key: cord-0979527-q0wizf2n authors: Kavirayani, Akhila; Charlesworth, James E G; Segal, Shelley; Kelly, Dominic; Wilson, Shaun; Qureshi, Amrana; Blanco, Esther; Weitz, James; O'Shea, Deirdre; Bailey, Kathryn title: The Lazarus effect of very high-dose intravenous anakinra in severe non-familial CNS-HLH date: 2020-10-15 journal: Lancet Rheumatol DOI: 10.1016/s2665-9913(20)30361-1 sha: b9abe1aa3e4b21ff55f0c3f753352af534b341bb doc_id: 979527 cord_uid: q0wizf2n nan BAL negative BAL -Aspergillus (month 2 of admission), Candida in urine, Pseudomonas Stenotrophomonas, Maltophilia and Bacillus species line infections Soluble CD25 (<2500 pg/mL) Not processed Control Perforin CD56+ Cells -90.3 % Patient Perforin CD56+ Cells -79.5 % Suboptimal perforin expression. Percentage is normal but the patient has slightly less bright perforin than would normally be expected. Perforin gene normal (homozygous polymorphism); Felt to be consistent with clinical condition. Control GRA CD8+CD107a+ -2.4 % Patient GRA CD8+CD107a+ -0.9 % Control GRA NK cells CD107a+ -11.1 % Patient GRA NK cells CD107a+ -Unable to analyse Normal cytotoxic granule release assay as detected by CD107a expression in response to CD3 (T cells) stimulation. Too few NKs for analysis. This suggests that this patient does not have HLH due to a defect in this pathway (including Syntaxin 11, Munc 13-4 and 18-2) Excludes FHL2,3,4,5*, Chediak-Higashi syndrome and Griscelli Syndrome *Including a novel gene recently described in Vienna 'TIGER' Primary Immunodeficiency panel All known genes for FHL negative TRAPS mutation (TNFRFF1AP.1334V) (unknown significance) Abbreviations: BAL -bronchoalveolar lavage, CRP -C-reactive protein, TRAPS -Tumour necrosis factor receptor-associated periodic syndrome, WCC -white cell count, FHL -Familial Haemophagocytic lymphohistiocytosis Necrotic lesion to the left arm of the patient is shown, taken 3 weeks following discharge, reproduced with consent. 2mg/kg/day (60mg/day) over 12 hours, 12mg/kg/day (360mg/day) over 36 hours, escalated to 48mg/kg/day (1440mg/day) over 72 hours, stepped down to 24mg/kg/day (720mg/day) over 6 days, then 12mg/kg/day (360mg/day) over 6 days before converting to SC. 100mg/day for 15 months, then reduced by 20mg weekly and discontinued. IV methyl prednisolone, 1 dose of IV Immunoglobulin, empiric antibiotics and antivirals-IV aciclovir and IV ceftriaxone, switched to meropenem/teicoplanin upon deterioration (doxycycline/clindamycin/co-amoxiclav also administered subsequently with co-trimoxazole/fluconazole prophylaxis) Inotropes for profound hypotension. IV methylprednisolone was substituted with dexamethasone with CNS symptoms, ciclosporin added when renal impairment allowed. Dexamethasone later changed to oral prednisolone. Candida and PCP prophylaxis., 1 dose of low dose etoposide alongside highest anakinra dose. TPN. Fluconazole for pulmonary aspergillosis. Antibiotics for line infection. Multiple transfusions of red cells, platelets, cryoprecipitate and FFP. Appendicectomy, haemofiltration, mechanical ventilation. Abbreviations: FFP -fresh frozen plasma, PICU -paediatric intensive care unit, PCP -Pneumocystis pneumonia, TPN -total parenteral nutrition Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patie nts Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome Therapeutic Role of Anakinra, an Interleukin-1 Receptor Antagonist, in the Management of Secondary Hemophagocytic Lymphohistiocytosis/Sepsis/Multiple Organ Dysfunction/Macrophage Activating Syndrome in Critically Ill Children*: Pediatric Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab: Alemtuzumab for Refractory HLH Central nervous system-restricted familial hemophagocytic lymphohistiocytosis responds to hematopoietic cell transplantation Pediatric CNS-isolated hemophagocytic lymphohistiocytosis Neurological associations of COVID-19