Clinical Picture and Pathogenesis

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Amur, Dobrava, Hantaan, Seoul, Puumala, and Saaremaa viruses all cause HFRS but the infections differ considerably in severity. All are characterized by acute-onset, fever, headache, abdominal pains, backache, temporary renal insufficiency (first oliguria, proteinuria, and increase in serum creatinine, and then polyuria), and thrombocytopenia, but the extent of hemorrhages (hematuria, petechiae, internal hemorrhages), requirement for dialysis treatment, hypotension, and case-fatality rates are much higher in HFRS caused by Amur, Dobrava, or Hantaan viruses than in NE caused by Puumala or Saaremaa viruses. About a third of NE patients experience temporary visual disturbances (myopia), which is a very characteristic if not pathognomonic sign of the disease. Notably, the clinical consequences of all of the hantaviral pathogens in humans vary from none to fatal. Severe NE is associated with a certain haplotype, HLA-B8, DR3, DQ2 alleles, severe HPS with HLA-B35, and mild NE with HLA-B27. Yet, although Puumala virus infection is generally associated with mild HFRS, NE may have significant long-term consequences. A 5-year followup study demonstrated that 20% of NE patients had a somewhat increased systolic blood pressure and proteinuria. This is important, since the infection is so common in many areas of Europe. In addition, in some patients, Puumala virus infection may infect the pituitary gland and lead to mortality or at least to hypophyseal insufficiency requiring hormone-replacement therapy.

The pathogeneses of HFRS and HPS are poorly understood. However, it is known that p3 integrins can mediate the entry of pathogenic hantaviruses and that hantaviruses can regulate apoptosis. Also, there is evidence that increased capillary permeability is an essential component in the pathogenesis of both HFRS and HPS, although different target tissues, kidneys and lungs, respectively, are affected in the two diseases. HFRS and HPS patients show activation of tumor necrosis factor a (TNF-a) in the plasma and tissues and high levels of urinary secretion of the pro-inflammatory cytokine interleukin 6 (IL-6) are seen in NE. Studies with a monkey model mimicking human Puumala virus infection and HPS-like disease in Andes virus-infected Syrian hamsters may assist in elucidating the mechanism of pathogenesis.

HPS is characterized by pulmonary edema but death often results from cardiac failure; thus the term hantavirus cardiopulmonary syndrome (HCPS) has been proposed for the disease. HFRS and HPS, although primarily targeted at kidneys and lungs, respectively, share a number of clinical features, such as capillary leakage, TNF-a, and thrombocytopenia; notably, hemorrhages and alterations in renal function occur also in HPS and pulmonary involvement is not rare in HFRS.

Of the four structural proteins, both in humoral and cellular immunity, the nucleocapsid protein appears to be the principal immunogen. Cytotoxic T-lymphocyte responses are seen in both HFRS and HPS and may be important for both protective immunity and pathogenesis in hantavirus infections.

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