BackgroundNephropathia epidemica (NE) is a Scandinavian type of hemorrhagic fever with renal syndrome caused by Puumala hantavirus. The clinical course of the disease varies greatly in severity. The aim of the present study was to evaluate whether plasma C-reactive protein (CRP) and interleukin (IL)-6 levels associate with the severity of NE.MethodsA prospectively collected cohort of 118 consecutive hospital-treated patients with acute serologically confirmed NE was examined. Plasma IL-6, CRP, and creatinine, as well as blood cell count and daily urinary protein excretion were measured on three consecutive days after admission. Plasma IL-6 and CRP levels higher than the median were considered high.ResultsWe found that high IL-6 associated with most variables reflecting the severity of the disease. When compared to patients with low IL-6, patients with high IL-6 had higher maximum blood leukocyte count (11.9 vs 9.0 × 109/l, P = 0.001) and urinary protein excretion (2.51 vs 1.68 g/day, P = 0.017), as well as a lower minimum blood platelet count (55 vs 80 × 109/l, P < 0.001), hematocrit (0.34 vs 0.38, P = 0.001), and urinary output (1040 vs 2180 ml/day, P < 0.001). They also stayed longer in hospital than patients with low IL-6 (8 vs 6 days, P < 0.001). In contrast, high CRP did not associate with severe disease.ConclusionsHigh plasma IL-6 concentrations associate with a clinically severe acute Puumala hantavirus infection, whereas high plasma CRP as such does not reflect the severity of the disease.

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The tumor necrosis factor (TNF)-alpha(-308) G/A polymorphism (TNF-2) is in linkage disequilibrium with the human leukocyte antigen (HLA)-B8-DR3 haplotype. Both factors have been associated with severe Puumala hantavirus-induced nephropathia epidemica (NE). To examine which part of this extended haplotype might show the strongest association with the outcome of NE, the HLA-B, HLA-DRB1, and TNF-alpha(-308) alleles in 116 hospital-treated patients with NE were analyzed. The findings pointing to clinically severe NE were strongly associated with HLA-B8-DR3 haplotype. There was a trend toward severe disease in persons positive for TNF-2. This was probably due to strong linkage disequilibrium with HLA-B8-DR3, since there were no differences in the clinical severity of NE when TNF-2-positive/B8-DR3-negative persons were compared with TNF-2-negative/B8-DR3-negative persons. It is concluded that the HLA-B8-DR3 haplotype is an important contributor to the course of NE. The data indicate that the TNF-2 allele is not an independent risk factor for severe NE but a passive component in the extended haplotype.