DR Prashant presented on 8th March at Yenepoya Medical college Click to connect with the author https://www.linkedin.com/in/prashanth-balanthimogru-a47ab438

1. DR.PRASHANTHA.B
CONSULTANT HEMATOLOGIST
DEPT OF ADULT HEMATOLOGY
ASSISTANT PROFESSOR
DEPT OF MEDICINE
KMC, MANIPAL UNIVERSITY
MANGALURU CAMPUS
Hemophagocytic Syndromes

3. Classification
 Primary
 Familial/Genetic
 May be associated with Immune Deficiencies – Chediak-Higashi
Syndrome, Griscelli syndrome, XLP, CGD etc.
 Onset of disease usually <1 year of age
 Rapidly progressing fatal syndrome due to genetic defects
 Male: Female::1:1
 Incidence - 1 in 3000 children admitted to tertiary care center
 Up to 25% of adults with HPS (Heterozygous mutations)

4. HLH – Familial vs Genetic
• FHL1 (OMIM 267700)
• FHL2 (OMIM 603553)
PRF1/Perforin
• FHL3 (OMIM 608898)
UNC13D/Munc13-4
• FHL4 (OMIM 603552)
STX11/Syntaxin 11
• FHL5 (OMIM 613101)
STXBP2/Munc18-2
• GS2 (RAB27A) (OMIM 603868)
• HPS2 (OMIM 608233)
•XLP1 (OMIM 308240)
• XLP2 (OMIM 300635)
• BLOC1S6 (OMIM 604310)
• CD27 (OMIM186711)
• ITK (OMIM186973)
• LYST (OMIM606897)
• MAGT1 (XMEN) (OMIM300853)
• SLC7A7 (OMIM 603593)
• XIAP (BIRC4) (OMIM 300079)

5. Pathophysiology
From Uptodate.com

6. Immunologic abnormalities
 Syndrome of excessive inflammation and tissue destruction due to
abnormal immune activation
 Caused by the absence of normal down regulation by activated
macrophages and lymphocytes
 Macrophages
 Professional APCs derived from circulating monocytes
 Present foreign antigens to lymphocytes
 Uncontrolled activation and secretion of cytokines

7. Immunologic abnormalities
 Natural killer cells
 NK cells eliminate damaged, stressed, or infected host cells such as
macrophages, in response to viral infection or malignancy
 MHC unrestricted
 Cytotoxic lymphocytes (CTLs)
 Activated T lymphocytes that lyse autologous cells such as
macrophages bearing foreign antigen in association with class I
histocompatibility proteins
 Macrophages are killed via perforin dependent cytotoxicity

9. In a nut shell

10. Cytokines
 IL 1 – Fever
 IL 1B – Hematopoiesis suppression, Elevated ferritin,
Plasminogen activation
 IL-6 – Fever, renal failure
 TNF Alpha – Hematopoiesis Suppression, DIC, Inhibition
of LP lipase leading to hyperTG
 IFN-Gamma – Hematopoiesis suppression, DIC, Liver
dysfunction

11. Clinical Presentation
 Febrile illness associated with multiple organ involvement
 Fever, Splenomegaly – most common (>90%)
 Other: Hepatomegaly, lymphadenopathy, jaundice (70-90%)
 CNS involvement: irritability, ataxia, hypotonia or
hypertonia, evidence of increased ICP, meningismus,
depressed mental status, cranial nerve palsies, and seizures
 ARDS like syndrome in 42%
 Initial stages, BP will be normal

12. Clinical Presentation
 Severe hypotension in late stages
 Renal dysfunction in 16%, SIADH
 Skin manifestations - generalized maculopapular
erythematous rashes, generalized erythroderma, edema,
panniculitis, inflamed papular lesions, petechiae, and
purpura (6-65%)
 Bleeding is common
 STXBP2 mutations --> hypogammaglobulinemia, severe
diarrhea, bleeding, and sensorineural hearing loss

13. Features
 CSF – 50% show pleocytosis, elevated protein, or hemophagocytosis
 MRI Brain - highly variable and include discrete lesions,
leptomeningeal enhancement, or global edema
 Retinal hemorrhages, swelling of the optic nerve, and infiltration of
the choroid –described
 Demyelination by macrophages leading to IDP

14. Work up
 Complete blood count
 PT, aPTT, fibrinogen, D-dimer
 Serum ferritin
 Liver function tests, LDH
 Serum triglycerides
 Cultures
 Viral PCRs
 BM studies
 ECG, ECHO, CXR, CECT, MRI Brain/ PET CT Scan
 Immunologic studies
 Genetic testing

15. Presentation – Lab work
 Cytopenias (Initially high counts in MAS)
 Severe anemia, neutropenia and thrombocytopenia
 Nearly all patients with HLH will have hepatitis
 Hypoalbuminemia, Hyponetremia
 Decreased Fibrinogen, prolonged PT and aPTT
 Elevated D-dimer (Poor prognosis)
 Normal ESR

16. Presentation – Lab work
 Elevated triglycerides, LDH, SGOT,SGPT
 Increased triglycerides and abnormal coagulation
parameters (especially elevated D-dimer) caused by hepatic
dysfunction
 Triglycerides may not be elevated until the liver has been
affected for some time

17. Presentation – Lab work - Ferritin
 Macrophages are a primary source of ferritin
 Can get elevated within several hours of onset of HLH
 A protein responsible for modulation of iron homeostasis,
growth differentiation factor 15, is dramatically upregulated
in patients with HLH and is responsible for increased serum
ferritin by enhancing the ferroportin mediated iron efflux

18. Ferritin
 >500 mcg/L – Sensitivity – 82% and specificity – 42%
 >2000 mcg/L – 70 and 68% respectively
 >10,000 mcg/L – Sensitivity -90% and specificity – 96%
DD for Ferritin >10000
HLH
AOSD
Histiocytic malignancies
Neonatal Hemochromatosis
Acute Fulminant Hepatic Failure

19. Hemophagocyte
 Macrophage engulfing RBCs,
WBCs and platelets
 Nucleated cell within
macrophage more specific
 Biopsies of immune tissues
(lymph nodes, spleen, liver) or
bone marrow aspirates/biopsies
 Neither pathognomonic of, nor
required for, the diagnosis of
HLH
 CD163 positive hemophagocytes
more specific
From Uptodate.com

20. Diagnostic Criteria
 Known Genetic Defect and/or
 Clinical and Laboratory (5 of 8)
 Fever (95%)
 Splenomegaly (89%)
 Cytopenia in ≥ 2 cell lines (Hb<9, ANC<1000, PLT<1lakh) (92%)
 Hypertriglyceridemia (>265) and/or hypofibrinogenemia(<150)
(90%)
 Elevated Ferritin (>500, >3000 more specific) (94%)
 Elevated soluble CD25 (Alpha chain of IL-2) (97%)
 Decreased or absent NK-cell activity (71%)
 Hemophagocytosis in bone marrow, CSF, or LN (82%)

21. Treatment
 HLH 2004 Protocol - Steroids + Etoposide +
Cyclosporine A
 Other considerations
 ATG
 IVIG
 Bone Marrow Transplant

22. Treatment
 EBV-associated
Rituximab
 Immunomodulatory
TNF-a blockade, infliximab
Emerging therapies: anti-IL-1, anti-CD25, anti-CD 20,
IFN-a, Anti-CD52 therapy

23. WHAT WE SEE IN MEDICINE/ICU WARDS
Hemphagocytic syndrome in tropics
or
Secondary Hemphophagocytic Syndrome

24. Secondary HLH
 Infections
 Viral: Herpes viruses, esp. EBV, CMV, HIV, Dengue
 Bacterial – Staph, TB, Lepto
 Fungal
 Protozoal – Malaria, Leishmania
 Malignancy
 Lymphoma, acute leukemia
 Rheumatologic Disease – sJIA, AOSD, SLE, RA, MCTD, SS, SjS –
MAS
 Chemotherapy/ immunosuppressive therapy, AlloSCT

25. Tropical diseases with definitive association with HLH
 Malaria
 Tuberculosis
 Hepatitis A
 Encephalitis
 Enteric fever
 Rickettsial diseases
 Leptospirosis
 Dengue
 Melioidosis
 Chikungunya
 Crimean-Congo hemorrhagic fever
 Brucellosis
 Q fever
 Meningococcemia
 HIV
 Infectious mononucleosis
Tropical diseases in the ICU: Please do not forget hemophagocytic lymphohistiocytosis Cascio et al
Journal of Critical Care 48 (2018) 468–470

26. Syndromic Presentation of tropical diseases
 “Fever with rash”
 “Fever with respiratory syndrome”
 “Fever and hepatic involvement”
 “Fever with renal syndrome”
 “Fever with altered mental status or seizures”
 “Fever with GI Syndrome”
 “Fever with thrombocytopenia or coagulopathy”
 “Fever with hypotension or shock”
Karnad DR, Richards GA, Silva GS, et al. Tropical diseases in the ICU: A syndromic approach
to diagnosis and treatment. J Crit Care 2018;46:119–26

27. Diagnostic Criteria for secondary HLH
 Known precipitating illness
 Clinical and Laboratory (5 of 8)
 Fever
 Splenomegaly
 Cytopenia in ≥ 2 cell lines (Hb<9, ANC<1000, PLT<1lakh)
 Hypertriglyceridemia (>265) and/or hypofibrinogenemia(<150)
 Elevated Ferritin (>500, >3000 more specific)
 Elevated soluble CD25 (Alpha chain of IL-2)
 Decreased or absent NK-cell activity
 Hemophagocytosis in bone marrow, CSF, or LN

28. Problems
 Most of the patients will have at least 4-5 criteria fulfilled
 Upto 60% of sepsis patients can have hemophagocytosis in marrow
 6th and 7th points – Not available easily
 Elevated ferritin level is less specific in adults due to the higher
incidence of other inflammatory conditions
 Some may have only 2 or 3 criteria, but also have CNS symptoms,
hypotension, and renal or respiratory failure
 High mortality warrants initiation of treatment in the absence of full
criteria met

29. Alternate criteria for secondary HLH
 3 of 4 clinical findings (fever, splenomegaly, cytopenias,
hepatitis) plus
 1 of 4 immune markers (hemophagocytosis, increased ferritin,
hypofibrinogenemia, absent or very decreased NK cell function)
 A patient with CNS symptoms, cytopenias, fever, and ferritin over
3000 ng/mL or rapidly rising ferritin
 A patient with CNS symptoms, hepatitis, coagulopathy, and
ferritin over 3000 ng/mL or rapidly rising ferritin
 A patient with hypotension, fever, no response to broad spectrum
antibiotics, and ferritin over 3000 ng/mL or rapidly rising
ferritin

30. H Score
An H score ≥250 confers a 99% probability of HLH
A score of ≤90 confers a <1% probability of HLH
A score of ≥169 confers 93% sensitivity, 86% specificity
Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score
for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66:2613.

31. Prognosis
 Mortality 22-59%
 Prognostic Factors predicting death
 >30 yo
 Underlying disease process
 Hb <10
 Platelet <100 k
 Ferritin > 500 ug/l
 Bili or alk phos elevation

32. What to do
 Serially look for rapidly increasing ferritin
 Give a trial of one or two doses of Dexamethasone 8mg IV 8 hours
apart
 In case of rapid recovery in signs and symptoms – continue steroids
for another 4-6 doses and then stop
 No improvement – secondary HLH unlikely
 Look for alternative etiology

33. Primary(genetic) vs. secondary(acquired) HLH
 No laboratory test or mode of presentation provides a means to
distinguish between primary or secondary
 Natural history are similar for both
 If untreated, can be fatal
 Death usually due to infection from prolonged neutropenia,
multiorgan failure, or cerebral dysfunction due to inflammatory CNS
lesions
 It should be emphasized that severity of the disease and not
classification should govern initial treatment

34. prashantha.b@manipal.edu
drprashanthbhat@gmail.com
Contact No: 9986045611
Thank you

35. Early Symptoms and Signs of Dengue with HLH
 Symptoms:
Second spike of fever
High fever inspite of adequate antipyretic cover
Abdominal pain with vomiting and diarrhoea
Blood in vomiting or stools
Jaundice
Blood in urine

36. Early Symptoms and Signs of Dengue with HLH
 Signs:
 Icterus
 Swelling of legs
 Mouth ulcers and angular cheilitis
 Splenomegaly, Hepatomegaly
 Tender liver
 Altered sensorium
 Uncontrolled HTN/Hypotension
 Active bleeding

37. Early Symptoms and Signs of Dengue with HLH
 Lab Works:
 Reducing Hemoglobin with severe thrombocytopenia (<15000)
 Gradual Fall in WBC counts
 Sequential rise in levels of liver enzymes >3 times normal
 Feritin levels > 3000 at any given time or rapidly rising ferritin
levels even when less than 3000 when patient is symptomatic
 Increased APTT
 Rise in creatinine levels
 Raised CRP