Immune-Pathological Correlates of Disease Severity in New World Kala-Azar: The Role of Parasite Load and Cytokine Profiles

Introduction: Kala-azar is a protracted disease caused by the zoonotic protozoa Leishmania infantum and by the anthroponotic L. donovani, transmitted by sandflies. Fever, anemia, and hepatosplenomegaly may be followed by hemorrhages and bacterial infections. The pathogenesis is related to exaggerated cytokine release that may provoke death. Patients and methods: Seventy-two hospitalized patients were studied. Clinical data and mortality were analyzed regarding the blood and bone marrow L. infantum load, and plasma IL-1, IL6, IL-8, IL10, IL-12, TNF-, and TGF- concentrations. Results: Cytokines were high. Blood and bone marrow L. infantum kDNA were correlated and increased with the time of disease. Blood and bone marrow load were higher in men, adults, and HIV-infected patients, and were strongly associated with mortality. IL-6 was independently associated with sepsis. In the multivariate analysis, IL-12 was the only one associated with blood L. infantum load, and the correlation was negative. Conclusions: Since L. infantum loads were associated with disease severity, but plasma cytokine levels were not, other mechanisms must be considered to explain disease progression leading to death. Plasma IL-12 appears to reduce blood parasite load in L. infantum kala-azar, suggesting the presence of a persistent, albeit weak, acquired immune response that is ultimately overwhelmed by a progressive, inflammatory, and inefficient innate systemic response.