Host Responses In The Hantavirus Cardiopulmonary Syndrome

Host responses to hantavirus cardiopulmonary syndrome (HCPS) can be divided into three clinical stages. Fever, myalgia and thrombocytopenia are present during the prodrome. After 2-8 days, patients enter the cardiopulmonary stage, which ranges from mild pulmonary disease to rapidly fatal disease. During the cardiopulmonary stage, rapidly progressive respiratory failure develops in 60% of the cases, requiring intubation and mechanical ventilation. However, in fatal cases, death almost invariably occurs from cardiogenic shock rather than from respiratory failure. As such, HCPS may be more accurate and descriptive than hantavirus pulmonary syndrome (HPS). The cardiopulmonary stage is followed by spontaneous diuresis. During the cardiopulmonary stage, non-cardiogenic pulmonary edema is associated with lymphocytic interstitial infiltrate, abundant viral antigen in pulmonary capillary endothelial cells but no endothelial cell cytotoxicity. In contrast. cardiogenic shock is associated with histologically normal myocardium.The role of the humoral immune system does not appear to be crucial in development of pulmonary edema and shock. IgM and Ige antibodies are present for several days before the onset of the cardiopulmonary stage, circulating immune complexes are absent and complement depletion is uncommon. In contrast, a major role for T cell-directed immune responses in the development of the cardiopulmonary stage is suggested by the appearance of circulating activated CD8(+) and CD4(+) cells coincident with the onset of shock and pulmonary edema. Moreover, fatal cases have higher levels of circulating cytokines interferon-gamma (IFN gamma), interleukin ((IL)-2, IL-6), circulating cytokine receptors (IL-2R, tumor necrosis factor (TNF) R 1 and 2) and soluble CD8 than survivors, persons with pneumonia or healthy controls. CD8(+), CD4(+) and CD16(+) cells, in that order, are the dominant cell phenotypes in pleural effusions, mirroring the ratios among mononuclear cells in peripheral blood during the cardiopulmonary stage. Finally, fatal HCPS or HCPS complicated by shock is associated with one class I allele, HLA-B35. Among 45 persons with HCPS diagnosed or treated at the University of New Mexico, 12 out of 18 with severe HCPS were HLA-B35-positive versus five out of 27 with mild HCPS (P < 0.001). These data are consistent with a major role for class I-restricted CD8(+) T-cell responses in the pathogenesis of shock and pulmonary edema.While host responses are triggered by virus infection and may be driven by continued virus replication, host immune responses probably play a major role in the pathogenesis of severe HCPS. These observations have important implications for the design of treatment studies. Treatments that should be considered for evaluation in clinical trials include early initiation of antiviral therapy to limit virus replication, immune modulation to reduce T-cell immune responses and cytokine expression, or a combination of the two treatments.