Hemophagocytic Syndromes

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children, although it can develop for the first time at any age.

According to a large, population-based study published in Sweden, it was estimated to occur in 1.2 cases per million children, which corresponds to 1 in 50,000 births.  However, this number may be higher, as there are probably many patients today who are not diagnosed.  For the autosomal-recessive forms of HLH (FHL), there is believed to be an equal number of males and females diagnosed with this disease.  In addition, there are two known X-linked forms of FHL, affecting only males.

HLH involves over-production and activation of normal infection-fighting cells called histiocytes and T cells.  In contrast, often NK cell function is decreased. NK cells are known as 'natural killer' cells because they kill virally infected cells and detect/control early signs of cancer, so in HLH, the NK cell function is impaired. Decreased NK function is related to the consequence of genetic mutations which cause HLH.  HLH is often referred to as either the “primary” form which is hereditary, or the “secondary” form associated with infections, viruses, autoimmune diseases, and malignancies (or cancers). Learn more about NK cells and HLH in this medical article.

In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. Since 1999, five genes have been identified which correspond with five subtypes of autosomal recessive HLH. The genes are PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A.  PRF1 encodes the protein (or toxin) normally involved in “killing” or eliminating abnormal immune cells. The proteins encoded by the other four genes facilitate the delivery of perforin to the cells which are to be killed.

While great progress has been made through research in recent years to define these genes, there remains a considerable proportion of FHL patients with as yet unknown underlying gene defects.

The onset of disease occurs under the age of 1 year in an estimated 70% of cases.  FHL is suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped.   Each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a 25% chance of not being affected and not carrying the gene defect.

So-called “secondary HLH” is often diagnosed in older patients, and there is no family history of this disease.  It may be associated with vaccinations, viral infections such as Epstein-Barr, cytomegalovirus (CMV), or herpes virus, and other underlying diseases, principally autoimmune disorders and cancers, as mentioned previously.

It is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar.  Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age.

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 from around the world who were interested in studying the histiocytic disorders gathered in Philadelphia and formed the Histiocyte Society.  Funds raised by the Histiocytosis Association, as well as national subgroups, have financed research that has led to significant breakthroughs in the diagnosis and treatment of HLH during the past 15 years.  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 immunosuppressive and anti-inflammatory therapy.

Latest HLH Educational Webinar

Symptoms

The symptoms of the primary and secondary forms 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.
  • 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.
  • Skin rash, variable (30% of patients).
  • Enlarged lymph nodes.

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.

CNS (central nervous system) involvement occurs in 50% of patients and may be present at the time of disease onset, or it can develop later.

A wide variety of symptoms of CNS disease include:

  • Irritability.
  • Seizures.
  • Fatigue.
  • Low or abnormally increased muscle tone.
  • Difficulty with coordination.
  • Weakness of face/eye nerves.
  • Sudden blindness.
  • Paralysis and coma (very rare).

On bone marrow examination, an abnormality in which histiocytes are “eating” other blood cells (also known as hemophagocytosis) can be detected. When prominent, this is a very useful diagnostic marker. Although the disease was named after this phenomenon, this symptom may be absent at onset or even throughout the course of the disease.

The Histiocyte Society has created diagnostic guidelines and recommendations concerning the treatment of HLH.  The HLH-2004 research study, concluded at the end of 2011, is used only at institutions with IRB (Institutional Review Board) approval and appropriate informal patient/family consent.   The Histiocyte Society recommends the use of the HLH-94 treatment in conjunction with HLH-2004 diagnostic criteria as the standard of care until further analysis/publications recommend otherwise.

Diagnosis and Treatment

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.   A set of diagnostic criteria was recommended by the Histiocyte Society for use in the HLH-2004 research protocol, and this was revised in 2007.  This includes diagnosis of a specific gene defect and/or the presence of at least five of the following eight criteria:  (Note:  The understanding of pathology underlying HLH/FHL disease is evolving, and recommended “diagnostic” criteria will be revised in upcoming years.)

  • Low or absent NK (natural killer) cell function.
  • Prolonged fever.
  • Blood cell abnormalities (low white cells, low red cells, low platelets).
  • Enlarged spleen.
  • Increased triglycerides (fat) or decreased fibrinogen (protein necessary for clotting) in the blood.
  • Increased ferritin (protein that stores iron) in the blood.
  • Abnormal bone marrow test evidence of hemophagocytosis but not malignancy or other cause.
  • Abnormally high CD25 (also known as sIL2ra) in the blood indicating abnormally increased T-cell activation.

The test for low or absent natural killer cell (NK) function has been found useful in assisting to make a clinical diagnosis of HLH.  This abnormality is found in many  patients with FHL, as well as in many cases of secondary disease but rarely in the X-linked forms.

However, it is just one piece of information and should not be used to determine the diagnosis of HLH as primary or secondary.  NK function cannot be determined before birth, and it may not be reliably studied until a child is at least 6 weeks of age. FHL is suspected if siblings have been diagnosed with HLH, if symptoms intensify during treatment for HLH, or if symptoms return after therapy has been stopped.

Since it is difficult to tell the difference between secondary HLH and FHL, any case of HLH should be considered for genetic testing to confirm the diagnosis.  Since 1999, at least seven defective genes have been identified.  Autosomal recessive:  PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A.  X-linked:  SH2D1A, BIRC4.

There are some FHL patients (approximately 30%) 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:

Cincinnati Children’s Hospital, Cincinnati, Ohio
http://www.cincinnatichildrens.org/hlh/

Karolinska University Hospital, Stockholm, Sweden
Jan-Inge Henter, MD
jan-inge.henter@ki.se

University Medical Center, Hamburg, Germany
Gritta Janka, MD
janka@uke.uni-hamburg.de

Gene Tests Clinic Directory
http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic?db=GeneTests

New Treatment Approved in 2018

US Federal Drug Administration (FDA) Approves Gamifant® (emapalumab-lzsg), the First and Only Treatment Indicated for Primary Hemophagocytic Lymphohistiocytosis (HLH). Read the full press release to get more information here.
*This is not an endorsement of any specific treatment or drug. All treatment should be reviewed by your medical team to ensure the best treatment plan is developed for you.

Additional Information

In 1994, as a result of an international cooperative effort, the Histiocyte Society created the first treatment protocol for patients with HLH/FHL.  This included a combination of chemotherapy, immunotherapy and steroids, as well as antibiotics and 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 week #8.  This protocol has been widely accepted internationally and is used in numerous countries on all continents but should only be used as a research study.  HLH-2004 closed at the end of 2011. A new pilot clinical trial for the treatment of HLH, called "HIT HLH," has opened in the U.S. at a network of participating sites (see www.clinicaltrials.gov) and a companion study is expected to open in Europe soon. This protocol combines two effective strategies for HLH treatment. In order to participate in this trial, patients must be treated at a participating center. There is also an update article available about the study and the role played by interferon gamma (INFγ) in the development and maintenance of HLH available here.

There are cases of secondary HLH that can resolve spontaneously or after treatment of the underlying disease, without the use of chemotherapy.  The treatment should be guided in part by the severity of the condition, as well as the cause of the disease.

FHL, however, when not treated, is usually rapidly fatal with an average historical survival of about 2 months.  The treatment included in the HLH-2004 research protocol is intended to achieve stability of the disease symptoms so that a patient can then receive a stem-cell transplant, which is necessary for a cure.

In recent years, some transplant centers have adopted the use of reduced intensity conditioning (or “RIC”) to prepare for the stem cell transplant. This approach offers the possibility of better survival with stem cell transplant than the intensive chemotherapy protocols previously used.

As research continues, the outcome for patients with HLH/FHL has improved greatly in recent years.  Approximately two-thirds of children with HLH who undergo transplantation can expect to be cured of their disease.  However, there are a number of complications that can occur during the process of transplant, 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 results of transplantation are generally better when the procedure is performed at a major pediatric transplant center where the doctors are familiar with this disease.  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.

HLH FAQ

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.

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.

Choose from the following Fact Sheets:

Histiocytic Disorders Overall FAQ