Registry for Hemophagocytic Lymphohistiocytosis (HLH)

A cooperative project of the Histiocyte Society (HS) and the European Society of Immunodeficiencies (ESID)


Hemophagocytic lymphohistiocytosis (HLH) is a rare and complex clinical syndrome caused by a life-threatening, excessive but ineffective inflammatory response of the immune system. It is characterized by strong activation of macrophages and T-cells invading tissues and secretion of large amount of cytokines. HLH can affect all age groups and can occur as an inherited or acquired disorder. Primary immunodeficiencies affecting lymphocyte cytotoxicity are summarized as primary or familial HLH (FHL2-5). Other immunodeficiencies predisposing to HLH include Chediak-Higashi-Syndrome (CHS), Griscelli Syndrome 2 (GS II), Hermansky-Pudlak Syndrome 2 (HPS2), and X-linked lymphoproliferative syndromes type I and II. Acquired, secondary manifestations of HLH are more frequent than genetic forms and are caused by a variety of underlying conditions such as severe infections, malignancies, and metabolic and rheumatological diseases. In both forms, primary and secondary HLH, activation of the immune system is mostly caused by an infectious trigger, mainly viruses of the herpes family. HLH standard of care encompasses management of the hyperinflammation using immunosuppression and/or chemotherapy as well as trigger-directed treatment (modified HLH-94 protocol by the Histiocyte Society (HS)). Subsequent HSCT is required for most hereditary conditions predisposing to HLH to circumvent reactivations. Monoclonal antibodies are currently being evaluated as primary therapy options. Although treatment options have remarkably improved the outcome (overall survival of 81% until HSCT), there is consensus both in the Histiocyte Society (HS) and in the European Society of Immunodeficiencies (ESID) that a randomized controlled interventional trial comparing two treatment regimes in their ability to induce remission of hyperinflammation would be ideal. There is also consensus that such a trial should primarily target patients with genetic disease predisposing to HLH and severe cases of patients with “infection-only” associated secondary HLH.


To create an international HLH Registry aimed to collect and analyze clinical, epidemiological, immunological, genetic, treatment and survival data for assessment of feasibility and design of future interventional studies on the treatment of HLH. Furthermore, the HLH Registry can improve the network of physicians collaborating in HLH and provide the framework for future clinical trials. The HLH Registry is a database implemented as a collaborative project of the HS and ESID in collaboration with the Inborn Errors Working Party (IEWP) of the European Bone Marrow Transplantation Group (EBMT) but is not limited to formal members as participants worldwide are encouraged to contribute to this effort.

Eligibility of centers:

All centers worldwide are eligible for participation after internal review board approval (according to local requirements) and (online) training in the registry database. The centers must decide if they prefer to document via the dedicated HLH registry data capture system run on the MARVIN platform or via the HLH tool of the general ESID immunodeficiency registry. Both databases are fully synchronized with identical datasets.

Subject Inclusion Criteria for the HLH Registry:

Patients are eligible after informed consent if at least one these criteria is fulfilled:
  • Diagnosis of a primary immunodeficiency predisposing to HLH
  • Active HLH that is not secondary to underlying conditions such as rheumatological disease, malignancy, metabolic disease or Leishmania infection (mostly “infection-only” HLH) with fulfillment ≥ 4/8 diagnostic criteria for HLH as defined by the Histiocyte Society AND HLH directed therapy (steroids are sufficient)
  • High suspicion of isolated CNS-HLH AND HLH directed therapy

Procedures to enroll a subject In the HLH registry:

  • Patient or legal representative obtains information about the study from the local investigator. Consent.
  • Participating centers submit a registration fax to 0049 40 7410 58250 where eligibility is confirmed and a registry ID is provided, ensuring confidentiality.
  • Patient data can then be entered into one of the two online databases (MARVIN database or ESID registry database, with an identical data set) used for data capture. No identifying information other than the patients’ identification number will be stored in the database. The database will contain clinical information as well as immunological/laboratory results.
  • After initial registration, patient data will be recorded after the initiating of treatment and after one year of follow-up. The dataset is strictly limited to essential information.


For questions or to register for the HLH Registry, contact:



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