An unfortunate answer
A few hours after the procedures, you receive an urgent call from the hematologist to come view the slides. The aspirate reveals numerous histiocytes in the process of hemophagocytosis. Vacuolized histiocytes are also visible in the CSF. The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is made and the patient is evaluated emergently by the oncology consultants for chemotherapy.
That night, your patient has an acute decompensation, with increased work of breathing, decreased O2 saturation, and hypotension. He is intubated and transferred to the PICU. The following day, chemotherapy with the HLH-2004 protocol—cyclosporine, etoposide, and dexamethasone is initiated.
Over the next week, the boy develops renal failure, fulminant hepatic failure, worsening coagulopathy, an inability to maintain serum glucose hemostasis, and persistent seizures. Eight days after the diagnosis was established, and one day short of being 3 months old, support is withdrawn and he is pronounced dead.
The challenge: A nonspecific presentation
Hemophagocytic lymphohistiocytosis, also known as hemophagocytic syndrome, encompasses a heterogeneous group of disorders that share a nonspecific clinical picture comprising fever, hepatosplenomegaly, and cytopenia resulting from uncontrolled macrophage activation and subsequent phagocytosis of blood cells.
Two distinct forms of the disease have been described: a primary, or familial, form, inherited as an autosomal-recessive disorder, and a secondary, or sporadic, form that has been associated with a variety of infections, autoimmune diseases, and malignancies, and with several genetic immunodeficiency syndromes.
A retrospective Swedish study estimated the annual incidence of familial HLH to be 1.2 cases for every 100,000 children.3 Peak age of diagnosis is between 1 and 6 months, with 70% to 80% of cases presenting before 1 year. Gender distribution is thought to be even.
Pathophysiology Although the pathophysiology of HLH is poorly understood, it is hypothesized to be a disorder of immune regulation, with a failure of cytolytic lymphocyte function resulting in hypersecretion of cytokines and subsequent uncontrolled activation of lymphocytes and macrophages. The sera of patients who have HLH have been found to have a strikingly high level of numerous cytokines, including interferon gamma, TNF alpha. Several studies have demonstrated markedly reduced or complete absence of cytotoxic T cell and natural killer activity in patients with HLH. The cytotoxic T lymphocytes and natural killer cells are effector lymphocytes that share a common cytotoxic pathway required for defense against viral infections. This cytotoxic pathway is disrupted in HLH; when the disruption occurs with intercurrent infection, it induces lethal immune deregulation (in some forms of HLH).
Two genetic mutations have been identified in patients with familial HLH. One gene is on chromosome 10 and encodes a protein called perforin, an important mediator of cytotoxic T cells and natural killer cell cytotoxicity. Cytotoxic cells kill their targets primarily through a localized secretion of toxic granules, and perforin is thought to be essential for this process. This mutation is estimated to account for 20% to 40% of cases of familial HLH. More recently, mutations in the hMunc13-4 gene, on chromosome 17, have been identified in a subset of patients with familial HLH. Like perforin, hMunc13-4 also participates in cytotoxic granule release. Without proper cytotoxic granule release, the activity of activated macrophages goes unchecked and leads to cytokine release and phagocytosis.
A variety of infectious agents can provoke secondary HLH and can trigger the familial form of the disorder. Viruses are most often implicated, with EBV reported to be the most common cause. Other viruses reported to trigger HLH include CMV, human herpesvirus, varicella-zoster virus, herpes simplex virus, adenoviruses, and parvovirus B19. EBV-associated HLH is important to diagnose because it is associated with a more fulminant course and higher mortality rate.
Diagnosis Signs and symptoms of HLH vary widely. The principal clinical features are fever and hepatosplenomegaly. Other common clinical findings include rash, lymphadenopathy, and neurologic symptoms. The latter are seen in as many as 75% of cases, may be the presenting sign, are highly variable, and include seizures, lethargy, cranial nerve findings, abnormal tone, and ataxia.
Common laboratory findings include pancytopenia, direct hyperbilirubinemia, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia. Hyponatremia, hypoalbuminemia, elevated LDH, coagulopathy, transaminitis, and CSF pleocytosis with mononuclear cells and an elevated protein level have also been reported.
The pathognomonic histopathologic finding is numerous histiocytes actively phagocytosing blood cells—erythrocytes, mostly, but also leukocytes and platelets. The most frequently involved organs are bone marrow, lymph nodes, the CNS, liver, and spleen. An initial bone marrow specimen may not demonstrate phagocytosis; repeat aspiration may be necessary to establish the diagnosis. A key learning point, therefore, is that an initially negative bone marrow specimen should not rule out HLH or delay immediate treatment if other diagnostic criteria are met.
The familial and the infectious forms of HLH are often indistinguishable clinically. Diagnosis of the familial form can be made by an established positive family history or demonstration of mutations in the perforin or hMunc13-4 genes. Also suspect familial HLH in the presence of parental consanguinity or age of onset earlier than 1 or 2 years. Measurement of perforin expression in natural killer cells and CD8+ lymphocytes and mutational analysis of the perforin and hMunc13-4 genes can be performed in patients with HLH.
Prognosis and therapy Without bone marrow transplantation, familial HLH is uniformly fatal soon after birth; median survival is two to three months. The prognosis is better in the majority of secondary forms, with recovery reported in 60% to 70% of cases. The exception is EBV-associated HLH, in which recovery is thought to be much less likely. In a 1996 study of 122 patients with HLH, overall estimated five-year survival was 22%. Among patients who underwent bone marrow transplantation, five-year survival was 66%; for those receiving chemotherapy with etoposide or another single chemotherapeutic agent, five-year survival was 10.1%.
In 1994, the Histiocyte Society initiated a prospective collaborative therapeutic study of the disorder (HLH-94) with the aim of improving survival. The protocol comprised an initial eight weeks of treatment with etoposide and dexamethasone. Following that, children with familial or recurring HLH, or both, continued with etoposide and dexamethasone in combination with cyclosporine for as long as one year. Subsequently, bone marrow transplantation (the only curative treatment for primary HLH) was performed if a donor became available. Intrathecal methotrexate was also used in cases of CNS involvement. This protocol resulted in an overall survival of 55% at median follow-up of 3.1 years and a three-year probability of survival of 62% after marrow transplantation. Although survival of children with HLH is still poor, therefore, it has greatly improved over the past decade. In the most recent revision of this protocol (HLH-2004), cyclosporine is administered at the start of therapy.
Although it can be difficult to distinguish the primary form of HLH from secondary forms, the distinction is important: Familial HLH is uniformly lethal without bone marrow transplantation. A child who has presumed secondary HLH and who has experienced complete resolution following immunochemotherapy should be monitored carefully for relapse.
Early treatment is thought to be beneficial when feasible because a response to treatment is less likely subsequent to CNS involvement and bone marrow failure.
The diagnosis of HLH is challenging—and often delayed for several reasons, including this rare disorder's variable, nonspecific manifestations and clinicians' lack of awareness of it. Because of the aggressive nature of HLH and the likely need for early treatment, early diagnosis is crucial. Consider HLH, therefore, in any child in whom fever, hepatosplenomegaly, and cytopenia go unexplained, because early treatment may be life-saving