Bihormonal fully closed-loop system for the treatment of type 1 diabetes: a real-world multicentre, prospective, single-arm trial in the Netherlands.

BACKGROUND: Management of insulin administration for intake of carbohydrates and physical activity can be burdensome for people with type 1 diabetes on hybrid closed-loop systems. Bihormonal fully closed-loop (FCL) systems could help reduce this burden. In this trial, we assessed the long-term performance and safety of a bihormonal FCL system. METHODS: The FCL system (Inreda AP; Inreda Diabetic, Goor, Netherlands) that uses two hormones (insulin and glucagon) was assessed in a 1 year, multicentre, prospective, single-arm intervention trial in adults with type 1 diabetes. Participants were recruited in eight outpatient clinics in the Netherlands. We included adults with type 1 diabetes aged 18-75 years who had been using flash glucose monitoring or continuous glucose monitors for at least 3 months. Study visits were integrated into standard care, usually every three months, to evaluate glycaemic control, adverse events, and person-reported outcomes. The primary endpoint was time in range (TIR; glucose concentration 3·9-10·0 mmol/L) after 1 year. The study is registered in the Dutch Trial Register, NL9578. FINDINGS: Between June 1, 2021, and March 2, 2022, we screened 90 individuals and enrolled 82 participants; 78 were included in the analyses. 79 started the intervention and 71 were included in the 12 month analysis. Mean age was 47.7 (SD 12·4) years and 38 (49%) were female participants. The mean preintervention TIR of participants was 55·5% (SD 17·2). After 1 year of FCL treatment, mean TIR was 80·3% (SD 5·4) and median time below range was 1·36% (IQR 0·80-2·11). Questionnaire scores improved on Problem Areas in Diabetes (PAID) from 30·0 (IQR 18·8-41·3) preintervention to 10·0 (IQR 3·8-21·3; p<0·0001) at 12 months and on World Health Organization-Five Well-Being Index (WHO-5) from 60·0 (IQR 44·0-72·0) preintervention to 76·0 (IQR 60·0-80·0; p<0·0001) at 12 months. Five serious adverse events were reported (one cerebellar stroke, two severe hypoglycaemic, and two hyperglycaemic events). INTERPRETATION: Real-world data obtained in this trial demonstrate that use of the bihormonal FCL system was associated with good glycaemic control in patients who completed 1 year of treatment, and could help relieve these individuals with type 1 diabetes from making treatment decisions and the burden of carbohydrate counting. FUNDING: Inreda Diabetic.

Type B lactic acidosis in solid malignancies.

BACKGROUND: Type B lactic acidosis is thought to be a rare complication of malignancy. It was first described in patients with acute leukaemia by Field et al. in 1963. Since then, it has been observed more often, in particular in haematological malignancies and rarely in solid tumours. METHODS: Previously reported cases of lactic acidosis in solid malignancy are reviewed. In addition, we report a case of type B lactic acidosis in a woman with metastatic breast cancer. Afterwards, we speculate on the elusive pathophysiology of this oncological emergency. RESULTS: 14 cases of lactic acidosis due to solid malignancies, without prior chemotherapy, were identified. The cases were published from the year 1978 to 2006. DISCUSSION: Several theories concerning the mechanism for type B lactic acidosis in solid malignancy have been postulated. During the last decade, more and more evidence supports the role of overproduction of lactic acid due to ischaemia in the neoplastic tissue bed and with cancer cells having an aberrant energy production.

Measuring disease activity to predict therapeutic outcome in Graves' ophthalmopathy.

OBJECTIVE: The concept of disease activity in Graves' ophthalmopathy (GO) might explain why as many as one-third of patients do not respond to immunosuppressive treatment, because only patients in the active stage of disease are expected to respond. The hypothesis was adopted that a parameter used to measure disease activity should be able to predict a response to immunosuppressive treatment. The aim of this study was to develop a multivariate prediction model in which all previous tested activity parameters are integrated. DESIGN AND PATIENTS: We included 66 consecutive patients with untreated moderately severe GO who had been euthyroid for at least 2 months. All patients were treated with radiotherapy. Measurements Treatment efficacy after 6 months follow-up was used as the primary outcome measure. Disease severity and 15 different disease activity parameters were assessed before treatment. Univariate and multivariate logistic regression models were used to predict response (model 1) or no change (model 2). RESULTS: In multivariate analyses, we found that duration of GO, soft tissue involvement, elevation, soluble interleukin-2 receptor (sIL-2R), soluble CD30 (sCD30), eye muscle reflectivity and octreotide uptake ratio were significant predictors of a response to radiotherapy. Gender, duration of GO, soft tissue involvement, eye muscle reflectivity, IL-6 and urinary glycosaminoglycan (GAG) excretion were significant predictors of no change upon radiotherapy. Prognostic score charts were developed for use in clinical practice to calculate the probability of response (model 1) and the probability of no change (model 2) for each new patient. Finally we used a combination of both models to define a recommended treatment modality for each individual patient, based on both the predicted probabilities of response and no change. We were able to identify the correct treatment (based on a comparison with the observed response) in 89% of the patients. CONCLUSIONS: Although we strongly recommend that our results should be confirmed in other studies, our findings are the first evidence for the idea that disease (in)activity should determine which kind of treatment should be used.

Smoking and disease severity are independent determinants of serum adhesion molecule levels in Graves' ophthalmopathy.

Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves' ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM-1, sVCAM-1 and sELAM-1 in 62 euthyroid Graves' patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves' patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM-1 300 [171--575] versus 244 [119--674], P < 0.001; sVCAM-1 457 [317--1060] versus 410 [238--562], P < 0.001; and sELAM-1 61 [19--174] versus 53 [23--118], P = 0.021. Euthyroid Graves' disease patients without GO had levels similar to controls: sICAM-1 273 138--453), sVCAM-1 386 [260--1041] and sELAM-1 46 [22--118]. Smoking had an independent effect and was associated with higher levels of sICAM-1 and lower levels of sVCAM-1 in both GO patients and controls; sELAM-1 levels were comparable. In the 62 GO patients, sICAM-1 correlated significantly with severity of eye disease (r = 0.40, P = 0.002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM-1 and sVCAM-1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM-1 and decreased sVCAM-1 levels; (ii) independent from smoking, euthyroid GO patients have higher levels of sICAM-1, sVCAM-1 and sELAM-1 than patients with euthyroid Graves' disease or healthy controls; (iii) the major determinant of sICAM-1 in GO patients is the severity of their eye disease.

Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments.

OBJECTIVE: The Graves' ophthalmopathy quality of life questionnaire (GO-QOL) is the first instrument available to measure health-related quality of life (HRQL) of patients with Graves' ophthalmopathy. The main objective of this study was to define a minimal clinically important difference (MCID) in score on the GO-QOL that can be considered an important improvement in HRQL by examining changes in GO-QOL scores in patients who subjectively report improvement from their treatment. A secondary objective was to test the longitudinal validity of the GO-QOL, using prespecified hypotheses about expected treatment effects. DESIGN: A prospective cohort study. PATIENTS: We included 164 patients who were scheduled for radiotherapy (23), orbital decompression (10 for sight loss, 38 for exophthalmos), eye muscle surgery (31), eyelid lengthening (43) or blepharoplasty (19). MEASUREMENTS: Patients completed the GO-QOL and three general HRQL questionnaires, before and three or six months after treatment, depending on the performed procedure. Clinical characteristics were collected from the medical records. Mean changes in GO-QOL scores and effect sizes were calculated after different treatments, and in subgroups of responders and nonresponders according to clinical characteristics and according to the patients themselves. RESULTS: A clinical response to treatment was associated with a change in GO-QOL scores of approximately 10--20 points after major treatments (radiotherapy or decompression), and with a change of approximately 3--10 points after minor surgery (eye muscle surgery, eyelid lengthening, blepharoplasty). Changes in GO-QOL scores of about 6--10 points were considered important improvements by the patients themselves. The direction and amount of change in GO-QOL scores after different treatments were in accordance with our prespecified hypotheses about treatment effects. Effect sizes in the GO-QOL subscales were generally higher than effect sizes of the general HRQL subscales, supporting the longitudinal validity of the GO-QOL. CONCLUSIONS: As a general guideline, one could consider a mean change of at least 6 points on one or both subscales an important change in daily functioning for patients. For more invasive therapies, a change of at least 10 points is recommended as a minimal clinically important difference.

The usefulness of quantitative orbital magnetic resonance imaging in Graves' ophthalmopathy.

BACKGROUND: Two-thirds of patients with Graves' ophthalmopathy (GO) respond to immunosuppressive treatment (prednisone or orbital irradiation), but one-third do not respond. Responders are likely to be in the active, oedematous stage of the eye disease, nonresponders in the inactive fibrotic stage. Clinical distinction between the two stages can be difficult. Quantitative magnetic resonance imaging (MRI) might be helpful in this respect, as T2 relaxation times are longer in oedematous than in fibrotic tissues. STUDY DESIGN: Prospective study on quantitative orbital MRI in healthy subjects and patients with moderately severe GO, evaluating T2 relaxation time of extraocular muscles (EOM): (a) in patients vs. controls, and (b) in patients, as a predictor of outcome to orbital irradiation. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers and 64 consecutive patients with moderately severe untreated GO, who were euthyroid for > or = 2 months and qualified for orbital irradiation. T2 relaxation times were measured at the site of the largest diameter in all eight EOM of each subject. Baseline T2 values in patients were related to outcome of radiotherapy, as assessed by an independent observer 6 months later according to predefined criteria. RESULTS: T2 relaxation times of the eight EOM were longer in GO patients than in controls: median [range] 126 [52--250] vs. 88 [50--126] msec; P = 0.003. Per subject the single eye muscle with the longest T2 time was selected to represent active inflammation (excluding the lateral muscles for technical reasons). Again patients were different from controls: 160 [68--250] vs. 103 [86--115] msec, P < 0.001. In the group of 34 responders to subsequent radiotherapy, these T2 times tended to be longer than in the 30 nonresponding patients: 168 [108--250] vs. 138 [68--216] msec, P = 0.07. Using a cut-off value of 130 msec (derived from a receiver-operator-characteristics curve) a positive predictive value of 64% and a negative predictive value of 92% for the outcome of radiotherapy was calculated. CONCLUSION: Quantitative orbital magnetic resonance imaging was found to be less accurate in predicting successful outcome of radiotherapy than expected. It seems more useful in detecting the fibrotic end-stage than the active stage of Graves' ophthalmopathy. It is therefore of limited use in the decision whether or not to apply immunosuppression in patients with moderately severe Graves' ophthalmopathy.

Both Th1- and Th2-derived cytokines in serum are elevated in Graves' ophthalmopathy.

Increased serum cytokine levels have been reported in patients with autoimmune thyroid disease, but less is known about their levels in patients with Graves' ophthalmopathy (GO). It is not known whether GO is a cell-mediated or humoral autoimmune disease. We investigated whether serum cytokines are elevated in GO patients and whether the cytokines were Th1- or Th2-derived. In addition, elevated cytokines might reflect the activity of GO, and thus we investigated whether cytokine levels could predict the clinical response to orbital radiotherapy. We studied 62 consecutive patients with moderately severe untreated GO and 62 healthy controls, matched for sex, age and smoking habits. Serum concentrations of IL-1RA, sIL-2R, IL-6, sIL-6R, tumour necrosis factor-alpha (TNF-alpha) RI and II and sCD30 were measured using highly sensitive ELISAs, in the patients before and 3 and 6 months after radiotherapy. All patients were euthyroid, with anti-thyroid drugs, before and during the entire study period. All baseline cytokine and cytokine receptor levels were significantly elevated in GO patients compared with healthy controls, except for IL-1RA. The levels did not correlate with parameters of the thyroid disease, nor with the duration, activity or severity of GO. However, backward logistic regression analysis showed that IL-6, sCD30 and TNFalphaRI were able to predict a beneficial response to orbital radiotherapy. We therefore conclude that both Th1- and Th2-derived cytokines are elevated in GO patients compared with its controls. IL-6, sCD30 and TNFalphaRI had some value for predicting therapeutic outcome to orbital irradiation, and may thus reflect active eye disease.

Assessment of disease activity in Graves' ophthalmopathy by orbital ultrasonography and clinical parameters.

OBJECTIVE: To study if A-mode ultrasonography (US) in combination with the Clinical Activity Score (CAS) and duration of Graves' ophthalmopathy (GO) could predict the response to immunosuppression in Graves' ophthalmopathy. DESIGN: A prospective clinical study. PATIENTS AND METHODS: Fifty-six consecutive patients with moderately severe GO were treated with retrobulbar irradiation (10 fractions of 2 Gy). Before treatment the internal reflectivity in the extraocular eye muscles, the CAS, and the duration of Graves' ophthalmopathy were assessed and related to the therapeutic outcome 26 weeks after irradiation. RESULTS: Twenty-eight (50%) of the patients responded favourably to radiotherapy (four patients became worse, and 24 did not change), and the eye muscle echogenecity indeed tended to be lower in the responders than in the non-responders (P = 0.09). From a receiver operator characteristics curve, a cut-off value of 30% yielded a good positive predictive value of 85%, but the negative predictive value was only 60%. The CAS (>/= 4/10) had a positive predictive value of 65%, and a negative predictive value of 56%. When combining the ultrasound with the CAS, the positive predictive value increased to 74% and the negative predictive value to 72%. Adding the duration of eye symptoms (cut-off 18 months), the prediction of response further improved: positive predictive value 79%, and negative predictive value 89%. CONCLUSIONS: A-mode ultrasonography has a rather good positive predictive value, but its poor negative predictive value precludes its use as sole activity parameter. By adding the Clinical Activity Score and duration of Graves' ophthalmopathy, the negative predictive value increased considerably. By using this combination, inactive disease can be identified more precise, permitting rehabilitative surgery at an earlier stage in these patients.

Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy.

OBJECTIVE: Graves' ophthalmopathy (GO) and Graves' hyperthyroidism are closely associated diseases and thought to be caused by the same autoimmune process. An obvious explanation for this would be the presence of autoantibodies reacting with an autoantigen present in the orbit and the thyroid gland. The TSH-Receptor (TSH-R) antibodies are a likely candidate, because they cause Graves' hyperthyroidism and the TSH-R appears to be present also in orbital tissues. If TSH-R antibodies are responsible for the ophthalmopathy one would expect their titres to correlate with clinical characteristics of the eye disease. The aim of the present study is to see whether TSH-R antibodies are related to the activity and severity of the thyroid-associated ophthalmopathy. DESIGN AND PATIENTS: TSH-R antibody levels were measured as TBII (TRAK assay), and TSI (cAMP response of a TSH-R transfected cell line) in serum of 63 patients with untreated moderately severe GO, accompanying Graves' thyroid disease; all patients had been euthyroid for > 2 months. RESULTS: TBII and TSI titres were strongly related to each other. TBII or TSI titres did not correlate with thyroidal or orbital disease duration, nor with TPO antibody levels. In contrast, we found a striking and highly significant correlation between the Clinical Activity Score (CAS) of the eye disease, and both TBII (r = 0.54; P < 0.0001) and TSI (r = 0.50; P < 0.0001). In addition, a weaker but significant relation was found between proptosis (in mm) and TBII (r = 0.36; P = 0.004) and TSI (r = 0.49; P = 0.0001). No correlation was found with eye muscle motility. CONCLUSION: TSH-R antibody levels correlate directly with clinical features of Graves' ophthalmopathy. The results support the hypothesis of a pathogenetic role of TSH-R antibodies and the TSH-R in the orbit of Graves' ophthalmopathy patients.

Test-retest reliability of the GO-QOL: a disease-specific quality of life questionnaire for patients with Graves' ophthalmopathy.

To assess the test-retest reliability of a recently developed disease-specific quality of life questionnaire for evaluative studies in patients with Graves' ophthalmopathy (the GO-QOL), measuring visual functioning and psychosocial consequences of changed appearance. Ninety-three patients were included and completed the GO-QOL. Additional information on general quality of life and disease characteristics was obtained. Construct validity and internal consistency of the two subscales was determined, based on principal component analyses, Cronbach's alpha's and correlations with MOS-24, three subscales of the SIP, and clinical measures. Eighty-nine patients completed a second GO-QOL after two weeks including four additional questions about perceived changes in health status. Test-retest reliability was assessed by calculating intraclass correlation coefficients (ICCs) and limits of agreement, using several definitions of stable patients. Slight modifications from the original questionnaire were evaluated for their effect on the validity and reliability. The construct validity of the two subscales was confirmed and Cronbach's alpha's were 0.89 for visual functioning and 0.87 for appearance. The substantial ICCs found for both scales of the GO-QOL (ICCs above 0.80) reflect that the errors of measurement were relatively small, which supports the value of this questionnaire for clinical studies with relatively small sample sizes. The modification of the appearance scale improved the validity of the scale and resulted in less missing values. Following the recommendations of the joint committee of thyroid associations, we recommend the inclusion of HRQL-measures in clinical studies that evaluate treatments for patients with GO. The GO-QOL is a promising tool for this purpose.

Octreotide-scintigraphy is a disease-activity parameter in Graves' ophthalmopathy.

OBJECTIVE: It is thought that immunosuppressive treatment of Graves' ophthalmopathy should be restricted to patients with active eye disease, but assessing disease activity is difficult. Octreotide scintigraphy has been claimed to differentiate active from inactive disease. Here we study the intraobserver variability and diagnostic accuracy of the quantitative measurement of orbital octreotide uptake. PATIENTS AND DESIGN: Twenty-two consecutive patients with moderately severe ophthalmopathy were treated with retrobulbar radiotherapy. Pretreatment octreotide scintigraphic data were related to the response at six months after radiotherapy, using Receiving-Operator-Characteristic curves. MEASUREMENTS: Octreotide uptake was measured at 4 and 24 h after i.v. injection of approximately 3 mCi (= 111 MBq; range 75-150 MBq) 111Indium-DTPA-Octreotide with a neuro-SPECT camera. Counts were measured in fixed regions-of-interest in 4 transversal slices of the orbit, the temporal and the occipital area. Measurements were done twice and intraobserver variability was analysed by coefficients of variations (CV). Uptake is expressed as orbital/background ratio. The nature of the temporal uptake was studied by matching an octreoscan with a technetium scan and MRI. RESULTS: Intra-observer variability of measuring octreotide uptake was acceptable, and the coefficient of variation slightly better using the orbital/occipital ratio (11%), than the orbital/temporal ratio (16%). From matching studies it appears that the temporal uptake takes place, in part, in the parotid gland. The orbital/occipital ratio was used to predict the outcome of radiotherapy. Mean (+/- SD) uptake on the 4 h scan was higher in responders (2.2 +/- 0.66) than in nonresponders (1.7 +/- 0.39; P = 0.04). From the Receiving-Operator-Characteristic curve we determined a cut-off value of 1.85, which yielded a positive predictive value of 92% and a negative predictive value of 70%. The 24 h scan could not predict a response. CONCLUSION: Quantitative measurement of orbital octreotide uptake is possible. Using the orbital/occipital ratio on the 4 h scan, the octreoscan seems useful in predicting response to subsequent radiotherapy. The 24 h scan seems not to be useful in predicting therapeutic outcome.

The use of colour slides in the assessment of changes in soft-tissue involvement in Graves' ophthalmopathy.

There is a need for more reliable and validated methods to assess the eye changes in Graves' disease. Such measurements are now available for the assessment of proptosis, eye muscle dysfunction, and optic nerve involvement. However, no validated objective measurement exists for NO SPECS class II signs. The present study compares the use of colour slides with clinical grading for assessing soft-tissue involvement. Forty-three patients were treated with retrobulbar irradiation. Pre-treatment, and 6 months post-treatment the severity of class II signs was graded from 0 to grade c in two ways; 1) Clinically, by two independent, experienced observers, who recorded their scores on the same day; 2) From colour slides, taken at the same visits, which were graded afterwards in one session independently by the same observers. Inter-observer agreement about clinical grading was low (Kappa 0.32), and was not improved by using the slides (Kappa 0.35). However, by using the clinical scores, the observers disagreed on treatment outcome in 21/43 patients (49%), whereas using the slides disagreement occurred in only 6/43 (14%, p < 0.01). It is concluded that the grading of soft-tissue involvement is highly subjective. However, the use of colour slides does provide a more reliable way to assess a treatment effect and should be used in clinical trials.

Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL.

AIM: To develop a reliable and valid disease specific quality of life questionnaire (the GO-QOL) for patients with Graves' ophthalmopathy (GO), that can be used to describe the health related quality of life and changes in health related quality of life over time as a consequence of disease and treatment. METHODS: 70 consecutive GO patients (age > 18 years) who were referred for the first time to the combined outpatient clinic of the orbital centre and the department of endocrinology completed the 16 questions of the GO-QOL. Additional information on general quality of life and disease characteristics was obtained. Construct validity and internal consistency of the disease specific questionnaire was determined, based on principal component analysis, Cronbach alphas and correlations with MOS-24, three subscales of the SIP, demographic, and clinical measures. RESULTS: The a priori expected subdivision of the questionnaire in two subscales, one measuring the consequences of double vision and decreased visual acuity on visual functioning, and one measuring the psychosocial consequences of a changed appearance, was confirmed in the principal component analysis. Both scales had a good reliability and high face validity. Correlations with other measures supported construct validity. Mean scores (range 0-100) were 54.7 (SD 22.8) for visual functioning and 60.1 (24.8) for appearance (higher score = better health). CONCLUSION: The GO-QOL is a promising tool to measure disease specific aspects of quality of life in patients with GO and provides additional information to traditional physiological or biological measures of health status.

Quality of life in patients with Graves' ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument.

To assess the impact of Graves' ophthalmopathy (GO) on quality of life using a general questionnaire, we performed a descriptive study on consecutive ophthalmopathy patients. We included 70 consecutive, euthyroid patients (age >18 years, 50 females, 20 males, mean +/- SD age 53 +/- 13 years) with varying degrees of severity of GO. General quality of life was assessed with the brief survey (24 questions) from the Medical Outcomes Study (MOS-24), and three subscales of the Sickness Impact Profile (SIP). In comparison with a large published reference group, low scores on the MOS-24 were found. Mean +/- SD scores (difference from reference group) were: physical functioning 58 +/- 31 (-28), role functioning 72 +/- 40 (-15), social functioning 78 +/- 25 (-14), mental health 67 +/- 18 (-10), health perceptions 46 +/- 22 (-26), and bodily pain 68 +/- 28 (-6). MOS-24 and SIP scores did not correlate with the duration, severity, or activity of the ophthalmopathy. In conclusion, we have shown that mild to moderately severe GO has a large influence on the quality of life of these patients. The negative impact on well-being seems not to be related to the usual clinical assessment. These results underscore the need for quality-of-life measurements in clinical trials.

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.