1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression. 2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown. 3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.

1. Aslında
diye bir şey yoktur!

2. • 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
2

4. 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.

5.  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)

6. • 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

7. Post-mortem kemik iliği;
28 sepsis, 8 kontrol grubu
Eur J Haematol 2006: 77

8. 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.

9. 9
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.

10. Pro-Inflammatory
Mediators
Anti-Inflammatory
Mediators (Inhibitors)
IL10
Time
Pro/Anti-Inflammatory
Mediators
TNF
Activation Depression
Time
Serial
Parallel
IL1
PAF
IL6
Mediator Levels Mediator Levels
Sitokin kaosu:
Nötrofil
Lenfositler
Prostaglandinler
Vasküler endotelyum
Nitrik oksid
Akut faz proteinler
Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003

11. apairesos

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

13. • 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.

14. Pediatric Logistic Organ Dysfunction Score
0 5 10 15 20 25 30
DAY
PELOD
100
80
60
40
20
0
Plasma Exchange
No Plasma Exchange
Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standard
error 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.
ADAMTS13 Activity and PEx vs No PEx
2F ANOVA p<0.05
Plasma Exchange
n = 4
No Plasma Exchange
n = 4
0 1 2 3 4 5 6 7 8
Day
ADAMTS13 Activity (% relative to controls)
100
80
60
40
20
0
-20
day vs pe cp
day vs nope cp
17 Nguyen, Carcillo et al., 2008

15. 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

16. İmmünsupresyon da hemofagositoza sebep olabilir!

17. 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.
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
Cancer. 2000 Apr 15;88(8):1964-9.

18. 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 !

19. 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.
Kemoterapi alanlarda mortalite %40 !
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
Kemoterapi alanlarda mortalite %83 Crit Care. 2011;15(2):R80. Epub 2011 Mar 2.

20. 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)
vs
primary 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

21. Ferritin level
(g/dL)
Thrombocyte
count (/mm3)
Lactate
dehydrosanase level
(U/L)

23. ANAKINRA TREATMENT IN SECONDARY HLH/MAS PATIENTS
Turkish 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

24. primum non nocere!

25. 25