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Hemophagocytic Syndromes Sourced From Histiocytosis Association of America

The Cavan Tommy Hoey Trust  Rare Disease Day Reception Northern Ireland Assembly 2010  Cavan Pictured on the day

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children. Although physicians have written about the disorder over the years, it has been only in the last few years that it has received more widespread attention. The prevalence of HLH is 1.2 in every 1,000,000 children under the age of 15.

In 1985, physicians from all over the world who were interested in studying the histiocyte and disorders related to this cell created the Histiocyte Society. Thanks to their research, in part financed by the Histiocytosis Association of America (HAA) and national subgroups, we now have a better understanding of the disease, as well as dramatically improved treatments. With growing knowledge, there is also increased awareness of the disease among nonspecialized physicians.

The disease usually presents with fever and sometimes other symptoms of an infection. In many cases, a pathogen (viral, bacterial, etc.) can be identified. The human body contains many cells including T-cells and histiocytes that fight infection. The activation of these cells causes an inflammatory reaction in the body. Normally, when the pathogen has been eliminated, the inflammatory reaction is turned off, and the immune system returns to its steady state. In HLH patients, due to defect of the immune system, the inflammatory reaction persists and causes the symptoms of HLH.

What is the cause of this severe immune dysregulation?

We currently know that HLH occurs either on the basis of a genetic defect or as a secondary form with underlying diseases such as infections, cancer, or rheumatic diseases. In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from both the mother and the father (autosomal recessive inheritance). FHL is diagnosed if there is more than one affected child in the family and/or a gene defect has been determined. FHL should be suspected if the symptoms do not disappear with treatment or if symptoms recur when therapy has been stopped. The onset of FHL is usually early in life, and a persistent cure can only be achieved with BMT (bone marrow transplantation). It is important to know that infections can trigger both the familial and the secondary disease.

So far, 3 gene defects have been identified, which account for approximately 50% to 80% of the familial cases, depending on the population that has been analyzed. Two of the genes, PRF1 and UNC13D, are responsible for the synthesis of proteins, perforin, and MUNC13-4 that are involved in the killing process of infectious pathogens. They are believed to also have a function in switching off immune responses. The precise mechanism, however, is not fully understood. A third defect affecting the Syntaxin 11 (STX11) gene has so far only been detected in patients of Turkish origin. The function of the mutated protein remains to be elucidated. There remains a considerable percentage of FHL patients with no known underlying gene defect.

In cases of secondary HLH, a condition of temporary immunodeficiency seems to contribute to the development of the disease.

Symptoms
Typical symptoms of HLH besides persistent fever are pallor (paleness), jaundice, liver and spleen enlargement, and neurological symptoms, such as irritability or even seizures. The involvement of the bone marrow, the site of blood cell production, can lead to severe decline of the blood cell counts (red and white blood cells and platelets). On bone marrow examination, histiocytes that are “eating” other blood cells (also known as phagocytosis) can be detected. Although the disease was named after this phenomenon, it can be absent at the onset or even throughout the course of the disease.

Because symptoms can vary widely, it is sometimes difficult for the physician to make a diagnosis of HLH early in the course of the disease without the help of specialized laboratory tests. To facilitate a rapid and accurate diagnosis, the Histiocyte Society has created diagnostic guidelines and recommendations concerning the treatment of HLH. This is known as the HLH-2004 treatment protocol.

Diagnosis & Treatment
How is HLH diagnosed?

It is sometimes difficult to establish the diagnosis of HLH, and the combination of the clinical picture and certain laboratory test criteria is required. A test that has been found very useful in substantiating a clinical diagnosis of HLH is absent or low NK (natural killer)-cell function. This is found in 90% of patients with FHL, as well as in many cases of secondary disease. Results of NK-cell function testing are generally reliable if the blood sample is properly shipped and tested in less than 24 hours. NK function cannot be determined prenatally, and it may not be reliably studied until a child is several weeks old. Notably, this test does not discriminate between familial and secondary disease.

Detection of perforin by staining of lymphocytes and analysis by flow cytometry is a highly reliable method for predicting the likelihood of the PRF1 gene mutation as the cause of FHL in a given patient. This test can also be used with reasonable predictive potential to screen parents and siblings to determine whether they might be carriers of PRF1 mutations. This test is not available prenatally.

Another test recently described analyzes the expression of a molecule on the surface of NK-cells (CD107) by flow cytometry that marks NK-cell degranulation. Reduced expression can predict mutations in the UNC13D gene. This test also requires specially prepared blood samples and cannot be used prenatally.

Genetic testing is recommended in cases of suspected FHL and confirms the diagnosis. Usually a blood sample is used. Even in the event of death, salvaged tissue can be tested. Once the genetic defect of a patient is known, the parents and siblings can be easily tested to determine if they are carriers for this specific defect. In such cases, prenatal diagnosis is possible as well.

How is HLH treated?

Without treatment, FHL is usually rapidly fatal with a median survival of about 2 months. The current treatment protocol, HLH 2004, provides recommendations for HLH therapy with a combination of immunosuppressive drugs and chemotherapy. The protocol has been accepted internationally and is used in many countries worldwide. In order to prevent early death or severe persisting organ damage, therapy must be initiated in a timely manner. In FHL cases, only temporary remission will be achieved. For a definite cure, the patient must undergo BMT.

With the former HLH-94 protocol and the now active HLH-2004 protocol, high remission rates and cure rates with BMT have been reported.

Secondary HLH sometimes resolves spontaneously or after treatment of the underlying disease. In some cases, modified immunochemotherapy can be applied, while in others, full immunochemotherapy is required.

How can a genetic counselor help?

Genetic counselors are members of the health care team who work closely with referring physicians and other health care professionals to provide accurate, relevant, and consistent information to families at risk of inherited diseases, including HLH and other immunodeficiency disorders. Genetic counselors are trained to identify families at risk, provide information to families about a specific disorder, analyze inheritance patterns and risk of recurrence in a family, and discuss available options for testing. For disorders in which genetic testing is available, the genetic counselor helps families evaluate the potential risks and benefits of genetic testing, arranges for appropriate testing and collection of samples, and interprets and communicates the results of genetic testing to families in a meaningfuland compassionate manner. Genetic counselors also provide supportive counseling throughout this process and can assist with referrals to other health care providers and support services. Genetic counselors do not make decisions for their patients; rather they provide the information that each family needs to make decisions that are consistent with their own values and beliefs.

Where do I get more information?

The study center of the international HLH-2004 protocol is located in Stockholm, Sweden. There are several subcenters throughout the world that have clinical expertise.

It is recommended that genetic testing be coordinated through and requested by referring physicians or genetic counselors. There are several institutions that provide information and perform genetic testing.

For more information, please contact the following persons:

North America
Lisa Filipovich, MD
Cincinnati Children's Hospital
Cincinnati, Ohio, U.S.A.
Lisa.Filipovich@cchmc.org

Northern Europe
Jan-Inge Henter, MD
Childhood Cancer Research Unit
Karolinska University Hospital
Stockholm, Sweden
jan-inge.henter@ki.se

Central and Eastern Europe
Gritta Janka, MD
Pediatric Hematology and Oncology
University Medical Center
Hamburg, Germany
janka@uke.uni-hamburg.de

Southern Europe
Maurizio Aricò, MD
Pediatric Hematology and Oncology
Children's Hospital
Palermo, Italy
arico@ospedalecivicopa.org

Japan
Eiichi Ishii, MD
Department of Pediatrics
Saga University
Saga, Japan
ishiei@med.saga-u.ac.jp

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