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  • Study in secondary HLH showed that lower percentage of glycosylated ferritin (~20%) in HLH confirmed patients, compared to HLH suspected but ‘unconfirmed’ had sensitivity of 86% and specifity of 71%, PPV of 91% and NPV of 63% ‘ Confirmed’ HLH included absent or decreased NK cell activity among 8 other strict criteria
  • Mas

    1. 1. “ Terrible T-cells and Troubling Thrombocytopenia” Rheumatology Case Conference Case and Review of Literature 12/11/2009 Mark Gorelik Fellow, Pediatric Rheumatology
    2. 2. Clinical History <ul><li>8/5/2009 –11 yo female w/o significant past history, who presented initially to OSH with </li></ul><ul><ul><ul><li>2 days of fever (104), </li></ul></ul></ul><ul><ul><ul><li>L ankle pain/limp, (?previous trauma) </li></ul></ul></ul><ul><ul><ul><li>abdominal pain, nausea, vomiting . </li></ul></ul></ul><ul><li>8/7/2009 - transferred to CHP with elevated ESR, CRP, r/o osteomyelitis. </li></ul><ul><ul><ul><li>Fever resolved </li></ul></ul></ul><ul><ul><ul><li>plain films of ankle normal </li></ul></ul></ul><ul><ul><ul><li>discharged with motrin, diagnosis ‘viral illness’ </li></ul></ul></ul>
    3. 3. Clinical History <ul><li>8/9/2009 – readmitted to OSH for fever, abdominal pain, left ankle pain/swelling. </li></ul><ul><ul><li>Labs show CBC 8.3/11/33/244 </li></ul></ul><ul><ul><li>nml LFTs, </li></ul></ul><ul><ul><li>Renal, Ua wnl </li></ul></ul><ul><ul><li>ESR 61 </li></ul></ul><ul><ul><li>Blood cultures x 2 negative. </li></ul></ul><ul><ul><li>MRI ankle ‘normal’ </li></ul></ul>
    4. 4. Clinical History <ul><li>8/11/2009 – continued abdominal pain – CT abdomen </li></ul><ul><ul><li>-- L basilar pneumonia: started on Nafcillin and Ceftriaxone </li></ul></ul><ul><li>8/14-8/15 – increasing resp distress, rash on inner thighs (erythematous blanching patches) </li></ul><ul><ul><li>ANA negative, ASO negative, Monospot negative, Lyme negative </li></ul></ul><ul><ul><li>CBC - 24.6/9.9/30/345 33N/ 9Bands/ 18L/3M </li></ul></ul><ul><ul><li>CRP was elevated at 24.1 and ESR was 35 </li></ul></ul><ul><ul><li>Placed on azithromycin, rocephin, clindamycin and vancomycin </li></ul></ul><ul><ul><li>Continued increasing resp distress </li></ul></ul>
    5. 5. Clinical History <ul><li>8/17/2009 – transferred to CHP again </li></ul><ul><ul><li>shock with respiratory distress, tachycardia, hypotension </li></ul></ul><ul><ul><li>Question hypoxic seizure, became unresponsive with eye deviation </li></ul></ul><ul><ul><li>Intubated </li></ul></ul><ul><ul><li>Started on Zosyn, Vanco, and Clinda. </li></ul></ul>
    6. 6. Clinical History <ul><li>8/17-18 </li></ul><ul><ul><li>Left ankle swelling again. Films again normal. </li></ul></ul><ul><ul><li>Mild hyponatremia (130), LFTs nml (AST 49), Albumin (2.8) </li></ul></ul><ul><ul><li>CBC 19.2/11.1/32/256 N 58/Bands 25/L 8 </li></ul></ul><ul><ul><li>ESR 40, CRP 18.7 </li></ul></ul><ul><ul><li>PT was slightly elevated at 18 and INR slightly elevated at 1.5. PTT nml. Fibrinogen normal </li></ul></ul><ul><ul><li>Echo showed small circumferential pericardial effusion </li></ul></ul><ul><ul><li>Head CT - normal ; EEG – no focal findings. </li></ul></ul><ul><ul><li>ANA again negative </li></ul></ul>
    7. 7. Clinical History <ul><li>8/18/2009 </li></ul><ul><li>Infectious Disease consult. </li></ul><ul><li>? Viral sepsis </li></ul><ul><ul><li>viral assay for Adeno (+) </li></ul></ul><ul><ul><li>Influenza (-) </li></ul></ul><ul><ul><li>Paraflu (-) </li></ul></ul><ul><ul><li>RSV (-) </li></ul></ul><ul><ul><li>EBV (-) </li></ul></ul><ul><ul><li>CMV (-) </li></ul></ul><ul><ul><li>NP viral culture, stool viral culture (-) </li></ul></ul><ul><ul><li>CSF viral culture (-) </li></ul></ul><ul><ul><li>Enterovirus PCR (-) </li></ul></ul><ul><ul><li>Mycoplasma PCR (-) </li></ul></ul>
    8. 8. Clinical History <ul><ul><li>With history of fever, rash, dry chapped lips and hyponatremia and hypoalbuminemia, ?Atypical Kawasaki's </li></ul></ul><ul><ul><ul><li>repeat Echo coronary arteries normal, showed previously mentioned pericardial effusion slightly increased in size. </li></ul></ul></ul><ul><ul><li>IVIG per infectious disease </li></ul></ul>
    9. 9. Clinical History <ul><li>8/18/2009 – 8/23 </li></ul><ul><li>Rheumatology consult - reviewed PMHx/FHx/SHx </li></ul><ul><ul><li>Left ankle swollen </li></ul></ul><ul><ul><li>rash – non specific, generally blanching, however some areas on trunk non blanching (biopsied…pending) </li></ul></ul><ul><ul><li>continued fever </li></ul></ul><ul><ul><li>Ferritin (8/18) 6,129; (8/20) 4,605 </li></ul></ul><ul><ul><li>WBC 17,000/10/30/239 63 segs, 25 bands, 6 Lymphs </li></ul></ul><ul><ul><li>Complements </li></ul></ul><ul><ul><ul><li>8/20 C3 89/ C4 7 </li></ul></ul></ul><ul><ul><ul><li>8/22 C3 74/ C4 <5 </li></ul></ul></ul><ul><ul><li>SSA, SSB, ANCA, and ACE negative </li></ul></ul><ul><ul><li>Bone marrow “normal” </li></ul></ul><ul><li>MRI brain </li></ul>
    10. 10. There are multiple bilateral foci of T2 and FLAIR signal hyperintensity associated withareas of restricted diffusion. They are present in bilateral frontal lobes parasagittally, with 2 on the left and 1 on the right; in the bilateral occipital lobes with 3-4 foci on the right and 1 on the left…consistent with multifocal infarctions.
    11. 11. Clinical History <ul><li>8/24 – 8/28 </li></ul><ul><ul><li>Pulse steroids started </li></ul></ul><ul><ul><li>Improvement in clinical course </li></ul></ul><ul><ul><li>Rash resolving through this period. </li></ul></ul><ul><ul><li>Rash biopsy from 8/21: “mild vacuolar degeneration, mild perivascular lymphocytic infiltrate, rare neutrophils… no vasculitis is seen ” </li></ul></ul><ul><ul><li>Extubated on 8/24 </li></ul></ul><ul><ul><li>Continued on daily steroids after pulse; 20mg IV q6 methylprednisone </li></ul></ul><ul><ul><li>Persistent O2 requirement </li></ul></ul>
    12. 12. Clinical History <ul><li>8/29/2009-8/30 </li></ul><ul><li>Marked acute change </li></ul><ul><ul><li>Fever to 39.9 </li></ul></ul><ul><ul><li>antibiotic re-started- vancomycin and zosyn. </li></ul></ul><ul><ul><li>Chest pain, and increased WOB, desat, hypotension, and required intubation, pressors. </li></ul></ul><ul><ul><li>return of rash that is an erythematous blanching maculopapular eruption covering her face, trunk and extremities. </li></ul></ul>
    13. 13. Clinical History <ul><ul><li>Lab abnormalities include </li></ul></ul><ul><ul><ul><li>extremely elevated WBC x2 (40-70,000) w/ very high segs. </li></ul></ul></ul><ul><ul><ul><li>Platelets 140s. </li></ul></ul></ul><ul><ul><ul><li>ALT/AST 103/65, </li></ul></ul></ul><ul><ul><ul><li>ferritin 11,120, </li></ul></ul></ul><ul><ul><ul><li>ESR 10, CRP 19, </li></ul></ul></ul><ul><ul><li>CT chest due to sudden onset of incr WOB, concern acute pulmonary process </li></ul></ul>
    14. 15. Clinical History <ul><li>8/30 – 8/31 </li></ul><ul><ul><li>Placement of pericardial drain </li></ul></ul><ul><ul><li>Resolution without other intervention with exception of discontinuing antibiotics </li></ul></ul><ul><ul><li>LFTs normalized, ESR 30 </li></ul></ul><ul><ul><li>Pericardial effusion showed abundant fibrin component, inflammatory cells including CD163 ‘activated’ macrophages </li></ul></ul><ul><ul><li>Subsequent improvement in clinical course </li></ul></ul>
    15. 16. Clinical History <ul><li>9/4-9/11 </li></ul><ul><ul><li>New thrombocytopenia with petechial rash, peeling of hands and feet, otherwise well appearing </li></ul></ul><ul><ul><li>CBC 26.6/12.5/36/9 72 segs, 6 bands, 25 lymphs, </li></ul></ul><ul><ul><li>Fibrinogen 148, ESR 10, CRP 1.0, </li></ul></ul><ul><ul><li>Triglyceride 600 </li></ul></ul><ul><ul><li>ferritin 9,482, ALT/AST 64/59, </li></ul></ul><ul><ul><li>complements 109/16 </li></ul></ul><ul><li>9/4/-9/10 </li></ul><ul><ul><li>Continued persistent thrombocytopenia, treated with IVIg and then steroid pulse, with modest but not sustained improvement (platelets to 51) </li></ul></ul>
    16. 17. Clinical History <ul><li>9/10-9/12 </li></ul><ul><ul><li>Increasing tachycardia, new fever (38.2) </li></ul></ul><ul><ul><li>CBC 21/12.3/35/22 75 segs, 3 bands, </li></ul></ul><ul><ul><li>ESR 41, CRP 5.07, </li></ul></ul><ul><ul><li>LFTs wnl, ferritin 11,349 </li></ul></ul><ul><ul><li>Re-review of bone marrow </li></ul></ul>
    17. 18. Bone marrow aspirate with myeloid hyperplasia
    18. 19. Bone Marrow Aspirate: Histiocytes (arrows) with phagocytosed red blood cells
    19. 21. Evangelista, F; Blood 1999;63:1991 CDC website
    20. 22. Diagnosis <ul><li>?Macrophage Activation Syndrome? </li></ul><ul><li>Fever, Rash </li></ul><ul><li>Hyperferritinemia </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Hypertriglyceridemia </li></ul><ul><li>Hypofibrinogenemia </li></ul><ul><li>Hemophagocytosis </li></ul>
    21. 23. Macrophage Activation Syndrome
    22. 24. Normal response to infection
    23. 25. Macrophage Activation Syndrome Edward M. Behrens Macrophage activation syndrome in rheumatic disease: What is the role of the antigen presenting cell? Autoimmunity reviews, Volume 7, Issue 4, Feb 2008, 305-308
    24. 26. Macrophage Activation Syndrome Online presentation
    25. 27. Macrophage Activation Syndrome <ul><li>Can be initial presentation of S-JIA, but also other conditions, lupus, Kawasaki, AOSD, as well as infection. </li></ul><ul><li>Failure of release or function of granzymes is a key molecular etiology </li></ul>Avcin, T, Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood J. Peds 148:5
    26. 28. List of effector proteins: Src kinases, Zap70, Lat, SLP-76, PLAC-gamma, ADAP, Dynein, FMNL1, Dia1, IQGAP, Cdc42, Pyk2, Erk, HDAC6, Rab27a, AP-3, Munc 13-4, Syntaxin-11, Slp1, Slp2, Paxillin, PKC-delta, WIP, Rab3d, Rab19, Syntaxin-4, SNAP23, WASP, Syntaxin-6, Perforin
    27. 29. Review of the literature <ul><li>Ravelli et al, Preliminary diagnostic guidelines for MAS complicating Systemic Juvenile Idiopathic Arthritis, J. pediatrics, 2005 </li></ul><ul><li>Retrospective study of clinical, laboratory and histopathologic variables in patients with MAS compared to patients with ‘a confusable disease’ </li></ul><ul><li>Study design: classification criteria approach – comparing index disease with confusable disease to find criteria that have a high sensitivity rate for disease in question and high specificity for other diseases </li></ul><ul><li>The index disease was MAS complicating systemic onset JIA, confusable condition was active Systemic- JIA. </li></ul>
    28. 30. Ravelli et al <ul><li>Patient selection through patients known by the authors, as well as literature review. </li></ul><ul><li>If ambiguous, reviewers met to reach consensus. 74 total patients with index case, 37 patients with confusable disease. 19 additional patients were disqualified because of insufficient data or not having systemic JIA. </li></ul><ul><li>Statistical analysis to calculate the greatest sensitivity and specificity from data within 95% confidence interval. </li></ul><ul><li>Study has low statistical power </li></ul>
    29. 34. Ferritin <ul><li>Major molecule for iron storage, plays a role in sequestration of iron </li></ul><ul><li>Can be found to be elevated in in multiple conditions of both health and disease, with moderate elevations in: </li></ul><ul><ul><li>Malignancies </li></ul></ul><ul><ul><li>Tylenol overdose </li></ul></ul><ul><ul><li>Hemochromatosis </li></ul></ul><ul><ul><li>Lupus </li></ul></ul>Coca A, Macrophage activation syndrome: Serological Markers and treatment with ATG Clinical Immunology, online Feb 17 2009
    30. 35. Ferritin as a red herring <ul><li>53 yo woman (from central PA) with 3 weeks of fevers, chills, weight loss, myalgias and arthralgias </li></ul><ul><li>CBC 4.5/10/28.6/95, AST 67, albumin 2.9, LDH 2075, ANA negative </li></ul><ul><li>Serum ferritin – 87,207mg/ml </li></ul><ul><li>Continued to have worsening pancytopenia, diagnosis of AOSD </li></ul><ul><li>Treated with steroids – had initial improvement, then had rapid decline in liver function </li></ul><ul><li>Liver biopsy revealed diffuse large B cell lymphoma </li></ul><ul><li>Most importantly… </li></ul><ul><li>… The patient survived! </li></ul>Haider F, Primary hepatic lymphoma presenting as fulminant hepatic failure with hyperferritinemia: a case report J. Medical Case Reports 19 Aug 2008
    31. 36. How to tell Bad from Worse Ferritin <ul><li>Ferritin is Glycosylated </li></ul><ul><li>Inflammatory conditions -- lower percentage of glycosylated ferritin as a percentage of total ferritin. </li></ul><ul><li>Studies in AOSD and HLH (retrospective) have been done to determine ferritin vs. glycosylated ferritin levels. </li></ul>Fautrel, B, Diagnostic value of Ferritin and Glycosylated Ferritin in AOSD, J. Rheum 2001 28:2; Wang et al, Early diagnostic value of low percentage of glycosylated ferritin in secondary HLH Int J Hematol, 05 August 2009
    32. 37. Fautrel, B, Diagnostic value of Ferritin and Glycosylated Ferritin in AOSD, J. Rheum 2001 28:2;
    33. 39. New diagnostic markers <ul><li>CD163 – hemoglobin/haptoglobin scavenger </li></ul><ul><ul><li>Expression identifies macrophages stimulated to have enhanced phagocytic activity </li></ul></ul><ul><li>S IL-2Ra – receptor for IL-2, </li></ul><ul><ul><li>increases along with B and T cell activation, found in autoimmune disease and transplant rejection, also very elevated in HLH/MAS. </li></ul></ul><ul><li>Multicenter prospective study of these markers in HLH/MAS to differentiate acute MAS from active S-JIA. MAS was diagnosed using criteria of Ravelli. </li></ul><ul><li>16 patients studied – </li></ul><ul><li>Increased CD 163 + macrophages on bone marrow also suggestive of MAS. </li></ul>Grom, A Diagnostic Significance of CD163 and sIL-2RA Arthritis and Rheumatism 27 Feb 2007 56:3 (pg/ml) (ng/ml) p = 0.003 p = 0.017 11672 pg/ml
    34. 40. Follow up on our patient <ul><ul><li>Started on Cyclosporine and increased steroid dose </li></ul></ul><ul><ul><li>Platelet counts improve </li></ul></ul><ul><ul><li>Discharged – initial outpatient labs showed steadily improving platelets (290), declining markers of inflammation, but still with hyperferritinemia </li></ul></ul><ul><ul><li>Last ESR 26, nml platelets, ferritin 77 and on 4mg prednisone qd, continued on cyclosporine </li></ul></ul>
    35. 41. Underlying Diagnosis Unknown… <ul><li>Atypical presentation of SJIA? </li></ul><ul><li>A process secondary to adenovirus infection? </li></ul><ul><li>ANA negative Lupus with MAS? </li></ul>
    36. 42. Summary <ul><li>Macrophage activation syndrome is due to uncontrolled CD8 T cell proliferation </li></ul><ul><li>Occurs in setting of sJIA, AOSD, Lupus, Kawasaki, infection (EBV) </li></ul><ul><li>May be misdiagnosed as ‘culture negative sepsis’ </li></ul><ul><li>Very high ferritin levels, hemophagocytosis or increased CD163 staining on marrow, thrombocytopenia are important markers </li></ul><ul><li>CAUTION - Very high ferritin levels can also represent neoplasia </li></ul>