Published onInternational Update
A previously healthy 7-year-old male presented with a six-day history of fever, right upper quadrant abdominal pain, vomiting and jaundice. Initial lab findings revealed: white blood cell count 15.6, hemoglobin 11, platelet 97, sodium 125, hyperbilirubinemia, elevated liver enzymes and coagulopathy. A CT scan of the abdomen noted ascites, diffuse lymphadenopathy and hepatosplenomegaly. An abdominal ultrasound revealed a mass near the porta hepatis and splenomegaly.
Further evaluation within the first days of the child’s hospitalization revealed his ferritin was elevated to 10,000 and his soluble IL-2 receptor was elevated to 22,000. His physical exam was significant for splenomegaly and lymphadenopathy. A bone marrow biopsy showed a slightly hypocellular marrow with trilineage hematopoiesis but no evidence of any hemophagocytosis or blasts. He was positive for the SAP gene mutation. He also presented with an EBV viremia/encephalitis and hepatitis. His hospital course prior to admission to The Children’s Hospital of Philadelphia was complicated by candida parapsilosis fungemia and seizures with an acute decline in mental status. He was diagnosed with X-linked lymphoproliferative syndrome and secondary hemophagocytic lymphohistiocytosis related to an EBV infection and admitted to inpatient rehabilitation due to severe deconditioning and severe cognitive and language deficits. During his hospitalization, the child received physical, occupational and speech therapies seven times per week. He also participated in cognitive group therapy five times per week with a special education teacher.
Hemophagocytic lymphohistiocytosis (HLH) is a disorder of the immune system in which there is excessive T cell activation and inflammatory cytokine production, resulting in progressive multiorgan failure if untreated. HLH is not a malignancy; it is a syndrome of excessive inflammation and tissue destruction due to an abnormal immune activation. Prompt and accurate diagnosis and timely treatment are critical.
HLH represents a spectrum of inherited and acquired conditions characterized by disturbed immune regulation. Primary or familial hemophagocytic lymphohistiocytosis (FHL) is a heterogeneous autosomal recessive genetic disorder seen primarily in infancy and early childhood. Secondary hemophagocytic lymphohistiocytosis is often diagnosed in older patients (children and adults), those with no family history associated with this form of disease, and for whom a clear trigger of the HLH episode has been identified. In practice, distinction between primary and secondary HLH is not essential for initial diagnosis and management. However, identification of a gene mutation is useful for subsequent medical management. Genetic information can be helpful in determining the likelihood of reoccurrence, the need for hematopoietic cell transplant, and the risk of HLH in family members.
Several aspects of the clinical presentation of HLH contribute to delayed diagnosis, including the rarity of the syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings. Initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis or encephalopathy. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect is identified. A set of diagnostic criteria was recommended by the HLH-2004 research protocol (revised in 2007). This includes diagnosis of a specific gene defect and/or presence of at least five of the following eight criteria:
- Fever ≥ 38.5°C
- Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for infants <4 weeks, hemoglobin <10 g/dL); platelets <100,000/microL; and absolute neutrophil count <1000/microL
- Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL)
- Hemophagocytosis in bone marrow, spleen, lymph node or liver
- Low or absent NK cell activity
- Ferritin >3000 ng/mL
- Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms
Often a diagnosis of HLH is made for a patient who only partially meets criteria because definitive HLH therapy must be initiated when there is inadequate
response to general supportive care and because of the high mortality rate of HLH in the absence of appropriate treatment. For all patients with suspected
HLH, urgent referral to a hematology or oncology specialist is required.
The goal of HLH treatment is to suppress lifethreatening inflammation by suppressing immune response. This can include a combination of chemotherapy, immunotherapy and steroids. Antibiotics and antiviral drugs may also be used. These treatments may be followed by a bone marrow or stem cell transplant in patients with persistent or recurring HLH or those with an HLH gene mutation and/or central nervous system disease.
The severe deconditioning and muscle atrophy associated with this disorder typically results in significant impairment in a child’s functional status
and compromises his or her ability to resume play and school activities. Inpatient rehabilitation and subsequent outpatient therapies, as well as the prescription of appropriate orthotic devices and assistive equipment, can be critical in facilitation of a child’s return to functional independence in daily
activities at home and in the community.
This child made significant gains in strength, endurance, cognition, balance, motor planning and coordination during his stay in rehabilitation. He is currently functioning close to baseline level of independence. The child was discharged with continued outpatient physical, occupational and speech therapies.