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
Lisa Filipovich, MD
Karolinska University Hospital, Stockholm, Sweden
Jan-Inge Henter, MD
University Medical Center, Hamburg, Germany
Gritta Janka, MD
Gene Tests Clinic Directory
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 is expected to close 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 www.histio.org/HITHLHtrial) 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 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.