Sekonder Hemofagositik Sendrom

Aslında

diye bir şey yoktur!

• 1987 Histiocyte Society: Histiyotik hastalıkları 3 grupta toparladı:- Langerhans histiocytosis, - non-Langerhans histiocytosis (HLH)- malignant histiocyte disorders

• 1997 de bu üç grubun isimleri değişti:- dendritic cell-related - macrophage related (HLH)- malignant

• 2007 son revizyon

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Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation.Castillo L, Carcillo J. Baylor College of Medicine, Houston, TX, USA

Pediatr Crit Care Med. 2009 May;10(3):387-92.

Twelve patients with toxic shock pathology findings included pronounced hemophagocytosis by RE macrophages (Larkin et al Ann Int Med 1982)

Histiocytic Medullary Reticulosis originally defined as a neoplastic disorder is actually reactive and caused by disseminated infections Bacteria associated hemophagocytic syndrome (Risdall J et al Cancer 1984)

Pathology evaluation of benign hemophagocytic proliferations. 230 consecutive adult autopsies found that 102 hemophagocytosis. Associated with recent blood transfusions and sepsis. Reactive HLH should be considered secondary and not ominous or malignant (Suster et al Hum Pathol 1988)

Thrombocytopenia, M-CSF and hemophagoctosis in sepsis. 50 consecutive patients; hemophagocytosis (64%) associated with MOF and infection. M-CSF increased with hemophagocytosis. (Francois B et al Am J Med 1997)

Hemophagocytosis has been described in 64.5% of 107 autopsies in critically ill medical patients with thrombocytopenia associated MOF, and all patients with hemophagocytosis had infection (Strauss R et al Crit Care Med, 2004)

• Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis.

Schaer DJ, Schaer CA, Schoedon G, Imhof A, Kurrer MO.Department of Medicine, University Hospital, Zurich, Switzerland Eur J Haematol 2006: 77: 432–436

• Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages.

Knutson MD, Vafa MR, Haile DJ, Wessling-Resnick M. Blood 2003;102:4191–4197.

• Heme oxygenase-1: unleashing the protective properties of heme. Otterbein LE, Soares MP, Yamashita K, Bach FH. Trends Immunol 2003;24:449–455.

1. Hemofagositoz sistemik inflamasyon sırasında sıklıkla görülen ortak bir süreçtir

2. Eritrofagositoz hem-oksijenaz 1 (HO-1) ekspresyonunu artırır

3. HO-1 sepsis sırasında ortaya çıkan enflamasyonu negatif yönde regüle eder

4. Artmış HO-1 aktivitesi: anti-enflamatuvar, anti-apopitotik ve anti-oksidatifdir

5. Enzimatik HO-1 aktivitesinin ürünleri bilirubin, karbon monoksit ve ferritin bu

etkilerden sorumludur (intraselüler hem demirinin açığa çıkmasıyla tetiklenir)

6. Rediküloendotelial sistemdeki eritrofagositik makrofajlar HO-1 kaynağıdır

Post-mortem kemik iliği; 28 sepsis, 8 kontrol grubu

Eur J Haematol 2006: 77

A. Macrophages constitute the principle HO-1 expressing cell compartment within the bone marrow of sepsis patients.

B. Ferritin expression – which reflects heme breakdown within the HO-1+ macrophages of sepsis patients.

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Hiperferritinemi sistemik inflamasyonun sonundaki ortak yolağın belirtecidir !

Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients.Bennett TD, Hayward KN, Farris RW, Ringold S, Wallace CA, Brogan TV. University of Washington, Seattle, WA.

CONCLUSION: In this pediatric population, with serum ferritin levels of >3000 ng/mL, there was increased risk for both receipt of critical care and subsequent death.

Pediatr Crit Care Med. 2011 Nov;12(6):e233-6.

Pro-Inflammatory Mediators

Anti-Inflammatory Mediators (Inhibitors)

Pro/Anti-Inflammatory Mediators

Activation Depression

Time

Time

Parallel

Serial

IL1TNF

PAF

IL10

IL6

Med

iato

r L

evel

sM

edia

tor

Lev

els

Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003

Sitokin kaosu:NötrofilLenfositlerProstaglandinlerVasküler endotelyumNitrik oksidAkut faz proteinler

SIRS vs CARS

apairesos

• TMA: TTP ve HÜS’e benzer. • TTP de PE ile mortalite >%90’dan %10-20’ye düşmüştür. • Sepsis de de ADAMS-13 eksikliği söz konusudur. • TAMOF’da da ADAMTS-13 ekikliği, ADAMTS13’e karşı

oluşmuş antikorlar ve artmış vWf multimerleri söz konusudur.

• Erken PE ile mortalite %90’dan %10’a düşmüştür. • DIC vs TMA

Hemofagositoz sırasında görülen trombositopeninin mekanizması henüz tam olarak açıklanamamış olsa da eş zamanlı devam eden mikroanjiopatiyle ilişkili olabilir!

• Nakakura H, Ashida A, Matsumura H, Murata T, Nagatoya K, Shibahara N, Inoue T, Tamai H: A case report of successful treatment with plasma exchange for hemophagocytic syndrome associated with severe systemic juvenile idiopathic arthritis in an infant girl. Ther Apher Dial 2009, 13:71-76.

• Song KS, Sung HJ: Effect of plasma exchange on circulating IL-6 levels in a patient with fatal hemophagocytic syndrome associated with bile ductopenia. Ther Apher Dial 2006, 10:87-89.

• Matsumoto Y, Naniwa D, Banno S, Suguira Y: The efficacy of theraupetic plasmapheresis for the treatment of fatal hemophagocytic syndrome by intravenous immunoglobulins. Ther Apher Dial 1998, 2:300-304.

• Satomi A, Nagai S, Nagai T, Niikura K, Ideura T, Ogata H, Akizawa T: Effect of plasma exchange on refractory hemopahocytic syndrome complicated with myelodisplastic syndrome. Ther Apher 1999, 3:317-319.

• Stegmayr BG: Apheresis as therapy for patients with severe sepsis and multiorgan dysfunction syndrome. Ther Apher 2001, 5:123-127.

• Busund R, Koukline V, Utrobin U, Nedashkousky E: Plasmapheresis in severe sepsis and septic shock: a prospective, randomized, controlled trial. Intensive Care Med 2002, 28: 1434-1439.

• Stegmayr BG, Banga R, Berggren L, Norda R, Rydvall A, Vikerfors T: Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003, 31:1730-1736.

Pediatric Logistic Organ Dysfunction Score

DAY

0 5 10 15 20 25 30

PE

LOD

0

20

40

60

80

100

Plasma ExchangeNo Plasma Exchange

Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standarderror for patients who received plasma exchange therapy (N = 5) and who did not receive plasma exchange therapy (N = 5) for each day x 28 days.

17 Nguyen, Carcillo et al., 2008

ADAMTS13 Activity and PEx vs No PEx

Day

0 1 2 3 4 5 6 7 8

AD

AM

TS

13

Act

ivity

(%

re

lativ

e to

co

ntr

ols

)

-20

0

20

40

60

80

100

day vs pe cp day vs nope cp

Plasma Exchangen = 4

No Plasma Exchangen = 4

2F ANOVA p<0.05

TAMOF Network

yaşlarının ortancası 12, PRISM ve PELOD skorları benzer

21 TAMOF

15 plasma değişimi

11 sağ(73%)

4 ex

6 standard tedavi

2 sağ(33%)

4 ex

İmmünsupresyon da hemofagositoza sebep olabilir!

Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia.Hurwitz CA, Silverman LB, Schorin MA, Clavell LA, Dalton VK, Glick KM, Gelber RD, Sallan SE.

Cancer. 2000 Apr 15;88(8):1964-9.

CONCLUSIONS: Substitution of dexamethasone for prednisone or methylprednisolone in an otherwise intensive conventional induction regimen for previously untreated children with ALL resulted in an alarmingly high incidence of septic episodes and toxic deaths

In contrast, high dose intravenous methyl prednisolone treatment did not increase mortality

Pateint Precipitating factors Diagnosis Treatment modalities Outcome

1 Metabolic crisis Propionic acidemia SHLH

5xTPE, Steroid,cyclosporine,etoposide Survived

2 Infection ALL/SLE/SHLH Steroid,cyclosporine,etoposide,IVIG, Ex (MODS)

3 Salmonella inf. SHLH 4XTPE ,Steroid,cyclosporine,IVIG Ex (MODS)

4 EBV inf XLP / SHLH 7XTPE , Steroid,cyclosporine,etoposide,IVIG,Rituximab Ex (MODS)

5 H1N1 inf. ALL / SHLH 18XTPE, Steroid,cyclosporine, etoposide, IVIG Ex (ARDS)

6 Infection JRA / MAS 11XTPE, Steroid, IVIG Survived

7 Infection JRA / MAS 1XTPE , Steroid,cyclosporine,IVIG Exitus(MODS)

8 Infectıon SLE / MAS 12xTPE,Steroid,IVIG,Anakinra Discharged Ex (Pulm. Hem.)

9 Infection Propionic acidemia SHLH

8xTPE,Steroid,IVIG ! Ex (Nasocomial sepsis)

10 Infection JRA/MAS 2xTPE,Steroid,IVIG,Etoposide,Anakinra Ex (MODS)

Doz ayarlaması !

Kemoterapi alanlarda mortalite %40 !

An unusual cause of multiple organ dysfunction syndrome in the pediatric intensive care unit: hemophagocytic lymphohistiocytosis.Karapinar B, Yilmaz D, Balkan C, Akin M, Ay Y, Kvakli K.Pediatric Intensive Care Unit, Faculty of Medicine, Ege University, Izmir, Turkey.

Pediatr Crit Care Med. 2009 May;10(3):285-90.

Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution.Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S.Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

Kemoterapi alanlarda mortalite %24, sadece IVIG veya steroid alanlarda %1 !

J Pediatr Hematol Oncol. 2009 Feb;31(2):81-4.

Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection.Beutel G, Wiesner O, Eder M, Hafer C et al. Hannover Medical School, Germany

Crit Care. 2011;15(2):R80. Epub 2011 Mar 2.Kemoterapi alanlarda mortalite %83

HYPERFERRITINEMIA IN THE CRITICALLY ILL CHILD WITH SECONDARY HLH/SEPSIS/MODS/MAS: WHAT IS THE TREATMENT?Demet Demirkol, Dincer Yildizdas, Benan Bayrakci et al.Turkish Secondary HLH/MAS Critical Care Study Group and Joseph A Carcillo.

Multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/Sepsis/MODS/MAS between December 2005 and April 2011

less immunosuppression (TPE and IVIG or methyl prednisolone) (n:17; survi %100)vsprimary HLH protocol (TPE and dexamethasone or cyclosporine A and/or etoposide) (n:6; survi %50)

56% (n=13) of these patients also met the diagnostic criteria for septic shock and 9% (n=2) for severe sepsis the expected mortality of septic patients in our cohort was 92%. The survival observed in our study was significantly better than expected

Ferritin level (g/dL)

Thrombocyte count (/mm3)

Lactate dehydrosanase level (U/L)

ANAKINRA TREATMENT IN SECONDARY HLH/MAS PATIENTSTurkish Secondary HLH/MAS Critical Care Study Group and Joseph A Carcillo.

IL-1Ra 1-2 mg/kg sc maksimum 5 gün

•IL-1, proenflamatuvar sitokinlerin prototipi

• Septik şokta IL-1 artıyor

•IL-1Ra biyolojik aktivitesini kompetatif olarak baskılıyor

•IL-1 converting enzyme veya IL-1R tip 1 eksik fareler endotoksik şoka dirençli

• Hayvan modellerinde IL-1Ra kullanılması enfeksiyon, şok, sistemik enflamasyon oluşumunu sınırlandırıyor

•IL-1Ra tedaviye dirençli MAS’da da kullanılıyor

primum non nocere!

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