Hemophagocytic Lymphohistiocytosis (HLH)

Question 1

hemophagocytic lymphohistiocytosis (HLH) - overview

Answer 1

*life threatening syndrome of excessive immune activation:
-defective triggering of apoptosis
-uncontrolled macrophages [start engulfing erythrocytes, leukocytes, platelets, and precursors]

note - HLH is secondary to something else, so you need to figure out the underlying cause

Question 2

hemophagocytic lymphohistiocytosis (HLH) - triggers

Answer 2

1. INFECTION (especially viral infections, including EBV, HIV, HSV, CMV)
2. MALIGNANCIES (especially hematological neoplasms: T-cell or NK-cell lymphoma, B-cell lymphoma, leukemia, etc)
3. other triggers (autoimmune diseases, transplants, idiopathic)

Question 3

hemophagocytic lymphohistiocytosis (HLH) - pathophysiology

Answer 3

*syndrome of excessive inflammation because activated cells don’t get downregulated:
-natural killer cells/cytotoxic T lymphocytes don’t kill the activated macrophages; therefore, the patient doesn’t have a stop to the cascade
*this leads to a CYTOKINE STORM of IFN-gamma, TNF-alpha, and interleukins
*can lead to multi-organ failure
*increased macrophage activity: CAN result in phagocytosis but this is NOT pathognomonic NOR required for diagnosis

Question 4

normal systemic inflammatory syndrome (which is dysregulated in HLH)

Answer 4

1. virus particle causes infection
2. infected monocyte ingests the viral particle
3. when the monocyte encounters the virus, it secretes cytokines to recruit other cells that are part of the immune system (cytotoxic T cells, dendritic cells, other monocytes)
4. these cells secrete more cytokines to try to fight the viral infection
5. the NK cells are responsible for halting this process so that it does not run out of control

note - NK-cell cytotoxicity is blocked in patients with HLH, so excess immune activation goes unchecked

Question 5

hemophagocytic lymphohistiocytosis (HLH) - clinical presentation

Answer 5

*FEVER (viral infection, if present; excess cytokine release)
*sx due to CYTOPENIAS [fatigue, pallor, infection, bleeding or bruising] (causes - cytokines suppress normal hematopoiesis; hemophagocytosis also contributes to the cytopenias;)
*sx related to DIC (causes - cytokines stimulate plasminogen activation; also sepsis increases risk of DIC)

Question 6

hemophagocytic lymphohistiocytosis (HLH) - workup

Answer 6

*look for the underlying cause:
1. infection:
-culture (everything)
-viral PCR studies
2. neoplasm:
-CT scans
-bone marrow biopsy

Question 7

hemophagocytic lymphohistiocytosis (HLH) - pathology

Answer 7

*increased numbers of lymphocytes & mature macrophages
*prominent HEMOPHAGOCYTOSIS in any of the following sites: spleen, lymph nodes, bone marrow, CNS, liver

Question 8

hemophagocytic lymphohistiocytosis (HLH) - diagnostic criteria

Answer 8

5 of the 8 clinical/lab criteria fulfilled:
*fever
*splenomegaly
*cytopenias of 2+ cell lines
*hypertriglyceridemia and/or hypofibrinogenemia
*FERRTIN >/= 500 [often excessively high: 5K-10K]
*sCD >/= 2400
*decreased or absent NK cell activity
*hemophagocytosis in BM, CSF, or lymph nodes

Question 9

hemophagocytic lymphohistiocytosis (HLH) - prognosis

Answer 9

*mortality: 22-59%
*prognostic factors predicting death:
- age > 30yo
-underlying disease process
-Hb < 10
-platelet < 100K
-FERRITIN > 5000
-increased alk phos or bilirubin

Question 10

hemophagocytic lymphohistiocytosis (HLH) - treatment

Answer 10

*supportive care for pancytopenia (antibiotics, pRBC transfusions, platelet transfusions)
*eliminate triggers (pathogen-directed tx)
*SUPPRESSION OF INFLAMMATORY RESPONSE: HLH-2004 protocol [DEXAMETHASONE + CHEMO (etoposide)]