1. Secondary Hemophagocytic Lymphohistiocytosis
Minh-Ha Tran

2. Case Presentation
35 year old Vietnamese male with quiescent SLE and diagnosed 5 months prior with left sided renal cell carcinoma metastatic to T8 vertebra
On HD -10 developed flu-like syndrome with fevers to 38.9C at home
Symptoms continued despite outpatient course of empiric levaquin
Presenting vital signs:
39.2, 101, 106/66, 20
Key initial findings:
Cytologic: pancytopenia
Inflammatory: Elevations in lactic acid, procalcitonin, CRP
But no elevations in anti-dsDNA
Electrolyte: Hyponatremia (SIADH), elevated lipase level

3. Case Presentation Treated supportively with broad-spectrum antibiotics
Fever:
Extensive ID workup, including LP, was unrevealing – see next slide
By HD#2
Mental status changes: intubated for airway protection
Pancytopenia: WBC 2.5 K/mcL, Hb 10.7 g/dL, Plt 89 K/mcL
Abdominal pain with rigidity
Obfuscating physical examination for organomegaly, but KUB ‘possible HSM’
Rising LFTs, diarrhea (negative C.diff)
Associated with rising CK (rhabdomyolysis)  peak 7546 U/L
Fevers despite aggressive cooling measures
Progressive coagulopathy now including DIC, T-Penia
HD 5 maximal values – PT 29.7, INR 2.91, PTT 63.5, fibrinogen 76 mg/dL
HD 9 platelet nadir – 25 K/mcL, Hb nadir 7 g/dL
No schistocytosis

4. Case Presentation – extensive ID workup negative

5. HLH Overview Hemophagocytic Lymphohistiocytosis (HLH)
Rare, life-threatening syndrome characterized by uncontrolled activation of lymphocytes and macrophages
Primary or secondary forms
Primary – related to a number of mutations in genes encoding proteins involved in transport of leukocyte granules and perforin
Secondary – triggered by
Infections
62% by latent herpesviruses (43% viral due to EBV), 9% by bacteria – (38% due to mycobacterium), 2-5% by parasitemia, esp leishmania
Malignancy
15-50% of adult HLH cases, especially lymphomas
Autoimmune Disorders
SLE, Adult-Onset Still’s Disease, 10% of systemic juvenile idiopathic arthritis develop clinically overt HLH (50% show subclinical evidence for HLH)

6. Pathogenesis Primary Genetic basis – see table later
Defects in cytotoxic killing and deactivation of immune response
Leading to…
Persistent antigenemia – impaired killing of infected and tumor cells
Ongoing antigen presentation – antigen-presenting dendritic cells persist, increase antigen presentation resulting in uncontrolled CTL activation
Impaired NK cell function and Treg function - impaired immune regulation
Cytokine storm - (IFN-gamma, IL-1, IL-6, IL-8, IL-10, IL-18, TNF alfa) – prolonged CTL- target cell synapse duration (fail to disengage) increase release of inflammatory cytokines

7. Pathogenesis Secondary Acquired defects in cytotoxicity
Suppression of NK cell cytotoxicity
Cytokine Storm and some viruses impair NK cell cytotoxicity
Prolonged Synapse formation
Viruses may encode anti-apoptotic proteins and render cells resistant to CTL induced apoptosis, tumor cells also resistant to apoptosis
Excessive activation of Innate Immunity
A Non-NK/CTL pathway involving exaggerated signaling of TLRs

8. Pathogenesis

9. Clinical Presentation, Adult HLH
Continuous High Fevers >38.5 (IL-1, IL-6, TNF alfa)
Adenopathy, Hepatosplenomegaly
80% have LFT abnormalities (IFN gamma and TNF alfa)
Encephalopathy, ascites, veno-occlusive disease, splenic rupture
Pulmonary involvement 42%
GI symptoms 18% - nausea, vomiting, diarrhea, abdominal pain
Neurologic 25% - coma, seizures, meningitis, encephalomyelitis
60% have coagulation disorders with hypofibrinogenemia and elevated D-Dimer in 50% - (IL 1 beta  fibrinolysis; IFN gamma and TNF alfa  DIC)
Hypertriglyceridemia (TNF alfa  stimulates synthesis, inhibits lipoprotein lipase)
Mortality rate 41%

10. Case Presentation, continued
Other diagnostics
Tmax 39.6
AST/ALT 547/118 U/L (14x and 2x elevation)
Hypoalbuminemia (2.7  1.8 mg/dL)
LDH 2833 U/L
Transferrin ↓99.3 mg/dL, TIBC ↓139 mcg/dL, Serum Fe ↓50 mcg/dL, TSAT 36%
Ferritin ↑↑↑7500 ng/mL  >15000 ng/mL
TG 500 mg/dL
NK Cell Function reduced –
Lytic Unit 30 value of 5 lytic sets (normal LU30 = sets)
Soluble IL-2 R level of 1112 pg/mL (normal ≼1033 pg/mL)

11. HLH Considerations ✓ ✓ ✓ ✓ ✓ ✓

12. Secondary HLH Diagnostic Scoring
302
105
169
219
238
268 18 67 90
150
190
200
220
230
240
250
<1%
25%
80%
88%
96%
98%
99%
>99%
Category
Item
Points
Clinical Features
Known Immunosuppression
No: 0
Yes: 18
High Temperature
<38.4: 0
: 33
>39.4: 49
HSM or Splenomegaly
Neither: 0
Either: 23
Both: 38
Five Biologic Features
TG (mg/dL)
<132.9: 0
132.9 – 354.3: 44
>354.3: 64
Ferritin (ng/mL)
<2000:0
:35
>6000:50
AST (U/L)
<30:0
≥30:19
Fibrinogen (mg/dL)
>250: 0
≤250:30
Number of Cytopenic Lineages
1:0
2:24
3:34
One Cytologic Feature
Hemophagocytosis
Yes: 35 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

13. Treatment: Dexamethasone 10 mg/m2 daily weeks 1&2, 5 mg/m2 weeks 3&4, 2.5 mg/m2 weeks 5&6, taper to zero by week 8.

14. Outcome Discharged HD 20 in ambulatory condition, doing well
Continues to follow with Hem/Onc for RCC

15. Conclusions Secondary HLH under-recognized, use H Score to diagnose
Primary HLH incorporates chemotherapy into treatment regimen
Secondary may if EBV/Lymphoma (Rituximab)
High dose dexamethasone
Other immunosuppressants have also been reported
Cyclosporine – especially in setting of autoimmune disease trigger
Reduce dose if liver dysfunction
Cyclophosphamide, IVIG, etc
Primary HLH – 8 week induction with Dex, Etoposide, IT MTX

16. References
Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Brit J Haemtol, 2016;174(2):
Brisse E, Matthys P, Wouters CH. Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options. Brit J Haematol, 2016;174(2):
Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet, 2014;383:
Fardet I, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the H-Score, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol, 2014;66(9):
Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, et al. Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol, 2016;145(6):
El-Masry M, Eisenbud L, Tran MH. Secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report. J Med Case Reports, 2017;11:56