Hemophagocytic
Lymphohistiocytosis
By: Michelina Kauffman, MD PGY-3
December 4, 2015
Disclosures
Neither Dr. Pirich nor I have any financial disclosures.
Objectives
• Untangle the differences between primary HLH,
secondary HLH, and MAS.
• Review the etiology and risk factors for HLH.
• Describe the variable clinical presentations of HLH.
• Review the HLH-2004 diagnostic criteria.
• Discuss treatment strategy and prognosis.
Which lab finding would be most
helpful in the diagnosis of HLH?
20%
1.
2.
3.
4.
5.
20%
20%
2
3
20%
20%
Hemoglobin 8.4 g/dL
Platelets 164 x 109/L
Neutrophils 4.1 x 109/L
Ferritin 11,900 mg/L
sIL-2R 150 U/mL
1
4
5
What is the genetic association for
secondary hemophagocytic
lymphohistiocytosis?
20%
20%
20%
2
3
20%
20%
1. None
2. PRF1
3. UNC13D
4. Chediak-Higashi
5. I don’t know.
1
4
5
An 8 mo M is admitted to the PICU with a four day
history of persistent fever and an erythematous rash. He is
found to have hepatosplenomegaly, anemia,
thrombocytopenia, and hyperferritonemia. You suspect
this patient may have HLH. What is the best study to
confirm this diagnosis?
1.
2.
3.
4.
MRI Brain
Lumbar puncture
Genetic testing
Bone marrow aspirate and
biopsy
5. Abdominal ultrasound
20%
1
20%
20%
2
3
20%
4
20%
5
For patients with familial HLH,
hematopoietic cell transplantation
remains the only long-term curative
treatment.
50%
50%
1.True
2.False
1
2
Case Presentation
A PH 6 wo AA F was taken to the ED for a fever of 101.4F at home. She
had felt subjectively warm for 3-4 days prior but no temperatures had been
obtained and no other symptoms were noted. On arrival, her temperature
was 103.4F and her exam was remarkable for fussiness and
hepatosplenomegaly. A full sepsis work up was performed and she was
empirically started on ampicillin and cefotaxime in the ED.
Lab work up was concerning for:
• CBC: WBC 4, Hgb 7.3, and Plt 65
• CMP: TB 6.2, AST 321, ALT 127
• CSF: P 73, G 52, WBC 22, RBC 0
• Coags: PT 23.6, PTT 52.9, INR 2, Fibrinogen 60
• Blood, Urine, and CSF Cx’s – P
Due to concern for sepsis and DIC the patient was admitted to the PICU
for further care.
History of HLH
• The first documented description of HLH was published
by Farquhar and Claireux at the University of Edinburgh
in 1952.
• They noted a constellation of symptoms in two
previously healthy infant siblings:
•
•
•
•
Recurrent, unexplained fevers
Progressive panhematopenia
Hepatosplenomegaly
Bruising
• At autopsy, they found “inflammatory cell infiltration”
and a “great proliferation of histiocytes.”
Introduction
• HLH is a non-malignant, aggressive, life-threatening
syndrome characterized by excessive immune activation.
• HLH typically affects infants from birth to 18 months of
age but can be seen in children and adults.
• Although the distinction is blurred, HLH has been
historically divided into primary and secondary types.
• Rapid recognition and initiation of treatment is necessary
for survival.
Immune System Review
Immune System Review
The normal elimination of activated macrophages
occurs via NK cells and CTLs that lyse target cells
through perforin-dependent cytotoxicity.
1 Create a pore in the macrophage
membrane.
2 Deliver cytolytic granules into
the macrophage.
3 Proteases, such as Granzyme B,
initiate cell death.
HLH Pathophysiology
• Excessive inflammation occurs due to overactive but
impaired immune function.
• There is a lack of normal feedback to activated
macrophages which leads to excessive activity.
• Most patients exhibit impaired cytotoxic function of NK
cells and CTLs.
• NK cells and/or CTLs fail to eliminate activated
macrophages.
• Tissue damage is caused by excessive cytokine
production otherwise known as a cytokine storm.
Cytokine Storm
A pro-inflammatory state is created which is ultimately
responsible for multi-organ failure and high mortality
without treatment or with delayed treatment.
Hemophagocytosis
• The pathologic finding of activated, histologically
benign macrophages engulfing host blood cells.
• Can be seen in biopsies of lymph nodes, spleen,
liver, bone marrow, and sometimes CNS.
• Hemophagocytosis alone is not pathognomonic, nor
required, for diagnosis of HLH.
• In 1996, of 122 children with HLH from the
Histiocyte Society’s International Registry, only 75%
had evidence of hemophagocytosis at diagnosis.
Primary vs. Secondary
HLH
Familial HLH
• Primary HLH is caused by inborn defects in the primary
cytotoxicity effector pathway in lymphocytes and NK cells.
• Autosomal Recessive
• Incidence 1:50,000
• Median survival is <2 months if left untreated.
• Onset is typically during infancy or early childhood.
• May be triggered by infection.
• Non-syndromic forms consist of 5 mutations, FHL 1-5.
• FHL 1 mutation is unknown.
Immunodeficiency Syndromes
• Chediak Higashi syndrome
• Mutations in CHS1/LYST
• Griscelli syndrome type II
• Mutations in RAB27A
• Hermansky-Pudlak syndrome
type II
• Mutations in AP3B1
• Partial oculocutaneous albinism,
immunodeficiency, and
neurologic abnormalities.
FHL-2
FHL-5
FHL-4
FHL-3
Secondary HLH
• sHLH develops as a consequence of a strong
immunologic response to a stimulus:
•
•
•
•
Infection
Rheumatologic illness such as JIA or SLE
Malignancy, either at presentation or during treatment
Immunodeficiency
• There is no inherited immune defect found in sHLH.
• More prevalent than FHL but incidence is poorly defined.
• Median age of onset is higher than FHL.
Epstein-Barr Virus
• The most frequent infectious trigger of familial and
secondary HLH.
• Of 219 patients diagnosed with infection associated HLH
from 1979 to 1995, 55% were attributed to EBV.
• Janka, G. (1998) Hematology/Oncology Clinics of North America
• EBV associated HLH varies from spontaneously
resolving inflammation to unrelenting disease requiring
HCT.
• EBV-HLH has been associated with acute infections in B
cells, T cells, and NK cells.
Macrophage Activation
Syndrome
• Life threatening complication of systemic inflammatory
conditions characterized by all of the clinical symptoms
and laboratory findings of HLH.
• JIA and SLE are the most common.
• Clinical manifestations include fever, hepatitis,
hepatosplenomegaly, lymphadenopathy, and DIC.
• Cytopenias are typically a late finding.
•
May be the first manifestation of the rheumatologic
disease.
• In patients with known JIA or SLE, infections, flares, or
changes in medication may trigger MAS.
Malignancy
• HLH has been reported with lymphomas or
leukemia of the T or NK cell lineage.
• Many patients have a simultaneous bacterial, viral,
or fungal infection that may trigger HLH.
• May occur during treatment for a known cancer in
clinical remission or as a manifestation of an
aggressive uncontrolled cancer.
• Iatrogenic immune dysregulation
Clinical Presentation
Clinical Presentation
• The presentation of HLH is variable and laboratory
findings are similar to more common disease processes.
• Typical findings include persistent fever, splenomegaly
with or without hepatomegaly, and cytopenias that affect
at least two cell lines.
• Less common initial findings include lymphadenopathy,
rash, jaundice, and edema.
• Clinical features may not be initially or simultaneously
present, however, patients are usually acutely ill at
presentation.
Liver Disease
•
Most patients have evidence of hepatitis on presentation.
•
Clinical findings include jaundice, hepatomegaly, and bleeding.
•
Autopsy findings of 22 out of 27 patients diagnosed with HLH
found infiltration of lymphocytes into the portal tracts similar to
what is seen in chronic persistent hepatitis.
• Ost, A. (1998). Histopathology
•
Lab findings include hypertriglyceridemia, elevated transaminases,
hyperbilirubinemia, and hyperferritonemia.
• A serum ferritin >10,000 mg/L is highly sensitive and specific.
•
Impaired synthetic function and clotting factor consumption leads
to hypofibrinogenemia as well as prolongation of PT and PTT.
Pulmonary Dysfunction
• In a review of radiographic
abnormalities in 25 patients,
17 had acute respiratory
failure with alveolar or
interstitial opacities.
• 88% fatal
• Worsening pulmonary
function is an ominous sign
and should suggest
inadequate control of HLH.
Bone Marrow Abnormalities
& Cytopenias
• Anemia and thrombocytopenia occur in >80% of
patients at presentation.
• The cellularity of bone marrow may be normocellular,
hypocellular, or hypercellular.
• Presence of hemophagocytosis ranges from 25-100%.
• Hemophagocytosis in the bone marrow may be seen in
other disease states.
• The diagnosis of HLH should never be made solely based
on the presence or absence of hemophagocytosis.
Neurologic Symptoms
• More than 1/3 of patients will present with neurologic
symptoms.
• Seizures, meningismus, decreased level of consciousness, cranial
nerve palsy, psychomotor retardation, ataxia, irritability,
hypotonia, or peripheral neuropathy
• CSF is abnormal in more than half of patients.
• Hyperprotienemia, pleocytosis, and hemophagocytosis
• Variable MRI findings that correlate with symptoms.
• Discrete lesions, leptomeingeal enhancement, or global edema.
• Retinal hemorrhages, swelling of the optic nerve, and
infiltration of the choroid has been seen in infants.
Skin Manifestations
Differential Diagnosis
• Viral infections
• Sepsis
• Malignancy
• Metabolic disorder
• Non Accidental Trauma
• If the patient improves clinically, it is most likely not HLH.
• Spontaneous partial remission has been observed but relapse is
inevitable without appropriate treatment.
Diagnostic Criteria HLH-2004
•
Molecular diagnosis consistent with HLH.
•
Or 5 of the 8 criteria listed below:
• Clinical criteria
• Fever
• Splenomegaly
• Laboratory criteria
• Cytopenias: Hgb <9 g/dL; platelets <100 x 109/L; neutrophils <1x109/L
• Fasting hypertriglyceridemia and/or hypofibrinogenemia
• Hyperferritinemia: >500 mg/L
• Elevated soluble CD25 (sIL-2R): ≥ 2400 U/L
• Low/Absent natural killer function
• Histopathologic criteria
• Hemophagocytosis in bone marrow, spleen, lymph node, or CSF
Treatment
Supportive Care
• Neutropenic precautions
• Prophylaxis for Pneumocystis jirovecii and fungal infections.
• IVIG supplementation.
• Fever should be evaluated for reactivation and opportunistic
infection.
• Broad spectrum antibiotics should be initiated.
• Bleeding
• Goal platelet count >50 x 109/L.
• Platelets, FFP, cryoprecipitate, and activated factor VII.
• Cardiac function
• Baseline cardiac function should be evaluated because patients
may present with or develop acute cardiac dysfunction.
Treatment
• Current management involves:
• Controlling the hyperinflammatory state.
• Control or eliminate the infectious trigger.
• Stop T-cell proliferation and activation.
• Stop or control the inflammatory process by blocking
excessive cytokine production and function.
• Correct the underlying genetic defect by allogeneic
HCT.
Treatment
• To control T-cell proliferation and activation, based
on the HLH-94 protocol, an 8-week course of
dexamethasone and etoposide therapy is used.
• Remission rate was 71% and 5 year post-HCT survival
probability was 54%±6%.
• The HLH-2004 protocol was developed in an effort
to improve remission rates.
• Intensification of initial therapy by adding cyclosporine
and intrathecal steroids.
CNS Treatment
• Patients may present with CNS involvement or
inflammation may recur as treatment doses are
being tapered.
• Patients with proven CNS disease should be treated
with weekly IT MTX and hydrocortisone until CSF
abnormalities and symptoms resolve.
• CNS involvement suggests a genetic etiology with
associated morbidity so HCT is recommended.
Treat the Underlying Disease
• EBV
• Rituximab
• Rheumatologic disorder
• Immunosuppression, IVIG
• Malignancy
• Treat malignancy first vs. HLH
Salvage Therapy
• If patients do not display at least a partial response
within 2-3 weeks of therapy, salvage therapy should
be considered.
• Alemtuzumab
• Monoclonal antibody to CD52.
• Induced partial response in 64% of patients.
• In HLH-2004 refractory patients, may be useful as a
bridge to transplant.
Hematopoietic Cell Transplant
•
HCT is the only long-term curative treatment for familial HLH.
•
Reasons to transplant:
• Proven familial/genetic disease
• Recurrent/refractory disease
• CNS involvement
•
Myeloablative Conditioning (MAC)
• Standard treatment with busulfan, cyclophosphamide, and etoposide with or
without antithymocyte globulin (ATG).
• Associated with high transplantation related mortality.
•
Reduced Intensity Conditioning (RIC)
• Alemtuzumab, fludarabine, and melphalan.
• Better outcomes in HCT, three year survival of 92%.
Risk Factors
• In October 2011, Trottestam et al., published a study
evaluating 232 children with HLH to determine risk
factors that predict mortality.
• At onset: hyperbilirubinemia, hyperferritinemia, and
CSF pleocytosis.
• Two weeks into therapy: hyperferritonemia and
thrombocytopenia.
• No improvement of fever and anemia.
Follow Up
• Relapse, if it occurs, generally occurs within the first
year.
• Close monthly follow up is necessary to evaluate for
recurrent disease.
• Signs of recurrent disease: fever, hepatosplenomegaly,
neurological abnormalities.
• Labs that indicate recurrence: cytopenia and elevated
ferritin, serum transaminases, and sIL-2R.
Resources
• www.histio.org
• https://go.cincinnatichildrens.org/service/hlhphysician/overview.php
Case Conclusion
•
PICU course: all cultures were found to be negative and antibiotics were
discontinued. Viral studies including HSV, CMV, and EBV were negative.
She was found to be adenovirus positive.
•
Due to persistent cytopenia and evidence of DIC in spite of aggressive
supportive management, Heme/Onc was consulted. Concern for HLH led
to investigation of ferritin, found to be elevated at 9045, and fasting
triglyceride of 164.
•
Bone marrow aspirate did reveal hemophagocytosis.
•
Lab studies sent to Cincinnati confirmed the diagnosis with:
• Elevated sIL-2R 49,724 and Perforin level close to zero, indicative of PRF1 gene
mutation.
•
Treatment was initiated per HLH-94 protocol and she was transferred to
MUSC for HCT.
Which lab finding would be most
helpful in the diagnosis of HLH?
20%
1.
2.
3.
4.
5.
20%
20%
2
3
20%
20%
Hemoglobin 8.4 g/dL
Platelets 164 x 109/L
Neutrophils 4.1 x 109/L
Ferritin 11,900 mg/L
sIL-2R 150 U/mL
1
4
5
What is the genetic association for
secondary hemophagocytic
lymphohistiocytosis?
20%
20%
20%
2
3
20%
20%
1. None
2. PRF1
3. UNC13D
4. Chediak-Higashi
5. I don’t know.
1
4
5
An 8 mo M is admitted to the PICU with a four day
history of persistent fever and an erythematous rash. He is
found to have hepatosplenomegaly, anemia,
thrombocytopenia, and hyperferritonemia. You suspect
this patient may have HLH. What is the best study to
confirm this diagnosis?
1.
2.
3.
4.
MRI Brain
Lumbar puncture
Genetic testing
Bone marrow aspirate and
biopsy
5. Abdominal ultrasound
20%
1
20%
20%
2
3
20%
4
20%
5
For patients with familial HLH,
hematopoietic cell transplantation
remains the only long-term curative
treatment.
50%
50%
1.True
2.False
1
2
References
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•
•
•
•
•
•
•
•
•
•
•
•
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References
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Thanks for listening! Any questions?
Thank you!