Puumala Virus Infection Research Articles

Blurred vision and myopic shift in Puumala virus infections are independent of disease severity

Puumala virus infection causes epidemic nephropathia (NE), a certain type of haemorrhagic fever with renal syndrome (HFRS). Myopic shift is considered a pathognomonic sign of NE and HFRS but rates of ocular involvement vary. The aim of the study was to evaluate whether clinical and laboratory findings are associated with ophthalmic involvement in NE in Austria. We found that blurred vision and myopic shift are frequent in Puumala virus infections in Austria but are independent of disease severity.

Occurrence of Immunoglobulin M Antibodies against Several Bacterial and Viral Pathogens in Acute Hantavirus Infection

Elevated levels of immunoglobulin M antibodies against various pathogens, most frequently Epstein-Barr-virus and Coxiella burnetii, were detected by immunoassay in 15 of 48 patients (31.3%) with acute Puumala virus infections. Although the mechanisms leading to this IgM response are not clear yet, polyspecific immunoglobulin M antibodies have to be taken into account to avoid misinterpretation of serological results in acute hantavirus infection.

IMPACT OF PUUMALA VIRUS INFECTION ON MATURATION AND SURVIVAL IN BANK VOLES: A CAPTURE-MARK-RECAPTURE ANALYSIS

Many zoonotic diseases are caused by rodent-borne viruses. Major fluctuations in the transmission of these viruses have been related to large changes in reservoir host population numbers due to external factors. However, the impact of the pathogen itself on the demography of its reservoir host is often overlooked. We investigated the impact of Puumala virus (PUUV) on survival and reproductive maturation probability of its reservoir host, the bank vole (Myodes glareolus). Three years (2004-06) of data from nine independent sites in southern Belgium were collected and analyzed with a capture-mark-recapture (CMR) method that includes statistical correction for the variation in capture probability of voles. A multistate model based on four states of reproductive activity and PUUV immunoglobulin G (IgG) antibody status was used to estimate survival and probability of transition from one reproductive or infection state to another. Although survival estimates for reproductively active voles were similar between infected and noninfected individuals, PUUV infection in reproductively inactive voles decreased mean monthly survival by 14%. PUUV infection was associated with a threefold increase in the probability of reproductive maturation in bank voles. Moreover, the probability of PUUV IgG seroconversion was three times higher for reproductively active voles compared to reproductively inactive voles. Our model indicates that PUUV infection may alter bank vole population dynamics by affecting both survival and maturation in its host. Additional studies, using CMR methodology with shorter time intervals between trapping sessions and possibly a longer duration, are needed to confirm these findings.

Puumala virus infection in Syrian hamsters (Mesocricetus auratus) resembling hantavirus infection in natural rodent hosts

The mechanism of hantavirus persistent infection in natural hosts is poorly understood due to a lack of laboratory animal models. Herein, we report that Syrian hamsters (Mesocricetus auratus) infected with Puumala virus (PUUV) at 4weeks old show persistent infection without clinical symptoms for more than 2months. IgG and IgM antibodies against the viral nucleocapsid protein and neutralizing antibody were first detectable at 14days postinoculation (dpi) and maintained through 70dpi. Viral RNA was first detected from 3dpi in lungs and blood clots, and was detected in all tissues tested at 7dpi. The viral RNA persisted for at least 70days in the lungs, kidney, spleen, heart, and brain. The highest level of RNA copies was observed at 14dpi in the lungs. Slight inflammatory reactions were observed in the lungs, adrenal glands, and brain. Immunohistochemical analysis revealed that PUUV antigen persisted until 56dpi in the kidneys and adrenal glands. Infected hamsters showed no body weight loss or clinical signs. These results indicate that PUUV infection in hamsters is quite similar to the hantavirus infection of natural host rodents.

Puumala Virus Infection

A 33-year-old male patient was admitted to our nephrology department with rapidly deteriorating general health, fever, respiratory difficulties, and acute renal failure. Computed tomography of the thorax revealed interstitial edema with thickening of the interlobular septa, peribronchial cuffing, ground-glass opacities, and small pleural and pericardial effusions. Polymerase chain reaction tests verified Puumala virus infection. The patient recovered with supportive treatment. Hantavirus infection should be considered in the differential diagnosis of young patients who present with acute renal failure of an unknown origin and the nonspecific radiologic finding of noncardiogenic interstitial edema, which in combination with typical clinical symptoms and laboratory parameters, can be indicative of this disease.

Procalcitonin in hantavirus infections

In hantavirus infections levels of serum leukocytes or C-reactive protein are usually elevated to levels found in serious bacterial infections. However, procalcitonin in patients infected with hantavirus has not yet been discussed in the literature. A total of 29 adult patients with hantavirus infection, 30 with sepsis, and 19 with tick-borne encephalitis were included in this observational retrospective study. The median procalcitonin level in patients with hantavirus infection was 0.53 μg/L (range 0.09–11.71 μg/L), in the group with sepsis 4.33 μg/L (range 0.08–161.1 μg/L) and in patients with viral meningitis 0.08 μg/L (range 0.05–0.12 μg/L). The difference between all three groups was statistically significant (p < 0.001). A higher procalcitonin level was found in patients with hemorrhagic fever with renal syndrome caused by Dobrava virus (0.74 μg/L; range 0.09–2.83 μg/L) than in those with Puumala virus infections (0.50 μg/L; range 0.10–11.71 μg/L). However, the difference was not statistically significant (p = 0.895). This study confirmed previous findings demonstrating the association of elevated procalcitonin with bacterial infection. However, increased procalcitonin serum level was also found in hantavirus infections with overlapping results between viral and severe bacterial infections.

Systematic literature review of symptoms, signs and severity of serologically confirmed nephropathia epidemica in paediatric and adult patients

The clinical picture of nephropathia epidemica (NE), a rodent-mediated Puumala virus (PUUV) zoonosis, appears to be different in paediatric and adult patients, since severe complications are seen only in adults. To confirm this clinical impression, we made a systematic literature review to determine whether the severity of NE is similar in children and adults. We searched PubMed for articles dealing with the clinical symptoms, physical signs and outcomes of patients with NE, published in English or the Nordic languages during the y 1968-2008, and found 53 containing sufficient original data in serologically confirmed cases. Forty-one of these described individual cases, 11 a series of consecutive patients and 1 both. The total number of patients was 537, of which 80 were paediatric cases. The frequency of benign symptoms and transient physical signs was quite similar in adults and children. However severe complications were reported only in adult patients (n = 26), of whom 9 died. The literature review confirmed the clinical impression that NE is milder in children than in adults. Children with PUUV infection rarely, if ever, need any invasive therapy.

Concomitant influence of helminth infection and landscape on the distribution of Puumala hantavirus in its reservoir, Myodes glareolus

BackgroundPuumala virus, the agent of nephropathia epidemica (NE), is the most prevalent hantavirus in Europe. The risk for human infection seems to be strongly correlated with the prevalence of Puumala virus (PUUV) in populations of its reservoir host species, the bank vole Myodes glareolus. In humans, the infection risks of major viral diseases are affected by the presence of helminth infections. We therefore proposed to analyse the influence of both helminth community and landscape on the prevalence of PUUV among bank vole populations in the Ardennes, a PUUV endemic area in France.ResultsAmong the 313 voles analysed, 37 had anti-PUUV antibodies. Twelve gastro-intestinal helminth species were recorded among all voles sampled. We showed that PUUV seroprevalence strongly increased with age or sexual maturity, especially in the northern forests (massif des Ardennes). The helminth community structure significantly differed between this part and the woods or hedgerows of the southern cretes pre-ardennaises. Using PUUV RNA quantification, we identified significant coinfections between PUUV and gastro-intestinal helminths in the northern forests only. More specifically, PUUV infection was positively associated with the presence of Heligmosomum mixtum, and in a lesser extent, Aonchotheca muris-sylvatici. The viral load of PUUV infected individuals tended to be higher in voles coinfected with H. mixtum. It was significantly lower in voles coinfected with A. muris-sylvatici, reflecting the influence of age on these latter infections.ConclusionsThis is the first study to emphasize hantavirus - helminth coinfections in natural populations. It also highlights the importance to consider landscape when searching for such associations. We have shown that landscape characteristics strongly influence helminth community structure as well as PUUV distribution. False associations might therefore be evidenced if geographic patterns of helminths or PUUV repartition are not previously identified. Moreover, our work revealed that interactions between helminths and landscape enhance/deplete the occurrence of coinfections between PUUV and H. mixtum or A. muris-sylvatici. Further experimental analyses and long-term individual surveys are now required to confirm these correlative results, and to ascertain the causal links between helminth and PUUV infection risks.

Temporal Variation in Individual Factors Associated with Hantavirus Infection in Bank Voles During an Epizootic: Implications for Puumala Virus Transmission Dynamics

Puumala virus (PUUV), the causal agent of nephropathia epidemica in humans, is one of the many hantaviruses included in the list of emerging pathogens. Hantavirus infection is not distributed evenly among PUUV reservoir hosts (i.e., bank voles [Myodes glareolus]). Besides environmental factors and local population features, individual characteristics play an important role in vole PUUV infection risk. Identifying the relative importance of these individual characteristics can provide crucial information on PUUV transmission processes. In the present study, bank voles were monitored during the nephropathia epidemica outbreak of 2005 in Belgium. Vole sera were tested for presence of immunoglobulin G against PUUV, and a logistic mixed model was built to investigate the temporal variation in individual characteristics and their relative importance to PUUV infection risk in bank voles. Relative risk calculations for individual vole characteristics related to PUUV infection in the reservoir host show that reproductive activity dominates infection risk. The gender effect is only found in reproductively active voles, where reproductively active males have the highest infection risk. Results also revealed a clear seasonal variation in the importance of reproductive activity linked to PUUV infection. In contrast to the main effect found in other trapping sessions, no difference in infection risk ratio was found between reproductively active and nonactive voles in the spring period. Combined with increased infection risk for the reproductively nonactive group at that time, these results indicate a shift in the transmission process due to changes in bank vole behavior, physiology, or climate conditions. Hence, our results suggest that mathematical models should take into account seasonal shifts in transmission mechanisms. When these results are combined with the seasonal changes in population structure during the epizootic period, we identify vole reproductive activity and length of the breeding season as potential drivers of PUUV epizootics in west-central European regions.

Associations between MHC genes and Puumala virus infection in Myodes glareolus are detected in wild populations, but not from experimental infection data

We analysed the influence of MHC class II Dqa and Drb genes on Puumala virus (PUUV) infection in bank voles (Myodes glareolus). We considered voles sampled in five European localities or derived from a previous experiment that showed variable infection success of PUUV. The genetic variation observed in the Dqa and Drb genes was assessed by using single-strand conformation polymorphism and pyrosequencing methods, respectively. Patterns were compared with those obtained from 13 microsatellites. We revealed significant genetic differentiation between PUUV-seronegative and -seropositive bank voles sampled in wild populations, at the Drb gene only. The absence of genetic differentiation observed at neutral microsatellites confirmed the important role of selective pressures in shaping these Drb patterns. Also, we found no significant associations between infection success and MHC alleles among laboratory-colonized bank voles, which is explained by a loss of genetic variability that occurred during the captivity of these voles.

Hantavirus outbreak in Western Europe: reservoir host infection dynamics related to human disease patterns

Within Europe, Puumala virus (PUUV) is the causal agent of nephropathia epidemica (NE) in humans, a zoonotic disease with increasing significance in recent years. In a region of Belgium with a historically high incidence of NE, bank voles (the PUUV reservoir hosts), were monitored for PUUV IgG antibody prevalence in nine study sites before, during, and after the highest NE outbreak recorded in Belgium in 2005. We found that the highest numbers of PUUV IgG-positive voles coincided with the peak of NE cases at the regional level, indicating that a PUUV epizootic in bank voles directly led to the NE outbreak in humans. On a local scale, PUUV infection in voles was patchy and not correlated to NE incidence before the epizootic. However, during the epizootic period PUUV infection spread in the vole populations and was significantly correlated to local NE incidence. Initially, local bank-vole numbers were positively associated with local PUUV infection risk in voles, but this was no longer the case after the homogeneous spreading of PUUV during the PUUV outbreak.

Headache and low platelets in a patient with acute leukemia

Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis -specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes.

Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases

Infection with the Puumala virus (PUUV), which belongs to the Hantavirus family, is a common but often neglected cause of acute kidney injury (AKI) in endemic areas of Europe. The objective of the present study was to systematically analyse clinical presentation and renal outcomes following PUUV infection. In a retrospective study, we analysed data from 75 patients who were admitted to two large hospitals in Germany over an 8-year period and who tested positive for PUUV infection. Clinical and laboratory data were collected from patient files; creatinine levels before admission and during follow-up were obtained from phone calls. Patients were between 16 and 82 years old (average +/- SD, 40.4 +/- 13.4) with a male to female ratio of 2.5:1. They showed a wide variety of clinical presentations with renal failure being the cause of admission in only 50%. AKI developed in 95% of patients who showed maximum creatinine levels of 4.3 +/- 0.3 mg/dl. Four patients required temporary dialysis, and one patient died from pulmonary complications. Thrombocytopaenia (137 +/- 11 x 10(3)/microl) was present in almost all cases, and elevated levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP) were observed in 57 and 100% of patients, respectively. Urinalysis revealed mild to nephrotic proteinuria in 85%, which was often associated with haemoglobinuria. All patients showed full recovery of renal function and return to pre-existing normal serum creatinine levels. In a majority of cases, PUUV infection results in thrombocytopenic AKI. Fever is a requirement for diagnosis, while elevated LDH and CRP values are also frequently observed. Overall, early renal outcomes were excellent.

Case-control study on Puumala virus infection: smoking is a risk factor

Puumala hantavirus (PUUV) is apparently transmitted to humans by inhalation of aerosolized secretions of carrier rodents (bank voles). The means of transmission and the associated risk factors are poorly defined. An epidemiological study during the peak of an epidemic season in Finland was conducted based on 282 acute clinical PUUV infections and 204 controls without PUUV infection or immunity. The main risk factors adjusted by age, sex and living environment were cigarette smoking [odds ratio (OR) 3.6, 95% confidence interval (CI) 2.1-5.9, P<0.0001] and buildings with holes allowing rodents to enter (OR 3.3, 95% CI 2.0-5.6); these results were similar in two subsets. Further, use of rodent traps (OR3.5, 95% CI 2.2-5.7) and handling firewood (OR 2.7, 95% CI 1.6-4.4) were associated with a risk. The risk attributed to smoking also remained high using simulated population controls with average smoking habits. The results suggest that hantavirus transmission occurs by inhalation mainly indoors and is dependent on the condition of the respiratory tract.

Survey and case-control study during epidemics of Puumala virus infection

In Baden-Wuerttemberg, a federal state in south-west Germany, a large outbreak of 1089 laboratory-confirmed human Puumala virus (PUUV) infections occurred in 2007. We conducted a survey to describe the disease burden and a case-control study to identify risk factors for acquiring PUUV. Case-patients were interviewed about clinical outcome and both case-patients and randomly recruited controls were interviewed about exposure. We calculated matched odds ratios (mOR) using a conditional logistic regression model. Multivariable analysis of 191 matched case-control pairs showed that case-patients were more likely than controls to have seen small rodents/their droppings (mOR 1.9, 95% CI 1.2-3.0), cleaned utility rooms (mOR 1.8, 95% CI 1.0-3.4) and visited forest shelters (mOR 3.9, 95% CI 1.1-14.3). Two thirds of case-patients required hospitalization. During PUUV epidemics rodent control measures and use of protective equipment should be considered in utility rooms and shelters.

Emergence of hantavirus in South Germany: rodents, climate and human infections

Human hantavirus (serotype Puumala) infections are prevalent throughout Europe. The bank vole is the main reservoir of the Puumala virus (PUUV). Between 2001 and 2006, the annual incidences in Germany ranged from 0.1 to 0.5 per 100,000 inhabitants. About half of the cases were reported from the state of Baden-Württemberg (BW) in southwest Germany. In 2007, 1,089 PUUV infections were reported from BW. This reflects an incidence of 10.1:100,000, which is more than 11 times higher than the mean incidence of the previous 6 years. Spatial analysis highlights incidences up to 90:100,000 in the most affected district. The winter season 2006/2007 showed an all time high in reported mean temperature. The previous summer and autumn led to a beech mast year, resulting in favourable feed conditions for bank voles in the winter season 2006/2007. The causes of the observed increase in PUUV infections in 2007 cannot be restricted to known cycles in the bank vole population. Favourable feed conditions, a mild winter and an early onset of spring may have influenced bank vole population size as well as human exposure to infectious rodent excretions. Further epidemiologic studies are necessary to better understand the interaction between environmental factors, occurrence of Puumala virus in bank voles and the risk for human disease.

Hantavirus disease (nephropathia epidemica) in Belgium: effects of tree seed production and climate

Recently, human cases of nephropathia epidemica (NE) due to Puumala virus infection in Europe have increased. Following the hypothesis that high reservoir host abundance induces higher transmission rates to humans, explanations for this altered epidemiology must be sought in factors that cause bank vole (Myodes glareolus) abundance peaks. In Western Europe, these abundance peaks are often related to high tree seed production, which is supposedly triggered by specific weather conditions. We evaluated the relationship between tree seed production, climate and NE incidence in Belgium and show that NE epidemics are indeed preceded by abundant tree seed production. Moreover, a direct link between climate and NE incidence is found. High summer and autumn temperatures, 2 years and 1 year respectively before NE occurrence, relate to high NE incidence. This enables early forecasting of NE outbreaks. Since future climate change scenarios predict higher temperatures in Europe, we should regard Puumala virus as an increasing health threat.

Outbreak of Puumala Virus Infection, Sweden

An unexpected and large outbreak of Puumala virus infection in Sweden resulted in 313 nephropathia epidemica patients/100,000 persons in Västerbotten County during 2007. An increase in the rodent population, milder weather, and less snow cover probably contributed to the outbreak.

Population, Environmental, and Community Effects on Local Bank Vole (Myodes glareolus) Puumala Virus Infection in an Area with Low Human Incidence

In this study, the distribution of Puumala hantavirus (PUUV) infection in local bank vole Myodes glareolus populations in an area with low human PUUV infection (nephropathia epidemica [NE]) incidence in northern Belgium was monitored for 2 consecutive years. Bank voles were trapped in preferred habitat and tested for anti-PUUV IgG. Infection data were related to individual bank vole features, population demography, and environmental variables. Rare occurrence of PUUV infection was found and PUUV prevalence was low compared with data from the high NE incidence area in southern Belgium. Small-scale climatic differences seemed to play a role in PUUV occurrence, vegetation index and deciduous forest patch size both influenced PUUV prevalence and number of infected voles in a positive way. The data suggested a density threshold in vole populations below which PUUV infection does not occur. This threshold may vary between years, but the abundance of bank voles does not seem to affect the degree of PUUV seroprevalence further. We found indications for a dilution effect on PUUV prevalence, dependent on the relative proportion of nonhost wood mice Apodemus sylvaticus in a study site. In conclusion, we regard the combination of a dilution effect, a possible threshold density that depends on local conditions, and a higher fragmentation of suitable bank vole habitat in our study area as plausible explanations for the sparse occurrence of PUUV infection and low prevalence detected. Thus, beside human activity patterns, local environmental conditions and rodent community structure are also likely to play a role in determining PUUV infection risk for humans.

Hantavirus RNA in Saliva from Patients with Hemorrhagic Fever with Renal Syndrome

Hantaviruses cause 2 zoonotic diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome. Infection is usually initiated after inhalation of virus-contaminated rodent excreta. In addition to the zoonotic infection route, growing evidence suggests person-to-person transmission of Andes virus. For this reason, we studied whether saliva from HFRS patients contained hantavirus. During an outbreak in northern Sweden of nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome, we collected saliva and plasma from 14 hospitalized NE patients with verified Puumala virus (PUUV) infection. PUUV RNA was detected in saliva from 10 patients (range 1,530-121,323 PUUV RNA copies/mL) by quantitative reverse transcription-PCR. The PUUV S-segment sequences from saliva and plasma of the same patients were identical. Our data show that hantavirus RNA could be detected in human saliva several days after onset of disease symptoms and raise the question whether interhuman transmission of hantavirus may occur through saliva.