What is HLH?

HLH or Haemophagocytic Lymphohistiocytosis in Children

Haemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is seen in children and adults of all ages. Depending on the etiology, HLH can be divided into genetic (i.e., primary) and acquired (i.e., secondary) forms. In recent years much progress has been made in understanding the underlying mechanism of primary HLH.

However, understanding secondary HLH has been much more of a challenge. Infection is a common trigger both in those with a genetic predisposition and in acquired cases. Other triggers include autoimmune disease and cancer. Prompt initiation of treatment is essential for the survival of affected patients. Often the greatest barrier to a successful outcome is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.

HLH is primarily a paediatric syndrome, with infants being most commonly affected. A large review from cases reported in the United States revealed a prevalence of 1 in 100.000 children (looking back during that period, 1 in every 100.000 children living in that area had a diagnosis of HLH). It is likely that this number is too low, as this does not include patients that had not been diagnosed before passing away.

Based on reports from several referral hospitals it is estimated approximately 1 child in 3000 children admitted to the hospital will have HLH. This estimation has increased from previous reports, presumably reflecting previous under diagnosis of the condition. Girls and boys are equally affected. In some families with proven primary HLH, subsequent children are at increased risk of also being affected with the genetic form of HLH.

HLH is a syndrome of excessive inflammation and tissue destruction due to abnormal immune activation. In general, the excessive inflammation is thought to be caused by a lack of normal control of activated macrophages and lymphocytes (white blood cells important for immune function).

Inflammation is triggered most commonly by a viral infection, though any infection can trigger HLH. Also autoimmune disorders such as arthritis and lupus, but also malignancies have been shown to trigger HLH.

Excessive inflammation leads to multiple organ failure:

• Respiratory failure is a common symptom, which may lead to an urgent need for mechanical ventilation or ultimately, death from acute respiratory distress syndrome.
• Severe hypotension (low blood pressure) often requires cardiac support including vasoactive medication.
• Renal dysfunction occurs in many patients and may require dialysis.
• Skin manifestations can be quite varied with all types of rashes described.
• Bleeding is also a common manifestation of HLH. It may be due to altered clotting capacity from liver failure, low platelets from bone marrow failure, or platelet function defects associated with an underlying genetic defect.

Clinical Presentation
HLH presents as a febrile illness associated with multiple organ involvement. Thus, initial signs and symptoms of HLH can mimic common infections. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect has been identified.

The most common symptoms of HLH are unremitting fever, enlarged spleen, and blood abnormalities called cytopenia (low platelets, red and white blood cells) and coagulopathies (bleeding and clotting disorders). Some severely ill patients, present with central nervous system involvement. Laboratory tests reveal very high ferritin levels, increased concentration of inflammatory mediators (cytokines), raised triglyceride levels, deranged clotting, and elevated liver enzymes. These derangements found in the blood are very similar to those seen in severe infection.

Diagnosis is based either on proving a known genetic defect for primary HLH or it has to be based on clinical signs and symptoms. However, these signs and symptoms are not specific to HLH and many are seen in infection too.

It has been agreed that if a patient has at least 5 of the following symptoms it is very likely HLH:

1. Fever ≥ 38.5°C
2. Enlarged spleen
3. Peripheral blood cytopenia (low blood cells)
4. Raised triglyceride levels or low fibrinogen
5. Signs of aggressive inflammation in spleen, lymph node, or liver (on biopsy)
6. Low NK cell (another specific immune cell) activity
7. Raised Ferritin
8. Elevated soluble CD25 (a cytokine receptor, inflammation molecule)

The first rule is not to overlook signs of excessive inflammation and to calm down the hyperactivated immunological state as soon as possible. In addition, to improve outcomes, it is essential to search for the disorders underlying the HLH and provide the disorder-appropriate treatment (antibiotics for bacterial infection, antivirals for some viral infections, cancer treatment for malignancies etc).
The first line of treatment is however supportive as described in the pathophysiology section. Often these patients require multiple organ support including ventilatory, cardiac, renal and liver. Finally anti-inflammatory treatment aimed at reducing the hyperactive state of the immune system is essential.

Prognosis in HLH is very serious. Genetic HLH is always lethal if adequate therapy is not administered. Similarly, severe acquired cases often lead to death. In case studies of children with secondary HLH mortality has been reported as high as 50-70%. Many patients with HLH do not survive once being diagnosed, due to severe bleeding disorders, secondary infections, or multiple organ failure. It is paramount to recognize HLH from serious infections, only then can appropriate treatment be initiated to increase the chance of survival.

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