Hormonal Defects Are Common during Puumala Hantavirus Infection and Associate with Disease Severity and Biomarkers of Altered Haemostasis.

Central and peripheral hormone deficiencies have been documented during and after acute hantavirus infection. Thrombocytopenia and coagulation abnormalities are common findings in haemorrhagic fever with renal syndrome (HFRS). The associations between coagulation and hormonal abnormalities in HFRS have not been studied yet. Forty-two patients diagnosed with Puumala virus (PUUV) infection were examined during the acute phase and on a follow-up visit approximately one month later. Hormonal defects were common during acute PUUV infection. Overt (clinical) hypogonadism was identified in 80% of the men and approximately 20% of the patients had overt hypothyroidism. At the one-month follow-up visit, six patients had central hormone deficits. Acute peripheral hormone deficits associated with a more severe acute kidney injury (AKI), longer hospital stay and more severe thrombocytopenia. Half of the patients with bleeding symptoms had also peripheral hormonal deficiencies. Patients with free thyroxine levels below the reference range had higher D-dimer level than patients with normal thyroid function, but no thromboembolic events occurred. Acute phase hormonal abnormalities associate with severe disease and altered haemostasis in PUUV infection.

Coagulopathy in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein-kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

Dendritic Cells (DCs) as "Fire Accelerants" of Hantaviral Pathogenesis.

Hantaviruses are widespread zoonotic pathogens found around the globe. Depending on their geographical location, hantaviruses can cause two human syndromes, haemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). HPS and HFRS have many commonalities amongst which excessive activation of immune cells is a prominent feature. Hantaviruses replicate in endothelial cells (ECs), the major battlefield of hantavirus-induced pathogenesis, without causing cytopathic effects. This indicates that a misdirected response of human immune cells to hantaviruses is causing damage. As dendritic cells (DCs) orchestrate antiviral immune responses, they are in the focus of research analysing hantavirus-induced immunopathogenesis. In this review, we discuss the interplay between hantaviruses and DCs and the immunological consequences thereof.

Hypopituitarism after Orthohantavirus Infection: What is Currently Known?

Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.

Sequential assessment of clinical and laboratory parameters in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Information on the sequential appearance, duration, and magnitude of clinical and laboratory parameters in hemorrhagic fever with renal syndrome (HFRS) is limited. METHODS: Analysis of clinical and laboratory parameters obtained serially in 81 patients with HFRS, of whom 15 were infected with Dobrava virus and 66 with Puumala virus. RESULTS: 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 Dobrava and Puumala viruses found several differences in the frequency, magnitude, and duration of abnormalities, indicating that Dobrava virus causes the more severe HFRS. CONCLUSIONS: In the majority of patients, the classic clinical distinction into febrile, hypotonic, oliguric, polyuric, and convalescent phases of illness is unclear.

Hemorrhagic fever with renal syndrome accompanied by panhypopituitarism and central diabetes insipidus: a case report.

Central diabetes insipidus (DI) was detected in a patient with hemorrhagic fever with renal syndrome (HFRS) who had been molecularly and serologically diagnosed with Hantaan virus infection. We recommend that clinicians differentiate central DI in HFRS patients with a persistent diuretic phase even when pituitary MRI findings are normal.

Hemorrhagic fever with renal syndrome in Albania. Focus on predictors of acute kidney injury in HFRS.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is a rodent borne zoonosis, caused by the members of the family Bunyaviridae, genus Hantavirus. The main clinical features of the infection by this virus family are fever, thrombocytopenia and acute kidney injury. OBJECTIVE: The aim of our study was to identify, for the first time, characteristic features of HFRS in the Albanian population. STUDY DESIGN: The study comprised 33 consecutive patients admitted with suspected HFRS from April 2011-April 2016 at one center. Clinical diagnosis was confirmed by ELISA and real-time PCR. Statistical analysis was performed to identify prognostic markers and indicators of disease severity. RESULTS: The virus strain causing HFRS was Dobrava type in all 33 cases. The disease outbreaks occurred during the period June-July. Mean hospital stay was 15.7±6.9days. 29 (88%) of the patients were male. The mean age was 39.7±14.1. 16 (48.5%) patients were from Northeast Albania. 8 (24.2%) patients required dialysis. The strongest correlation was the inverse relationship of nadir platelet count with urea and creatinine, p<0.0001, p<0.0079 respectively. Creatinine and hyponatremia were inversely correlated p=0.0007, whereas hyponatremia and nadir platelet count had the highest sensitivity and specificity for development of severe AKI, 92.6%, 100%; 88.9%, 83.3% respectively. Mortality rate was 9.09%. CONCLUSION: HFRS is a severe viral disease in Albania caused by Dobrava strain. It is associated with high mortality, 9.09% in our cohort. In our study, thrombocytopenia, urinary volume, hyponatremia were indicators of more severe disease.

Sustained High Levels of Both Total and High Molecular Weight Adiponectin in Plasma during the Convalescent Phase of Haemorrhagic Fever with Renal Syndrome Are Associated with Disease Severity.

Haemorrhagic fever with renal syndrome (HFRS) is characterised by an uncontrolled immune response that causes vascular leakage. Adiponectin (APN) is an adipocytokine involved in prorevascularisation and immunomodulation. To investigate the possible effects of APN in the pathogenesis of HFRS, total and high molecular weight (HMW) APN levels in the plasma of patients with HFRS were quantified using enzyme-linked immunosorbent assay (ELISA). Compared with those in healthy controls, the plasma total and HMW APN levels in patients were elevated to different degrees from the fever onset and remained high at the convalescent phase. Consistent with these results, western blot analysis additionally showed that low molecular weight (LMW), middle molecular weight (MMW), and HMW APN levels were all elevated and contributed to the elevation of the total APN level. Importantly, sustained high levels of total and HMW APN at the convalescent phase were significantly higher in patients with critical disease than those in patients with mild or moderate disease. Moreover, total and HMW APN levels negatively correlated with white blood cell count and positively correlated with platelet count and serum albumin level. These results may provide insights into understanding the roles of total and HMW APN in the pathogenesis of HFRS.

Thrombocytopenia associates with the severity of inflammation and variables reflecting capillary leakage in Puumala Hantavirus infection, an analysis of 546 Finnish patients.

BACKGROUND: Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Hantavirus infections are characterized by thrombocytopenia. Our objective was to assess the association of thrombocytopenia with disease severity in HFRS induced by Puumala hantavirus (PUUV). METHODS: Altogether 546 patients treated for acute serologically confirmed PUUV infection during 1982-2013 at Tampere University Hospital, Finland, were examined. Blood platelet count was determined daily and analysed in relation to different variables reflecting disease severity. The patients were divided into two groups according to the minimum platelet count: severe thrombocytopenia (<69 × 10(9)/L, i.e. below median) and no severe thrombocytopenia (≥69 × 10(9)/L). RESULTS: Thrombocytopenia (platelet count <150 × 10(9)/L) was detected in 90% of patients, and in 28% of patients platelet count was <50 × 10(9)/L. Patients with severe thrombocytopenia had longer stay (8 versus 7 days, p = 0.002) and greater weight gain (2.8 versus 2.0 kg, p < 0.001) at the hospital, higher blood leukocyte count (11.2 × 10(9)/L versus 9.6 × 10(9)/L, p < 0.001), plasma C-reactive protein (81 versus 59 mg/L, p < 0.001), maximum hematocrit (0.44 versus 0.42, p < 0.001), urinary protein excretion (1.7 versus 1.1 g/24 h, p = 0.002), and lower plasma albumin concentration (27 versus 32 g/L, p < 0.001) than patients without severe thrombocytopenia (comparisons between medians). Maximum creatinine concentration did not differ between patients with or without severe thrombocytopenia (median 235 versus 214 µmol/L, p = 0.217). CONCLUSIONS: The severity of thrombocytopenia associates with the degree of inflammation and variables reflecting capillary leakage, but not with the severity of acute kidney injury in PUUV infected Finnish patients.

History of incomplete vaccination may associate with occurrence of hemorrhagic fever with renal syndrome with relieved clinical symptoms.

OBJECTIVE: This retrospective study is aimed to investigate the clinical features of the patients with history of incomplete vaccination against hemorrhagic fever with renal syndrome (HFRS). METHODS: Data of 140 cases of hospitalized patients with HFRS were collected. The patients were divided into incomplete vaccinated group (n = 10) and unvaccinated group (n = 130) according to vaccination status. Demographic, clinical, and laboratory characteristics of the two groups' patients were compared through t test, Pearson χ(2) test, and Mann-Whitney test. RESULTS: In comparison with the unvaccinated group, the incidence rate of vomiting and hypotensive-shock, the white blood cell (WBC) and platelet count, the level of blood urea nitrogen and albumin, total number of dialysis and hospitalization cost of patients in the incomplete vaccinated group have statistically significant differences. CONCLUSION: HFRS disease may still occur in individuals with a history of HFRS incomplete vaccination although the symptoms may be mild. Effective vaccination against HFRS needs sufficient doses and booster shot of the vaccine.

Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients.

BACKGROUND: Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. METHODS: Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. RESULTS: The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. CONCLUSIONS: HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

[Actual nutrition of patients suffered from hemorrhagic fever with renal syndrome].

The aim of the article is to study actual ration of patients suffered from hemorrhagic fever with renal syndrome (HFRS) and its interaction with the development of arterial hypertension (AH). 296 men aged 20­59 suffered from HFRS were under the care of physician within the period of 1 to 6 years. Among this group 49 cases of arterial hypertension have been registered after HFRS. Frequency method of food product consumption was used to define nutrition. A Russian questionnaire published by Institute of Nutrition (1997) was used. Actual nutrition in men suffered from HFRS is marked by basic nutrients unbalance that is: excessive cholesterol and fat consumption (due to saturated fatty acid), polyunsaturated fatty acid deficiency, sugar overuse and animal protein prevalence over vegetable proteins in patient ration. Atherogenic shift in a ration of patients with AH and suffered from HRFS has been exposed more strongly in all aged group but mostly evident in patients aged 40 and after. Alcohol consumption in men with AH and suffered from HFRS is higher than in healthy peers. Interaction between atherogenic unbalance on the main nutrients in patients with HFRS and arterial hypertension has been defined. Consumatory behavior correction is to be taken to prevent arterial hypertension in recovered patients suffered from HFRS.

Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany.

Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.

[A hantavirus killed an Israeli researcher: hazards while working with wild animals].

An Israeli researcher working in Finland with Bank Voles, contracted an infectious viral disease and died. This was a rare event, but it is important to learn about this class of viruses and to be aware of the hazards while working in the field in close contact with wild animals. The virus termed Puumala belongs to the genus Hanta from the Bunyaviridae family. The natural reservoir is rodents, mice, rats and Bank Votes for the Puuamala strain. The disease is termed HFRS (hemorrhagic fever with renal syndrome), is prevalent in Asia and Europe, affecting 200,000 people a year, with 5-15% percent mortality (although in Finland mortality rate is 0.1%). The New World strains cause HPS (hemorrhagic pulmonary syndrome) affecting 200 people a year with 40% mortality. Virus is present in all rodents excretions, and route of infection is by aerosols, hand to mucus membranes contamination, by rodents bites and by contaminated food or water. More than 226 work related infections were documented. Treatment with Ribavirin helps in HFRS but not in HPS. The virus is stable in the environment for long periods, and research must be carried out at biosafety level 3. Working outdoors in rodent infested area, should be carried out using protective clothing, gloves, googles and face mask whenever aerosol producing tasks are performed. Both indoor and outdoor, it is important to adhere to self-hygienic procedures, especially hand washing.

Old World hantaviruses: aspects of pathogenesis and clinical course of acute renal failure.

Hantavirus-associated diseases represent emerging infections that are ranked in the highest priority group of communicable diseases for surveillance and epidemiological research. In the last years, several novel hantavirus species were described and the number of host reservoir species harboring hantaviruses is also increasing. Reports of cases with severe or atypical clinical courses become also more frequent. These facts raise more and more questions concerning host reservoir specificity, pathogenicity and molecular mechanism of pathogenesis. Hantavirus disease is characterized by vascular leakage due to increased capillary permeability. The infection manifests often in the lung (hantaviral cardiopulmonary syndrome; HCPS) or in the kidney (hemorrhagic fever with renal syndrome, HFRS). The underlying mechanisms of both syndromes are probably similar despite the difference in organ tropism. Characterization of hantaviral replication cycle and of patient-specific determinants will help to identify factors responsible for the clinical symptoms and course.

Plasma B-type natriuretic peptide (BNP) in acute Puumala hantavirus infection.

BACKGROUND: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Acute infection causes transient kidney injury, permeability disorder, and fluid retention, for example. METHODS: B-type natriuretic peptide (BNP) and N-terminal peptide (NT-proBNP) during NE were investigated; disease severity and development of clinical symptoms were considered. RESULTS: Mean concentrations were 80.2 pg/mL and 55.2 pg/mL for BNP, and 2362.5 pg/mL and 1057.0 pg/mL for NT-proBNP in males and females, respectively. Hospitalization was 6.3 versus 5.2 days (P = 0.01) and 5.9 versus 4.4 days (P = 0.01) for patients with elevated BNP (> 100 pg/mL) or NT-proBNP (> 300 pg/mL), respectively, compared to those with normal peptide concentrations. Weight change during hospitalization was -2.8 or -0.3 kg (P <0.05) in patients with elevated or normal BNP, respectively. Heart rate (r = -0.46, P = 0.001 and r = -0.37, P = 0.01), creatinine clearance (r = -0.46, P = 0.001 and r = -0.56, P = 0.000), blood haemoglobin concentration (r = -0.55, P = 0.000 and r = -0.52, P = 0.000), and C-reactive protein (r = -0.47, P = 0.001 and r = -0.36, P = 0.01) measured when the peptide samples were collected correlated with BNP and NT-proBNP, respectively. In addition, anterior chamber depth of eye and plasma BNP (r = -0.39, P < 0.05) displayed a correlation. CONCLUSIONS: BNP and NT-proBNP levels are associated with severity of several clinical features of acute NE.

HFRS and hantaviruses in the Balkans/South-East Europe.

Hemorrhagic fever with renal syndrome is endemic in the Balkans with epidemic outbreaks and sporadic cases that have been recorded yearly since the disease was first recognized. The incidence of Balkan HFRS is modest, with approximately one hundred cases reported in most years. Seroepidemiological investigations conducted in several Balkan countries revealed an overall seroprevalence of 6% in Bosnia and Herzegovina, 1.6% in Croatia, 4% in Greece and 1.7% in Slovenia, respectively. The complex ecology of the Balkan Peninsula supports the existence of diverse rodent and insectivore species which harbor several pathogenic and non-pathogenic hantaviruses. Among them only Dobrava (DOBV) and Puumala (PUUV) viruses are associated with disease in humans. Comprehensive clinical studies compared clinical signs and symptoms between patients infected with either virus. A spectrum of clinical picture of the disease ranges from mild illness typical of PUUV infections to a severe form with fulminant hemorrhagic fever and an overall mortality rate of 9.8% among DOBV infected patients. While severe DOBV cases are recognized from Slovenia in the North to Greece in the South, PUUV infections are more frequent in northern part of the area. Balkans represent an area with a potential need for hantavirus vaccines, but due to co-existence of DOBV and PUUV causing HFRS in the same region, a universal vaccine is required.

Hemorrhagic Fever with Renal Syndrome in the New, and Hantavirus Pulmonary Syndrome in the Old World: paradi(se)gm lost or regained?

Since the first clinical description in 1994 of the so-called "Hantavirus Pulmonary Syndrome" (HPS) as a "newly recognized disease", hantavirus infections have always been characterized as presenting in two distinct syndromes, the so-called "Hemorrhagic Fever with Renal Syndrome" (HFRS) in the Old World, with the kidney as main target organ, in contrast to HPS in the New World, with the lung as main target organ. However, European literature mentions already since 1934 a mostly milder local HFRS form, aptly named "nephropathia epidemica" (NE), and caused by the prototype European hantavirus species Puumala virus (PUUV). Several NE reports dating from the 1980s and early 1990s described already non-cardiogenic HPS-like lung involvement, prior to any kidney involvement, and increasing evidence is now mounting that a considerable clinical overlap exists between HPS and HFRS. Moreover, growing immunologic insights point to common pathologic mechanisms, leading to capillary hyperpermeability, the cardinal feature of all hantavirus infections, both of the New and Old World. It is now perhaps time to reconsider the paradigm of two "different" syndromes caused by viruses of the same Hantavirus genus in the same Bunyaviridae family, and to agree on a common, more logical disease denomination, such as simply and briefly "Hantavirus fever".

Cardiopulmonary involvement in Puumala hantavirus infection.

BACKGROUND: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection. METHODS: Twenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data. RESULTS: Two-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered. CONCLUSIONS: In a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients' recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms.

Sustained high level of serum VEGF at convalescent stage contributes to the renal recovery after HTNV infection in patients with hemorrhagic fever with renal syndrome.

To investigate the role of vascular endothelial growth factor (VEGF) in the increased permeability of vascular endothelial cells after Hantaan virus (HTNV) infection in humans, the concentration of VEGF in serum from HTNV infected patients was quantified with sandwich ELISA. Generally, the level of serum VEGF in patients was elevated to 607.0 (542.2-671.9) pg/mL, which was dramatically higher compared with healthy controls (P < 0.001). There was a rapid increase of the serum VEGF level in all patients from the fever onset to oliguric stage, at which the serum creatinine reached the peak level of the disease, indicating that VEGF may be involved in the pathogenesis of renal hyper-permeability. Moreover, the serum VEGF level at convalescent stage was positively correlated with the degree of the disease severity. The sustained high level of serum VEGF at convalescence was observed in critical HFRS patients, suggesting that VEGF would probably contribute to the renal recovery after the virus clearance. Taken together, our results suggested that the VEGF would be involved in the pathogenesis of renal dysfunction at the oliguric stage after HTNV infection, but may function as a recovery factor during the convalescence to help the body self-repair of the renal injury.