Hemophagocytic Lymphohistiocytosis: Unveil the Mystery
Introduction/Background/Significance: Hemophagocytic Lymphohistiocytosis (HLH) can be primary (Genetic) or Secondary (Acquired). Secondary causes of HLH include infections, malignancy, autoimmune conditions, and transplantation. HLH is a severe hyperinflammatory syndrome that ranges from mild to rapidly progressing, life-threatening disease. This is a complex case of Secondary HLH.
Materials and Methods/Case Presentation/Objective: A 57-year-old female with Rheumatoid arthritis on prednisone, leflunomide, and upadacitinib presented with generalized weakness for one week. She was febrile (100.6°F), tachycardic (121/minute), and hypotensive, requiring ICU admission and transient vasopressors. Empiric antibiotics were initiated. Laboratory evaluation revealed pancytopenia with Hemoglobin (Hb) 9.1 g/dL, White blood cell count (WBC) 3.09 ×109/L, and platelet count (PLT) 18 ×109/L, hyponatremia 133 mEq/L, mild transaminitis with hyperbilirubinemia. The peripheral smear showed pancytopenia with a left shift, lymphocytopenia, and abnormal lymphocytes, but without any morphological abnormalities. Hemolytic workup showed elevated Lactate dehydrogenase (LDH) with normal Haptoglobin and reticulocyte count. Computed Tomography (CT) of the abdomen and pelvis showed evidence of splenomegaly (14 cm). It was initially attributed to Leflunomide-induced marrow suppression, leading to its discontinuation. Despite this, the patient's cytopenias worsened (Hb 6.1 g/dL, PLT 4 ×109/L). A bone marrow biopsy (BMB) was performed. While awaiting the results, her clinical condition continued to worsen with multiorgan dysfunction. An extensive workup for infectious and autoimmune etiologies was conducted. Testing for HIV, Hepatitis, cytomegalovirus, parvovirus, Ehrlichia, Leptospira, murine typhus, ADAMTS13, ANCA, serum Ceruloplasmin, and alpha-1 antitrypsin were within normal limits. However, Ferritin (11,552 ng/mL) and triglycerides (382 mg/dL) were elevated, along with Low Natural Killer cell activity. BMB revealed high-grade B-cell Lymphoproliferative disorder with evidence of HLH. Anakinra was not available, and Tocilizumab was initiated. She also received Cyclophosphamide, Vincristine, and steroids. Despite these interventions, she developed tumor lysis syndrome with clinical deterioration. The family opted for comfort care, and the patient succumbed to the acute illness.
Results/Description/Main Outcome Measures: HLH occurs in many underlying conditions as a consequence of a severe, uncontrolled hyperinflammatory reaction. A unique aspect of this case is the role of the patient's underlying Rheumatoid Arthritis and her chronic immunosuppressant use, which placed her at an increased risk for both severe infections and malignancies, including lymphoma. It is plausible that the chronic immunosuppression contributed to the development of the B-cell lymphoproliferative disorder, which subsequently acted as the trigger for HLH. Her initial presentation could be attributed to either RA flares, drug side effects, or opportunistic infections, which are common in immunocompromised individuals, which shows how HLH, often referred to as a "great masquerader," becomes even more challenging to diagnose.
Conclusions: This case depicts the clinical dilemma in assessing the cause for secondary HLH in the setting of uncontrolled autoimmune illness, and the possibility of a new lymphoproliferative disorder. The need for necessary immunosuppression, while beneficial for the primary condition, can inadvertently elevate the risk for lymphoproliferative disorders that could lead to HLH. This highlights the imperative for heightened vigilance for malignancy and HLH in immunocompromised patients who present with systemic inflammatory symptoms.
