Is hypothermia a sign of Hemophagocytic Lymphohistiocytosis (HLH)?

From the Guidelines

Hypothermia can be a sign of hemophagocytic lymphohistiocytosis (HLH), though it is not among the most common or diagnostic features. HLH is a severe systemic inflammatory syndrome characterized by excessive immune activation that can present with fever, hepatosplenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, and hemophagocytosis in bone marrow or other tissues. While persistent fever is a hallmark feature of HLH, paradoxical hypothermia can occasionally occur, particularly in severe cases or advanced disease states. This hypothermia may result from cytokine dysregulation affecting the hypothalamic temperature regulation center or from overwhelming systemic inflammation leading to cardiovascular compromise. If hypothermia is observed in a patient with other features suggestive of HLH, prompt diagnostic workup should be initiated, including complete blood count, ferritin, triglycerides, fibrinogen, soluble IL-2 receptor levels, and bone marrow examination. Key features to consider in the diagnosis of HLH, as suggested by studies such as 1, include the presence of fever, hepatosplenomegaly, and cytopenias, along with elevated levels of ferritin, triglycerides, and soluble CD25. Treatment of HLH typically involves immunosuppressive therapy with dexamethasone and etoposide according to HLH-94 or HLH-2004 protocols, along with treatment of any underlying triggers such as infections or malignancies, as outlined in studies like 1 and 1. It's also important to note that hypothermia can be a sign of sepsis, as indicated in 1, which may be a related or complicating condition in patients with HLH. The presence of hypothermia in suspected HLH may indicate severe disease requiring urgent intervention. Some key points to consider in the management of HLH include:

• Prompt recognition and diagnosis of HLH
• Initiation of immunosuppressive therapy
• Treatment of underlying triggers
• Monitoring for complications such as sepsis and organ dysfunction. Overall, the management of HLH requires a comprehensive approach that takes into account the severity of the disease, the presence of underlying triggers, and the potential for complications.

From the Research

Clinical Manifestations of HLH

• Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can result in end-organ damage and death 2
• The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics 2, 3
• HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm 2

Diagnostic Criteria for HLH

• The HLH-2004 protocol used in the diagnosis of HLH includes eight criteria: fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels 4
• Five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH 4

Hypothermia as a Sign of HLH

• There is no direct mention of hypothermia as a sign of HLH in the provided studies 2, 3, 5, 4, 6
• However, the studies do mention that HLH can present with a wide range of clinical manifestations, including fever, jaundice, edema, and elevated creatinine 2, 5

Treatment and Management of HLH

• Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response 2
• The HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids 4
• Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease 4