Hantavirus antigen detection in kidney biopsies from patients with nephropathia epidemica.

Renal biopsies collected from ten patients with serologically confirmed Puumalavirus (PUUV) infection in the acute stage with renal dysfunction who lived in the same PUUV endemic area in The Netherlands, were studied histologically, immuno-histochemically and subsequently examined for the presence of viral antigen by immunoperoxidase staining. Interstitial hemorrhages and deposition of IgM, complement component C3 and fibrin along the basal side of the tubular epithelial cells, were found in PUUV seropositive patients. In six of these patients viral antigen was detected in the cytoplasm of renal tubular epithelial cells with focal distribution in the cortical and medullary areas of the kidneys. Surprisingly, also in two of the ten renal biopsies from PUUV seronegative patients, PUUV antigen was demonstrated, with essentially the same localization. Comparison of severity and extent of the lesions in the seropositive group with those of these two patients showed no significant differences between tubular and interstitial abnormalities. These findings indicate that the demonstration of certain histopathological alterations and the detection of viral antigen by immunoperoxidase techniques in kidney biopsies, may be useful as additional tools for the diagnosis of PUUV infection.

Hantavirus nephropathy in The Netherlands: clinical, histopathological and epidemiological findings.

Until 1995, 39 cases of serologically confirmed hantavirusnephropathy in humans, caused by the Puumala type of Hantavirus, have been documented in the Netherlands. Thirty-two of these occurred in Twente, a small region in the eastern part of the country, in which the presence of Puumala-like Hantavirus in feral rodents has recently been demonstrated. Sixteen of the cases documented in humans occurred in 1993. Here we present an overview of clinical, histopathological and epidemiological findings of hantavirus infections. All the clinical and laboratory findings of the 39 documented cases were similar to those found in infections with the same virus in neighbouring countries. Complete recovery of renal function occurred in all patients. One patient developed a Guillain-Barré syndrome after having recovered from her renal failure. Histopathological examination of kidney biopsies collected from 13 of the patients in the acute stage, confirmed the presence of acute interstitial inflammation of differing severity in these individuals. A serological survey carried out amongst 4232 healthy blood donors in the endemic area showed a seroprevalence of 0.7%. This suggests that less severe or perhaps even subclinical infections occur.

Hantavirus infections in The Netherlands: epidemiology and disease.

A serological survey for the prevalence of hantavirus infections in The Netherlands was carried out on > 10,000 sera, from selected human populations, and different feral and domestic animal species. Hantavirus-specific antibodies were found in about 1% of patients suspected of acute leptospirosis, 10% of patients with acute nephropathia, and in less than 0.1% haemodialysis and renal transplant patients. Among individuals with a suspected occupational risk, 6% of animal trappers, 4% of forestry workers, 2% of laboratory workers and 0.4% of farmers were seropositive. The majority of the seropositive individuals lived in rural and forested areas. The main animal reservoir of the infection was shown to be the red bank vole (Clethrionomys glareolus). Epidemiological, clinical and laboratory findings seen in serologically confirmed human cases were similar to those associated with nephropathia epidemica.

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.

OBJECTIVE: To determine whether alfacalcidol--used in management of overt renal bone disease--may safely prevent renal bone disease when used earlier in course of renal failure. DESIGN: Double blind, prospective, randomised, placebo controlled study. SETTING: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. SUBJECTS: 176 patients aged 18-81 with mild to moderate chronic renal failure (creatinine clearance 15-50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. INTERVENTIONS: Alfacalcidol 0.25 micrograms (titrated according to serum calcium concentration) or placebo given for two years. MAIN OUTCOME MEASURES: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. RESULTS: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P < 0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P < 0.001). There was no difference in rate of progression of renal failure between the two groups. CONCLUSION: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure.

Class and subclass distribution of Hantavirus-specific serum antibodies at different times after the onset of nephropathia epidemica.

Sera from Dutch and Belgium individuals who suffered from nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome (HFRS), were tested for the distribution of classes and subclasses of Hantavirus (HV)-specific antibodies at different times after the onset of the disease, with class- and subclass-specific Ig capture enzyme-linked immunosorbent assays (ELISAs). In the acute, early convalescent, and convalescent phases, predominantly specific IgA, IgM, and IgG3 antibodies were detected. Specific IgG2 antibodies were only detected at low levels in the early convalescent and convalescent phases. In the late convalescent phase specific IgG1 and IgG3 antibodies were found, whereas in the late postconvalescent phase only specific IgG1 antibodies proved to be present. Specific IgG4 antibodies were not detected in any of the respective phases. These data show that the simultaneous determination of classes and subclasses of HV specific serum antibodies allows the estimation of the time elapsed after the onset of NE.

Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection.

The subcutaneous administration of epoetin alfa preparations may cause pain at the injection site. To identify the pain-causing substance in these formulations we performed two double-blind, placebo-controlled, randomized order, cross-over studies. Differences in pain experienced after subcutaneous injection of an epoetin alfa solution and its vehicle were assessed in 36 patients. The vehicle and its component parts, albumin and citrate, were compared in 36 volunteers. Normal saline served as a placebo control in both studies. Pain scores were obtained from visual analogue pain scales with no divisions and from five point verbal descriptive pain scales. Both the epoetin alfa solution and its vehicle caused significantly more pain than normal saline (P < 0.0001) in the patients studied. In volunteers the pain scores with the vehicle or its citrate component were significantly higher (P < 0.0001) when compared with normal saline or with the albumin component of the vehicle. In conclusion, the local pain experienced after subcutaneous administration of epoetin alfa preparations is mainly caused by the citrate component of the buffered solution. Epoetin alfa and the albumin component of the preparation do not play a role in this phenomenon.

Serum antibodies to structural proteins of Hantavirus arise at different times after infection.

An enzyme-linked immunosorbent assay (ELISA) was developed for the quantification of serum antibodies against group-specific epitopes of the glycoproteins (G1, G2) and nucleoprotein (NP) of the genus Hantavirus. This assay was used to study the kinetics of the development of serum antibodies after natural infection with Puumala-like virus in humans. To this end a panel of 34 serum samples collected from individuals at different times after natural infection was tested by the ELISA. The samples were also tested for specific IgM and IgG levels against Puumala-like virus, which provided confirmatory data about the presumed timing of infection. It was shown that serum antibodies against the G1 epitope were present in the acute and early convalescent period just before antibodies to the NP epitope could be demonstrated. In contrast, antibodies to two G2 epitopes were present not earlier than in the convalescent and late convalescent period. Since all these categories of antibodies seem to persist for long periods, antibodies against the G1 epitope and the NP epitope may be of specific diagnostic value. Furthermore, levels of G1-specific antibodies and antibodies to either NP or G2 may allow estimation of the time elapsed following initial infection.

Chronic lymphocytic leukaemia presenting as renal failure with lymphocytic infiltration of the kidneys.

A case of renal failure is reported in a 60-yr-old male as the first clinical manifestation of chronic lymphocytic leukaemia (CLL). It appeared to be due to a massive interstitial infiltration of both kidneys by small lymphocytes. Combination chemotherapy consisting of monthly courses of cyclophosphamide, vincristine and prednisone (COP), resulted in a rapid improvement of the renal function and in an apparent haematological and clinical remission of the CLL. After six courses, the COP therapy was stopped and replaced by a maintenance treatment with oral chlorambucil. During follow up, now lasting more than 3 years, no deterioration of renal function has been noted.

Theophylline intoxication, clinical features, treatment and outcome: a case report and a review of the literature.

Severe theophylline intoxication is a medical emergency that can lead to cardiac arrhythmias, convulsions and cardiovascular collapse not infrequently leading to permanent morbidity or mortality. We describe a 30-yr-old patient with a peak serum theophylline level of 87 mg/l treated with haemoperfusion using a coated charcoal-filled column. A review of the literature concerning theophylline toxicity, supportive care, outcome and the possible indications for the use of extracorporeal haemoperfusion is given. A summary of possible conservative measures is given. It is concluded that haemoperfusion is the extracorporeal treatment of choice and should be considered in case of theophylline serum levels above 80 mg/l even without signs of major toxicity. For certain patients with conditions increasing the risks of prolonged or severe toxicity even lower serum theophylline levels may warrant the use of haemoperfusion.

[Hantaan virus infection in Twente]. / Hantavirusinfecties in Twente.

OBJECTIVE: To find out if Hantavirus infection, as a cause of acute renal failure, has been overlooked in the past. To determine if Hantavirus can be found in wild rodents, particularly in red bank voles (Clethrionomys glareolus), living in the area. SETTING: General hospital, Twente area. PATIENTS, MATERIAL AND METHODS: Retrospective selection of patients, hospitalised between 1970 and 1989 with renal failure due to biopsy-proven or clinically probable acute interstitial nephritis of unknown aetiology. Sera from the acute phase of the disease, if still available, or sera taken in 1989 were tested for anti-Hantavirus antibodies. Red bank voles, trapped in the area were tested for Hantaviral antigen and specific antibodies. RESULTS: Out of 12 patients, 10 could be investigated. Anti-Hantavirus antibodies were detected in 5 patients. All patients had very probably acquired the infection in the Twente area. In 4 of 10 red bank voles Hantaviral antigen and specific antibodies were found. CONCLUSION: The findings suggest that Hantavirus infections have been occurring in this area over a long period of time and are underdiagnosed.