HLH is not a single disease, but a group of rare disorders of the immune system. Children and adults with these disorders develop a hyperactive yet ineffective immune response, commonly following infections or when the child or adult has cancer or an underlying rheumatologic condition.
In healthy individuals, white blood cells known as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells respond to infected, cancerous or activated cells by secreting cytokines (chemicals that recruit and activate immune cells) and releasing lytic granules that kill target cells. In patients with HLH, CTLs and NK cells commonly exhibit reduced killing activity and as a result they cannot properly halt infections or respond properly to other challenges. .
Over time, the immune system becomes over activated, with immune cells growing out of control, which damages the liver, spleen, bone marrow and brain. If HLH is not properly recognized and treated, these activated immune cells can lead to severe organ damage and death.
HLH occurs in two major forms:
Primary HLH is caused by alterations (also called mutations) at specific areas within a person's genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as genes. Genes provide the necessary instructions that our cells need to perform their different functions within our bodies.
In primary HLH, one of four genes can be affected, including PRF1, UNC13D, STX11 and STXBP2. HLH can also occur in individuals with primary immunodeficiencies such as X-linked lymphoproliferative disease (XLP1 or XLP2), Griscelli Syndrome, Chediak Higashi Syndrome and ITK deficiency. These immunodeficiencies are caused by genetic mutations.
Together these mutations (in the genes associated with HLH and the genes associated with primary immunodeficiencies) account for up to 90 percent of primary HLH cases. These mutations are believed to lead to HLH by interfering with the processes normally required to promote NK and CTL activation and killing. The genetic causes of HLH in the remaining patients with primary HLH are not known.
The mechanisms leading to secondary HLH are not well understood, but scientists think this form of the disease might occur when the function of certain cells in the immune system such as NK or CTLs are temporarily suppressed, at the same time that a trigger, like an infection, is introduced to the body.
With the exception of egg and sperm cells, each cell of the body normally has two working copies of each gene. Primary HLH caused by mutations in PRF1, UNC13D, STX11, STXBP2 is an autosomal recessive disorder. This means that both copies of one of these HLH-associated genes must be altered within the cells of the body in order for HLH to occur.
A person with primary HLH usually develops the disease because they inherit an altered copy of an HLH-associated gene from each parent. The parents are considered HLH carriers; they carry one normal and one altered copy of an HLH-associated gene in the cells of their bodies. Although they carry an altered gene copy, HLH carriers usually remain healthy and do not develop the signs and symptoms of HLH. The genetic mechanisms causing PID-associated HLH are more diverse and include both autosomal recessive (RAB27A, CHS, ITK) and X-linked (SH2D1A, XIAP) patterns of heredity.
HLH is diagnosed when an individual meets established diagnostic criteria. Currently, these criteria include:
Presence of a known HLH-causing mutation OR five of the following eight signs and symptoms:
HLH must be recognized and treated at the earliest stages to achieve the best outcomes. To diagnose this disease, specialized immunologic and genetic tests are often performed. The immunologic tests will help to determine the killing activity of NK and CTLs.
The genetic tests will determine whether a patient carries mutations in any of the known HLH-associated genes. These tests usually involve taking a blood sample, from which the white blood cells are isolated and used as a source of DNA. Subsequently, each of the HLH-associated genes is analyzed for any changes. If changes are found, they are further analyzed to determine whether they are causative of HLH or simply normal variations.
It is important to note that even if genetic test results are normal, an affected individual may still have primary HLH since scientists haven’t identified all of the genes known to cause primary HLH. Therefore, if tests don’t find an alteration in one of the known HLH genes, that does not exclude the possibility of primary HLH.
The best treatment for HLH is not known, but doctors and scientists have developed a variety of treatment protocols that are offered depending on the underlying cause and severity of symptoms. Due to the challenging and complex nature of HLH, treatment should be discussed with or given by doctors who are familiar with the disorder. At The Children’s Hospital of Philadelphia our HLH Treatment Team will care for your child.
For children with primary HLH, the first step is generally suppressing the overactive immune system. This is often done using a combination of steroids and chemotherapy, with the goal of putting the disease in remission.
After this initial treatment, children with primary HLH usually undergo allogeneic stem cell transplantation, replacing their defective immune system with a healthy one from a different person. This offers the best chance of a cure.
For children with secondary HLH, the aim is to identify and treat the underlying cause of the HLH (such as the infectious or malignant trigger). In many cases, this puts the HLH into remission. However, it is sometimes necessary to use steroids and/or chemotherapy, as in the case of primary HLH.
It should be emphasized that the severity of HLH and not its classification as primary or secondary is the deciding factor in the use of steroids and/or chemotherapy.
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Reviewed by: Kim Nichols, MD, Nishant Patel
Date: December 2013
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