Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial.

Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM.

Penicillin minor determinants: History and relevance for current diagnosis.

OBJECTIVE: To review the history of the penicillin minor determinants and evaluate their relevance for current diagnosis. DATA SOURCES: Skin testing to detect immunoglobulin E (IgE) sensitivity to penicillins in patients with a history of penicillin allergy has been the subject of more than 55 years of published research involving tens of thousands of patients. STUDY SELECTIONS: Selection of data was based on its relevance to the objective of this article. RESULTS: It was established early on that testing with the major penicilloyl determinant using the polyvalent penicilloyl-polylysine (PPL) is negative in a substantial portion (10% to 64%, including recent increases) of those at risk for immediate hypersensitivity reactions. A variety of minor penicillin determinants are clinically significant in that their use in skin testing is essential to detect all those at risk. In particular, a minor determinant mixture of benzylpenicillin, benzylpenicilloate, and benzylpenilloate, used in conjunction with PPL, has been shown in numerous studies to achieve an average negative predictive value (NPV) of 97.9% in history-positive patients. Benzylpenicillin alone, as the sole minor determinant, leaves many skin test-positive patients undiscovered. Use of amoxicillin as an additional minor determinant reagent appears to identify another 2% to 8% of skin test-positive patients in some populations. CONCLUSION: IgE skin testing, using both the major and appropriate minor determinants of penicillin, can identify, with a high degree of reliability (NPV ∼97%), penicillin allergy history-positive patients who can receive beta-lactam antibiotics without concern for serious acute allergy, including anaphylaxis. The few false-negative skin tests reported globally are largely confined to minor, self-limited cutaneous reactions.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

RATIONALE: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. OBJECTIVES: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. METHODS: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. MEASUREMENTS AND MAIN RESULTS: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. CONCLUSIONS: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.

BACKGROUND: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. OBJECTIVE: We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma. METHODS: eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. RESULTS: Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. CONCLUSIONS: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

Adherence to inhaled corticosteroids: an ancillary study of the Childhood Asthma Management Program clinical trial.

BACKGROUND: Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited. OBJECTIVE: We sought to compare subjective and objective measurements of children's adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes. METHODS: In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 µg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes. RESULTS: Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, -0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes. CONCLUSION: Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.

The Evolution of Our Understanding of Penicillin Allergy: 1942-2022.

This article reviews our evolving understanding of penicillin hypersensitivity at the 80th anniversary of penicillin's clinical introduction. Penicillin breakdown products covalently bond to serum proteins, leading to classic drug hypersensitivity. Penicillin remains the most frequently reported drug "allergy." Adverse reactions were presumed, in retrospect incorrectly, to implicate a risk for anaphylaxis, and therefore skin testing for IgE became the focus. Skin test positivity may wane over time. This insight has led to the radical conclusion that penicillin hypersensitivity may not be "forever." Atopic background, other drug allergies, family history, gender, and race are apparently not risk factors for penicillin hypersensitivity. Confirmed penicillin hypersensitivity has declined since the 1960s, potentially due to "cleaner" penicillin products and lower dose oral, instead of parenteral, use. Avoiding penicillins, without evaluation, caused unanticipated problems that have been appreciated only recently including longer hospital stays, increased cost of care, suboptimal outcomes from serious infections, and greater toxicities and costs with alternative antibiotics. There are personal and public health advantages with broadly implemented penicillin allergy delabeling based on a reaction history-based risk assessment. Limited skin testing followed by an oral challenge, if negative, for higher-risk histories, and direct oral challenges in lower-risk individuals are currently the reference standard tests to confirm current tolerance.

The impact of self-identified race on epidemiologic studies of gene expression.

Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4(+) lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10(-16)). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV(1)). Though unadjusted linear models of FEV(1) identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV(1) and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.

Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes.

Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10(-91) to 7 × 10(-4)). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10(-6)), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.

A genome-wide association study on African-ancestry populations for asthma.

BACKGROUND: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization.

Allergic immune-mediated hypersensitivity reactions are known potential complications of enzyme replacement therapy. Sebelipase alfa, recombinant lysosomal acid lipase (LAL), is a potentially life-altering treatment for patients with LAL deficiency. There is very little information on the diagnosis and management of immediate hypersensitivity reactions to this drug. Here we present three unique cases of hypersensitivity reactions to sebelipase alfa, spanning a broad age spectrum from infancy to adulthood, each managed with successful rapid desensitization.

Controversies in Drug Allergy: Beta-Lactam Hypersensitivity Testing.

All beta-lactam use is associated with a certain rate of adverse reactions. Many of these adverse reactions result in an allergy to the beta-lactam being entered into the patient's medical record. Unfortunately, only a small minority of these recorded allergies are clinically significant immunologically mediated drug hypersensitivity. An unconfirmed allergy to beta-lactams is a significant public health risk, because patients so labeled typically do not receive narrow-spectrum penicillins and cephalosporins when clinically indicated. The alternative antibiotics they receive result in poorer clinical outcomes, increased incidence of serious antibiotic-resistant infections, prolonged hospitalizations, and greater health care utilization. There is a wide variation in beta-lactam allergy incidence and prevalence around the world, based in part on the specific beta-lactams used and overused. There is a wide variation in specific protocols used to confirm current tolerance of beta-lactams and remove these inaccurate allergy reports. Harmonizing testing protocols, when possible, may lead to more widespread use of narrow-spectrum beta-lactams, when clinically indicated, and improve patient safety worldwide. Further research is needed to better understand the regional differences in reporting beta-lactam allergy as this relates to regional differences in beta-lactam use and overuse, the frequency of clinically significant immunologically mediated beta-lactam hypersensitivity, and the optimal testing strategies to confirm current tolerance, based on presenting clinical symptoms.

Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit.

BACKGROUND: Ten percent of the population claims an allergy to penicillin, but 90% of these individuals are not allergic. Patients labeled as penicillin-allergic have higher medical costs, longer hospital stays, are more likely to be treated with broad-spectrum antibiotics, and develop drug-resistant bacterial infections. Most penicillin skin test reagents are not approved by the Food and drug Administration or readily available to evaluate patients labeled penicillin-allergic. OBJECTIVE: To determine the negative predictive value (NPV) of the Penicillin Skin Test Kit containing the major allergenic determinant (penicilloyl polylysine), a minor determinant mixture (penicillin G, penicilloate, penilloate), and amoxicillin, produced according to Food and Drug Administration standards. METHODS: This was a prospective, multicenter, open-label investigation of penicillin skin testing using the Penicillin Skin Test Kit. Skin test-negative subjects were challenged with 250 mg amoxicillin, whereas skin test-positive patients were not challenged. The primary end point was NPV of the Penicillin Skin Test Kit, defined as the percentage of subjects with negative skin test results who did not experience an IgE-dependent reaction within 72 hours of amoxicillin challenge. RESULTS: In total, 455 patients with a history of penicillin allergy underwent skin testing and 63 (13.8%) had 1 or more positive test results; 65% of the positive test results were to the minor determinant mixture and/or amoxicillin alone. In the per protocol group of 373 skin test-negative subjects, 8 developed potential IgE-dependent reactions following oral amoxicillin challenge, translating to an NPV of 97.9% (95% CI, 95.8-99.1; P < .0001). All but 1 of the reactions was mild or moderate, and most subjects who required treatment received only antihistamines. CONCLUSIONS: The Penicillin Skin Test Kit, containing all relevant penicillin allergenic determinants, demonstrated very high NPV. Removal of a penicillin allergy label in a large majority of currently mislabeled patients has substantial personal and public health implications.

Anaphylaxis during cardiac surgery: implications for clinicians.

During surgery, patients are exposed to multiple foreign substances including anesthetic drugs, antibiotics, blood products, heparin, polypeptides (aprotinin, latex, and protamine), and intravascular volume expanders, which have the potential to produce life-threatening allergic reactions termed "anaphylaxis." The hallmark of perioperative anaphylaxis is acute cardiovascular and pulmonary dysfunction. Patients undergoing cardiac surgery have extensive monitoring that permits rapid recognition and treatment when anaphylaxis occurs. Initial, smaller doses of drugs, often called test doses, administered before the therapeutic dose may produce anaphylaxis, and so clinicians need to be prepared to treat reactions if they occur. Institution of cardiopulmonary bypass for hemodynamically unstable patients can be a life-saving maneuver, and should be considered in patients with refractory cardiovascular dysfunction. Arginine vasopressin should also be considered for patients with vasodilatory shock. In this review, we focus on recent concepts in understanding the incidence and management approaches for patients at risk for anaphylaxis in the operating room setting, with an emphasis on cardiac surgical patients.

Immunogenicity studies of cosmetically administered nonanimal-stabilized hyaluronic acid particles.

BACKGROUND: Hypersensitivity resulting from humoral or cellular immunologic mechanisms is the least well-documented of adverse events associated with dermal fillers. OBJECTIVE: Humoral and cellular immunogenicity of nonanimal-stabilized hyaluronic acid (NASHA) was studied in prospective clinical trials involving nasolabial fold augmentation. METHODS: In two randomized clinical studies, 150 (10 centers) and 283 (17 centers) subjects received NASHA as Restylane and/or Perlane (both QMed, Uppsala, Sweden; mean, 69 mg) for dermal augmentation. Serum immunoglobulin (Ig)E and IgG anti-NASHA were measured by immunoassay at 0, 6, and 24 weeks and IgE anti-NASHA by intradermal skin testing (ID-ST) at 0 and 24 weeks. The 24-week ID-ST site was biopsied 3 days later for histopathologic evidence of cell-mediated immunity. RESULTS: Of 433 subjects, 42 systemic adverse experiences were reported by 37 participants; all but 1 were judged by investigators to be unrelated to NASHA administration. All ID-STs and IgE anti-NASHA results were negative, indicating no IgE sensitization. Serologically, 91.8% of 425 subjects were negative for IgG anti-NASHA (<1.5 microg/mL) at all time points, whereas 7.8% had positive enrollment IgG anti-NASHA (range, 1.5-18.5 microg/mL) that remained essentially unchanged over the study period. The 24-week ID-ST biopsies showed no histological evidence for NASHA-induced cell mediated lymphocytic inflammatory reactions (Type IV hypersensitivity) or superficial dermal edema (Type 1 hypersensitivity). CONCLUSION: NASHA administration does not elicit clinical/laboratory evidence for cellular or humoral immune responses in 98% of individuals, supporting the conclusion that Restylane and/or Perlane are not commonly immunogenic or allergenic.