Hemophagocytic Lymphohistiocytosis (HLH) as a Mimicker of Sepsis in the Emergency Department

Introduction

Healthcare personnel often meet patients presenting with a variety of symptoms in the fast-paced, high-stress setting of the Emergency Department (ED), demanding frequent prompt and correct evaluation and treatment. Hemophagocytic lymphohistiocytosis (HLH) stands out as a particularly challenging disease, as seen by ED doctors. Uncontrolled immune system activation, which can resemble the clinical signs of sepsis, is the hallmark of HLH, which is a rare and possibly fatal condition. HLH presents a substantial difficulty for identification and diagnosis in the ED due to its rarity and symptoms that overlap with sepsis.

Sepsis, a sickness caused by the body's intensified reaction to infection, frequently presents in the ED when prompt treatment is essential. But HLH's clinical signs, such as fever, hepatosplenomegaly (enlarged liver and spleen), cytopenias, and coagulopathy, are quite similar to sepsis. Due to these similarities, HLH frequently goes unnoticed or is incorrectly diagnosed, possibly delaying the start of life-saving therapy for these seriously sick individuals.

What Is Hemophagocytic Lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a fatal, hyper-inflammatory illness that causes multi-organ failure. HLH develops when lymphocytes and histiocytes start attacking the body instead of only germs and viruses. Histiocytes are specialized phagocytes and, hence, can engulf and get rid of infections. Lymphocytes are a kind of white blood cell that includes T cells and NK (natural killer) cells. The immune system is controlled in large part by T cells and NK cells. They create cytokines, which can directly destroy infected cells and serve as signaling molecules to coordinate immune responses. However, both histiocytes and lymphocytes become excessively active in the setting of hemophagocytic lymphohistiocytosis (HLH). The overproduction of cytokines caused by this excessive activity might result in a condition described as a "cytokine storm." These hyperactive cells begin attacking numerous bodily components, such as blood cells, bone marrow, spleen, liver, lymph nodes, skin, and even the brain, in addition to releasing hazardous cytokines. This unchecked immune reaction can result in serious tissue damage and a number of potentially fatal consequences.

What Are the Distinguishing Features Seen in HLH and Not in Sepsis?

Several clinical characteristics can aid in separating HLH from sepsis:

• Fever - HLH patients frequently have a persistent fever that does not respond to broad-spectrum medications.

• Hyperferritinemia - HLH is characterized by abnormally high ferritin levels (typically more than 10,000 nanograms per milliliter), which are uncommon in sepsis.

• Hemophagocytosis - It is a characteristic of HLH that may be identified by the presence of activated macrophages engulfing blood cells in bone marrow or other organs. Hemophagocytosis is not commonly observed in sepsis.

• Cytopenias Out of Proportion - In HLH, cytopenias are frequently worse than what is typical in sepsis.

• Hypertriglyceridemia and Hypofibrinogenemia - Both hypertriglyceridemia and hypofibrinogenemia are consistently linked to HLH in laboratory tests.

It can be difficult to diagnose HLH, although certain criteria (HLH-2004 criteria) have been devised to help with diagnosis. At least five out of the eight below-mentioned criteria should be present.

• Extremely high ferritin levels (greater than 500 micrograms per liter) are a crucial indicator.

• Evidence of cytopenias affecting at least two of the three lineages of the peripheral blood (neutrophils, platelets, and hemoglobin).

• Hemophagocytosis should be seen in the lymph nodes, spleen, or bone marrow.

• Elevated levels of soluble CD25 (soluble interleukin 2 receptors) are frequently seen.

• Both hypertriglyceridemia and hypofibrinogenemia should be present, according to the results of the lab tests.

• Persistent fever.

• Enlarged spleen.

• NK cells are either absent or present in fewer numbers.

What Is the Role Played by Clinicians in the ED in Distinguishing Hemophagocytic Lymphohistiocytosis (HLH) From Sepsis?

Hemophagocytic lymphohistiocytosis (HLH) exhibits vague signs and symptoms, postponing diagnosis and effective treatment. Frequent signs and symptoms of HLH include fever, splenomegaly (enlarged spleen), hyperferritinemia (increased ferritin level), cytopenias (low level of red blood cells, white blood cells, or platelets), coagulopathies (bleeding disorder), abnormal liver tests, and hypertriglyceridemia (increased triglycerides). The presenting symptoms may resemble frequent ED presentations, such as sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like conditions like coronavirus disease 2019 (COVID-19). If the doctor recognizes HLH as a component of the differential diagnosis, the majority of the required screening may be started in the ED. Diagnostic assessment methods have been developed to risk-stratify individuals. While the majority of the first care consists of routine resuscitation for underlying triggering causes, disease-targeted medications can be taken into consideration early if the conversation with a hematologist is started.

• Clinical Assessment: The first step is to acknowledge the possibility of HLH, particularly in patients who exhibit fever, cytopenias (low blood cell counts), hepatosplenomegaly (enlarged liver and spleen), and hyperferritinemia (elevated ferritin levels), which are crucial HLH symptoms that might resemble sepsis.

• Diagnosis:

  • A complete blood count (CBC), liver function tests, a coagulation profile, ferritin levels, and inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), should all be ordered as part of a comprehensive series of laboratory testing.

  • Bone marrow aspiration is performed to check for hemophagocytosis, a defining feature of HLH in which immune cells consume blood cells in the bone marrow.

  • Perform a thorough infectious workup simultaneously to rule out other frequent causes of sepsis. This includes blood cultures, viral serology, and imaging scans to find any probable sources of infection.

• Consultation: Due to the complexities in HLH diagnosis and therapy, seek the advice of a hematologist for additional assessment and direction.

• Treatment:

  • Consider using immunosuppressive drugs like corticosteroids (like Dexamethasone) and drugs that target the immune system (like Etoposide) as an interim measure in situations where HLH is suspected but not yet proven.

  • Provide supportive care, which includes close monitoring, managing organ dysfunction, and treating any underlying infections.

• Monitoring: Keep a close eye on the patient's clinical condition, test results, and therapy response. Based on the patient's clinical course and HLH-specific characteristics, modify the treatment as necessary.

• Communication: Explain the diagnosis, the course of therapy, any potential side effects, and the significance of follow-up care to the patient and their family.

• Documentation: Keep complete and accurate records of the patient's clinical progress, diagnostic results, treatment procedures, and therapeutic response.

• Follow-up: Ensure that the patient receives the proper follow-up treatment from experts after being stabilized and released from the ED.

What Is the Treatment of HLH?

When HLH is identified, it has to be treated right away. High-dose corticosteroids, chemotherapy, and hematopoietic stem cell transplantation are frequently used as treatments (particularly for primary HLH). Treatment for the underlying disease that prompted the immune response may be necessary for secondary HLH.

Conclusion

HLH is a severe yet underestimated disease condition. Emergency doctors can play a crucial role in the early diagnosis and start of the necessary testing to speed up the course of therapy. In the emergency room, it is crucial to take into account HLH as a possible sepsis mimicker, do a thorough examination that includes laboratory and imaging testing, and work with experts to solidify the diagnosis. Increasing knowledge of HLH as a possible differential diagnosis for sepsis and training medical professionals can result in earlier identification and more successful treatment, thereby increasing patient survival rates. To deepen the knowledge of this complicated illness and increase patient treatment in emergency situations, more research and ongoing medical education are crucial.