Hemophagocytic lymphohistiocytosis

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What is the definition of hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal clinical syndrome of severe pathologic immune activation, characterized by signs and symptoms of excessive inflammation. It commonly appears in infancy but can be found in any age group. There are both genetic (primary) and acquired (secondary) forms. Immunologic basis for HLH is presumed because of its inflammatory nature and findings of specific cytotoxic and immune abnormalities in patients. HLH remains a syndromic disorder with a unique pattern of clinical findings and diagnostic criteria.

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What are the clinical signs of HLH?

• Fever

• Hepatosplenomegaly

• Lymphadenopathy

• Jaundice

• Rash

• Easy bruisability and pallor

• Central nervous system (CNS) involvement (seizures, ataxia, hemiplegia, mental status changes, and irritability)

• Abdominal pain, vomiting, and diarrhea

• Feeding problems with failure to thrive (especially in infants)

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How is HLH diagnosed?

The prompt diagnosis of HLH can be difficult because individual signs or symptoms may overlap with a number of clinical entities. A methodical approach is necessary to initiate effective treatment in a timely manner. Most of the diagnostic patterns of HLH are caused by pathologic inflammation. The Histiocyte Society used a standard definition of HLH in the HLH-94 clinical trial, which was later revised for the HLH-2004 trial and serves as the current diagnostic criteria for HLH ( Box 44.1 ). Confirmatory genetic testing is useful to predict the risk of future recurrence, determine criteria for hematopoietic cell transplant (HCT), and identify predisposition syndromes that may affect additional family members but should not delay diagnosis and initiation of treatment.

A high index of suspicion is required for diagnosing HLH; children with unexplained fever of more than 5 days duration should have a serum ferritin checked. Ferritin is an acute phase reactant. Ferritin levels of greater than 3000 ng/mL should raise suspicion for HLH and levels greater than 10,000 ng/mL are strongly associated with HLH. It is advisable that serum ferritin is analyzed on a few occasions because in the early phase of HLH ferritin may not be very elevated.

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What are pathologic features of HLH?

The pathologic hallmark of this disease is an aggressive proliferation and accumulation of lymphocytes and mature macrophages, often displaying hemophagocytosis ( Figure 44.1 ), seen anywhere within the spleen, lymph nodes, bone marrow, liver, and cerebral spinal fluid in affected patients. The uncontrolled growth is nonmalignant and does not appear clonal. In the liver, histology consistent with chronic persistent hepatitis is commonly found.

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What leads to the development of HLH?

The development of HLH is centered around triggering of the immune system, with the majority of cases triggered by viral infection. Nevertheless, any infectious agent can result in HLH in a susceptible host. The primary defense mechanism against viruses is provided by natural killer (NK) cells. Patients with familial HLH have defective NK cell function in which NK cells are unable to eliminate viruses, which results in the activation of T-cells. Because T cells do not have prior memory of eliminating viruses, ineffective activation and proliferation of T cells occurs, and these T cells secrete various cytokines, leading to the activation of macrophages. Activated macrophages further secrete various cytokines, leading to various symptoms related to HLH and ultimately organ injury ( Figure 44.2 ).

Primary HLH is linked to chromosomes 9 and 10 and in approximately 50% to 75% of patients, the disease is hereditary, with an autosomal recessive trait pattern. Various mutations, deletions, or insertions that cause frameshift or missense mutation in perforin genes (PRF1 and PRF2) , MUNC 13-4, and syntaxin 11 and others have been reported ( Table 44.1 ). These lead to impaired perforin production and function, granule exocytosis, intracellular trafficking, and cytolytic activity involving the interactions between NK cells and its target. In patients with acquired HLH, the impairment of NK cells and cytotoxic T cells is less understood but may be related to viral and/or cytokine effects on specific immune functions.

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