AUTHOR INFORMATION

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Authored by Nicole L Lacz, MD, Staff Physician, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Coauthored by Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Franklin Desposito, MD, Professor of Pediatrics and Clinical Director, Center for Human and Molecular Genetics, UMDNJ-New Jersey Medical School; Consulting Staff, Department of Pediatrics, UMDNJ-University Hospital

Nicole L Lacz, MD, is a member of the following medical societies: Alpha Omega Alpha, and Phi Beta Kappa

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Nicole L Lacz, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, May 15 2006, VOLUME 7, Number 5

INTRODUCTION

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Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease of normal but overactive histiocytes (macrophages) and lymphocytes (white blood cells) that commonly appears in infancy, although it has been seen in all age groups. Fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, and rash often comprise the initial presentation. Cutaneous involvement occurs in up to 65% of patients (Morrell, 2002). Varied skin manifestations of hemophagocytic lymphohistiocytosis exist, including erythroderma, generalized purpuric macules and papules, and morbilliform eruptions. Detection of cutaneous involvement can assist in the initial diagnosis of HLH and potentially signify recurrences.

Primary HLH (ie, familial erythrophagocytic lymphohistiocytosis [FEL]), an inherited form of HLH syndrome, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary HLH (ie, acquired HLH) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment (Feldman, 2002). The clinical picture, differential diagnosis, workup, and treatment options are discussed.

Pathophysiology: The pathological hallmark of this disease is the aggressive proliferation of activated macrophages and histiocytes, which phagocytose other cells, namely red blood cells, white blood cells, and platelets, leading to the clinical symptoms. The uncontrolled growth is nonmalignant and does not appear clonal in contrast to the lineage of cells in Langerhans cells histiocytosis (histiocytosis X). The spleen, lymph nodes, bone marrow, liver, skin, and membranes that surround the brain and spinal cord are preferential sites of involvement (Arico, 2002).

Over the past 2 decades, the underlying pathophysiology of HLH has been characterized, although the processes are not entirely understood. A current accepted theory involves an inappropriate immune reaction caused by proliferating and activated T cells associated with macrophage activation and inadequate apoptosis of immunogenic cells (Imashuku, 2001). Although the precise mechanism remains unclear, many research teams propose convincing pictures for the role of perforin and natural killer (NK) cells in the HLH subtypes (Risma, 2006; Katano, 2005; Rieux-Laucat, 2005). Perforin or pore-forming protein (PFP), gene map location 10q22, is one of the major cytolytic proteins of granules contained in cytotoxic cells (Menasche, 2005). When activated by a challenge, NK cells release granules that contain perforin and granzymes, which form pores in the target cell membrane and cause osmotic lysis and protein degradation, respectively. Additionally, the endocytotic and exocytotic mechanisms may also be affected (zur Stadt, 2005). Patients with perforin deficiency may have impaired defenses against intracellular pathogens and cancers, as has been demonstrated in animal models.

Although the mechanism is yet to be determined, decreased NK cell activity results in increased T-cell activation and expansion, with resulting production of large quantities of cytokines, including interferon gamma (IFNg), tumor necrosis factor-a (TNF–a), and granulocyte-macrophage colony-stimulating factor (GM-CSF). This causes sustained macrophage activation and tissue infiltration as well as production of interleukin-1 (IL–1) and interleukin-6 (IL-6). The resulting inflammatory reaction causes extensive damage and the associated symptoms (Arico, 2001).

Frequency:

• Internationally: Incidence is reported to be 1.2 cases per million persons per year. However, unpublished observations estimate that the figures have slightly increased over time because of improved detection (Malloy, 2004). This amounts to 1 case per every 50,000 births (Sung, 2002).

  Perforin mutations account for approximately 20% of cases of FEL, with a somewhat higher prevalence (30%) in children of Turkish descent. Chromosome arm 9q mutations account for approximately 10% of familial cases; the remainder of FEL cases are caused by mutations in as yet unidentified genes (Ericson, 2003).

Mortality/Morbidity: Familial HLH is uniformly fatal if not treated; the median survival time reported in various studies is 2-6 months after diagnosis. The historical series collected by the International HLH Registry reports a less than 10% probability that the patient will live 3 years. Even with treatment, only 21-26% can be expected to survive 5 years. Remission is always temporary, as the disease inevitably returns. Bone marrow transplant is the only hope for cure. One study found that 50% of deaths from FEL were due to invasive fungal infections, which are probably underdiagnosed (Sung, 2002). The outcomes of secondary HLH vary.

Race: HLH has not been epidemiologically shown to have a predilection for persons of any race. A sample of European countries, including Sweden, England, and Italy, has reported similar statistical incidences as previously mentioned (Arico, 2001).

Sex: The disease has an equal distribution among males and females.

Age: The age of onset is usually in people younger than 1 year for the familial form but can be later for the secondary sporadic form, usually after age 6 years (Imashuku, 2005). Although the familial form of the disease frequently affects infants from birth to 18 months of age, familial forms have been reported in individuals up to 8 years of age, and reports of adult onset exist. At this point, no criteria for age have been established, and an upper age limit does not exist (Sung, 2002).

CLINICAL

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History: The diagnostic criteria set forth by the Histiocyte Society for inclusion in the International Registry for Hemophagocytic Lymphohistiocytosis (HLH) is as follows. All 5 criteria must be met to establish a diagnosis of HLH (Henter, Elinder, Ost, 1991):

• Fever - Seven or more days of a temperature as high as 38.5°C (101.3°F)



• Splenomegaly - A palpable spleen greater than 3 cm below the costal margin



• Cytopenia - Counts below the specified range in at least 2 of the following cell lineages:


• • Absolute neutrophils less than 1000/mL
  
  
  
  • Platelets less than 100,000/mL
  
  
  
  • Hemoglobin less than 9.0 g/dL
  
  
  
• Hypofibrinogenemia or hypertriglyceridemia - (1) Fibrinogen less than 1.5 g/L or levels greater than 3 standard deviations below the age adjusted reference range value or (2) fasting triglycerides greater than 2.0 mmol/L or levels greater than 3 standard deviations above the age-adjusted reference range value



• Hemophagocytosis - Must have tissue demonstration from lymph node, spleen, or bone marrow without evidence of malignancy



• Rash - Skin findings are evident in more than half of patients (Morrell, 2002). In addition to diffuse scaly and waxy lesions, rashes have been seen on the scalp and behind the ear.



• Less obvious symptoms may include swollen or hemorrhagic gums that can result in tooth loss. Feeding problems are especially prominent in infants. Abdominal pain, vomiting, diarrhea, and weight loss are also seen.

Physical:

• Clinical findings, including evidence of infection due to decreased immunity and white cell killing defects, easy bruisability, and pallor, are related to pancytopenia secondary to bone marrow infiltration or splenic sequestration.



• Evidence of a coagulopathy with an increased activated partial thromboplastin time (aPTT) is present.



• Jaundice is often present due to hyperbilirubinemia.



• Up to 65% of patients have a nonspecific rash that is often vaguely termed maculopapular although it has also been described as ranging from erythroderma to generalized purpuric macules and papules to morbilliform eruptions (Morrell, 2002).



• One Swedish study described nearly 75% of patients having some form of CNS involvement, with half showing neurologic symptoms including seizures, ataxia, hemiplegia, mental status changes, or simply irritability.



• Because of the predilection of the disease for certain tissues, lymphadenopathy is commonly found on physical examination.



• Other common constitutional findings such as malaise, anorexia with or without weight loss, and failure to thrive can occur (Henter, Elinder, Ost, 1991).



• The skin can be involved in a variety of ways; this is clinically best characterized as erythroderma, generalized purpuric macules and papules, or morbilliform eruptions.

Causes: See Pathophysiology.

DIFFERENTIALS

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Other Problems to be Considered:

Primary versus secondary HLH
Langerhans cell histiocytosis
Rosai-Dorfman disease
Solitary histiocytoma with macrophage phenotype
Leukemias
Lymphomas
Sarcomas
X-linked lymphoproliferative syndrome
Chediak-Higashi syndrome
Griscelli syndrome
DiGeorge disease
Metabolic disorders
Seborrheic dermatitis
Juvenile xanthogranuloma
AIDS
Macrophage activation syndrome

WORKUP

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Lab Studies:

• Because NK cell function or activity is decreased in up to 90% of patients, it is one of the most useful laboratory tests. NK cell number is usually not diagnostic.



• In addition to pancytopenia, hypofibrinogenemia, and hypertriglyceridemias, as previously mentioned, other laboratory abnormalities have been linked to hemophagocytic lymphohistiocytosis (HLH). Ferritin has been observed as a marker for HLH, with the serum levels paralleling the course of the disease (Imashuku, 2001). Liver damage has also been reported as evidenced by hyperbilirubinemia, hypoalbuminemia, and elevated findings on liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (Hafsteinsdottir, 2002).



• The presence of a PRF1 gene mutation can be determined based on flow cytometry by staining perforin contained in lymphocytes.

Imaging Studies:

• No specific imaging patterns are diagnostic of HLH. CT or ultrasound findings may include ascites, gallbladder wall thickening, increased periportal echogenicity, lymphadenopathy, and pleural effusion (Matthias, 2004). MRI may show CNS involvement, but the diagnosis is clinical and molecular, as is discussed below (Clementi, 2002).

Other Tests:

• In October 2002, the Arico group proposed an approach to the diagnostic workup of a patient with suspected HLH. A detailed clinical history should be obtained to exclude other associated conditions, such as the metabolic disorders or the DiGeorge syndrome. However, if the diagnostic HLH criteria are fulfilled and the findings for associated conditions are negative, initial testing involves perforin expression by NK cells using flow cytometry. Patients lacking perforin expression should be analyzed for the PRF1 gene mutation. NK cell activity should also be determined to aid in differentiating between the HLH subtypes. Normal activity is suggestive of the reactive form of HLH rather than the familial type. DNA samples and fresh cells are suggested to be stored in case of need for future use in familial cases for which no genetic defect can be identified (Arico, 2002).

Procedures:

• A skin biopsy can be performed for histological examination. Lymph node biopsy, bone marrow biopsy, or liver biopsy may demonstrate the characteristic hemophagocytosis.

Findings in up to two thirds of initial bone marrow aspirates may be nondiagnostic; thus, a negative examination finding may not rule out HLH. An additional bone marrow finding includes dyserythropoiesis, which has been observed in the absence of hemophagocytic histiocytes. Additional studies, including lymph node biopsy, should be undertaken, and treatment should not be delayed if all other criteria have been met (Macheta, 2001). Although problematic in a patient with a coagulopathy, a liver biopsy demonstrating a picture similar to chronic persistent hepatitis can support the diagnosis, as can the presence of mononuclear cells in the cerebrospinal fluid.

TREATMENT

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Medical Care:

• A pediatric hematology-oncology specialist is best equipped to manage this rare and potentially life-threatening disease. The newest protocol, HLH-2004, opened on January 1, 2004, and is based on the Histiocyte Society's original HLH-94 protocol, which had previously opened on January 1, 1995, with some minor modifications. The full HLH-2004 protocol is available by contacting the Histiocytosis Association of America. It represents a consolidation of the various approaches to treatment, with the goals being to first achieve clinical stability and then to cure with bone marrow transplantation (BMT). Antimycotic prophylaxis is used during the initial doses of dexamethasone. Sulfamethoxazole and trimethoprim (ie, cotrimoxazole) is continuously administered as prophylaxis for Pneumocystis carinii because of immune suppression. More details are discussed below (Henter, 2002).



• One group found that IV immunoglobulin (IVIG) was effective in suppressing symptoms when administered within hours of disease onset. Serum ferritin was used as a marker for macrophage activation, and treatment was administered accordingly (Emmenegger, 2002). Patients may be classified into high- and low-risk groups, with only the high-risk groups receiving the etoposide (ie, VP-16) regimens. Patients who are at low risk may be treated as effectively with only cyclosporine, corticosteroids, or IVIG (Imashuku, 2001). More studies, including randomized control trials, are needed.

Surgical Care: BMT is performed when a suitable donor can be found and the patient is stable. A recent study has found favorable long-term disease control in patients who received a reduced-intensity conditioned regimen instead of the conventional stem cell transplant (Cooper, 2006). If the patient is experiencing life-threatening respiratory difficulty or uncontrolled hypersplenism, splenectomy is an option.

Consultations: Consultation with a gastroenterologist may be helpful, especially if a transcutaneous liver biopsy is necessary.

• If the primary form of hemophagocytic lymphohistiocytosis is suspected, a genetic counselor may be helpful. In addition to analyzing inheritance patterns and determining risk, they can provide supportive counseling to the patient and family.

MEDICATION

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Initial therapy consists of etoposide and dexamethasone for 8 weeks in varying doses as described below. In the HLH-2004 protocol, cyclosporine is added in the beginning. Intrathecal methotrexate is used only with persistently abnormal CSF or progressive neurologic symptoms. Resolved nonfamilial hemophagocytic lymphohistiocytosis (HLH) does not require continuation of the therapy regimen unless disease reactivation occurs after completion of the initial therapy or unless patients are undergoing BMT. For the remaining children with persistent nonfamilial disease or familial disease, continuation therapy with etoposide IV infusions, dexamethasone pulses, and cyclosporine PO is instituted at week 9 from the start of initial treatment (Henter, 2002). HLH associated with malignancies demands prompt therapy directed at the neoplasm.

Drug Category: Antineoplastic agents -- These agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Name	Etoposide (Toposar, VePesid) -- Also called VP-16. Inhibits topoisomerase II and results in DNA strand breakage causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.
Pediatric Dose	Induction (weeks 1-8): 150 mg/m2 IV 2 times/wk for 2 wk, then qwk for remaining 6 wk Continuation (initiate at week 9): 150 mg/m2 IV infusion q2wk (alternate with dexamethasone)
Contraindications	Documented hypersensitivity
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding and severe myelosuppression may occur; mucositis, hypotension, liver toxicity, and diarrhea can also be seen

Drug Name	Methotrexate (Rheumatrex) -- Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response observed 3-6 wk following administration. Adjust dose gradually to attain satisfactory response.
Pediatric Dose	PO/IM: 7.5-30 mg/m2 PO/IM q1-2wk IV: 10-12,000 mg/m2 IV bolus or continuous IV infusion over 6-42 h; may repeat up to 4 doses (ie, at weeks 3, 4, 5, 6) IT: <1 year: 6 mg/dose IT 1-2 years: 8 mg/dose IT 2-3 years: 10 mg/dose IT >3 years: 12 mg/dose IT May administer up to 4 doses IT if progressive neurologic symptoms exist or abnormal CSF has not improved
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	PO aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX Probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs; mucositis is known toxicity

Drug Category: Corticosteroids -- These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli.

Drug Name	Dexamethasone (Decadron, Hexadrol) -- Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Postulated mechanisms of action of corticosteroids in tumors include reduction in vascular permeability, cytoxic effects on tumors, and inhibition of tumor formation.
Pediatric Dose	Induction (weeks 1-8): 10 mg/m2/d PO for 2 wk, then 5 mg/m2/d for 2 wk, 2.5 mg/m2/d for 2 wk, then 1.25 mg/m2/d for 1 wk, continue tapering and discontinue during week 8 Continuation (initiate at week 9): Pulses of 10 mg/m2/d PO for 3 d q2wk (alternate with etoposide)
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, pancreatitis, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Category: Immunosuppressant agents -- These agents may be used in combination with corticosteroids and immune globulin in patients at low risk.

Drug Name	Cyclosporine (Sandimmune, Neoral) -- Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. In children and adults, base dosing on ideal body weight.
Pediatric Dose	Initiate after dexamethasone 8-wk induction regimen completed Initial dose: 6 mg/kg/d PO divided bid Continuation therapy: Adjust PO dose to maintain target trough levels of 200 mcg/L
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; concomitant administration with PUVA or UVB radiation in psoriasis (may increase risk of cancer)
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma levels of each drug
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Category: Immune globulins -- Immune globulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is comprised of 4 subclasses of antibodies, approximating the distribution of human serum.

Drug Name	Immune globulin, intravenous (Gamimune, Gammagard, Sandoglobulin) -- Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-g. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%).
Pediatric Dose	400 mg/kg/d IV for 5 d; alternatively, 1 g/kg/d IV for 2 d
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before administering IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion) Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes mellitus, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

FOLLOW-UP

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Further Outpatient Care:

• Supportive care is needed to ensure that the patient remains stable until a bone marrow donor can be found. This includes transfusions of red blood cells, platelets, and fresh frozen plasma, as well as nutritional support in addition to the treatment protocol (Henter, 2002). Patients should be continually monitored for evidence of infection because of their immunosuppressed state. Be aware of the possibility of underlying malignancy. Biopsies and diagnostic cytogenetics may be needed in addition to selective radiographic imaging (Sung, 2002).

Complications:

• Complications of individual drugs in the regimen were outlined above (see Medication).



• Complications due to a subsequent transplant are numerous and include both acute and chronic graft versus host disease, acute inflammatory events, respiratory distress syndrome, and exacerbation of neurologic symptoms (Filipovich, 2005).

Prognosis:

• Although the prognosis varies between studies and with different approaches to treatment, the disease is invariably fatal if not treated. The median survival rate has been reported to be 2-6 months without treatment, but survival time has dramatically improved with the advent of the HLH-94 protocol already discussed. A study of 122 patients from the International Registry for Hemophagocytic Lymphohistiocytosis (HLH) found that the overall estimated 5-year survival rate was 21%, with 66% of patients who received BMT surviving 5 years versus only 10.1% of patients treated with chemotherapy alone (Arico, 1996). More recent studies have shown that the HLH-94 protocol resulted in an overall survival rate of 55%. Success or failure of an allogeneic BMT is the most important long-term prognostic factor. Unfortunately, many cases are diagnosed late in the course of the disease, after irreversible damage has occurred.

Patient Education:

• All physicians who treat young patients must be aware of life-threatening diseases such as HLH. Pediatricians, dermatologists, and neurologists should especially take note because the presenting symptoms of HLH are likely to bring the patient into their offices. Any suspicion warrants a referral to a pediatric hematologic-oncologist who is equipped with the necessary tools to make a rapid diagnosis.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Be aware of this disease, both in its typical onset and when it occurs later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia. Cases of hemophagocytic lymphohistiocytosis (HLH) erroneously labeled as child abuse have been reported in the literature (Rooms, 2003). Failure to make the diagnosis of HLH may result in adverse consequences.

Special Concerns:

• Although rare, the disease onset can occur later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia. Physicians should be aware of this atypical presentation and consider HLH in their differentials (Clementi, 2002).

TEST QUESTIONS

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CME Question 1: The initial presentation of hemophagocytic lymphohistiocytosis is usually evidenced by which of the following?

A: A fever, cardiomegaly, thrombocytosis, lymphadenopathy, and a rash
B: A fever, hepatosplenomegaly, thrombocytosis, lymphadenopathy, and alopecia areata
C: Hypothermia, hepatosplenomegaly, thrombocytosis, lymphadenopathy, and a rash
D: A fever, hepatosplenomegaly, thrombocytosis, lymphadenopathy, and a rash
E: A fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, and a rash

The correct answer is E: A fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, and a rash often comprise the initial presentation. Cutaneous involvement occurs in up to 65% of patients.

CME Question 2: Which of the following correctly describes familial hemophagocytic lymphohistiocytosis (FHL), an inherited form of hemophagocytic lymphohistiocytosis (HLH) syndrome?

A: A homogeneous autosomal dominant disorder
B: A heterogeneous autosomal dominant disorder
C: A heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity
D: A homogeneous X-linked recessive disorder found to be more prevalent with parental consanguinity
E: A heterogeneous autosomal dominant disorder found to be more prevalent with parental consanguinity

The correct answer is C: FHL (ie, primary HLH), an inherited form of HLH syndrome, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.

Pearl Question 1 (T/F): Secondary hemophagocytic lymphohistiocytosis (HLH) occurs after strong immunologic activation.

The correct answer is True: Secondary HLH (ie, acquired HLH) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy.

Pearl Question 2 (T/F): Both primary and secondary hemophagocytic lymphohistiocytosis are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment.

The correct answer is True: Primary HLH (ie, familial erythrophagocytic lymphohistiocytosis [FEL]), an inherited form of HLH syndrome, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary HLH (ie, acquired HLH) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment.

Pearl Question 3 (T/F): In cases of hemophagocytic lymphohistiocytosis (HLH), skin biopsy findings are usually diagnostic, demonstrating the characteristic hemophagocytosis.

The correct answer is False: A skin biopsy can assist in distinguishing this disorder from other systemic and potentially neoplastic diseases, such as Langerhans cell histiocytosis, myofibrosis, extramedullary hematopoiesis, and leukemia cutis. However, skin biopsy findings are usually not diagnostic and only rarely show hemophagocytosis. Hemophagocytosis must be demonstrated in the bone marrow, spleen, or lymph nodes from appropriate specimens.

Pearl Question 4 (T/F): In hemophagocytic lymphohistiocytosis (HLH), an associated rash resembles that of histiocytosis X, showing seborrheic dermatitislike findings on the scalp.

The correct answer is False: The skin can be involved in a variety of ways; this is clinically best characterized as erythroderma, generalized purpuric macules and papules, or morbilliform eruptions.

BIBLIOGRAPHY

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