Familial hemophagocytic lymphohistiocytosis

Disease Description (Causes and Symptoms)

• Definition and causes
  • Familial hemophagocytic lymphohistiocytosis (FHL) is a hereditary disease in which deficient function of cytotoxic T cells and natural killer (NK) cells leads to uncontrolled immune activation, excessive cytokine secretion, and macrophage activation, causing tissue damage and systemic inflammation. It usually follows an autosomal recessive inheritance pattern, and related genes including PRF1 (FHL2), UNC13D/MUNC13-4 (FHL3), STX11 (FHL4), and STXBP2 (FHL5) have been reported. It is rare, with a prevalence of approximately 1 in 50,000 people, and survival is very short without treatment (approximately 2 months on average in standard reports).
• Summary of pathophysiology
  • Genetic defect → impaired cell-death-inducing mechanisms of cytotoxic cells (e.g., abnormal perforin secretion) → failure to eliminate stimuli such as viruses → persistent T-cell/macrophage activation → excessive cytokine secretion (e.g., IFN-γ) → tissue infiltration, hemophagocytosis, and multiorgan damage.
• Major symptoms and signs
  • Persistent fever (usually 7 days or longer), progressive splenomegaly and hepatomegaly, pancytopenia (anemia, neutropenia, and thrombocytopenia), extremely high ferritin levels (hyperferritinemia), hypertriglyceridemia and hypofibrinogenemia, evidence of hemophagocytosis in the bone marrow, spleen, liver, or lymph nodes, and, with central nervous system involvement, increased intracranial pressure, seizures, movement disorders, changes in consciousness, and other symptoms.
• Diagnostic criteria (key points)
  • Confirmation of a genetic etiology (mutation in a causative gene) OR fulfillment of at least 5 of the Histiocyte Society criteria: persistent fever, pancytopenia (at least 2 lineages), splenomegaly, hypertriglyceridemia/hypofibrinogenemia, evidence of hemophagocytosis, decreased NK-cell function, hyperferritinemia, and increased plasma sCD25 (soluble IL-2 receptor).

Treatment Methods and Precautions

• Standard treatment principles
  • Initial (trigger-control) treatment: Immunosuppressive and antineoplastic therapy based on the HLH-94/HLH-2004 protocols (mainly dexamethasone plus etoposide, etc.), with cyclosporine used when necessary. In cases of central nervous system involvement, intrathecal treatment (e.g., methotrexate) may be considered.
  • Targeted therapies and newer drugs: In relapsed or refractory cases or certain situations, an IFN-γ inhibitor (e.g., emapalumab) may be used (indications and access depend on local guidelines and insurance coverage). The use of the JAK inhibitor ruxolitinib has been reported in research and case-level settings.
  • Definitive treatment (with curative intent): Allogeneic hematopoietic stem cell transplantation (HSCT)—HSCT is recommended as the only curative treatment for patients with genetic FHL. The indication and timing of transplantation are determined based on disease control status, the patient's overall condition, and the underlying genotype.
• Adjunctive and supportive treatment
  • Infection control (antibiotics and antivirals), transfusions (red blood cells and platelets), correction of coagulation abnormalities, organ-function support (liver and kidney protection), and nutritional management.
• Precautions and self-management points
  • Immunosuppressive/antineoplastic treatment increases the risk of infection → immediate evaluation is necessary if fever or respiratory symptoms occur.
  • Monitoring for treatment-related hematologic, liver, and kidney toxicities is necessary.
  • Long-term follow-up is necessary for complications before and after HSCT (graft-versus-host disease, infection, organ toxicity, etc.).
• Complications
  • Central nervous system damage (permanent neurological deficits), multiorgan failure, bleeding and DIC, relapse and treatment-related toxicity, and transplantation-related complications.

Checklist Before an Outpatient Visit (Including Items to Bring and Example Questions)

• Items to bring (recommended for the appointment)
  • List of currently used medications and supplements (including dosing times and amounts)
  • Copies of previous test results: recent CBC, ferritin, triglycerides, fibrinogen, liver function tests, bone marrow examination results, CSF results (if available), and imaging studies (abdominal ultrasound/CT/MRI)
  • Family history (similar symptoms, early deaths, and history of blood disorders) and previous genetic test results (if available)
  • Records of the pattern and duration of fever, bleeding, bruising, fatigue, shortness of breath, and neurological symptoms (such as seizures and movement disorders)
• Examples of symptoms to report to the doctor first during the outpatient visit
  • Fever persisting for 7 days or longer, respiratory or gastrointestinal infection symptoms, new rash or bleeding, and whether changes in consciousness or seizures have occurred
• Recent tests to show the doctor (copies if possible)
  • CBC (including detailed values), ferritin, triglycerides, fibrinogen, liver enzymes, blood culture results, bone marrow biopsy findings, and NK-cell function test and sCD25 results (if available)

Examples of General Questions to Ask the Doctor

• "What is the basis for the current diagnosis, and what additional tests are needed?"
• "What initial (induction) treatment plan do you recommend? What is the expected treatment duration, and what are the treatment goals?"
• "What are the major side effects of this medication (or treatment), and how are they managed?"
• "Is hematopoietic stem cell transplantation necessary, what are the indications, and when is the appropriate time?"
• "What is the prognosis (short- and long-term survival rates), and what is the risk of relapse?"

Examples of Disease-Specific Questions

• "Which gene (e.g., PRF1, UNC13D, etc.) was found to have a mutation in the genetic test results? How does that type affect the prognosis or the need for transplantation?"
• "In our (or the patient's) case, how quickly should we prepare for HSCT? Could you explain the suitable donor options (family donor, cord blood, or unrelated donor)?"

(Note: The diagnostic and treatment plan varies depending on the individual patient's condition, age, underlying genotype, and the institution's experience. In an emergency (persistent high fever, coma, seizures, sudden respiratory or circulatory instability, etc.), immediately visit the emergency room or contact the treating doctor.)