For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic ...reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population.
We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160.
Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8–44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61–80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 who received placebo met the primary outcome of desensitisation (risk difference RD 69%, 95% CI 59–79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755–5005) for peanut oral immunotherapy versus 5 mg (0–105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13–30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10–28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0–2755) for peanut oral immunotherapy and 0 mg (0–55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy.
In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy.
National Institute of Allergy and Infectious Disease, Immune Tolerance Network.
Purpose Compared to radical nephrectomy, partial nephrectomy better preserves renal parenchyma and function. Although several clinical factors may impact renal function after partial nephrectomy ...including preoperative function, age, gender and comorbidities, the contributions of tumor and surgical factors have not been well studied. We evaluate independent factors predicting functional outcomes after partial nephrectomy. Materials and Methods Preoperative and all postoperative serum creatinine values for 1,169 patients undergoing partial nephrectomy were used to estimate glomerular filtration rate. Postoperative nadir glomerular filtration rate and ultimate glomerular filtration rate were analyzed using multiple pertinent covariates. Results Median preoperative, postoperative nadir and ultimate glomerular filtration rates were 77, 57 and 71 ml per minute per 1.73 m2 , respectively. Increasing age, gender, lower preoperative glomerular filtration rate, solitary kidney, tumor size, ischemia time and longer time to nadir glomerular filtration rate significantly predicted postoperative nadir glomerular filtration rate and ultimate glomerular filtration rate. Acute loss of renal function predicted lower ultimate glomerular filtration rate. In the entire cohort, in patients with normal preoperative renal function, and in those with baseline stage 3 and those with stage 4 chronic kidney disease the incidence of postoperative acute kidney injury after partial nephrectomy was 3.6%, 0.8%, 6.2% and 34%, and the incidence of chronic end stage renal disease after partial nephrectomy was 2.5%, 0.1%, 3.7% and 36%, respectively. Conclusions Lower preoperative glomerular filtration rate, solitary kidney, older age, gender, tumor size and longer ischemic interval all predicted lower glomerular filtration rate after partial nephrectomy. Therefore, duration of renal ischemia is the strongest modifiable surgical risk factor for decreased renal function after partial nephrectomy, and efforts to limit ischemic time and injury should be pursued in open and laparoscopic partial nephrectomy.
CPAP versus oxygen in obstructive sleep apnea Gottlieb, Daniel J; Punjabi, Naresh M; Mehra, Reena ...
The New England journal of medicine,
06/2014, Letnik:
370, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often ...suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.
We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea-hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.
Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (-2.4 mm Hg; 95% confidence interval CI, -4.7 to -0.1; P=0.04) or the group receiving supplemental oxygen (-2.8 mm Hg; 95% CI, -5.1 to -0.5; P=0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.
In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800 .).
Asthma phenotypes in inner-city children Zoratti, Edward M., MD; Krouse, Rebecca Z., MS; Babineau, Denise C., PhD, MS ...
Journal of allergy and clinical immunology,
10/2016, Letnik:
138, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored ...management approaches. Objective We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm3 ), and allergen sensitizations (15 of 22 tested). Conclusions Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.
To address whether treatment of sleep apnea improves glucose tolerance.
Randomized, double-blind crossover study.
Sleep clinic referrals.
50 subjects with moderate to severe sleep apnea (AHI > 15) ...and impaired glucose tolerance.
Subjects were randomized to 8 weeks of CPAP or sham CPAP, followed by the alternate therapy after a one-month washout. After each treatment, subjects underwent 2-hour OGTT, polysomnography, actigraphy, and measurements of indices of glucose control.
The primary outcome was normalization of the mean 2-h OGTT; a secondary outcome was improvement in the Insulin Sensitivity Index (ISI (0,120). Subjects were 42% men, mean age of 54 (10), BMI of 39 (8), and AHI of 44 (27). Baseline fasting glucose was 104 (12), and mean 2-h OGTT was 110 (57) mg/dL. Seven subjects normalized their mean 2-h OGTT after CPAP but not after sham CPAP, while 5 subjects normalized after sham CPAP but not after CPAP. Overall, there was no improvement in ISI (0,120) between CPAP and sham CPAP (3.6%; 95% CI: -2.2%, 9.7%; P = 0.22). However, in those subjects with baseline AHI ≥ 30 (n = 25), there was a 13.3% (95% CI: 5.2%, 22.1%; P < 0.001) improvement in ISI (0,120) and a 28.7% (95%CI: -46.5%, -10.9%, P = 0.002) reduction in the 2-h insulin level after CPAP compared to sham CPAP.
This study did not show that IGT normalizes after CPAP in subjects with moderate sleep apnea and obesity. However, insulin sensitivity improved in those with AHI ≥ 30, suggesting beneficial metabolic effects of CPAP in severe sleep apnea. Clinical trials information: ClinicalTrials.gov Identifier: NCT01385995.
Objectives
To determine whether elderly adults with a low glomerular filtration rate (GFR) are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia.
Design
Retrospective study.
Setting
...Veterans Affairs Medical Center.
Participants
Thirteen thousand eight hundred seventy‐four veterans aged 65 and older with chronic kidney disease (CKD) and a GFR between 15 and 60 mL/min per 1.73 m2. Their average age was 79.
Measurements
Anemia was defined as a hemoglobin level of less than 10 g/dL, hyperkalemia as a potassium level greater than 5.5 mEq/L, acidosis as a bicarbonate level of less than 21 mEq/L, and hyperphosphatemia as a phosphorus level greater than 4.6 mg/dL. Multivariable logistic regression was used to evaluate whether age modifies the effect of low GFR on metabolic complications by including an interaction term between age and GFR in each model.
Results
The average GFR of participants was 46.5 mL/min per 1.73m2, 3.1% had anemia, 2.5% hyperkalemia, 2.3% acidosis, and 4.4% had hyperphosphatemia. Lower GFR was associated with higher rates of metabolic complications across all age groups (odds ratio per 5‐mL/min per 1.73 m2 decrease in GFR in multivariable models was 1.21 for anemia, 1.26 for hyperkalemia, 1.45 for acidosis, and 1.72 for hyperphosphatemia). There was no significant interaction between age and GFR in models including only age and GFR or in multivariable models (P‐values for age by GFR interaction term: 0.66 for anemia, 0.19 for hyperkalemia, 0.54 for acidosis, and 0.22 for hyperphosphatemia).
Conclusion
Elderly adults with CKD are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia; age does not modify the relationship between GFR and development of metabolic complications. Elderly adults with low GFR should be monitored for metabolic complications, regardless of age.
Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly ...understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
Immunotherapy is promising as an efficacious treatment for food allergy. Other food allergy treatments are also under development. However, adverse allergic events during treatment, as well as during ...oral food challenges, are common and reporting is not standardized.
A more nuanced grading scale is needed to create a comprehensive and universal system to categorize adverse events and their severity for food allergy clinical trials.
Starting with the 2012 Consortium for Food Allergy Research (CoFAR) Grading Scale and the World Allergy Organization Grading System, we developed the CoFAR Grading Scale for Systemic Allergic Reactions, Version 3.0, in collaboration with industry partners with expert opinion.
The revised CoFAR Grading Scale for Systemic Allergic Reactions has 5 levels of increasing severity, ranging from generalized urticaria, localized angioedema, rhinitis, and abdominal pain (grade 1) to death (grade 5). Systemic reactions are further categorized within each grade by relevant organ system. Mild, single-system reactions are differentiated from mild, multisystem reactions. Lower respiratory tract symptoms are graded on the basis of response to therapy; those that are refractory to standard treatment (eg, requiring >3 doses of intramuscular epinephrine, continuous intravenous epinephrine infusion, and continuous albuterol nebulization) and respiratory compromise requiring mechanical ventilation are classified as grade 4, life-threatening reactions.
Universal and consistent use of the revised CoFAR Grading Scale beyond the CoFAR centers would allow for better data aggregation and safety comparisons in clinical trials for food allergy.
Rhinitis and asthma are linked, but substantial knowledge gaps in this relationship exist.
We sought to determine the prevalence of rhinitis and its phenotypes in children and adolescents with ...asthma, assess symptom severity and medication requirements for rhinitis control, and investigate associations between rhinitis and asthma.
Seven hundred forty-nine children with asthma participating in the Asthma Phenotypes in the Inner-City study received baseline evaluations and were managed for 1 year with algorithm-based treatments for rhinitis and asthma. Rhinitis was diagnosed by using a questionnaire focusing on individual symptoms, and predefined phenotypes were determined by combining symptom patterns with skin tests and measurement of serum specific IgE levels.
Analyses were done on 619 children with asthma who completed at least 4 of 6 visits. Rhinitis was present in 93.5%, and phenotypes identified at baseline were confirmed during the observation/management year. Perennial allergic rhinitis with seasonal exacerbations was most common (34.2%) and severe. Nonallergic rhinitis was least common (11.3%) and least severe. The majority of children remained symptomatic despite use of nasal corticosteroids with or without oral antihistamines. Rhinitis was worse in patients with difficult-to-control versus easy-to-control asthma, and its seasonal patterns partially corresponded to those of difficult–to-control asthma.
Rhinitis is almost ubiquitous in urban children with asthma, and its activity tracks that of lower airway disease. Perennial allergic rhinitis with seasonal exacerbations is the most severe phenotype and most likely to be associated with difficult-to-control asthma. This study offers strong support to the concept that rhinitis and asthma represent the manifestations of 1 disease in 2 parts of the airways.
Objectives
To develop and validate a model to predict 1‐year risk of end‐stage renal disease (ESRD) in elderly subjects with advanced chronic kidney disease (CKD).
Design
Retrospective.
Setting
...Veterans Affairs Medical Center.
Participants
Individuals aged 65 and older with CKD with an estimated glomerular filtration rate (eGFR) less than 30 mL/min per 1.73 m2.
Measurements
The outcome was ESRD within 1 year of the index eGFR. Cox regression was used to develop a predictive model (Veterans Affairs (VA) risk score) that was validated in a separate cohort.
Results
Of the 1,866 participants in the developmental cohort, 77 developed ESRD. Risk factors for ESRD in the final model were age, congestive heart failure, systolic blood pressure, eGFR, potassium, and albumin. In the validation cohort, the C index for the VA risk score was 0.823. The risk for developing ESRD at 1 year from lowest to highest tertile was 0.08%, 2.7%, and 11.3% (P < .001). The C‐index for the recently published Tangri model in the validation cohort was 0.780.
Conclusion
A new model using commonly available clinical measures shows excellent ability to predict the onset of ESRD within the next year in elderly adults. The Tangri model also had good predictive ability. Individuals and physicians can use these risk models to inform decisions regarding preparation for renal replacement therapy in individuals with advanced CKD.
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