Allergy and Immunology

Study reveals asthma phenotypes in inner-city children

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What’s known

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation, or 6.3 million kids, have asthma, a disease characterized by wheezing and coughing associated with airway obstruction, bronchial hyperresponsiveness, and inflammation of the airway. However, children with asthma with low socioeconomic status who live in inner cities experience a disproportionately high burden of illness. While treatment guidelines provide uniformity in managing allergy and allergic inflammation, such approaches may be misdirected when kids have asthma symptoms but lack allergy or allergic inflammation. Knowledge of distinct disease phenotypes can help to improve care.

What’s new

The Asthma Phenotypes in the Inner City study enrolled school-aged kids living in nine U.S. inner cities, including Washington, DC. The research team collected data about their asthma at the beginning of the one-year study and every two months as the kids’ asthma was managed according to accepted guidelines. Phenotypic analysis for 616 of these kids found their asthma clustered into five distinct groups. Cluster “A” was characterized by lower allergy, lower inflammation, and minimal symptoms. Fifteen percent of the kids fit within “A.” Another 15 percent of kids’ asthma fit within Cluster “B.” They had highly symptomatic asthma despite high step-level treatment and relatively low allergy and inflammation. Cluster “C” was distinguished by minimal symptoms, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Some 24 percent of kids fit within this group. The remaining kids fit within Cluster “D” or “E” and experienced progressively higher asthma and rhinitis symptoms as well as allergy and inflammation.

Questions for future research

Q: How does exposure to allergens, viruses, and irritants like tobacco smoke—taken individually as well as in combination—influence asthma severity and symptoms for these at-risk youths?
Q: What approaches to treatment might result from these studies?

Training developing immune systems to prevent wheezing early in life

Stephen Teach does an asthma exam

Extensively engaging stakeholders such as parents, families and local service providers in the actual study design transformed a planned research project into a more patient-centered study.

For the small number of U.S. children who grow up on working farms, activities such as feeding the cows and clearing spent hay from the barn are little changed from a thousand years ago. Through such close contact with dirt and farm animals, rural kids’ immune systems develop more normally and better distinguish common bacteria from household allergens like dust, molds, pets, and pests. Rates of allergy and asthma continue to be lower in children who grow up in those conditions.

By contrast, rates of asthma have spiked among urban and disadvantaged kids, who have far less exposure to dirt and animals early in life. Today, leading pediatric institutions, such as Children’s National Health System, are “awash in emergency department (ED) visits for asthma” with each ED visit associated with 10 to 15 missed school days annually on a population basis, says Stephen J. Teach, MD, MPH, Director and Principal Investigator of IMPACT DC , a care, research, and advocacy program focused on under-resourced and largely minority children with asthma.

A paradigm-shifting multicenter clinical trial aims to reverse that trend by going old school and safely exposing very young infants to the type of immune system training they would have experienced if they grew up closer to the earth.

The five-year study, named “Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children,” is funded by a $27 million cooperative agreement grant from the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health. Children’s National, one of eight participating sites across the nation, will enroll an estimated 150 children in the study and will receive at least $2.5 million of that grant.

“It is currently thought by many, including me, that asthma and allergic diseases are a result of disordered development of the immune system very early in life,” says Dr. Teach, who is also Chair of the Department of Pediatrics at George Washington University. The immune system development process begins to unfold in the last few months of pregnancy and continues through infancy, meaning “the die is cast, we think, at a very young age.”

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation have asthma, but in the District of Columbia, a disproportionately higher number of children suffer from the respiratory ailment. Once children experience early wheezing, changes begin to occur in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, and resulting in a heightened tendency for the airways in the lungs to become inflamed and to excrete more mucous. As a result, the children’s poorly trained immune system becomes hyper vigilant, ready to recognize a multitude of things as potentially allergenic.

“We’ve got to do something to change the course of the disease and to make it less common and less severe,” Dr. Teach says.

The study will identify 1,000 babies who range in age from 6 months to 18 months who are the highest risk for asthma, either through family history, being diagnosed with eczema, or both. The infants will receive safe doses of the inactivated bacteria, which is marketed under the name Broncho-Vaxom®. The therapy comes in capsule form, which for two years will be sprinkled into bottles or onto food. The children will be followed to gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

“The rationale if we can expose these very young children to the benefits, but not the risks, of early life bacterial exposure, they may reap the benefits of developing a more properly functioning and less allergic immune system,” Dr. Teach says.

He says the Children’s National research team has had “remarkable success” engaging young children and their parents in such long-term studies, losing few to attrition.

“Going for five years will be breaking new ground. But all of our experience suggests that we will succeed if we show the families we care, we stay in touch with them, and we form these therapeutic partnerships by saying: ‘We want to partner with you. We can do this safely with mutual benefit.’ Families will get on board,” he says.

Related resources: Learn more about the clinical trial | Research at a Glance

Training kids developing immune systems to prevent wheezing

What’s Known
Some 6.3 million U.S. children younger than 18—or 8.6 percent of the nation’s kids—have asthma. The disease is characterized by an inflammation of the airways, and    symptoms may be triggered by breathing in such allergens as animal dander, pollen, dust, or mold.

Once children experience early wheezing, changes begin in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, which can result in a heightened tendency for the airways in the lungs to become inflamed.

What’s New
Asthma and allergic diseases are thought to result from disordered development of the immune system, a process that begins in the womb. A paradigm-shifting multicenter clinical trial will enroll patients at eight locations, including Children’s National Health System, to provide the type of “immune system training” that infants would experience if they grew up in rural settings—where most children’s immune systems develop more normally. The five-year study funded by the National Heart, Lung, and Blood Institute will identify 1,000 babies aged 6 months to 18 months who are at risk for asthma to receive safe doses of an inactivated bacteria to help them develop more properly functioning immune systems. The University of Arizona Health Sciences in Tucson will lead the national research effort. Researchers will gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

Questions for Future Research

Q: What will be the longer-term effects of preventing early wheezing? Will the children develop asthma less frequently?
Q: If intervention with young children occurs early enough to interrupt the disease cycle—preventing asthma, wheezing, and allergies—will they miss fewer days of school when they are older?
Q: Will families be willing to consistently follow the complex regimen necessary to administer the inactivated bacterial products on a long-term basis?

Source: Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children.

Enroll in this clinical trial—https://clinicaltrials.gov/ct2/show/NCT02148796

Allergy and immunology update: asthma care, microbial signatures

June 16, 2016 – Increased identification of the primary care provider as the main source of asthma care among urban minority children
The research team used electronic communication between an asthma specialty clinic and short-term care coordination to encourage parents of urban youth with asthma to identify their primary care provider as the key source for episodic asthma care – rather than the emergency department. Guardians of 50 children were enrolled in the prospective cohort study, whose findings were published in Journal of Asthma. The youths’ median age was 5.8 years; 64 percent were male, 98 percent were African American. At three and six months after the intervention, 85 percent and 83 percent, respectively, reported that the primary care provider was their child’s primary asthma healthcare provider, compared with 70 percent at baseline. 

June 16, 2016 – Two sampling methods yield distinct microbial signatures in the nasopharynges of asthmatic children
The nasopharynx acts as an anatomical reservoir from which pathogenic microbes spread to the lower and upper respiratory airways, causing respiratory infections. A team led by Children’s National researchers used targeted 16S rRNA MiSeq sequencing and two techniques – nasal washes and nasal brushes – to characterize the nasopharyngeal microbiota in 30 children with asthma aged 6 to 17. The authors report in Microbiome that the children’s nasopharyngeal microenvironments contain microbiotas with different diversity and structure.

Nov. 30, 2015 – Alex’s Lemonade Stand Foundation grant to develop immune-based therapy
Physician-scientist Conrad Russell Y. Cruz, MD, PhD, was awarded a $450,000, grant from the Alex’s Lemonade Stand Foundation to develop novel cell-based therapies to combat pediatric cancer. The “A” grant encourages scientists to develop innovative treatments and cures that impact children with cancer and will provide Dr. Cruz and his team funding for three years.