The prevalence of HLH is estimated to occur in 1.2 cases per million, but like most rare diseases, it is difficult to estimate its true prevalence and incidence. FHL occurs in about 1 in 50,000 individuals. Secondary HLH is more common that FHL and both are often found in young infants and children but can present itself at any age.
 

Primary / Familial Hemophagocytic Lymphohistiocytosis (FHL) is found in those individuals that have an altered or mutated form of certain genes. There are 4 genes that cause FHL identified. Those 4 genes are PRF1, UNC13D, STX11, and STXBP2. Normally, these genes play a critical role in the body’s immune response to an infection. But in FHL, these genes are mutated, meaning that the proteins they encode are either ineffective or absent and therefore the immune system can not do its job properly. The immune system cells begin to attack the body as opposed to the infection, and slowly these abnormal cells begin to accumulate leading to inflammation. The inflammation causes tissue destruction, and the cycle continues.

    Those who are diagnosed with Secondary Hemophagocytic Lymphohistiocytosis have no known genetic predisposition nor a family history of the disease. Rather, they typically have an underlying condition such as a bacterial, fungal, or viral infection, an autoimmune disease, or cancer. In these instances, the underlying disease or condition triggers a heightened or abnormal immune response in the body for reasons not yet fully understood. Like FHL, the immune cells attack healthy tissues and causes inflammation in Secondary HLH. Some conditions associated with Secondary HLH are Epstein-Barr virus, systemic lupus erythematosus, and non-Hodgkin lymphoma.

Patients with HLH have a variety of symptoms; many of which are nonspecific. Nonspecific symptoms are symptoms that are common among a number of ailments, making a correct diagnosis very tough. Symptoms may include persistent high fever, enlarged liver, jaundice, spleen and lymph nodes, skin rash, irritability and fatigues and coordination problems.
 

A correct diagnosis can only be made after a thorough clinical evaluation, examining patient’s medical history, and utilizing specialized tests. A diagnosis can be established if a genetic test has identified a mutation in one of the genes that cause FHL. A diagnosis can also be made if 5 out of the following 8 symptoms are present. These 8 symptoms are:

1) Persistent high fever

2) Enlarged spleen

3) Low number of blood cells

4) Elevated  fat molecules call triglycerides in the blood

5) Hemophagocytosis which is destruction of blood cells in the bone marrow

6) Low NK/immune cell activity

7) Ferritinemia which is high levels of a molecule that binds to iron

8) Elevated IL-2 receptors in the blood.

The treatment process for HLH typically requires a team of specialists. The specific care depends on numerous factors such as the severity of symptoms, the age of onset and the underlying condition or cause. In Secondary HLH, it may be necessary to treat the underlying condition, potentially with antibiotics or antiviral medication. In some cases of HLH, treatment could include immunosuppressive drugs that target and destroy the hyperactive immune system cells. If a patient has not responded well to the first line treatment options, they may be recommended for allogeneic stem cell transplant, which is a procedure where healthy stem cells from a matched donor is transplanted to the patient. In 2018, the FDA approved Gamifant® (emapalumab), indicated for the treatment of pediatric and adult patients with FHL who have refractory, recurrent or progressive disease or cannot tolerate conventional HLH therapy.

HLH typically has a high mortality rate, including cases treated adequately. FHL prognosis is poor; those that do not receive treatment have a median survival of 2-6 months whereas of those who do receive treatment only 25% will survive 5 years. The prognosis for those with Secondary HLH varies and is correlated with the underlying condition.
 

https://www.histio.org/document.doc?id=243

https://en.wikipedia.org/wiki/Hemophagocytic_lymphohistiocytosis

https://rarediseases.info.nih.gov/diseases/6589/hemophagocytic-lymphohistiocytosis

https://rarediseases.org/rare-diseases/hemophagocytic-lymphohistiocytosis/