2. Case Presentation(1)
• 38 yo male presenting with 1 week history of
– Yellowish discolouration of eyes
– Fever
– Bleeding gums intermittently
– Fatigue and lethargy
– Abdominal Fullness
3. • Past History:Not significant
– Pt is concious,oriented
– PR-104/min regular ,BP-Wnl
– Febrile
– pallor+,Icterus+,no
cyanosis,Lymphadenopathy,Clubbing
– Spleen enlarged 4 cm below LCM
– Other systems-N
5. • Next line of
Investigation
• Probable Differential
diagnosis.
6. Pathophysiology of HLH
• Hemophagocytosis
Engulfment of blood cells including WBC, RBC, and Patelets
• Lymphohistiocytosis
Excessive activation and number of
lymphocytes (T and B cells) and
histiocytes (macrophages and dendritic cells)
plt
nRBC
plt
WBC
nRBC
Excessive “unchecked” activation of cytotoxic T-
cells, NK cells, and macrophages leading to
cytokine storm, and acute tissue injury.
8. Genetic basis but requires clinical diagnosis
• Have to rule out other causes like sepsis,active
infection,tropicaldisease,malignancies,autoim
mune diseases.
• These criteria do not reflect typical clinical or
lab features of patients with HLH such as
– Liver injury
– Neurologic symptoms – seizure, meningismus, cn
palsy
– Skin findings – purpura, petechiae, panniculitis
– Pulmonary dysfunction
9. Adult ‘HLH’ – making the diagnosis
• There are no distinct diagnostic features
• Overlap with other clinical syndromes (sepsis,
sirs) is inherent
• Workup is time consuming – bone marrow
biopsy and genetic sequencing.
• Requires relative expertise – bone marrow
biopsy
• Cannot be measured routinely and known
value for diagnosis in adult population is
unknown: sCD25, NK function
11. Pathogenesis
• Inability of the immune system to adequately
restrict stimulatory effects of various triggers.
• Mendelian inherited defects in the
cytolytic function of cytotoxic T
cells and/or NK cells.
• Defects in inflammasome
regulation
• Non-Mendelian HLH)
• Infections (mainly viruses, such as EBV, HIV, and
CMV, bacteria, parasites, and fungi.
• Malignancies (mainly malignant lymphoma)
• Macrophage activation syndrome in autoimmune
disorders.
• Other causes (organ or stem cell transplantation;
metabolic, traumatic, iatrogenic
[immunosuppression, vaccination, surgery,
hemodialysis] and, rarely, pregnancy)
Primary/Familial HLH
Secondary HLH
12. • Pt was started on
Dexamethasone,Etoposi
de and Cyclosporine.
• Cytopenia and bilirubin
improved and over a
period of 1 month.
DIAGNOSIS
• Primary HLH
• Overall 50-60% of
patients have a CR .
• Rest 30-40% have poor
prognosis and requires
more cytotoxic
therpaies and
transplant.
16. Case 2
55 y/o female with h/o RA on Abatacept presented with
joint pains and fever 4 months ago, treated with
prednisone burst 50 mg with a prolonged taper.
After completing a 8 week long taper showed
worsening transaminitis. AST 1312, ALT 255, Bili 2.3,
ALK Phos 463. Wbc 1.3, HGB 10. Plt 104. LDH 1300.
Ferritin 168,000. Fibrinogen < 60, INR 2.4.
Extensive infectious work up negative, no new drugs,
Liver US normal. Afebrile, vitally stable.
17. • PET CT showed FDG avid HSM (SUV 8), diffuse
uptake in bone marrow, multiple small FDG avid
cervical nodes.
• FNA from cervical LN read as Diffuse large B cell
lymphoma.
• Patient decompensates, intubated for hypoxia, high
lactate and metabolic acidosis.
Chemotherapy(CHEOP) started within 3 days
• Became asymptomatic and was dischrged on Day5.
18. Incidence of Malignancy-Associated HLH
• 1% in patients with heme malignancy
(0.36/100,000 pt-yrs)
• 4-9% in AML after induction/HSCT
*infection related
-32/343 France, 7+3, single-center 5yr, 24 w/ infection
- 24/554 Japan, stem-cell transplant setting
• 2.8% in malignant lymphoma
• T/NK lymphoma (35%)
• B-cell lymphoma (32%)
• Hodgkin’s (6%)
• Solid tumors 3% *ICI, CAR-T
5-year overall survival ranging from 10-30%
19. • 19-year old woman presented with cholestatic
hepatitis he was initially admitted to the
Gastroenterology department and the
following days she developed respiratory
distress and multiorgan insufficiency that
necessitated intubation and support in the
Intensive Care Unit. Fever, splenomegaly,
hypertriglyceridemia, increased ferritin levels
and hemophagocytosis in the bone marrow
were found.
20.
21. Case report
• 11-year-old boy presented with persistent fevers, multisystem
organ dysfunction, and continued rise in ferritin (>20 000
ng/mL), splenomegaly
– Dexamethasone and Etoposideclinical response
– Clinical deterioration at day 10 one dose of anakinra pulmonary
edema mechanical ventilation
– Alemtuzumab not available ruxolitinib 2.5 mg BID extubated in 3
days
Broglie et al. Blood Advances. 2017
23. • Provisional diagnosis:EBV induced HLH
• The patient was started on Dexamethasone
and IVIG O.4gram/day for 5 days.
• His jaundice and organ failure imroved slowaly
over 1 week and the patient was extubated
and discharged in stable condition.
24. Case 2.
60 y/o M presents to OPD for fevers and night sweats FOR 3
WEEKS.Infectious and rheumatologic work up unrevealing. Found
to have splenomegaly to 22 cm, WBC 15.5, HGB 6.6 and PLT 12K.
Bone marrow biopsy at OSH showed normocellular marrow,
mildly increased lymphocytes with B-cell predominance, and
hemophagocytosis. No significant blasts. LDH 1300. Ferritin 2100.
Lactate 11!
Started on Prednisone 100 mg daily for HLH and referred to
hematology.
Does this patient have HLH
26. Background
• Rare
• Potentially fatal
• All age groups
• Predominantly in children but adults are also
affected
Henter, Acta Paediatr Scand 1991 Apr;80(4):428-35
Janka, Br J Haematol 2004 Jan;124(1):4-14
28. Classification
• Genetic (Primary)
• Autosomal recessive or X – linked
• 1 in 50,000 births
• Predominantly in children of age < 1year
• 1.2 cases per million persons per year
• Male-to-female ratio close to 1:1
29. Classification
• Acquired (secondary)
• Occurs in all age groups
• Usually triggered by an infection – viral and
non viral
• Other associations – malignancies and auto
immune disorders
Risdall, Cancer 44 (1979), pp. 993–1002
Janka, Hematol Oncol Clin North Am 12 (1998), pp. 435–444
30. • Elevated levels of pro-inflammatory cytokines
• Due to activation of antigen presenting cells
and lymphocytes
• Both inherited and acquired HLH are
associated with abnormal NK cell activity
Egeler, Am J Ped Hem Onc 1996; 18:340–345
31. • Clinical studies have reported abnormal cell
mediated immnuity
• In one study of 13 consecutive patients
• Decreased NK cytotoxic function (13/13)
• Severely decreased to absent T cell
cytotoxicity (11/12)
Egeler, J Pediatr Hematol Oncol 1996 Nov;18(4):340-5
32. • Genome wide genetic linkage analysis studies
in familial HLH
– 10q21-22 was identified as a locus for familial HLH
in 10 out of 17 FHL families in Europe and
Australia
– 9q21.3-22 was identified by homozygosity
mapping in four inbred FHL families of Pakistani
descent
Ohadi, Am J Hum Genet. 1999 Jan;64(1):165-71
Dufourcq-Lagelouse, Am J Hum Genet. 1999 Jan;64(1):172-9.
33. Perforin
• Perforin is an important mediator of
lymphocyte cytotoxicity
• Gene encoding for perforin is located at
10q21-22
• 8 unrelated 10q21-22-linked FHL patients
were analyzed for perforin gene mutations
• Revealed homozygous nonsense mutations in
4 patients & missensemutations in the other 4
patients
Stepp, Science 1999 3;286:1957-9
35. • 10 FHL patients who did not lack perforin the
locus was mapped to 17q25
• Mutations involving hMunc13-4 family of
genes were reported
• 6q24 was identified as a locus in Kurdish
families with FHL
• Mutations of syntaxin 11 (STX 11) gene
located on 6q24 were also identifed in this
population
Feldmann, Cell 2003 Nov 14;115(4):461-73
zur Stadt, Hum Mol Genet 2005 Mar 15;14(6):827-34
38. • Mechanisms leading to impairment of NK cells
and CTL’s in acquired HLH are not well
understood
• Possible role for viruses or high cytokine levels
to inactivate these cells
39. Clinical features
• HLH is a hyperinflammatory condition
characterized by
– Fever
– Cytopenias
– Hepatosplenomegaly
– Hemophagocytosis by activated, morphologically
benign macrophages
43. • The clinical presentation is due to
– Increased levels of inflammatory cytokines
• IL1 and IL6 fever
• TNF-α and IFN-γ pancytopenia
– Organ infiltration by lymphocytes resulting in
hepatosplenomegaly and neurologic symptoms
– Activated macrophages secrete ferritin and
plasminogen activator
44. Pathologic findings
• Proliferation of normal histiocytes and T-
lymphocytes
• Phagocytosis of RBC and WBC
• No atypia in the macrophages
• Organ infiltration by lymphocytes and
histiocytes
48. • Identify secondary causes and treat
– Infection
– Auto immune disorders
– malignancies
• In older patients with acquired HLH treatment
with corticosteroids ± cyclosporin may be
sufficient
49. HLH 94 protocol
• FHL mortality in 1980 was 90%
• HLH 94, n = 86
• 8 weeks of dexamethasone + VP16 induction
• IT methotrexate in 11/24 patients with CNS
disease
• Maintenance with cyclosporin and alternating
weekly pulses of etoposide & dexamethasone
until SCT
Horne, Br J Haematol 2005 Jun;129(5):622-30
50. • Pre transplant conditioning regimen at the
discretion of the treating center
• Busulfan/Cytoxan/VP16 – recommended
conditioning regimen
54. • Retrospective review of 48 consecutive
patients with FHL
• Overall survival - 58 % with median f/u of 5.8
years
• Non-myeloablative HCT was attempted in a
series of 12 patients
• median f/u 30 months, 9/12 are alive & in CR
Ouachee-Chardin M ,Pediatrics. 2006 Apr;117(4):e743-50
Cooper, Blood. 2006 Feb 1;107(3):1233-6
57. Conclusion
• HLH is a fatal disease if untreated
• Disease presentation is due to
hyperinflammation due to inherited or
acquired immune defects
• Allogenic SCT based on HLH 94 protocol
results in cure rate of ≈ 50%
Editor's Notes
Inherited variations in HLH-associated genes, which are well characterized in pediatric HLH, may play a role in adult-onset HLH.
but acquired immune dysfunction in response to infections, malignancies, and autoinflammatory/autoimmune disorders seems to be the leading cause in adults.
