splenomegaly. No sepsis Bone Marrow – no haematological malignancy

5. Clinical Course Deterioration over 1/52 Sepsis, renal deterioration, thrombocytopenia Metabolic acidosis, resp compensation Blood cultures – coag negative staph, enterococcus Broad spectrum antibiotics – linezolid, meropenem, rifampicin, clarithromycin

6. Clinical Course CD4 90 to 220 DDx: MAI, IRIS On cover for MAI, enterococcus, atypicals, MRSA Truvada switched to Kivexa as deteriorating renal function Repeat CD4 30 – in setting of sepsis

7. Admission to ICU RR >40, temp >40 o C, resp failure, AKI, pancytopenia ARV stopped - ?contributing to metabolic acidosis Antibiotics continued, vanganciclovir added for CMV cover Repeat CT CAP – no cause identified

8. Discussed with haematology Serum ferritin > 40,000 Repeat BMB too risky – low plts, coagulopathy. Fib 1.01 Likely diagnosis HLH secondary to HIV Precipitated by sepsis/IRIS Commenced methylprednisolone and ciclosporin

9. Acute Deterioration Sudden worsening sats/BP/HR Requiring inotropes Progressive acidosis, pulmonary oedema Death secondary to upper GI bleed and cardiac arrest

10. Patient 2 JC, 41 year old male Admitted unwell over last year Recent worsening – weight loss, fatigue, pyrexia >38 o C Pancytopenia, hyponatraemia Commenced Tazocin/Gentamicin for sepsis ?cause HIV test positive, CD4 120

11. Relevant History MSM, long term partner (negative) Under investigation with neurology for speech disturbance/tremor of 5 years’ duration

12. Investigations Syphilis positive – RPR 8, IgM negative CT CAP – widespread lyphadenopathy, splenomegaly LN biopsy – follicular hyperplasia OGD – mild gastritis only Echo (TTE) normal Parvovirus/CMV/CRAG negative

13. Treatment IV benzylpenicillin for ?neurosyphilis – no improvement in speech Commenced ARV – Truvada/Darunavir/ritonavir Pyrexia settled, discharged

14. Subsequent Course Well for 6/52 then pyrexia returned CD4 rose from 120 to 270, commenced on prednisolone for possible IRIS Temps controlled on steroids; recurred when stopped STI screen negative Blood/urine/stool cultures negative Atypical pathogens all negative Ferritin 2297

15. 3 futher admissions PUO 38-40 o C, diarrhoea, thrombocytopenia BM biopsy – no evidence malignancy. Haemolysis on blood film. Repeat ferritin 4000 Repeat CT CAP similar to previous Further bloods – malaria (travel to Egypt), Leishmania all negative. Colonoscopy normal CT PET – generalised bone marrow uptake Initial response to presumptive MAI treatment – clarithromycin/ethambutol – disharged

16. Readmission Daily fevers despite MAI Rx Raised inflammatory markers Drugs adjusted ?drug fever All viral/bacterial screen repeated EBV PCR positive, high titre Ferritin 13676, lipids normal BM biopsy – features in keeping with haemophagocytosis CT CAP unchanged TOE abandoned – vomiting

17. Acute Deterioration Acute confusion – CT brain normal Likely hepatic encephalopathy Jaundiced, coagulopathic, acute kidney injury Hepatology review – malignancy most likely Admitted to ICU with hepatorenal failure Seen by haematology – considered chemo (Etoposide) but likely to precipitate deterioration Death following asystolic arrest PM – disseminated Hodgkin’s lymphoma, EBV positive

18. Haemophagocytic Lymphohistiocytosis (HLH) Rare, potentially fatal disease of overactive histiocytes and lymphocytes More common in infancy Fever, hepatosplenomegaly, pancytopenia, rash Cutaneous involvement in 65% Primary: familial erythrophagocytic lymphohistiocytosis (FEL) Secondary: strong immunologic activation – infection, immunodeficiency, malignancy Both forms: overwhelming activation of normal T lymphocytes and macrophages

19. Pathophysiology Aggressive proliferation of activated macrophages/histiocytes – phagocytose other cells (RBCs, WBCs, platelets) Spleen, LNs, BM, skin, brain, spinal cord main sites Highly stimulated, but ineffective immune response to antigens Exact mechanism unclear Decreased NK cell activity leads to increased T cell activation – large quantities of cytokines produced Resulting inflammatory reaction – extensive damage and symptoms EBV – commonly triggers infection-related HLH Familial: 5 genetic defects identified, account for 90% of pts

20. Epidemiology 1.2 cases per million per year Familial HLH fatal if untreated; median survival 2-6 months 21-26% 5 year survival with Rx, recurs Variable outcome with secondary HLH All races affected, men=women Age: 6 years secondary

21. Diagnostic Criteria (Histiocyte Association) At least 5 of: Low or absent NK cell function Prolonged fever Blood cell abnormalities (pancytopenia) Splenomegaly Increased fasting triglycerides or decreased fibrinogen Increased ferritin Evidence of haemophagocytosis on BM, but not malignancy or other cause Abnormally high CD25 (sIL2ra) indicating abnormally increased T-cell activation

22. Other Clinical Features Evidence of infection Coagulopathy Jaundice Rash (up to 65%) CNS involvement (up to 75%) – seizures, ataxia, hemiplegia, irritability Lymphadenopathy Constitutional symptoms

23. Investigations NK cell function decreased in up to 90% Raised ferritin – levels follow course of disease Pancytopenia/low fibrinogen/raised TGs Liver damage – raised bilirubin/low albumin/raised transaminases Perforin (PRF1) gene mutation No imaging diagnostic Store DNA samples if no genetic defect identified

24. Histology Haemophagocytosis on LN, BM, liver biopsy Skin biopsy – differentiate from other disease eg. Langerhans cell histiocytosis Initial BM may be non-diagnostic in 2/3 Liver biopsy may be difficult (coagulopathy)

25. Management Rapid diagnosis and treatment essential Goal to achieve clinical stability then cure with bone marrow transplant High risk: chemotherapy Low risk: ciclosporin, steroids, IVIG Splenectomy may be considered Genetic counselling in primary HLH

26. Treatment Initial therapy: Etoposide (VP-16) and dexamethasone for 8 weeks, with ciclosporin (HLH-2004) Intrathecal Methotrexate only if abnormal CSF, progressive neurological symptoms If resolved, non familial: discontinue therapy If persistent non familial, familial: continue > week 9 Alemtuzumab for refractory disease Therapy directed at neoplasm if malignancy- associated

27. Follow Up Ensure patient stable until BMT Monitor for infections, malignancy Be aware of other complications eg. GvsHD Median survival 2-6 months without Rx 66% survival at 5 years with BMT, 10% chemo Overall survival 55%, many diagnosed late Steroids/IVIG may be sufficient Rx

28. Thank You Any questions?