Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of inflammation that was first thought to affect only young infants and children but is increasingly recognized in older children and adults.
According to a large, population-based study from Sweden, it was estimated to occur in 1.2 cases per million children, corresponding to 1 in 50,000 births. However, this number is probably an underestimation as physicians appear to recognize HLH more readily now than when this was published decades ago. According to a large Japanese study, around 40% of cases occur in adults.
HLH occurs when the immune system is triggered (most often by a virus) and overreacts in specific ways that make the patient severely ill. Thus, HLH is best thought of as a problem of proper immune regulation. Poor immune regulation may be caused by genetic defects (called familial HLH, or FHL) or it may occur in patients with various infections, rheumatologic diseases, or cancers, for reasons that are not entirely understood (sometimes called secondary HLH). The HLH process is like a storm of inflammatory factors, called cytokines, which involves many organs and various immune cells (macrophages/histiocytes and lymphocytes, the cells referred to in HLH’s name).
In the familial form of HLH, FHL, defective genes are inherited from both parents (called ‘autosomal recessive’) or more rarely, inherited from just the mother (called ‘X-linked’). While great progress has been made through research in recent years to define these genes, there remains a portion of FHL patients with yet unknown underlying gene defects. Most patients with FHL get sick before the age of 1 year. Though two X-linked forms usually only affect males, other genetic causes are seen equally in males and females. Because FHL runs in families and tends to reoccur in an affected child (if not treated), other family members including siblings may also be affected. Each full sibling of a child with the most common forms of FHL has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which usually does not give any risk of disease), and a 25% chance of not being affected and also not carrying the gene defect.
Secondary/reactive HLH is usually diagnosed in older patients with no family history of this disease. When HLH occurs in someone who has a rheumatologic disorder (most commonly systemic onset juvenile idiopathic arthritis, or so-JIA) or cancer, the HLH is best viewed as a complication of these conditions, or ‘secondary’ to these underlying problems. HLH also occurs in children and adults after infections, particularly viral infections such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Similarly, HLH can be thought of as secondary to these infections, though infection also triggers FHL, so the presence of infection does not define the underlying cause of HLH. Finally, immune-activating treatments for cancer such as CAR-T therapy may cause a cytokine storm, which shares many features with HLH.
If someone has familial HLH, also referred to as primary HLH, the HLH will likely recur once treatment is stopped. To prevent it from returning, most of these patient receive a bone marrow transplant from someone who is not at risk for HLH, either a family member or an unrelated volunteer donor. The new bone marrow replaces the recipients immune system with a healthy one. Learn more about bone marrow transplant.
It is difficult to know whether a patient has familial or secondary HLH based on symptoms, which may be very similar. Therefore, genetic testing is usually recommended for young children or adults with recurrent or unexplained HLH. Learn more about genomic profiling (genetic testing).
The first description of HLH was published in 1952, but it has only been in recent years that it has received more widespread attention. In 1985, physicians worldwide interested in studying histiocytic disorders including HLH gathered in Philadelphia and formed the Histiocyte Society. Funds raised by the Histiocytosis Association and national subgroups have financed research that has led to significant breakthroughs in the diagnosis and treatment of HLH during the last decades. As awareness and understanding of this disease have increased worldwide, the diagnosis and survival rates have improved significantly. However, HLH remains a rapidly progressive disease requiring effective anti-inflammatory therapy.
The information on this page has been written and reviewed by the Histiocytosis Association Board of Trustees Scientific Committee and a member of the Histiocyte Society, and subsequently audited by patients and families to ensure enough information was captured. The most recent update to this page was in August of 2023.
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The symptoms of hemophagocytic lymphohistiocytosis (HLH) include:
- Persistent fever, often high. Sometimes a microbial (often viral) cause is found, but this is common as a trigger of HLH/FHL
- Skin rash, variably (less than 30% of patients)
- Abdominal swelling
A wide variety of symptoms related to brain involvement include:
- Low or abnormally increased muscle tone
- Difficulty with coordination
- Weakness of face/eye nerves
- Paralysis and coma (very rare)
Signs of hemophagocytic lymphohistiocytosis (HLH) include:
- Abnormal blood tests such as a) low red blood cells, b) low platelets, and c) low neutrophils
- Other blood abnormalities (liver dysfunction, elevated triglycerides, low sodium level, and low albumin level)
- Enlarged spleen or liver
Combined with evidence of immunologic dysfunction:
- Decreased NK-cell function
- Increased T-cell activation as evidenced by increased sIL2ra (soluble IL-2 receptor alpha) in the blood
- Increased histiocyte activation as evidenced by increased ferritin
An abnormality in which histiocytes are "eating" other blood cells (also known as hemophagocytosis) can be detected on bone marrow examination. When prominent, this is a very useful diagnostic marker. Although the disease was named after this phenomenon, this sign is not limited to HLH and may be absent at HLH onset or even later during the disease.
Other typical signs of HLH include:
- CNS (central nervous system) involvement occurs in 30-50% of patients and may be present at the time of disease onset or develop later. Objective signs of CNS involvement include an abnormal lumbar puncture test (e.g., elevated protein or white blood cell count in the cerebrospinal fluid) or abnormal Magnetic resonance imaging.
- Liver injury, sometimes severe
The Histiocyte Society has created diagnostic guidelines and recommendations concerning the treatment of HLH. The HLH-2004 inclusion criteria are being used to date as the diagnostic criteria for most subtypes of HLH, though specific diagnostic tools have developed through the years. Treating physicians may contact the Histiocytosis Association for information about the HLH-2004 protocol and can also visit the Histiocyte Society website for Consensus Guidelines for HLH.
Diagnosis and Treatment
In January 2023, the Histiocyte Society published HLH/MAS Consensus Management Efforts, Expert Help Diagnosing and Managing HLH, which curates the most recent consensus-based guidance manuscripts, organized by the HS and/or affiliated organizations and authored by HS experts, to assist with the diagnosis and management of HLH across many different contexts. Read more here.
It is sometimes difficult to establish the diagnosis of hemophagocytic lymphohistiocytosis (HLH), and the combination of the physical symptoms and certain laboratory tests is required. Therefore, the Histiocyte Society recommended a set of diagnostic criteria for use in the HLH-94 research protocol, revised for the HLH-2004 protocol. The criteria include diagnosis of a specific gene defect and/or the presence of at least five of the following eight criteria:
- Prolonged fever
- Blood cell abnormalities (low white cells, low red cells, low platelets)
- Enlarged spleen
- Increased triglycerides (a type of fat in the blood) or decreased fibrinogen (protein necessary for clotting) in the blood
- Increased ferritin (a protein that stores iron and reflects the activation of macrophages) in the blood
- Abnormal bone marrow test evidence of hemophagocytosis
- Abnormally high sCD25 (also known as sIL2ra) in the blood indicates abnormally increased T-cell activation
- Low or absent NK (natural killer) cell function.
The test for low or absent natural killer cell (NK) function has been found useful in establishing a clinical diagnosis of HLH. This abnormality is found in many patients with FHL and many cases of secondary disease but rarely in X-linked forms. A newer test, called a degranulation or CD107 mobilization assay, appears to be more consistent and is replacing NK function in many practices. However, these tests are just one piece of information, and the diagnosis requires a full clinical and laboratory pattern, as well as to determine the diagnosis of HLH as primary or secondary.
Another tool to help in the diagnosis of HLH is the HScore. The HScore comprises typical signs and symptoms for HLH diagnosis and has a web-based calculator HScore for Reactive Hemophagocytic Syndrome - MDCalc. Patients and families are encouraged to share this with their healthcare providers.
People with an underlying rheumatologic disease such as Juvenile Idiopathic Arthritis, which imposes laboratory abnormalities by itself, are diagnosed with specific diagnostic criteria, the "2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis." Patients with malignancies can also have abnormal clinical features caused by the malignancy, and a recent international retrospective analysis established a diagnostic and prognostic index for these patients, comprising of sCD25 and ferritin named the "Optimized HLH Inflammatory" (OHI) index. Patients experiencing extreme immune activation after CAR T-cell therapy, reflected by extremely high ferritin and prolonged blood cytopenia, may have what is sometimes called ‘carHLH’ that needs cytokine-directed therapy.
After diagnosing HLH, it is important to find any immune-activating triggers, to stop the immune-activating cycle. FHL is important to identify as these patients almost always need bone marrow transplantation to survive long term. FHL should be suspected, and genetic testing should be performed in infants and young children, those with refractory HLH, and patients with a positive family history of HLH. There are some FHL patients (less than 50%) with no identified gene defect, so normal genetic test results do not necessarily rule out the diagnosis of FHL. Genetic testing is usually done on blood, although other kinds of tissue samples can be used. Once the genetic cause is known, the parents can quickly be tested to confirm that they are carriers for that specific genetic type of FHL. Other siblings can also be easily tested, even before birth, once the genetic cause of the disorder in the family is known. Even in the event of death, salvaged tissue can be tested to determine if siblings are at risk.
It is recommended that genetic testing be coordinated through and requested by a referring physician or genetic counselor. Test results are generally available in about one month to six weeks. The cost of genetic testing is covered by most insurance companies. There are several hospitals that provide information and perform genetic testing on a clinical basis, including:
Karolinska University Hospital, Stockholm, Sweden
Jan-Inge Henter, MD
University Medical Center, Hamburg, Germany
Gritta Janka, MD
Gene Tests Clinic Directory
Please contact the Histiocytosis Association team for other options and for specific questions: email@example.com or +1-856-589-6606.
If no genetic cause is found, further investigation is warranted, such as actively searching for hematologic malignancy, searching for viruses such as Epstein Barr Virus and Cytomegalovirus, and a not yet diagnosed rheumatologic disease. Finding the specific trigger is sometimes the key to successful treatment.
Treatment & Research Opportunities
There are cases of secondary/reactive HLH that can resolve spontaneously or after treatment of the underlying disease or after anti-inflammatory steroids (and without chemotherapy). Therefore, the treatment should be guided in part by the severity of the condition and the cause of the disease.
FHL, however, when not treated, is usually rapidly fatal, with an average historical survival of about two months. In 1994, due to an international cooperative effort, the Histiocyte Society created the first treatment protocol for patients with HLH/FHL. This included a combination of chemotherapy, steroids, other immune suppressants, and antibiotics/ antiviral drugs, followed by a stem-cell transplant in patients with persistent or recurring HLH or those with FHL. The HLH-2004 protocol was based on the HLH-94 protocol with minor changes such as cyclosporin, an immunosuppressant drug, being started at the onset of therapy rather than after eight weeks. HLH-2004 closed at the end of 2011. The HLH-2004 study confirmed the efficacy of the combined treatment of etoposide and steroids. However, protocol modifications, such as adding cyclosporine to the treatment upfront, did not significantly change the prognosis. Other approaches include use of anti-T cell antibodies (called ATG or alemtuzumab) alone or in combination with etoposide. These strategies are not generally considered standard.
In 2018, the first targeted therapy for FHL or primary HLH, an antibody called emapalumab (or gamiphant) was approved by the FDA for salvage therapy of recurrent/refractory FHL after a successful clinical trial against the inflammatory cytokine interferon gamma (INFγ). Read the full press release to get more information here.
In addition, other targeted therapies such as ruxolitinib (a JAK inhibitor) and tadekinig (recombinant human IL-18 binding protein) are being investigated in clinical trials for the treatment of HLH. Search for clinical trial opportunities at Clinical Trials | Histiocytosis Association, www.clinicaltrials.gov, https://www.clinicaltrialsregister.eu/, clinical trials Canada, and other similar sites for your region of the world.
The treatment included in the HLH-2004 research protocol/ the novel targeted therapy is intended to achieve stability of the FHL disease symptoms so that a patient can then receive a bone marrow transplant (BMT), which is necessary for a cure. Some transplant centers have adopted reduced-intensity conditioning (or "RIC") to prepare for stem cell transplants in recent years. This approach offers the possibility of better survival with stem cell transplants than the intensive chemotherapy protocols previously used. As research continues, the outcome for patients with HLH/FHL has greatly improved. As a result, approximately two-thirds of children with HLH who undergo transplantation can expect to be cured of their disease. However, several complications can occur during the transplant process, including severe inflammatory reactions, anemia, and graft-versus-host disease.
Long-term follow-up of survivors of transplants for HLH/FHL indicates that most children return to a normal or near-normal quality of life. The transplantation results are generally better when the procedure is performed at a major pediatric transplant center where the doctors are familiar with this disease. Therefore, early and accurate diagnosis is essential. However, there is still a high rate of death, indicating the education of the medical community regarding prompt diagnosis and management of the diseases, as well as improvement in managing therapy to provide optimal outcome, still requires support for clinical research of this group of disorders.
Patients with the rheumatologic form of the disease (also known as MAS, Macrophage Activation Syndrome) are usually treated with steroids and targeted therapy (such as anakinra, an IL-1 receptor inhibitor). In addition, some of the patients are treated with etoposide and steroids, and even BMT.
HLH associated with malignancies is a major therapeutic challenge as there is not enough evidence or a strong consensus of the appropriate treatment. However, the common approach is to control the cytokine storm (with steroids or etoposide) to enable malignancy-specific therapy. Either way, these patients are suffering from poor survival, and improved therapeutic strategies are required.
Lastly, patients with HLH/cytokine storms triggered by immune-activating therapies are usually treated with cytokine-specific treatment to preserve the anti-cancer effect.
Improving understanding of the different subtypes and mechanisms causing HLH will hopefully improve the therapeutic outcomes in the upcoming years.
Research & Registries
Because of the rarity of the disease, conducting clinical studies on HLH is challenging. There are two major efforts to gather research data through HLH disease registries. The Histiocyte Society has a worldwide registry to collect and analyze clinical, epidemiological, and genetic data to assess the feasibility and design of future interventional studies on the treatment of HLH. Also, Cincinnati Children's Medical Center collaborates with Texas Children, North American Consortium for Histiocytosis (NACHO), and SOBI to develop a registry called INTO-HLH, which is only for patients in North America and aims to gain new insight into the natural history of HLH. You can ask your physician about your options to enroll in one/both of these registries. Clinical Trials | Histiocytosis Association
The INTO-HLH Registry: (Insight into the Natural history and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis) will enroll pediatric and adult patients with HLH. The proposed study, a collaboration between Cincinnati Children's Hospital Medical Center (CCHMC), Texas Children's Hospital, the North American Consortium for Histiocytosis (NACHO), and Sobi Inc. aims to establish a robust registry that will enable investigators to better define the natural history of HLH. FAQs for the study can be found here, and the clinicaltrials.gov page, here. Visit the study website: https://hlhregistry.org. Download the Brochure or Scan the QR Code
Adult HLH Registry - Europe: A register database was established at the Jena University Hospital for the systematic collection of patient cases with HLH in adults. This web-based register database was created in cooperation between the Jena Center for Clinical Studies and the Department of Hematology and Oncology at the Jena University Hospital. Clinical and laboratory chemical data are registered in an anonymous form.
Histiocyte Society (HS) and European Society of Immunodeficiencies (ESID) HLH Registry: 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. This international HLH Registry is 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.
*If you have already enrolled in one of the above studies, you are welcome to enroll in the others, so long as you meet the eligibility criteria. You can also ask your physician or the registry's team if enrolling in one automatically enrolls you in another. Multiple registries exist due to the need to focus on a particular set of information, such as geographic location (i.e., Europe v North America). The registry information or team will inform you about collaborative efforts with other existing registries or studies. *
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What Do I Do Now?
A new diagnosis of a histiocytic disorder can bring feelings of being overwhelmed, bewildered, scared, angry, sad, disappointed, helpless, and sometimes even feelings of guilt. It is a time filled with unknowns, change, and new people and situations. Most parents feel ill-equipped to understand what is happening to their child and how to navigate through the illness to recovery. There are, however, strategies and resources that can help you, your child, and other family members get through the uncertain times that lie ahead. One step at a time, you can gather information, create a support system, learn how to cope with stress, and become a strong advocate for your Histio Warrior as part of the medical team. The following tips and suggestions are provided to help guide you through this journey toward your Histio Warrior's good health.
Articles and Links
- US FDA Approves Gamifant® (emapalumab-lzsg), the First and Only Treatment Indicated for Primary Hemophagocytic Lymphohistiocytosis (HLH)
- Overview of Histiocytosis (Including Hemophagocytic Syndromes)
- The Importance of Clinical Trials in the Fight Against Histiocytosis
- How We Treat Hemophagocytic Lymphohistiocytosis
- Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
- Hemophagocytic Lymphohistiocytosis, Familial
- Treatment of HLH with HLH-94
- Approach to Hemophagocytic Syndromes
- Familial Haemophagocytic Lymphohistiocytosis: Advances in the Genetic Basis, Diagnosis and Management from Clinical and Experimental Immunology
- US National Library of Medicine list of articles on L
- Familial Hemophagocytic Lymphohistiocytosis (FHL)-Information on Genetic Testing
- Histiocytic Disorders of Children and Adults: Basic Science, Clinical Features and Therapy
- Search National Institutes of Health Medical Dictionary and Drug Information
- HLH Study Information
Printable Fact Sheets
Learn more about the different types of histiocytic disorders from these helpful fact sheets. Printing these for family and friends is a quick and easy way to teach them about the disease. More extensive information can be found in the Disease Information section of our website.
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