Hemorrhagic fever with renal syndrome (HFRS) is a systemic disease targeting different organs and organ systems. The clinical spectrum ranges from asymptomatic infection to a severe course with fatal outcome. The pathogenesis of HFRS is only partially understood. Capillary leakage is the characteristic of hantavirus disease, resulting in tissue and organ failure. Cytokines may play more than one role by exerting various functions in local and time-dependent manner; such multifactorial function might explain why different studies have shown their diverse impacts on the disease outcome. One such cytokine, assesed in several studies is vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR2).
The aim of our study was to gain detailed insight into HFRS dynamics in patients infected with Puumala (PUU) and Dobrava (DOB) virus by analyzing sequential values of selected clinical and laboratory parameters. We also evaluated the importance of factors causing endothelial dysfunction in the pathogenesis os HFRS. To study kinetics of secretion of VEGF and sVEGFR2 serial blood and serial urine samples were analyzed. Levels of VEGF and sVEGFR2 in plasma and urine samples were compared with selected clinical and laboratory parameters to evaluate the usefulness of VEGF and sVEGFR2 as biomarkers for disease severity.
The initial signs/symptoms, appearing on median day 1 of illness were fever, headache, and myalgia. These were present in 86 %, 65 %, and 40 % of patients and had a median duration of 4, 4, and 5.5 days, respectively. The signs/symptoms were followed by myopia (appearance on day 5), insomnia (day 6), oliguria/anuria (day 6), polyuria (day 9), and sinus bradycardia (day 9.5). These were present in 35 %, 30 %, 28 %, 91 %, and 35 % of patients; their median duration was 2, 2, 2, 7, and 1 day, respectively. Laboratory abnormalities, including thrombocytopenia, elevated alanine aminotransferase, CRP, procalcitonin, creatinine, diminished glomerular filtration rate, and leukocytosis, were ascertained on admission to hospital or on the following day (day 5 or 6 of illness) and were established in 95 %, 87 %, 99 %, 91 %, 94 %, 87 %, and 55 % of patients, and had a median duration of 4, 3, 7, 3, 9, 8, and 2 days, respectively. Comparison of patients infected with DOB and PUU viruses found several differences in the frequency, magnitude, and duration of abnormalities, indicating that Dobrava virus causes the more severe HFRS. In the majority of patients, the classic clinical distinction into febrile, hypotonic, oliguric, polyuric, and convalescent phases of illness is unclear.
In assessment of VEGF and sVEGFR2 kinetics in serial plasma samples from HFRS patients, most plasma VEGF levels were not significatly higher than in the control group. However, differences were observed in VEGF secretion in relation to virus species. In PUU-infected group, VEGF levels peaked between day 10 and day 15 of illness, at the time when patients usually enter the recovery stage of disease and are discharged from hospital; however, in DOB-infected patients no peak was seen. In DOB-infected patients, VEGF levels in urine were considerably elevated throughout the disease course. Comparison of VEGF dynamics in plasma and urine showed its pronounced secretion in the urine. Increase in plasma VEGF was associated with an increased platelet count, which is one of the first markers of clinical improvement; in contrast, the urine VEGF level was negatively associated with platelet count and diuresis. These results suggest a dual role of VEGF: first, local secretion of VEGF in kidneys following by renal impairment; and second, involvement in the repair, as implied by higher levels of plasma VEGF and improvement of clinical parameters. In concomitant samples of plasma and urine, in PUU-infected patients, higher VEGF levels were detected in urine samples, with peak in the first days of illness. The finding of normal plasma VEGF levels and lower plasma sVEGFR2 levels suggests a substantial difference in the circulating active VEGF levels. A decrease of plasma sVEGFR2 could be a potential mechanism for VEGF-directed systemic permeability, where VEGF cotributes to capillary leak by not being inactivated by receptor. In our study, the plasma level of sVEGFR2 was negatively associated with viral load, but positive linear association between plasma sVEGFR2 levels and both, platelet count and diuresis, was recognized, with higher levels in the polyuric stage of the disease. The urine levels of sVEGFR2 in PUU-infected patients decreased rapidly in a few days, but in DOB-infected patients they remained high up to day 17 of illness. In urine, sVEGFR2 levels negatively associated with platelet count and diuresis in both virus species groups (PUU and DOB). Significant association was confirmed between sVEGFR2 and viral load, where an increase of viral load correlated with decresed plasma sVEGFR2. Patients with hemorrhagic manifestations had very high plasma and urine VEGF levels and also high levels of urine sVEGFR2. Measuring a local secretion of sVEGFR2 in urine might be a useful biomarker for identifying those HFRS patients who will progress to severe disease.
In our work, we only confirmed the thesis, that the severe course of HFRS is associated with elevated VEGF concentrations in urine and that sVEGFR2 concentrations are altered in urine in plasma.
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