Cosby A. Stone

Understanding the Association of Human Rhinovirus with Asthma

ABSTRACT Human rhinoviruses are ubiquitous seasonal pathogens. They have known associations with first onset of wheezing illnesses in children and with asthma exacerbations in patients of all ages. It is not yet certain whether human rhinoviruses play a direct role in the pathogenesis of asthma by activating deleterious inflammatory responses or if they only serve as a catalyst to accelerate the disease in genetically predisposed individuals. There have been previously demonstrated reductions in the development of the asthmatic phenotype with passive immunization against respiratory syncytial virus; however, in the case of rhinovirus, there are barriers to effective vaccine development, such as the lack of a common antigenic target due to alterations of surface markers among subtypes. It remains to be determined whether certain subtypes of human rhinovirus are more asthmagenic and therefore worthy of greater attention as vaccine candidates, but several studies have suggested that RV-C and certain RV-A strains may be more strongly linked with asthma.

Pharmacogenomics of off‐target adverse drug reactions

Off‐target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drugs therapeutic effect. Off‐target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off‐target drug‐induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune‐mediated (IM)‐ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM‐ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.

The 3 Cs of Antibiotic Allergy—Classification, Cross-Reactivity, and Collaboration

Antibiotic allergy labeling is highly prevalent and negatively impacts patient outcomes and antibiotic appropriateness. Reducing the prevalence and burden of antibiotic allergies requires the engagement of key stakeholders such as allergists, immunologists, pharmacists, and infectious diseases physicians. To help address this burden of antibiotic allergy overlabeling, we review 3 key antibiotic allergy domains: (1) antibiotic allergy classification, (2) antibiotic cross-reactivity, and (3) multidisciplinary collaboration. We review the available evidence and research gaps of currently used adverse drug reaction classification systems, antibiotic allergy cross-reactivity, and current and future models of antibiotic allergy care.

Pharmacogenomics of Off-target ADRs

Off‐target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drugs therapeutic effect. Off‐target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off‐target drug‐induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune‐mediated (IM)‐ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM‐ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.

Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth

&NA; We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha‐ and gamma‐tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha‐tocopherol at 1 month after birth.

Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States

Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States Cosby Stone, MD, MPH, Tebeb Gebretsadik, MPH, Capt Rees L. Lee, MD, Amber M. Evans, MPH, Tina V. Hartert, MD, Edward Mitchel, MS, James Morrow, Ann C. Wu, MD, Carlos Iribarren, MD, Melissa G. Butler, PharmD, MPH, PhD, Emma K. Larkin, PhD, Kedir N. Turi, PhD, and Pingsheng Wu, PhD, MS

Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia

Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions.

The impact of modifiable risk factor reduction on childhood asthma development

Childhood asthma is responsible for significant morbidity and health care expenditures in the United States. The incidence of asthma is greatest in early childhood, and the prevalence is projected to continue rising in the absence of prevention and intervention measures. The prevention of asthma will likely require a multifaceted intervention strategy; however, few randomized controlled trials have assessed such approaches. The purpose of this review was to use previous meta-analyses to identify the most impactful risk factors for asthma development and evaluate the effect of risk factor reduction on future childhood asthma prevalence. Common and modifiable risk factors with large effects included acute viral respiratory infections, antibiotic use, birth by cesarean section, nutritional disorders (overweight, obesity), second hand smoke exposure, allergen sensitization, breastfeeding, and sufficient prenatal vitamin D level. Evaluation and estimates of risk factor modification on populations at risk should guide scientists and policymakers toward high impact areas that are apt for additional study and intervention.

Infant Viral Respiratory Infection Nasal-Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze

Rationale: Recurrent wheeze and asthma are thought to result from alterations in early life immune development following respiratory syncytial virus (RSV) infection. However, prior studies of the nasal immune response to infection have assessed only individual cytokines, which does not capture the whole spectrum of response to infection. Objectives: To identify nasal immune phenotypes in response to RSV infection and their association with recurrent wheeze. Methods: A birth cohort of term healthy infants born June to December were recruited and followed to capture the first infant RSV infection. Nasal wash samples were collected during acute respiratory infection, viruses were identified by RT‐PCR, and immune‐response analytes were assayed using a multianalyte bead‐based panel. Immune‐response clusters were identified using machine learning, and association with recurrent wheeze at age 1 and 2 years was assessed using logistic regression. Measurements and Main Results: We identified two novel and distinct immune‐response clusters to RSV and human rhinovirus. In RSV‐infected infants, a nasal immune‐response cluster characterized by lower non‐IFN antiviral immune‐response mediators, and higher type‐2 and type‐17 cytokines was significantly associated with first and second year recurrent wheeze. In comparison, we did not observe this in infants with human rhinovirus acute respiratory infection. Based on network analysis, type‐2 and type‐17 cytokines were central to the immune response to RSV, whereas growth factors and chemokines were central to the immune response to human rhinovirus. Conclusions: Distinct immune‐response clusters during infant RSV infection and their association with risk of recurrent wheeze provide insights into the risk factors for and mechanisms of asthma development.

Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema

Nonsteroidal antiinflammatory agents, β-lactam antibiotics, non-β lactam antibiotics, and angiotensin-converting enzyme inhibitors are the most common classes of drugs that cause angioedema. Drug-induced angioedema is known to occur via mechanisms mediated by histamine, bradykinin, or leukotriene, and an understanding of these mechanisms is crucial in guiding therapeutic decisions. Nonallergic angioedema occurs in patients with genetic variants that affect metabolism or synthesis of bradykinin, substance P, prostaglandins, or leukotrienes, or when patients are taking drugs that have synergistic mechanisms. The mainstay in treatment of nonallergic drug-induced angioedema is cessation of the offending agents.