Nephropathia epidemica (hemorrhagic fever with renal syndrome) in children: clinical characteristics.

The clinical characteristics of serologically verified nephropathia epidemica, the Scandinavian form of hemorrhagic fever with renal syndrome, were studied in Swedish children who were < 15 years of age. In 1990 to 1992, 14 cases were prospectively followed. A retrospective survey during 1984 to 1990 disclosed another 18 cases. Among the 32 cases (20 boys, 12 girls, 3 to 15 years of age; median age, 11 years), the most common symptoms were fever (100%), headache (100%), abdominal pain (93%), vomiting (91%) and back pain (76%). Laboratory findings included elevated serum creatinine concentration (19 of 28) and thrombocytopenia (7 of 22). Urinalysis showed proteinuria (31 of 31 patients) and hematuria (24 of 30). Six children had mild hemorrhagic manifestations (epistaxis, metrorrhagia, and petechiae). No severe complications occurred. The clinical symptoms of children with nephropathia epidemica seem to be similar to those found among adult nephropathia epidemica cases.

Hantavirus antigen detection using human serum immunoglobulin M as the capturing antibody in an enzyme-linked immunosorbent assay.

An enzyme-linked immunosorbent assay (ELISA) was developed to detect different hantavirus antigens in cell culture; i.e. Puumala (PUU), Hantaan (HTN), and Dobrava (DOB) viruses. The assay was based on binding human serum immunoglobulin M (IgM) antibodies to the solid phase by use of goat anti-IgM antibodies. The captured IgM antibodies were present in the acute phase serum from two patients: one infected in Sweden and the other in Bosnia. Antigens being bound to the solid phase by the human anti-PUU and anti-DOB/HTN IgM antibodies were detected by a broadly reacting polyclonal rabbit anti PUU-recombinant nucleocapsid protein antiserum. The IgM isotype was proven to be at least five times more efficient than IgG when used as the capturing antibody. The sensitivity of the PUU antigen ELISA was approximately 0.5 ng/ml, as measured by titration with a PUU recombinant nucleoprotein antigen. Cell-associated PUU antigen in tissue culture was seen after 48 hr by the PUU-ELISA and after 96 hr by immunofluorescent assay. When tested for capacity to discriminate between PUU, DOB, and HTN viruses, significant differences were found: the Swedish serum detected PUU antigen at high titers, whereas no reactivity was found against DOB and HTN; the Bosnian serum detected both DOB and HTN at high titers but had a low reactivity to PUU. The method was also tested for its usefulness in detecting PUU antigen in bank vole (clethrionomys glareolus) lungs. Of 59 animals captured from the surroundings of patients with nephropathia epidemica, three became positive with a high activity in the PUU-ELISA, but with low reactivity in the DOB/HTN-ELISA. It is concluded that a sensitive ELISA has been developed to detect different hantaviruses in cell culture and lungs of bank voles.

An epidemiologic study of hemorrhagic fever with renal syndrome in Bashkirtostan (Russia) and Sweden.

The incidence and antibody prevalence of hemorrhagic fever with renal syndrome (HFRS) in Bashkirtostan (European part of Russia) and northern Sweden was compared with the abundance of Clethrionomys glareolus (bank voles) in the two areas. In Bashkirtostan, 10% of the women and 15% of the men were found to be antibody positive. The corresponding figures for Sweden were 8% and 16% for women and men, respectively. The annual incidence of HFRS in Bashkirtostan was 50 cases per 100,000 inhabitants, with a male:female ratio of 4.6:1. The incidence in the endemic area of Sweden was seven cases per 100,000 inhabitants, with a male:female ratio of 1.8:1. A similar age distribution of cases, with a peak in the middle age groups, especially in men, was found in both Bashkirtostan and Sweden. The incidence of HFRS in humans and the abundance of bank voles varied with time in both Bashkirtostan and Sweden, but the study failed to find any significant correlation between the two variables. The study showed that HFRS causes significant human morbidity in the areas studied but that both incidence and possibly bank vole abundance was higher in Bashkirtostan than in northern Sweden.

Specific serum IgA, IgG and IgM antibody determination by a modified indirect ELISA-technique in primary and recurrent herpes simplex virus infection.

Twenty-three patients with a herpetic infection as diagnosed by a positive culture of herpes simplex virus (HSV) were studied with respect to serological responses of IgA, IgG and IgM antibodies in paired serum samples by an indirect (sandwich) enzyme linked immunosorbent assay (ELISA). Eight of the patients had a primary infection and 15 a recurrent one. In the ELISA test a detergent treated cell lysate of HSV type 1 was used as antigen. In the IgM assay all sera were pretreated with antihuman IgG with the purpose to precipitate IgG of the samples. The conjugate was a F(ab)2-fragment of antihuman-IgM. In primary infections all patients had significant titre rises of IgG and presence of high IgM titres in the convalescent serum. IgA antibodies were found in all of them, while titre rises were detected in 5/8. In recurrent infections titre rises of IgG and IgA antibodies were found in 4 and 5, respectively. Six had detectable IgM in one or both of the paired samples. The IgG titres were higher in recurrent infections than in primary, in contrast to IgM of which much higher titres were found in primary infections. It is concluded that in primary infections a conclusive serological diagnosis was established in all patients, whereas in recurrent infections this was achieved in two of three patients. The indirect ELISA method used for IgM detection was sensitive, reliable and convenient. Interfering rheumatoid factor was effectively eliminated by treatment with antihuman IgG.

Different trends in antibiotic resistance rates at a university teaching hospital.

OBJECTIVES: To investigate long-term trends in antibiotic resistance of common bacterial species isolated at a university hospital and in its intensive care units (ICUs). METHODS: Levels of antibiotic resistance of common bacterial pathogens were investigated at the Karolinska Hospital during the 12-year period 1988-99. Resistance rates were analyzed for the entire hospital, as well as for ICUs combined. RESULTS: At the Karolinska Hospital, we found increased ciprofloxacin resistance among Escherichia coli isolates, from 0% in 1991 to 11% in 1999. In the ICUs, the corresponding increase was from 0% to 4.8% during the same period. Co-trimoxazole resistance levels increased from 7.5% to 14%, with lower levels for the ICUs. For ampicillin, cefuroxime, and gentamicin, the levels of resistance were similar in the whole hospital and in the ICUs. Among Pseudomonas aeruginosa isolates, imipenem resistance was higher in the ICUs. For ciprofloxacin, resistance increased from 2.5% in 1991 to 13% in 1999 in the whole hospital, with similar figures for the ICUs. CONCLUSION: The resistance rates at the Karolinska Hospital were still generally low, but were increasing for some antibiotic-microbe combinations. The results emphasize the importance of including all sectors of a hospital in resistance surveillance studies, and also the value of long surveillance periods.

Central nervous system and ophthalmic involvement in nephropathia epidemica (European type of haemorrhagic fever with renal syndrome).

Central nervous system (CNS) - related symptoms occur in haemorrhagic fever with renal syndrome (HFRS). To study the CNS and ophthalmic involvement in nephropathia epidemica (NE), the European type of HFRS, we included 26 patients in a prospective study. Most common CNS-related symptoms were headache (96%), insomnia (83%), vertigo (79%), nausea (79%), and vomiting (71%). Ophthalmic symptoms were reported by 82% of patients; 41% had photophobia and 50% had impaired vision. A transient loss of vision was recorded in one patient, who also had a generalized seizure. Minor white matter lesions were found in about half of the patients investigated with brain magnetic resonance imaging (MRI). Electroencephalography (EEG) showed severe alterations in only one patient, and slight and reversible patterns in another two patients. Neopterin, interleukin-6 and interferon-gamma levels in the cerebrospinal fluid (CSF) were elevated, which may indicate immune activation. However, we found no evidence of intrathecal NE virus replication. We conclude that CNS-related symptoms are common in NE, and transient ophthalmic involvement can be demonstrated in about half of the patients.

Glomerular basement membrane antibodies in hantavirus disease (hemorrhagic fever with renal syndrome).

The prevalence of antibodies against glomerular basement membrane (GBM) antigens in sera from 47 patients with serologically verified hantavirus (Puumala serotype) infection were investigated. Antibodies were measured by immunoassays using as antigen a crude human GBM preparation and the NC1 portion of type IV collagen (Goodpasture antigen), respectively. Seventy-seven percent of the patients had IgM antibodies against the non-Goodpasture glomerular basement membrane (non-GP GBM) in their acute phase serum samples as compared to only 4% seropositivity rate in convalescent phase samples. However, there was no correlation between the non-GP GBM IgM antibody levels and the decrease in GFR as measured by Cr EDTA clearance. None of the patients had antibodies against the Goodpasture antigen. In a control group of 10 patients with influenza and parainfluenza infections serum IgM against non-GP GBM could not be demonstrated, neither in acute phase nor in convalescent phase sera. The possible pathophysiological implications of these findings are discussed.

[2 cases of severe Streptococcus group A infection]. / Två fall av allvarlig grupp A-streptokockinfektion.

During recent years there have been several cases of death due to severe infection caused by GAS. Here we report two cases treated at our hospital, one of a patient presenting with preshock (case 1), the other of a patient with septic shock (case 2), in both of whom the concentrations of various coagulation factors and platelet counts were low. Other clinical findings common to both cases were scarlet coloured maculopapular exanthema, relative bradycardia, excessive tendency to develop oedema, and impaired function both in the lungs, kidneys and brain; and both patients were devoid of antibodies against the most predominant toxins (B and C) of the GAS strains isolated. Initial treatment comprised extensive administration of fluids, antibiotics, antithrombin, and low dose hydrocortisone. Plasma exchange by continuous centrifugation (CS 3000 Travenol Baxter) was given twice in case 1 and five times in case 2. In case 2, besides human immunoglobulin with a high anti-GAS (toxins A, B and C) antibody content given at admission, the patient received respiratory support, infusion of inotropic drugs and CAVH. Both patients recovered. The risk of death is high in cases of progressive multiple organ failure during the course of septic shock; and where conventional treatment combinations fail to remedy the condition, adjuvant treatment components may prove successful.

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.

[Pulmonary syndrome caused by Hantavirus--a new syndrome with high mortality]. / Hantavirus-orsakat pulmonellt syndrom--ny infektionssjukdom med hög dödlighet.

An outbreak of a previously unknown, severe infectious disease with rapidly fatal respiratory distress was reported from Southwestern USA in May 1993. The case fatality rate was about 60 per cent. Using PCR hantavirus RNA could be demonstrated in lungs and other tissues from patients. Mice and others rodents, e g Peromyscus maniculatus, were shown to be a reservoir of the virus. This new virus, designated Four Corner virus, has been further characterised and seems to be closely related to Puumala virus that causes nephropathia epidemica (hemorrhagic fever with renal syndrome) in Scandinavia and Central Europe.

Nephropathia epidemica (hemorrhagic fever with renal syndrome) in Scandinavia.

Nephropathia epidemica (NE) in Scandinavia is a zoonosis caused by Puumala virus. The main animal reservoir is the bank vole. NE predominantly affects men. Its annual incidence varies in a cyclic fashion, with peaks occurring every third to fourth year. The clinical picture of NE in Scandinavia is similar to that of hemorrhagic fever with renal syndrome in other parts of the world, although NE generally has a milder course. The case-fatality rate is approximately 0.2%. The most common clinical findings in NE are an acute onset of symptoms, fever (greater than or equal to 38 degrees C), oliguria, headache, back pain, and polyuria. Hemorrhagic manifestations are seen in about one-third of cases, and up to 5% of patients have gastrointestinal bleeding or disseminated intravascular coagulation. Thrombocytopenia occurs in a majority of patients. In the acute phase, the glomerular filtration rate is markedly decreased and tubular dysfunction is evident. Most patients with NE recover within 6 months.

Detection of specific serum immunoglobulin M in nephropathia epidemica (Scandinavian epidemic nephropathy) by a biotin-avidin-amplified immunofluorescence method.

A biotin-avidin-amplified indirect immunofluorescence method was used to demonstrate specific serum immunoglobulin M (IgM) antibodies in nephropathia epidemica, the Scandinavian type of hemorrhagic fever with renal syndrome. The antigen in the test was the cross-reacting agent of Korean hemorrhagic fever, Hantaan virus. Sixty-two serum samples from 15 patients with clinically typical nephropathia epidemica were analyzed. Eleven patients had specific IgM in one or more serum samples. The IgM could be demonstrated from day 2 up to day 37, and all patients had detectable specific IgM within 15 days after the onset of disease. In 49 control serum samples, no specific IgM could be detected, indicating a high specificity for the method. The findings demonstrate that the biotin-avidin-amplified immunofluorescence IgM assay is a useful tool in the diagnosis of early nephropathia epidemica disease.

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.

Detection of serum IgM antibodies to glomerular basement membrane in two cases of nephropathia epidemica.

We report two serologically verified cases of nephropathia epidemica (NE) who developed high serum levels of non-Goodpasture IgM antibodies against glomerular basement membrane (anti GBM) in the acute phase of the disease. Moreover, in one of the patients a renal biopsy showed granular deposits of complement factor 3 along the glomerular capillary walls. The possible pathogenic significance of these findings is discussed.

Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome.

Plasma levels of cytokines were measured by EIA in 15 subjects hospitalized with nephropathia epidemica, a European form of hantavirus-induced hemorrhagic fever with renal syndrome. Concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were increased in all patients at admission, and the concentration of IL-10 was increased in most. TNF-alpha concentrations were still increased 1 week after onset of disease; levels of IL-6 and IL-10 were normalized. TNF-alpha was undetectable by the WEHI cell assay in serum samples obtained throughout the acute phase of disease. Serum levels of the two soluble TNF receptors p55 and p75 correlated with levels of the cytokine, indicating that receptor binding may be the reason for lack of bioactivity in vitro. TNF-alpha is known to induce pathophysiologic and clinical changes similar to those seen in nephropathia epidemica and in diseases caused by other hantaviruses.