HLH Disease Burden Report

In our latest Report Review, Sobi™ looks at the impact of Haemophagocytic lymphohistiocytosis (HLH) on patients, carers, and healthcare professionals and how policymakers can help.

By Sobi™

Sobi™ is an international biopharmaceutical company focused on rare diseases.

29 Oct 2020

Haemophagocytic lymphohistiocytosis (HLH) is a severe and potentially fatal disorder of the immune system that most often affects infants or young children but can also present in adulthood in some cases. It occurs as a genetic (primary) or acquired (secondary) disorder.

Once a diagnosis of primary HLH has been established and treatment begins, in most cases it is followed by a stem cell transplantation (HSCT), the physical/ practical, emotional, and social issues that patients and their caregivers experience can have a significant, long-lasting impact on their lives.

HLH patients and their caregivers report that the journey from the first appearance of symptoms to receiving a diagnosis can be challenging, frightening, and lengthy. HLH is a life-threatening condition with a very low survival rate if left untreated.

This report, which focuses mainly on primary HLH, draws on the experiences of HLH experts, presents a detailed picture of the primary HLH disease burden. It is an essential tool for raising awareness of HLH and for supporting discussions aimed at improving the standard of care for patients and increasing support for their caregivers and families across Europe and the wider world.

“My personal view is that what is unique to HLH is the brutality with which the symptoms arrive and very quickly threaten the child’s life, much more so than with leukaemia or cancer, where there is ‘a little time’ to treat. The disease is complicated to explain and the outcome uncertain.” Professor Jean Louis Stephan


One of the challenges of HLH is that its symptoms can be confused with those of other common childhood illnesses, especially severe infections such as sepsis. Some of the more typical symptoms are:

  • Persistent fever
  • Paleness (anaemia)
  • Signs of bleeding (thrombocytopenia)
  • Distended abdomen (enlargement of liver and spleen)
  • CNS symptoms, including irritability, convulsions, and ataxia (poor coordination)

HLH involves an overactivation of specifi c types of white blood cells called T cells and macrophages, which normally combat infection. This overactivation causes severe infl ammation and damage to tissues and organs, such as the liver, spleen, and bone marrow, as well as the central nervous system (CNS).


Over the past 20 years, the outlook for children with HLH has improved due to increased recognition of the disease, improved diagnostic tests, and the availability of better treatment options. However, the report highlights that patients and their caregivers continue to experience a considerable burden on their physical, emotional, and social well-being, which can be exacerbated by potential delays in diagnosis, inappropriate treatment, and a lack of available information about HLH. There are also considerable burdens placed on patients and their families such as long-distance travel and overnight accommodation that is often required if the HLH treatment centre is far from home.


The disease can be diagnosed if there is a mutation in a known causative gene, or if at least five of the following eight diagnostic criteria are met:

  1. Fever
  2. Enlarged spleen
  3. Cytopenia in at least two of the following cell lineages:
    1. Haemoglobin (protein in red blood cells that transports oxygen in the blood)
    2. Platelets (cells that help the blood form clots)
    3. Neutrophils (type of white blood cell)
  4. High levels of ferritin (the major iron storage protein) in the blood
  5. Elevated levels of triglycerides (type of fat) or low levels of fibrinogen (clotting factor) in the blood
  6. Elevated blood levels of soluble CD25 (a measure of immune cell activation)
  7. Haemophagocytosis (the destruction of blood cells by histiocytes) on bone marrow sample in cerebrospinal fluid or lymph node biopsy
  8. Reduced or absent natural killer (NK) cell activity


The priority for healthcare professionals treating HLH is to reduce inflammation by suppressing the immune system, which is usually done with corticosteroids, and in severe cases, with chemotherapy and/or immunotherapy, followed by haematopoietic stem cell transplantation (HSCT) - historically referred to as bone marrow transplantation. In many cases, HSCT potentially offers a long-term cure for primary HLH, and over the last 30 years, long-term survival rates have improved to a five-year probability of survival of primary treatment and HSCT of 61 percent. Without HSCT, primary HLH has a mortality rate of over 95 percent.


Because HLH is such a rare condition, the level of awareness of the disease and its symptoms among non-specialist healthcare professionals is still generally low, despite an increase in understanding of the condition over the last few decades. To ensure optimal care, patients require rapid transfer from primary or secondary care to a tertiary referral centre where HCPs have experience in treating HLH.



  • Support from European Institutions and platforms, like the European Reference Networks, to ensure greater connectivity between small HLH patient groups at Member State level, as well as support to create a standalone disease awareness website.
  • In the context of such a rare disease, patients are often missed (not properly diagnosed). Is it vital to enhance the capabilities and resources of these networks to support the specialists with the diagnosis and the patient management.
  • Establishment of, and greater collaboration between, national and European patient registries to gather long-term data in understanding the disease, disease prognosis and treatment efficacy.
  • Creation of National and European networks for HCPs treating rare diseases to share knowledge and best practices that would contribute to increasing awareness of the disease and its symptoms.
  • Provision of any communication tools which can support parents/carers to explain HLH to siblings and/or extended family members and widespread translation of these materials into languages of nationalities commonly affected.
  • A referral awareness campaign in secondary care hospitals on febrile illness, which does not subside and is not associated with any typical aetiologies.

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