Intestinal infection at onset of mycophenolic acid-associated chronic diarrhea in kidney transplant recipients.

BACKGROUND: Chronic diarrhea after kidney transplantation is often attributed to mycophenolic acid (MPA) toxicity. We hypothesize that intestinal infections contribute to the pathogenesis of chronic MPA-associated diarrhea. METHODS: In this retrospective study, all patients (n = 726) receiving a kidney transplant between 2000 and 2010 at the University Hospital Zurich were followed until July 2014 for occurrence of chronic diarrhea (≥4 weeks). Infectious triggers at diarrhea onset were assessed by reviewing medical history, stool microbiology, and histology of colon biopsies. RESULTS: In 46 patients (6.3% of the cohort), a total of 51 episodes of chronic diarrhea during MPA treatment were documented. The diarrhea episodes were often severe, as confirmed by significant weight loss. The cumulative incidence of chronic diarrhea was uniformly distributed throughout the post-transplant period, with 2.0%, 5.1%, and 9.6% at 1, 5, and 10 years, respectively. Evidence was found for intestinal infection at diarrhea onset in 38 episodes (74.5%). Occurrence of diarrhea onset showed a seasonal distribution with peaks in April and October/November. Specific antimicrobial treatment alone was associated with a 19% resolution rate only, whereas combination with dose reduction of MPA or switch from mycophenolate mofetil to enteric-coated mycophenolate sodium resulted in a 22.7% and 76.5% resolution rate, respectively. Change to an MPA-free regimen was associated with a 100% resolution rate. CONCLUSION: These results provide first evidence for a contribution of intestinal infections in chronic post-transplant diarrhea associated with MPA treatment.

Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials.

The results of our third trial on epicutaneous allergen-specific immunotherapy (EPIT) will be presented and discussed in the context of our previous trials. This monocentric, placebo-controlled, double-blind phase I/IIa trial included 98 patients with grass pollen rhinoconjunctivitis. Prior to the pollen season 2009, patients received six patches (allergen extract: n = 48; placebo: n = 50) with weekly intervals, administered onto tape-stripped skin. Allergen EPIT produced a median symptom improvement of 48% in 2009 and 40% in the treatment-free follow-up year 2010 as compared to 10% and 15% improvement after placebo EPIT (P = 0.003). After allergen EPIT but not placebo EPIT, conjunctival allergen reactivity was significantly decreased and allergen-specific IgG4 responses were significantly elevated (P < 0.001). In conclusion, our three EPIT trials found that allergen EPIT can ameliorate hay fever symptoms. Overall, treatment efficacy appears to be determined by the allergen dose. Local side-effects are determined by the duration of patch administration, while risk of systemic allergic side-effects is related to the degree of stratum corneum disruption.

Patients at risk for contrast-induced nephropathy and mid-term effects after contrast administration: a prospective cohort study.

OBJECTIVES: Determine the incidence of patients at risk for contrast-induced nephropathy (CIN), the incidence of CIN and mid-term effects (renal replacement therapy/death < one month) to measure the impact of CIN in a general patient population undergoing intravenous contrast-enhanced computed tomography (CECT). METHODS: We conducted a prospective study in consecutive patients undergoing intravenous CECT from October 2012 to May 2013. Data were obtained through scripted interviews and the electronic patient records. Presence of risk factors and kidney function before and after CECT and the follow-up for one month were evaluated. RESULTS: We included 998 patients (mean age: 60 years). Estimated GFR was ≥ 60 ml/mg/1.72 m2 in 886 (88.8%) patients, 30-59 ml/mg/1.72 m2 in 108 (10.8%) patients and < 30 ml/min/1.73 m2 in 4 (0.4%) patients. We found diabetes mellitus in 137 (13.7%), anaemia in 70 (7.0%) congestive heart failure in 92 (9.2%), peripheral arterial disease in 34 (3.4%), age > 75 years in 126 (12.6%) patients and 301 (30.2%) used nephrotoxic medication. Fifty-eight (5.8%) patients were at risk for CIN; 35 (60.3%) risk patients received intravenous prophylactic hydration. Of the hydrated patients, 11 underwent follow-up within one week; of the non-hydrated patients seven underwent follow-up within one week. Two (2/58: 3.4%) patients developed CIN (increased serum creatinine ≥ 44 µmol/l or ≥ 25%); there was no difference between hydrated and non-hydrated patients (1/35:1/23). The incidence of renal replacement therapy and death within one month was zero for both. CONCLUSION: The number of patients at risk is low. CIN incidence is low, even in patients not receiving prophylactic hydration. No patients received renal replacement therapy or died. The impact of CIN is low. Extensive CIN prevention guidelines seem superfluous.

Cost of screening strategies for kidney disease before intravenous contrast administration.

PURPOSE: To assess whether selective use of estimated glomerular filtration rate (eGFR) in patients with risk factors for kidney disease is more cost-effective than measuring eGFR in all patients undergoing contrast-enhanced computed tomography (CECT). METHODS: Risk factors and costs were assessed in consecutive patients. eGFR was evaluated in all patients, considering a tenability of 12 months. For the three-month tenability and the pre-selection strategy based on risk factors for kidney disease, we extrapolated data by assuming equal distribution of patient characteristics. RESULTS: We included 1001 patients, mean age 59.9 ± 13.6 years. Strategy with eGFR in all patients: eGFR measurements specifically performed for CECT in 645/1001 (in 356 patients the eGFR was already known). The total cost including costs of an extra visit to the hospital (49 patients) and absence from work (11 patients) were € 6037.20. Considering a tenability of 3 months, eGFR had to be measured in 786 patients, 60 would have paid an extra visit and 14 would have been absent from work: total cost € 7443.54. Pre-selection strategy: 807 patients had risk factors, necessitating eGFR measurement and an extra visit would be paid by 61. Fourteen patients would have been absent from work: total cost € 7585.16. Of the patients with an eGFR <60 ml/min/1.73 m(2), 94.8% were identified including all with an eGFR <45 ml/min/1.73 m(2). CONCLUSION: Determining eGFR based on risk factors for kidney disease is not more cost-effective than eGFR testing in all patients if the eGFR is tenable for 12 months or for 3 months.

Multivalent paediatric allergy vaccines protect against allergic anaphylaxis in mice.

BACKGROUND: Almost a quarter of the world population suffers from IgE-mediated allergies. T cells and IgG-producing B cells can produce protection, but treatment for disease is laborious with unsatisfactory patient compliance. OBJECTIVE: We sought to identify whether paediatric allergy vaccines affected later allergen sensitization and onset of disease when used prophylactically. METHODS: A murine model of anaphylaxis was applied. Mice were first immunized with monovalent or multivalent allergy vaccines that also contained aluminium hydroxide and CpG oligodeoxynucleotide as adjuvants. Later, the mice were sensitized by multiple low-dose injections of aluminium-adsorbed allergen. After a dormant period, the mice were challenged systemically with high-dose allergen, and the clinical signs of anaphylaxis were recorded. Throughout the immunization and sensitization periods, blood was collected for serological testing. RESULTS: Immunization with allergy vaccines produced antigen-specific protection against sensitization as measured by systemic anaphylaxis in mice. The long-term effect was observed both after juvenile (5-6 weeks) and neonatal (7 days) vaccination. Monovalent and pentavalent vaccines were protective to a similar level. Protection was associated with increased secretion of IgG2a and production of IFN-γ. Protection could also be transferred to sensitized mice via serum or via CD25-positive CD4 T cells. CONCLUSION AND CLINICAL RELEVANCE: Prophylactic and multivalent allergy vaccines in juvenile and neonatal mice protected against later sensitization and anaphylaxis. Such treatment may provide a rational measure for future management of allergen-related diseases and their strong socio-economic impact on daily life.

The contact sensitizer diphenylcyclopropenone has adjuvant properties in mice and potential application in epicutaneous immunotherapy.

BACKGROUND: Epicutaneous vaccination has gained increasing interest during the past decade as it offers a safe, needle-free, and patient-friendly alternative to invasive vaccine administrations. Recently, the safety and early efficacy of epicutaneous immunotherapy were also demonstrated in patients with hay fever, as an alternative to conventional subcutaneous allergen-specific immunotherapy (SCIT). One major challenge to epicutaneous vaccination is the barrier function of the stratum corneum, which must be overcome either by abrasive methods or by hydration. Such barrier function of the stratum corneum also hampers the use of common adjuvants used to enhance the efficacy of vaccination. METHODS: In a mouse model of allergy, we tested the adjuvant potential of diphenylcyclopropenone (DCP), a strong contact sensitizer, which is currently used for the treatment of a T cell-mediated hair loss disease (alopezia areata). RESULTS: Diphenylcyclopropenone enhanced antigen-specific IgG2a antibody responses as well as IL-10 cytokine production after epicutaneous immunization with ovalbumin (OVA). Epicutaneous allergen-specific immunotherapy (EPIT) with OVA and DCP also protected sensitized mice from anaphylaxis and asthma. The protective effect was more robust than that of conventional SCIT, which did not significantly alleviate the symptoms of allergy in the murine models of anaphylaxis and asthma. CONCLUSIONS: This preclinical study confirmed previous clinical data that have demonstrated the potential of the skin as a target for allergen immunotherapy. The study also suggests that epicutaneous immunization or immunotherapy can be improved when an appropriate adjuvant such as DCP is used.

Epicutaneous allergen administration: is this the future of allergen-specific immunotherapy?

IgE-mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 30% of the population in industrialized countries. Allergen-specific immunotherapy (SIT) either subcutaneously or via the sublingual route is effective, but only few patients (<5%) choose immunotherapy, as treatment takes several years and because allergen administrations are associated with local and, in some cases, even systemic allergic side-effects because of allergen accidentally reaching the circulation. In order to resolve these two major drawbacks, the ideal application site of SIT should have two characteristics. First, it should contain a high number of potent antigen-presenting cells to enhance efficacy and shorten treatment duration. Secondly, it should be nonvascularized in order to minimize inadvertent systemic distribution of the allergen and therefore systemic allergic side-effects. The epidermis, a nonvascularized multilayer epithelium, that contains high numbers of potent antigen-presenting Langerhans cells (LC) could therefore be an interesting administration route. The present review will discuss the immunological rational, history and actual clinical experience with epicutaneous allergen-specific immunotherapy.

Noninvasive quantification of coronary blood flow reserve in humans using myocardial contrast echocardiography.

BACKGROUND: We hypothesized that coronary blood flow (CBF) reserve could be quantified noninvasively in humans using myocardial contrast echocardiography (MCE). METHODS AND RESULTS: Eleven patients with normal epicardial coronary arteries (group I) and 19 with single-vessel coronary stenosis (group II) underwent quantitative coronary angiography, MCE, and CBF velocity measurements at rest and during intravenous adenosine infusion. In group I patients, MCE-derived myocardial blood flow (MBF) velocity reserve (2.4+/-0.08) was similar to CBF velocity reserve using a Doppler flow wire (2.4+/-1.1). Patients with a single risk factor had a significantly higher MBF reserve (3.0+/-0.89) than those with >/=2 risk factors (1.7+/-0.22). In group II patients, significant differences were found in MBF velocity reserve in patients with mild (<50%), moderate (50% to 75%), or severe (>75%) stenoses (2.2+/-0.40, 1.6+/-0.65, and 0.55+/-0.19, respectively; P=0.005). A linear relation was found between flow velocity reserve determined using the 2 methods (r=0.76, P<0.001), and a curvilinear relation was noted between the percent coronary stenosis measured using quantitative coronary angiography and velocity reserve using both methods. CONCLUSIONS: CBF reserve can be measured in humans using MCE. This method may allow the noninvasive assessment of coronary stenosis severity and the detection of microvascular dysfunction.

Enhancement of left ventricular cavity opacification by harmonic imaging after venous injection of Albunex.

Venous injection of Albunex does not consistently produce left ventricular (LV) cavity opacification during conventional echocardiography. We postulated that by increasing the signal-to-noise ratio, harmonic imaging will result in more successful LV cavity opacification and provide a better assessment of regional LV systolic function. Forty-two patients with poor baseline endocardial delineation were given 10 ml intravenous injections of Albunex during continuous fundamental and harmonic imaging. Change in segmental wall-thickening scores and the confidence levels for these scores were assessed for 3 observers with various levels of experience. Compared with fundamental imaging, harmonic imaging significantly improved the success of LV cavity opacification (83% vs 62%, p <0.05). The background-subtracted video intensity within the central two thirds of the LV cavity increased threefold (from 10 +/- 15 to 31 +/- 29, p <0.05) with harmonic imaging. The spatial extent of opacification increased from 40% of the LV cavity during fundamental imaging to 65% with harmonic imaging (p <0.001). The confidence level for assessing regional LV systolic function improved (p <0.05) after contrast administration, particularly when observer experience was limited. We conclude that in patients with poor endocardial definition, injection of intravenous Albunex should be combined with harmonic imaging to improve LV cavity opacification.

Influence of various instrument settings on the flow information derived from the power mode.

To evaluate the factors influencing flow information displayed by the power operating mode, color Doppler flow mapping was used to image the flow in an in vitro left heart pulse duplicator system. The effect of changing one instrument setting, such as pulse repetition frequency, color filter and frame rate while keeping all other instrumental settings constant, was noted on the displayed flow areas. The flow areas derived using power and velocity modes were also compared. An increase in pulse repetition frequency and color filter decreased the flow areas significantly, and a flow area increase occurred with a decrease in frame rate. No significant difference was observed between the flow areas derived using the two operating modes. Like the velocity mode, the power mode display is also influenced by instrument settings. Although low velocity flows are better delineated using this mode, however, no significant difference occurred in the flow areas measured by this mode and velocity mode. Further studies need to be conducted to address its potential applications in the clinical setting and in quantitation.