Course Of Nephropathia Epidemica Research Articles

Smoking Is a Risk Factor for Severe Acute Kidney Injury in Hantavirus-Induced Nephropathia Epidemica

Background/Aims: Hantaviruses are zoonotic pathogens causing emerging diseases worldwide. Patients typically present with fever, acute kidney injury (AKI) and thrombocytopenia. Puumala virus (PUUV) that causes nephropathia epidemica (NE) is common in Germany. Recently, a study from Finland revealed an association between nicotine consumption and the severity of AKI in NE. Differences between individuals in Finland and Germany might modulate the effect; therefore, the aim of our study was to prove that smoking is a risk factor for a severe course of NE in Germany. Methods: A cross-sectional prospective survey of 485 patients with hantavirus infections was performed. Clinical and laboratory data during the acute course of the disease were obtained from medical reports and files, while follow-up (including smoking status) data were collected prospectively. Results: Smoking information was available for 298 out of 485 patients (61%). Male was the predominant gender (67%), median age at the time of diagnosis was 50 (interquartile range, IQR 41-60) years and 34% of patients were current smokers during the phase of acute NE. Patients in the smoking group were significantly younger than in the non-smoking group (p < 0.0001). Peak serum creatinine levels were significantly higher in the smoking group than in the non-smoking patients (median 301 (IQR 186-469 μmol/l) vs. median 240 (IQR 137-469 μmol/l), p < 0.05). In addition, severe AKI (stages 2 and 3 using KDIGO criteria) was more common in current smokers (80%) than in the non-smokers (68%, p < 0.05). Conclusion: Current smoking is a risk factor for severity of AKI in patients with acute PUUV infection in Germany. Therefore, information about smoking habits needs to be an integral part of the documentation in patients with suspected acute PUUV infection, and increased monitoring of kidney function should be done in NE patients who are current smokers.

Determination of Procalcitonin Levels in Patients with Nephropathia Epidemica - A Useful Tool or an Unnecessary Diagnostic Procedure?

Background/Aims: Puumala virus causes nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome that occurs in Central and Northern Europe. Several studies have sought to identify risk factors for severe NE. However, elevated procalcitonin (PCT) levels have not previously been investigated as a predictive marker for a severe course of NE. Methods: A cross-sectional prospective survey of 456 adults with serologically confirmed NE was performed. Results: PCT levels at the time of diagnosis were available for 43 out of 456 patients, and in 24 of these patients (56%) PCT levels were elevated (“PCT positive”). C-reactive protein (CRP) levels at admission to hospital and peak CRP levels during the acute course of the disease were higher in the PCT-positive compared with the PCT-negative group (p<0.05). Severe acute kidney injury (AKI) (RIFLE I and F) was present in similar numbers of PCT-positive and -negative patients (p=0.7), but antibiotics were more frequently used in the PCT-positive than the PCT-negative group (p<0.05). Within the PCT-positive group, PCT levels were similar among those receiving and not receiving antibiotics (p=0.13), and neither the duration of hospital stay nor CRP peak levels were lower in those treated with antibiotics (p=0.12 and p=0.13, respectively). Conclusions: Elevated PCT levels are common in patients with acute NE. There was no association between PCT levels and severity of disease, including AKI or thrombocytopenia. It is important to distinguish Puumala virus infection from other causes of AKI with thrombocytopenia. However, PCT might not be useful in differentiating hantavirus infection from bacterial infection.

Polyuria in Hantavirus Infection Reflects Disease Severity and Is Associated with Prolonged Hospital Stay: A Systematic Analysis of 335 Patients from Southern Germany

Background/Aims: Puumala virus (PUUV) infection leads to nephropathia epidemica (NE), especially in endemic areas in Central Europe. The clinical course of NE is characterized by acute kidney injury (AKI) with thrombocytopenia followed by polyuria to a different degree. The prevalence of polyuria and its associated risk factors have not been reported in a large cohort of NE patients. Methods: Clinical and laboratory data during the acute phase of the disease were obtained from the medical reports and files of 335 patients who received in-hospital treatment during acute hantavirus infection. Comprehensive statistical models were developed to estimate the probability of polyuria. Results: The median age at diagnosis was 47 years (interquartile range, IQR 40-59) and 48% of the patients developed polyuria with a urinary output of 5,100 ml/day (IQR 4,200-7,300). The hospital stay was significantly longer in the polyuric group compared to the nonpolyuric group [8 days (IQR 6-10) vs. 6 days (IQR 5-8); p = 0.04]. Using logistic regression analysis, male gender (odds ratio, OR = 1.6; 95% confidence interval, CI 1.05-2.58; p = 0.03), oliguria/anuria during NE (OR = 2.56; 95% CI 1.65-4.01; p < 0.001), severe AKI (OR = 1.87; 95% CI 1.22-2.9; p < 0.001), and hematuria (OR = 1.78; 95% CI 1.02-3.15; p = 0.04) were significantly associated with the development of polyuria. In a multivariate model, the probability of polyuria was 0.19 (SEM ± 0.05) in female patients presenting with mild/moderate AKI without anuria/oliguria. Conclusions: Almost 50% of hospitalized NE patients developed polyuria, which was associated with a prolonged hospital stay. The probability of the development of polyuria was lowest in female patients with mild/moderate, non-oliguric/anuric AKI.

Magnetic resonance renography findings and their clinical associations in nephropathia epidemica

To evaluate, with magnetic resonance renography (MRR), the dynamics of renal function in patients with nephropathia epidemica (NE) and to correlate the findings with the clinical course of NE. MRR was performed on 20 hospitalized NE patients during the acute phase of the disease. A repeat MRR study was done 5-8 months later. Primary and repeat MRR studies were compared and functional findings evaluated. The uptake slope of the contrast enhancement curve was abnormal in the primary study in 14 patients, maximum level of enhancement in 11, decreasing slope of contrast enhancement curve in 14, and signal drop at time in 10 patients when the primary and repeat studies were compared. The greater change in the uptake slope of contrast enhancement, maximum level of enhancement, decreasing slope of enhancement, and signal drop at time between primary and repeat MRR studies evinced a mild association with the severity of clinical renal insufficiency and fluid volume overload. Measurable functional MRR findings were recorded in 14/20 NE patients. The severity of the findings was mildly associated with the degree of clinical renal insufficiency and fluid volume overload.

Value of ultrasonography in acute renal failure: analysis of qualitative features in patients with nephropathia epidemica

To assess the value of renal ultrasonography (US) and the frequency of qualitative pathology in patients with nephropathia epidemica (NE) and to determine whether these features are related to the clinical course of NE. Renal US was undertaken in 23 hospital-treated NE cases during the acute phase of the disease (first study). A second US study was performed 3-6 months later. Captured US images were used in the analysis. From acute to control phase the overall rating of kidney status improved in 20 patients, parenchymal swelling decreased and corticomedullary border differentiation improved in 21, echogenicity decreased in 18, and patchy pattern in parenchymal echo-texture decreased in 15. The severity of findings in US evinced some association with fluid volume overload, high blood pressure level and blood leukocyte count, and severe clinical renal insufficiency. The degree of parenchymal swelling had more statistically significant associations with clinical course than other US features. Qualitative US features are as sensitive as quantitative US parameters in assessment of NE patients' clinical course and recovery, assuming that a comparative study is available. US using only qualitative features is fairly limited in evaluating NE patients' clinical situation.

Human Leukocyte Antigens B8-DRB1*03 in Pediatric Patients With Nephropathia Epidemica Caused by Puumala Hantavirus

In adults, HLA haplotype B8-DRB1*03 is clearly associated with a severe clinical course of nephropathia epidemica caused by Puumala hantavirus. We investigated whether the same applies in pediatric patients. This HLA haplotype was found in 20 of 39 (51%) of the patients, a significantly higher figure than in the Finnish population (19%). There were, however, no significant differences in the clinical picture between patients with and without HLA B8-DRB1*03.

Medical imaging in nephropathia epidemica and their clinical correlations

Background This study was designed to evaluate radiological findings in chest and sinus radiographs and renal ultrasound (US) in patients with nephropathia epidemica (NE) and to determine whether changes in these medical images are related to each other or to the clinical course of NE. Methods Radiological findings and clinical course were studied in 380 hospital-treated NE patients during the years 1982–1998. Results In 35% of the patients there were clear changes in chest radiographs. Pleural effusion, atelectasis, and interstitial infiltration were the most common X-ray findings. Forty-seven percent had changes in renal US, with increased cortical echoicity and cortical swelling being the most common findings. Thirty-three percent of the patients with clinical symptoms of sinusitis had changes in sinus radiographs. Abnormal findings on chest radiographs were clearly associated with fluid volume overload, high blood pressure level, leukocytosis, degree of clinical renal insufficiency, and thrombocytopenia. Abnormal findings in renal US were associated to some extent with fluid volume overload and degree of clinical renal insufficiency. Conclusions Some 35% of patients had clear changes in chest radiographs and 47% showed changes in renal US. Abnormal findings in chest radiographs were clearly associated, and abnormal findings in renal US were associated to some extent, with the severity of the clinical course of NE.

Renal MRI findings and their clinical associations in nephropathia epidemica: analysis of quantitative findings.

Morphologic renal magnetic resonance imaging (MRI) findings in patients with nephropathia epidemica (NE) were evaluated, and these findings were correlated with the clinical course of NE. Renal MRI was performed in 20 hospitalized NE patients during the acute phase of their disease. A repeat MRI study was made 5-8 months later. Renal parenchymal volume, renal length and parenchymal thickness were decreased in all patients in the repeat study. Edema/fluid collections were found bilaterally in 16 patients in the primary MRI study. Greater change in parenchymal volume, renal length and parenchymal thickness between the primary and the repeat MRI study as well as the presence of edema/fluid collections in the primary study evinced mild association with clinical fluid volume overload, high blood pressure level, inflammation, thrombocytopenia and severe clinical renal insufficiency. Change in parenchymal volume was associated with a severe clinical course more markedly than the other MRI findings. Measurable renal MRI changes occurred in every NE patient. The severity of the findings in MRI evinced mild association with clinical fluid volume overload, high blood pressure level, inflammation, thrombocytopenia and severe clinical renal insufficiency. Based on this study and our previous ultrasound (US) findings, we prefer US as the primary examination mode in NE patients.

Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism.

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.

Renal ultrasound findings and their clinical associations in Nephropathia epidemica. Analysis of quantitative parameters

Purpose: To evaluate renal US findings in patients with nephropathia epidemica (NE) and to determine whether changes in these findings are related to the clinical course of NE. Material and Methods: Renal US was undertaken in 23 hospital-treated NE patients during the acute phase of their disease (first study). The second US study was performed 3–6 months later. Results: The resistive index (RI) was abnormal in 12 patients and fluid collections (perirenal, pleural, pericardial, ascites) were found in 13 patients in the first study. Renal length decreased in every patient, cortical parenchymal thickness in 19 patients and RI in 18 patients from the first to the second studies. The mean change was significant in all parameters. Increased RI and presence of fluid collections in the first study as well as a greater change in length and RI between the first and the second studies were associated with high maximum daily urine excretion, substantial change in body weight between the anuric and polyuric phases, high maximum serum creatinine and urea concentration, high blood leukocyte count and low hematocrit value. Conclusion: Renal US changes occurred in every patient with NE. The severity of the findings was associated with fluid volume overload and degree of clinical renal insufficiency.

Polymorphism of the cytokine genes in hospitalized patients with Puumala hantavirus infection.

Nephropathia epidemica (NE) is a mild type of haemorrhagic fever with renal syndrome caused by Puumala (PUU) hantavirus. The clinical course of NE varies from asymptomatic to fatal. The aim of this study was to establish whether polymorphisms in the cytokine genes are associated with susceptibility to and outcome of NE. The genotypes of the genes of tumour necrosis factor alpha (TNFalpha), interleukin-1alpha (IL-1alpha), IL-1beta and IL-1 receptor antagonist (IL-1RA) were analysed by polymerase chain reaction in 87 subjects, all hospital-treated for serologically confirmed acute NE. The control group comprised 400 healthy blood donors. Nineteen out of these 400 (5%) controls were PUU virus-seropositive. IL-1RA allele 2 and IL-1beta (base exchange polymorphism at position -511) allele 2 were strongly associated with each other in both groups. NE patients were more often IL-1RA-2 negative/IL-1beta-2 negative than PUU-seronegative blood donors (38 vs 27%, odds ratio 1.65, 95% confidence interval 1.0-2.7). However, there were no differences in the clinical severity of NE between the IL-1RA-2 negative/IL-1beta-2 negative and the other patients. The other allele frequencies studied evinced no statistically significant differences between the groups. Thirty-three out of 87 (38%) patients and 121 out of 381 (32%) seronegative controls were carriers of the high-producer genotype TNF2 allele. Several parameters showed the clinical course of NE to be more severe in TNF2 carriers than in non-carriers. These data suggest that non-carriage of the IL-1RA allele 2 and IL-1beta (-511) allele 2 may contribute to susceptibility to NE. Furthermore, TNFalpha polymorphism seems to be associated with the outcome of NE.

Clinical aspects of nephropathia epidemica (Puumala virus infection) in Europe: a review.

Nephropathia epidemica (NE) is a prevalent zoonosis throughout Europe and is caused by the Puumala type of hantavirus. The incidence of NE varies in a cyclic fashion, with peaks occurring every 3rd to 4th year, coinciding with peaks in vole populations. The clinical course of NE is generally milder than haemorrhagic fever with renal syndrome caused by hantaviruses in other parts of the world. Typically, NE has a sudden onset with fever, headache, backpain and gastrointestinal symptoms. However, severe complications, e.g. gastrointestinal haemorrhage, occur and fatal cases have been reported. Renal involvement is prominent and manifests as initial oliguria and later as marked polyuria. Tests of renal function show pronounced glomerular and tubular involvement. Vaccine against Puumala virus infection as well as specific treatment for NE are still lacking.

Association of HLA B27 with benign clinical course of nephropathia epidemica caused by Puumala hantavirus.

Both the severe course of nephropathia epidemica (NE) caused by Puumala hantavirus, and the fast progression of human immunodeficiency virus (HIV) disease, are associated with the HLA B8 DRB1*0301 haplotype. As HLA B27, on the contrary, is associated with the slow progression of HIV disease, we wanted to test whether the same is true for NE. Only six (8%) NE patients, half the figure expected, had the HLA B27 allele in 74 randomly selected hospital-treated patients. All six had a benign overall clinical course of NE; none had any severe complications, the severity of renal failure was also mild, and the treatment time at the hospital was half that needed for HLA B27- patients (P = 0.004). Patients who were HLA B27 had maximal blood leucocyte count > 10.000 x 10(9)/L (P = 0.020) more often, probably reflecting differences in immune response. Thus, similar HLA associations can be found in both HIV infection and NE caused by Puumala virus.

Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus

Nephropathia epidemica (NE) caused by Puumala hantavirus is one type of hemorrhagic fever with renal syndrome (HFRS). There is considerable variability in the clinical severity of NE. Many infections are subclinical but the disease can even be fatal. We questioned whether the wide spectrum in the outcome of NE is dependent, on host-related immunological factors by determining the major histocompatibility complex markers (MHC) in 74 adult patients with NE. Patients with the most severe course of the disease had a very high frequency of HLA B8, C4A*Q0, and DRB1*0301 alleles. HLA B8 was found in all 7 (100%) patients with shock and in 9 of the 13 (69%) patients who required dialysis, versus in only 25 of 74 (34%) in the entire population, and in 14 of 93 (15%) controls. In addition, various other clinical findings pointing to a severe form of NE were found to be associated with these alleles. Interestingly, the same MHC alleles are risk factors for various autoimmune diseases. This is the first study where a certain HLA haplotype is found to be associated with the clinical course of an acute viral disease or acute nephritis.

Pulmonary involvement in nephropathia epidemica as demonstrated by computed tomography.

In a prospective study 19 adult patients with nephropathia epidemica were examined in the acute phase of disease with computed tomography (CT) of the lungs and conventional chest radiography. Infiltrates and/or pleural effusions were seen in ten of 19 patients. In two of the patients, abnormalities were disclosed only by CT. Patients with pathologic radiography findings had a more pronounced inflammatory response, as measured by C-reactive protein and leukocyte count, than did those with normal radiography findings. It is concluded that radiological evidence of pulmonary involvement is a common finding early in the course of nephropathia epidemica. The possibility that the lung may be a site of viral replication merits further investigation.