Chronic beryllium disease as a re-emerging occupational disorder possibly misdiagnosed as sarcoidosis : a Swiss study project

Background: Beryllium (Be) is increasingly used worldwide for numerous industrial applications. Occupational exposure to Be may lead to Be sensitization (BeS), a CD4-mediated immune response. BeS may progress to chronic beryllium disease (CBD), a granulomatous lung disorder closely resembling sarcoidosis. The recognition of CBD requires detection of Be exposure at occupational history, and detection of BeS on blood or BAL lymphocytes. Since methods for CBD detection are not routinely available in Switzerland, we hypothesized that CBD cases are not recognized but misdiagnosis as sarcoidosis. Objective: To present an ongoing Swiss study screening patients with sarcoidosis in search of Be exposure, BeS, and CBD. Methods: Both a prospective and a retrospective cohort are being studied. In the prospective cohort, the main steps include: 1) recruitment of 100 consecutive patients with newly diagnosed pulmonary sarcoidosis at 2 centers (Lausanne, Bern). 2) screening for possible occupational Be exposure by self-administered patient questionnaire. 3) standardized detailed occupational interview and clinical visit by occupational health specialist. If step 3 is positive, then 4) blood and BAL sampling for detection of BeS by specifically developed Elispot assay and CFSE flow cytometry, with subsequent comparison to the classical Be lymphocyte proliferation test. If step 4 is positive, then 5) review of medical records and diagnostic revision from sarcoidosis to CBD. 6) appropriate measures for exposure cessation and case reporting to SUVA as occupational disease. The retrospective cohort will include 400 patients with previously diagnosed pulmonary sarcoidosis, either treated or untreated, recruited through the SIOLD Registries. Steps 2 to 5 will be peformed as above, except for a) end of study after step 2 if screening questionnaire does not reveal Be exposure, and b) step 4 done on blood sample only (BAL not needed). Current status: Self-administered screening questionnaire and tools for standardized occupational interview have been developed. BeS testing has been implemented and undergoes validation. Inclusions in the prospective phase have started at both study sites. The retrospective phase is in preparation. Conclusion: The current study status allows to conclude to technical feasibility of the project. The prospective phase if this study is funded by the SUVA. The SIOLD Registries are supported by the Swiss Pulmonary League.

Antidiabetic drugs and kidney disease - Recommendations of the Swiss Society for Endocrinology and Diabetology.

Patients with diabetes are at risk of early renal function decline. Therefore, kidney function needs monitoring at least once per year. Once the glomerular filtration rate (GFR) is less than 60 ml/min, the pharmacokinetics of antidiabetic drugs may be altered. Sulfonylurea and glinide therapies are associated with a risk of hypoglycaemia which is increased in the presence of renal impairment. Most sulfonylureas must be discontinued once GFR is <60 ml/min. Some glinides may be continued beyond this threshold, in particular repaglinide, which may be used in dialysis patients. In the absence of comorbidities, metformin can be continued at lower doses until a GFR of 45 ml/min, but must be withdrawn in case of dehydration or during the administration of a nephrotoxic drug including dye for radiological investigations. Glitazones may worsen water and sodium retention in patients with renal impairment. The pharmacokinetics of all DPP-IV inhibitors except linagliptin are altered with impaired renal function. Only sitagliptin, saxagliptin and linagliptin may be used in advanced kidney disease, but experience is as yet very limited. GLP-1 agonists are contraindicated in moderate to advanced kidney disease.

Surgery and granulocyte transfusions for life-threatening infections in chronic granulomatous disease.

We report two patients with chronic granulomatous disease (CGD) and life-threatening infections: a 10 10/12-year-old boy had Aspergillus fumigatus spondylitis with destruction of the 11th vertebral body and paravertebral abscess formation, and an 8 5/12-year-old boy had multiple Staphylococcus aureus hepatic abscesses with subphrenic abscess formation. Both patients failed to respond to intense antimicrobial therapy but showed a remarkable recovery following surgical drainage combined with granulocyte transfusions. These results suggest that antimicrobial therapy and surgical drainage followed by granulocyte transfusions may be the ideal mode of treatment for severe infections in patients with CGD.

The significance of pre-existing minority Y181C mutations on virological failure of NNRTI-based, first-line antiretroviral therapy

Background: Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

Clinical and laboratory status of patients with chronic Chagas disease living in a vector-controlled area in Minas Gerais, Brazil, before and nine years after aetiological treatment

Twenty-eight Chagas disease patients (CD), 22 with the indeterminate clinical form (IND) and six with the cardiac or digestive form (CARD/DIG), were treated with benznidazole and underwent clinical and laboratorial analysis before (IND and CARD/DIG) and nine years after [patients after treatment (CDt), patients with the indeterminate clinical form at treatment onset (INDt) and with the cardiac or digestive form at treatment onset (CARD/DIGt)] treatment. The data demonstrate that 82.1% of CDt patients (23/28) remained clinically stable and 95.4% of the INDt (21/22) and 33.3% of the CARD/DIGt (2/6) patients showed unaltered physical and laboratorial examinations. The clinical evolution rate was 2%/year and was especially low in INDt patients (0.5%/year) relative to CARD/DIGt patients (7.4%/year). Positive haemoculture in treated patients was observed in 7.1% of the cases. None of the INDt (0/21) and 33.3% of the CARD/DIGt (2/6) patients displayed positive cultures. The PCR presented a positive rate significantly higher (85.2%, 23/27) than haemoculture and two samples from the same patient revealed the same result 57.7% of the patients. Conventional serology-ELISA on 16 paired samples remained positive in all individuals. Semi-quantitative ELISA highlighted significant decreases in reactivity, particularly in INDt relative to IND. Non-conventional serology-FC-ALTA-IgG, after treatment, showed positive results in all sera and 22 paired samples examined at seven and nine years after treatment, demonstrated significantly lower reactivity, particularly in INDt patients. This study was retrospective in nature, had a low number of samples and lacked an intrinsic control group, but the data corroborate other results found in the literature. The data also demonstrate that, even though a cure has not been detected in the none-treated patients, the benefits for clinical evolution were selectively observed in the group of INDt patients and did not occur for CARD/DIGt patients.

Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina

The purpose of this review is to describe research findings regarding chronic Chagas disease in Argentina that have changed the standards of care for patients with Trypanosoma cruzi infection. Indirect techniques (serological tests) are still the main tools for the primary diagnosis of infection in the chronic phase, but polymerase chain reaction has been shown to be promising. The prognosis of patients with heart failure or advanced stages of chagasic cardiomyopathy is poor, but a timely diagnosis during the initial stages of the disease would allow for prescription of appropriate therapies to offer a better quality of life. Treatment of T. cruzi infection is beneficial as secondary prevention to successfully cure the infection or to delay, reduce or prevent the progression to disease and as primary disease prevention by breaking the chain of transmission. Current recommendations have placed the bulk of the diagnostic and treatment responsibility on the Primary Health Care System. Overall, the current research priorities with respect to Chagas disease should be targeted towards (i) the production of new drugs that would provide a shorter treatment course with fewer side effects; (ii) the development of new tools to confirm cure after a full course of treatment during the chronic phase and (iii) biomarkers to identify patients with a high risk of developing diseases.

Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy

The pathogenesis of Chagas disease cardiomyopathy (CCC) is not well understood. Since studies show that myocarditis is more frequent during the advanced stages of the disease, and the prognosis of CCC is worse than that of other dilated cardiomyopathies of non-inflammatory aetiology, which suggest that the inflammatory infiltrate plays a major role in myocardial damage. In the last decade, increasing evidence has shown that inflammatory cytokines and chemokines play a role in the generation of the inflammatory infiltrate and tissue damage. CCC patients have an increased peripheral production of the inflammatory Th1 cytokines IFN-³ and TNF-± when compared to patients with the asymptomatic/indeterminate form. Moreover, Th1-T cells are the main producers of IFN-³ and TNF-± and are frequently found in CCC myocardial inflammatory infiltrate. Over the past several years, our group has collected evidence that shows several cytokines and chemokines produced in the CCC myocardium may also have a non-immunological pathogenic effect via modulation of gene and protein expression in cardiomyocytes and other myocardial cell types. Furthermore, genetic polymorphisms of cytokine, chemokine and innate immune response genes have been associated with disease progression. We will review the molecular and immunological mechanisms of myocardial damage in human CCC in light of recent findings.

Assisted reproductive technology and obstetric outcome in couples when the male partner has a chronic viral disease.

BACKGROUND Assisted reproductive technology (ART) with washed semen can achieve pregnancy with minimal risk of horizontal and vertical transmission of chronic viral diseases (CVD) such as human immunodeficiency virus (HIV), hepati- tis C virus (HCV) and hepatitis B virus (HBV) among serodiscordant couples. How- ever, few studies have been made of the use made by these couples of ARTs or of the obstetric results achieved. MATERIALS AND METHODS In this retrospective study, 93 men who were seropositive for HIV, HCV or HBV and who underwent assisted reproduction treatment at our centre (Hospital Universitario Virgen de las Nieves, Granada, Spain) were included. Washed semen was tested to detect viral particles. Non-infected women were tested before and after each treatment, as were the neonates at birth and after three months. RESULTS A total of 62 sperm samples were washed, and none were positive for the detec- tion of viral molecules. Semen samples from 34 HBV positive males were not washed since the female partner had immunity to hepatitis B. In total, 38 clinical pregnancies were achieved (22% per cycle and 40.9% per couple) out of 173 cycles initiated, and 28 births were achieved (16.2% per cycle and 30.1% per couple), producing 34 live births. The rate of multiple pregnancies was 21.4%. Obstetric and neonatal results were similar in the groups of couples studied. At follow-up, no seroconversion was detected in the women or neonates. CONCLUSION Sperm washing and intracytoplasmic sperm injection are shown to be a safe and effective option for reducing the risk of transmission or super infection in serodiscordant or concordant couples who wish to have a child. Pregnancies ob- tained by ART in couples when the male is CVD infected achieve good obstetric and neonatal results.

Modulation of Trypanosoma cruzi-specific T-cell responses after chemotherapy for chronic Chagas disease

The aim of this review is to describe the contributions of the knowledge of T-cell responses to the understanding of the physiopathology and the responsiveness to etiological treatment during the chronic phase of Chagas disease.T-helper (Th)1 and interleukin (IL)-10Trypanosoma cruzi-specific T-cells have been linked to the asymptomatic phase or to severe clinical forms of the disease, respectively orvice versa, depending on the T. cruziantigen source, the patient’s location and the performed immunological assays. Parasite-specific T-cell responses are modulated after benznidazole (BZ) treatment in chronically T. cruzi-infected subjects in association with a significant decrease in T. cruzi-specific antibodies. Accumulating evidence has indicated that treatment efficacy during experimental infection with T. cruziresults from the combined action of BZ and the activation of appropriate immune responses in the host. However, strong support of this interaction in T. cruzi-infected humans remains lacking. Overall, the quality of T-cell responses might be a key factor in not only disease evolution, but also chemotherapy responsiveness. Immunological parameters are potential indicators of treatment response regardless of achievement of cure. Providing tools to monitor and provide early predictions of treatment success will allow the development of new therapeutic options.