Final Diagnosis -- Hemophagocytic lymphohistiocytosis and systemic histoplasmosis




Hemophagocytic lymphohistiocytosis (HLH) is also known as the autosomal recessive familial hemophagocytic lymphohistiocytosis (FHL), familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS). This aggressive and potentially life-threatening disease most often affects infants from birth to 18 months of age, but cases in older children and adults have been reported.

Usually, primary HLH denotes the presence of an underlying genetic disorder, but secondary HLH denotes the presence of HLH phenomenon occurring secondary to another condition (eg, viral or fungal infections). However, the same gene mutations can be present in both situations and there is no specific test with the ability to quickly define these two categories. With few exceptions, the clinical presentation and outcome are the same for both.


Studies have suggested that the central abnormality in HLH is cytokine dysfunction, which is further leading to an uncontrolled accumulation of activated T-lymphocytes and activated histiocytes in many organs. Cytokines that have been found at extremely high levels in HLH patient plasma include interferon- , TNF- , interleukin (IL)-6, IL-10, IL-12, and soluble IL-2 receptor (CD25). Studies have also demonstrated a depressed or non-existent natural killer (NK)-cell and cytotoxic T cell activity in HLH patients. Defective NK cell function is associated with decreased amounts of the pore-forming protein, perforin, which may also be important in regulating T cell function.

The importance of perforin expression, as well as the cytotoxic function of T and NK cells in HLH has been documented. HLH patients have been found to lack intracellular perforin in cytotoxic cell types. A murine model of HLH with perforin-deficient mice has been developed in which the CD8(+) T cells were shown to be critical in causing HLH. Besides perforin, defects in two other proteins of the cytolytic pathway have been associated with defective T cell control and HLH. The MUNC13-4 protein is important for packaging of the cytolytic granzymes. Patients with the Griscelli syndrome often develop HLH and have been shown to lack a protein rab27a that controls secretion of lytic granules. Studies have demonstrated that MUNC 13-4 must link with rab27a to allow fusion of secretory granules with the plasma membrane. Patients with Chediak-Higashi syndrome also have a high frequency of HLH. In these patients the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) does not move from secretory lysozomes to the cell membrane. Another cellular defect in HLH relates to defective apoptosis, as less spontaneous activation of caspase-3-like enzymes was found in activated lymphocytes of some HLH patients.

Clinical and pathologic findings

Initial presentation - Early clinical signs may include fever, hepatomegaly, splenomegaly, neurologic symptoms, rash, and lymphadenopathy. Many of HLH patients have clinical and radiologic findings similar to the acute respiratory distress syndrome, with alveolar-interstitial opacities and pleural effusions. The initial presentation of HLH may simulate a number of common conditions such as febrile illness, multiple organ failure syndrome, etc.

Pathologic findings - The pathologic findings of HLH result from the aggressive proliferation of normal histiocytes and T-lymphocytes in various tissues. Hemophagocytosis of red cells (erythrophagocytosis), other white blood cells, or platelets in the bone marrow, spleen, or lymph nodes is the key diagnostic finding. Infiltration of the liver and bone marrow with histiocytes and the antiproliferative effects of cytokines result in damage to these organs.

Diagnostic Criteria for HLH

Since HLH is often fatal, one must have a high index of suspicion of HLH for patients who present with several of the following: high fevers, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, coagulopathy, abnormal liver function tests, and high serum ferritin.

Major criteria:

  1. Fever: Peak temperature >38.5C for seven or more days.
  2. Splenomegaly: Spleen palpated >3 cm below the left costal margin.
  3. Cytopenia involving two or more cell lines: hemoglobin <9.0 g/dL, or platelets <100,000/L, or absolute neutrophil count <1,000/L.
  4. Hypertriglyceridemia or hypofibrinogenemia: fasting triglycerides >2.0 mmol/L, or more than 3 standard deviations (SD) above the normal value for age, or fibrinogen <1.5 g/L, or more than 3 SD below the normal value for age.
  5. Hemophagocytosis: demonstrated in bone marrow, spleen, or lymph node. No evidence for malignancy.

Alternative criteria:

  1. Low or absent natural killer.
  2. Serum ferritin level >500 g/L.
  3. Soluble CD25 (sIL-2 receptor) >2400 U/mL.

The diagnosis of HLH requires the presence of all five major criteria. Either criterion (a) or a combination of criteria (b) and (c) may substitute for one of the major criteria. If a patient meets only four criteria and the clinical suspicion for HLH is high, one must initiate appropriate treatment, as delays may be fatal.

Specialized testing - Some of the following tests may be helpful in supporting the diagnosis, including histologic evidence of chronic persistent hepatitis, low natural killer cell activity, coagulopathy with markedly prolonged activated partial thromboplastin time, and increased concentrations of circulating soluble interleukin (IL)-2 (sIL-2R) receptor (sCD25). Serum NSE (neuron-specific enolase) levels were found to be inversely proportional to the platelet count, and sequential changes in NSE levels appeared to reflect the clinical course. The soluble hemoglobin-haptoglobin scavenger receptor CD163 levels track closely with disease activity and correlate with serum ferritin.


HLH-94 protocol - This protocol included induction therapy with dexamethasone, etoposide (VP-16), cyclosporine (started at week 9), and intrathecal methotrexate, followed by pulses of dexamethasone and VP-16 for up to one year. Results of this study showed an overall survival of 55 percent at a median follow-up of 3.1 years.

HLH-2004 protocol - A new version of the HLH treatment program was initiated in January, 2004. This protocol can be obtained from the Histiocytosis Association of America.

Hematopoietic cell transplantation - Allogeneic hematopoietic cell transplantation (HCT) seems to provide the best overall cure rate for HLH patients. HCT is indicated in patients who have homozygous mutations in the various genes associated with HLH, those who responded poorly to the initial eight weeks of therapy, and those with CNS disease.


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Contributed by Zaibo Li MD and Sara Monaghan MD

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