what is new - macrophage activation syndrome in aird - prof a v ramanan
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Macrophage activation syndrome secondary to Rheumatic diseases
A.V. RamananProfessor of Paediatric Rheumatology
Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic Diseases, Bath
Case report
13 year old with fever, rash and breathlessnessSudden worsening of repiratory symptomsIVIG x1 dose – no responseIntubated, HFO ventilationIn ITU for 45 days
Laboratory Values at Different Time Points
Case - 2
• 14 year old girl• 2 week h/o fever, rash• subtle knee effusion
Treatment given None. Methylpred.- 2 doses
Methylpred.Cyclosporin,IgG, Prednisolone
Methylpred.Cyclosporin,IgG, Prednisolone, IL-1 Blockade - one month after starting
Variable(Normal value) At Admission One week after
admission3 weeks after admission
2 months after admission
Haemoglobin g/dl 8.0 9.9 7.0 12
White cell count *103 9.2 9.2 25.0 5.5
Neutrophils *103 7.8 7.8 23.0 4.5
Platelets *103 396 201 391 233
ESR (1-15 ) mm/hr 120 - 155 50
Fibrinogen (150-450) mg/dl - 553 683 309
D-dimer - positive - positive
Ferritin ng/ml 44366 132206 29082 236
AST (15-41) IU/L 52 86 35 -
Prothrombin time (10.5-13) secs 13.7 17 17 13
APPT (24-35) secs 31.3 24 25 24
Outline
NomenclatureClassification of Histiocyte disordersRheumatic diseases associated with HLHEtiopathogenesisDiagnostic criteriaTreatment
Nomenclature
“MAS”, hemophagocytic syndrome, HLHMAS is secondary HLH!Important for - diagnostic, prognostic and therapeutic
reasons
Genetic, primary HLH• FHLH - Chromosome 9 linkage - PRF1 mutations - UNC13d mutations - Unknown mutations
• Immune deficiency syndromes - CHS - Griscelli syndrome - XLP
Acquired, secondary HLH• Exogenous agents - infectious organisms, toxins (VAHS, IAHS)
• Endogenous products - tissue damage - radical stress - metabolic
• Rheumatic diseases (MAS)
• Malignancies
HLH
Genotype-phenotype correlations in primary HLH
Normal Setting
HLH Setting
Threshold model of the HLH spectrum
Rheumatic Diseases Associated with MAS/HLH
SoJIA Systemic SclerosisPolyarticular JIA MCTDERA Rheumatoid arthritisCINCA SarcoidosisAOSD Sjogren’s syndromeSLE Polyarteritis nodosaJuvenile dermatomyositisKawasaki disease
Potential Triggers of MAS/HLH in Rheumatic Diseases
Drugs:
Aspirin Non steroidal anti-inflammatory drugsMethotrexateGold salts (particularly second dose of IM gold)EtanerceptSulfasalazineMorniflumateASCT
Potential Triggers of MAS/HLH in Rheumatic Diseases
Viruses: EBV Varicella zoster virusCoxsackie virusParvovirus B19Hepatitis A virusSalmonella enteritidisPneumocystis cariniiEnterococcal sepsis
Release of proinflammatory cytokines activates effector cells
Antigen presentation drives activation of cytotoxic T cells
Ineffective cytotoxicity leads to persistent viral infectionEffector cells amplify
inflammation leading to systemic hypercytokinemia
Continuous activation of PRRs synergizes with the
inflammatory cytokine milieu to activate innate immune cells
Chronic viral infection drives potent antigen
presenting cell activation
Pattern recognition receptors
Autoinflammatory Trigger Infectious
Trigger
Comparison of Clinical and Laboratory Features of SoJIA and MAS
Comparison of Clinical and Laboratory Features of SoJIA and MAS
SLE and HLH
80 adult patients with SLE73/80 had elevated liver enzymes7/73 –hemophagocytic syndromeCytopenia, fever, elevated liver enzymes – part
of “disease activity” in SLE
JSLE and MAS
38 pts with definite or possible lupus ferritinLDHtriglyceridesfibrinogen
Ravelli et al, A&R 2009 Nov
Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering
disease and early treatment with etoposide Arca et al, BJH, 2014
• 162 patients with HLH• 33 deaths within 30 days
Clinical characteristics of patients on diagnosis according to outcome.
Patients characteristics (N = 162)
Survivors(N =129)
Non-survivors(N =33)
P-value
Age (years) 47 (44-49) 56 (50-61) 0.004
Platelet count (x109/l) 75.8 (66.3-85.4) 40.6 (31.1-50) 0.0005
Aspartate aminotransferase (iu/l) 159 (105-213) 529 (183-1241) 0.04
Lactate dehydrogenase (iu/l) 1607 (1288-1927) 2550 (161-3938) 0.04
Underlying immunodeficiency (HIV infection) 54 7 0.029
Main triggering condition
Lymphoma 52 22
Infection or other condition* 36 4 0.04†
Multicentric Castleman disease 17 0
Arca et al, A&R, 2014
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Clinical Characteristics and Treatment Outcomes of Autoimmune-Associated Hemophagocytic Syndrome in
Adults Kumukura et al, A&R, Aug 2014
• 116 patients• SLE – 61, AOSD – 31• Normal or low CRP in SLE patients with HLH• Mortality of 12.9%• Male sex, anaemia and DM – poor prognosis
Clinical characteristics and treatment outcomes
Patients still living(n=101)
Patients deceased(n-15)
Age, mean ± SD years 40.9 ± 17.7 45.8 ± 24.9
Male sex, no. (%) 19 (18.8) 9 (60.0)
Physical findings
Fever, no./total no.(%) ‡ 85/99 (85.9) 14/15 (93.3)
Lymphadenopathy, no./total no.(%) 27/69 (39.1) 5/9 (55.6)
Hepatomegaly, no./total no.(%) 20/55 (36.4) 8/12 (66.7)
Splenomegaly, no./total no.(%) 34/77 (44.2) 6/11 (54.5)
Laboratory findings
WBC count 3.7 ± 5 7.2 ± 11.8
Hgb 9 ± 2 8.8 ± 2.3
Platelet count 130.6 ± 131.7 83.3 ± 104
Coagulopathy 33/69 (47.8) 7/10 (70)
AST 224.8 ± 448.2 571.2 ± 1034
ALT 164.1 ± 318.9 302.7 ± 514.9
LDH 1,196 ± 1,571 1,714 ± 1,784
CRP 7.5 ± 10.4 9.3 ± 8.1
Ferritin 12,963 ± 27,982 32,133 ± 66,866
Kumakura et al, A&R, 2014
Clinical characteristics of the adults with AAHS
Total
(n=116)Underlying SLE
(n=61)Underlying AOSD
(n=31)P
Age, mean 41.6 ± 18.7 34.4 ± 14.2 43.5 ± 17.4 0.014Male:Female ratio 1:3 1:4.1 1:4.2
Physical findings
Fever 99/114 56/60 30/31 NS
Lymphadenopathy 32/78 16/40 13/24 NS
Hepatomegaly 28/67 12/29 10/20 NS
Splenomegaly 40/88 15/43 16/25 NS
Laboratory findings
WBC count 4.1 ± 6.08 2.2 ± 1.2 6.8 ± 6.6 0.002Hgb 8.9 ± 2 8.7 ± 1.8 9.6 ± 1.9 NS
Platelet count 98.1 ± 96.8 81.9 ± 52.2 141.9 ± 142 NS
Coagulopathy 40/79 24/35 12/27 NS
AST 264.2 ± 548 211.3 ± 341 423.4 ± 757.9 NS
ALT 183 ± 351 96.1 ± 117 315.9 ± 402 0.029LDH 1,251 ± 1,592 1,012 ± 974 1,923.1 ± 1,721 NS
CRP 7.7 ± 10.2 2.8 ± 4.0 14.9 ± 12.6 0.00002
Ferritin 15,334.1 ± 35,181 5,849.5 ± 10,47240,136.4 ± 64,069.7
0.003
Kumakura et al, A&R, 2014
Diagnostic Criteria for HLH
Familial disease/known genetic defectClinical and laboratory criteria (five of eight criteria)• Fever• Splenomegaly• Cytopenia 2 cell lines Haemoglobin <90 g/l (below 4 weeks <120 g/l) Platelets <100 X 109/l Neutrophils <1 X 109/l• Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides 3 mmol/l Fibrinogen <1.5 g/l• Ferritin 500 µg/l• sCD252 2400 U/ml• Decreased or absent NK-cell activity• Haemophagocytosis in bone marrow CSF or lymphnodes
Date of prep: September 2016 NP-1338
Patient samples evaluated in the study and results of web-based expert evaluations.
Angelo Ravelli et al. Ann Rheum Dis 2016;75:481-489
©2016 by BMJ Publishing Group Ltd and European League Against Rheumatism
Criteria for the classification of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis.
Angelo Ravelli et al. Ann Rheum Dis 2016;75:481-489
©2016 by BMJ Publishing Group Ltd and European League Against Rheumatism
Development and validation of a score for the diagnosis of reactive hemophagocytic syndrome (HScore)
Fardet et al, A & R, Sept 2014
• Consensus by experts• 312 patients• 116 with HS• Median H score for HS patients is 230• H score for non HS patients 125
The HScore
Parameter No. of points (criteria for scoring)
Known underlying immunosuppression* 0 (no) or 18 (yes)
Temperature (°C) 0 (<38.4), 33 (38.4–39.4), or 49 (>39.4)
Organomegaly0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly)
No. of cytopenias† 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages)
Ferritin (ng/ml) 0 (<2,000), 35 (2,000–6,000), or 50 (>6,000)
Triglyceride (mmol/l) 0 (<1.5), 44 (1.5–4), or 64 (>4)
Fibrinogen (gm/l) 0 (<2.5) or 30 (≤2.5)
Serum glutamic oxaloacetic transaminase (IU/l) 0 (<30) or 19 (≥30)
Hemophagocytosis features on bone marrow aspirate
0 (no) or 35 (yes)
* The best cut off value for HScore was 169, corresponding to a sensitivity of 93%, a specificity of 86%, and accurate classification of 90% of the patients.
Date of prep: September 2016 NP-1338
HLH and Sepsis/MODS/SIRS
Part of same spectrumSIRS/MODS non specificImportance of terminology is in managementImmunosuppression for HLH/SIRS/MODS seen in
sepsis
Ferritin and HLH
Ferritin in trauma – with ARDS (638ng/ml), without ARDS (185ng/ml)
Pneumococcal sepsis – under 75 yrs of age (653), >75 yrs of age (312)
Ferritin and HLH
Allen et al; Peditr Blood Cancer; 2008330 Pts >500Ferritin>10,000 – 90% sensitive and 96% specific
for HLH10 patients with PUO
Ferritin distributions over the major 11 disease categories
HLH in PICU – Chennai data
• 2007-2008• 33 children diagnosed with HLH• 18(55%) required PICU admission• PICU admission – severe sepsis or
respiratory distress• 7 required ventilatory support
Ramachandran et al, Indian Pediatrics, Aug 2010 (e pub)
HLH in PICU – Chennai data
• Mean age 46 months (2mo -14 yrs)• CNS symptoms in 36%• HB(<9) – 97%, Plt (<100) – 72%• Hyperferritenemia – 97%• fibrinogen and LDH – 92%• Marrow haemophagocytosis – 82%
Ramachandran et al, Indian Pediatrics, Aug 2010
HLH in PICU – Chennai data
5 Dengue, 3 EBV, 1CMV, 1TB and 5 bacterial infections
Steroids -67%, IVIG – 64%, cyclosporine – 33%, etoposide – 15%
Survival – 76%
Ramachandran et al, Indian Pediatrics, Aug 2010
n Median 25th centile 75th centile
HLH total 123 4,123 1,584 11,210
FHL alone 76 3,624 1,519 11,803
VA-HLH alone 37 5,573 1,740 10,796
Controls 320 1,341 796 2,662
Distribution of ferritin values
Lehmberg et al, A&R, 2014
Dengue Associated Hemophagocytic Lymphohistiocytosis: A Case Series P PAL, P P GIRI AND *AV RAMANAN
Indian Paediatrics, 2014
• Dengue outbreak 2013• 358 Dengue cases• 8 had HLH• All did well with steroids
Figure 4. EBV has high similarity to DENV and inflammatory syndromes.
Dunmire SK, Odumade OA, Porter JL, Reyes-Genere J, et al. (2014) Primary EBV Infection Induces an Expression Profile Distinct from Other Viruses but Similar to Hemophagocytic Syndromes. PLoS ONE 9(1): e85422. doi:10.1371/journal.pone.0085422http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085422
Figure 2. Ferritin levels and fold change are associated with viraemia.
van de Weg CAM, Huits RMHG, Pannuti CS, Brouns RM, et al. (2014) Hyperferritinaemia in Dengue Virus Infected Patients Is Associated with Immune Activation and Coagulation Disturbances. PLoS Negl Trop Dis 8(10): e3214. doi:10.1371/journal.pntd.0003214http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0003214
Poor Prognostic factors
Renal involvementSevere neutropeniaSevere coagulation abnormalitiesCNS involvement
Ramanan et al, 2005
Treatment of HLH/MAS in rheumatic diseases
Supportive careCorticosteroidsIVIGCyclosporinEtoposideIL-1 BlockadeHLH-94 protocol
IVIG in HLH
Useful alone or in conjunction with steroidsUseful when diagnosis unclear7/20 pts in one study treated with IVIG
(Emmenegger et al)Good response with one group in Switzerland
Cyclosporin in HLH
EffectiveBeware of neurotoxicity when given
parenterallySeveral reports of success, part of HLH-94?DMARD of choice in SoJIA patients at high risk
of HLH
Etoposide in HLH
Very effectivePerhaps not used enough by RheumatologistsConsider outside the context of HLH-94
Recombinant IL-1 receptor antagonist
4 weeks of spiking pyrexias resolved with IL-1 blockade
Prednisolone weaned
Well off all medication for past year.
Benefit of IL-1 Blockade for MAS among sJIA Patients
Suggested Management According to Risk Groupsat Initial Diagnosis
Schematic algorithm of our approach to the diagnosis and treatment of adult HLH.
Alison M. Schram, and Nancy Berliner Blood 2015;125:2908-2914
©2015 by American Society of Hematology
Ebola fever and ferritin as biomarker
• EF outbreak in Sudan 2000-01• Samples analysed for multiple biomarkers• Death and haemorrhage associated with
thrombomodulin and serum ferritin levels
Viremia as a function of clinical outcome.
McElroy A K et al. J Infect Dis. 2014;210:558-566
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Markers of inflammation associated with a fatal outcome (black bars) or hemorrhagic manifestations (red bars). *P ≤ .05.
McElroy A K et al. J Infect Dis. 2014;210:558-566
HLH-94 protocol
Henter et al, 2002
Questions?