Visceral Leishmaniasis as a Cause or Mimicker of Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and HLH-04 Criteria Limits

Background: Visceral leishmaniasis (VL) is a systemic disease caused by Leishmania species. It is a life-threatening condition often presenting with nonspecific symptoms that can mimic other conditions such as hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory syndrome defined by HLH-04 criteria. Although HLH-04 criteria show limitations in distinguishing these conditions, a differentiation of VL from HLH is crucial for initiating appropriate therapy promptly and improving patient outcomes. This report discusses 2 pediatric cases of VL presenting with HLH-like features. This highlights the importance of being more aware of these overlapping conditions and developing clearer guidelines to tell them apart effectively. Case presentations: A 21-month-old girl with a persistent fever, unresponsive to antibiotics, was admitted with suspected systemic viral infection. Physical examination revealed pallor, asthenia and hepatosplenomegaly. Laboratory tests showed pancytopenia, elevated CRP, triglycerides and ferritin. A nasopharyngeal swab was performed to screen for respiratory pathogens in the context of suspected secondary HLH, yielding a positive result for influenza virus. However, bone marrow aspiration revealed the presence of Leishmania amastigotes, subsequently confirmed by reverse transcription PCR. A 16-year-old girl with intermittent fever, asthenia, dysuria and abdominal pain was admitted to our pediatric emergency room. Initial investigations showed mild splenomegaly, thrombocytopenia and leukocytosis, empirical antibiotic therapy was ineffective. Further tests revealed moderate anemia, leukopenia, hyperferritinemia and hypertriglyceridemia. Suspecting HLH, a bone marrow aspirate revealed Leishmania amastigotes, confirmed by reverse transcription PCR. Both patients were treated with liposomal Amphotericin B, showing rapid clinical improvement. Conclusions: VL is a neglected disease with a challenging diagnosis due to its strong resemblance to HLH. Although both conditions share overlapping clinical and laboratory findings, they have distinct pathogenic mechanisms. The HLH-04 criteria show limitations in distinguishing these conditions. While anemia and elevated ferritin might be more specific biomarkers for HLH, additional invasive tests, like bone marrow aspiration, are often essential due to the subtle symptoms and difficult diagnosis between the 2 conditions.