More Glucocorticoid, Not LABA, May Control Black Kids' Asthma

Diana Swift

September 27, 2019

Although asthma burden is greater and more debilitating in blacks, historically, blacks have been underrepresented in asthma trials, which have primarily been conducted in white populations with little concern for genetic ancestry. Treatment guidelines are based largely on results in whites.

Now research from the Best African American Response to Asthma Drugs (BARD) trials show that some black children respond quite differently to treatment escalation than other groups ― in a way that could change clinical practice and perhaps reduce medication costs.

In contrast to black adolescents and adults and to whites of any age, some black children experienced better asthma control with stepped-up glucocortoid treatment than with add-on long-acting beta-adrenergic receptor agonist (LABA) therapy, which is the usual first-line step-up recommendation for poorly controlled asthma.

Results in these children diverged from those in previous studies of white children. "These findings suggest that data cannot be extrapolated from clinical trials involving mixed populations to specific subgroups, including those of different ages and races," write senior author Michael E. Wechsler, MD, a pulmonologist and professor of medicine at the National Jewish Health in Denver, Colorado, and colleagues.

In one of two parallel studies published online September 25 in the New England Journal of Medicine, the researchers were surprised to see that 46% of children aged 5 to 11 years for whom at least one grandparent identified as black improved through use of a higher dose of an inhaled glucocorticoid rather than an add-on LABA.

"Our data show that for half the kids with uncontrolled asthma, adding salmeterol [multiple brands] was not the right answer," senior coauthor Eliot Israel, MD, of Harvard Medical School, who is also a pulmonologist at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.

"The SMART [Salmeterol Multicenter Asthma Research Trial] study had shown years ago a greater mortality in black asthma patients with the addition of a LABA, and in designing this research, we hypothesized that genetic ancestry might play a role," Wechsler told Medscape Medical News.

Step-up Therapies Compared

The two parallel, prospective, randomized, double-blind trials were conducted at nine US centers from January 2014 to March 2016. One study enrolled 280 children aged 5 to 11 years (mean, 8.5 years); the second enrolled 294 patients aged 12 years and older (mean overall age, 37.3 years). To be eligible for the trials, patients had to have at least one grandparent who identified as black.

The majority of participants in the children's trial were male (60.7%), whereas the majority in the adolescent/adult trial were female (67.7%). The median percentage of African ancestry was 81% in children and 82.1% in adolescents and adults.

For patients in both trials, symptoms were inadequately controlled with low-dose inhaled glucocorticoid therapy (fluticasone 50 μg twice a day in children and 100 μg twice a day in youth and adults).

The children's trial compared the efficacy of the following twice-daily protocols:

  • a double dose of fluticasone propionate to 100 μg twice daily

  • a double dose of fluticasone to 100 μg plus 50 μg of the LABA salmeterol

  • a quintuple dose of fluticasone to 250 μg

  • a quintuple dose of fluticasone to 250 μg plus 50 μg of salmeterol

The adolescents/adults trial compared these twice-daily regimens:

  • adding salmeterol at 50 μg to baseline twice-daily fluticasone at 100 μg

  • increasing fluticasone by a factor of 2.5 to 250 μg

  • a quintuple dose of fluticasone to 500 μg

  • increasing fluticasone by a factor of 2.5 to 250 μg plus 50 μg of salmeterol

During the 56-week trial, each treatment period lasted 14 weeks. Endpoints included asthma exacerbations, asthma-control days, and lung function.

When Wechsler's group compared a quintuple dose of fluticasone with salmeterol plus a double dose of fluticasone, they found a superior response in 46% of the children's group with quintupled fluticasone, but also a superior response in 46% of the children with a double dose of fluticasone plus added salmeterol (P = .99).

"Instead of going to first-line step-up therapy with an LABA, treatment might be less expensive and more accessible if we just increased the dose of glucocorticoid. That could have an immediate impact on treatment," Wechsler said.

However, in both adolescents and adults, adding an LABA was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid, which is what has been seen in previous trials with predominantly white enrollment.

The authors found no significant between-group differences in rates of pneumonia or respiratory tract infections. Children younger than 8 years, however, showed a decrease in the ratio of urinary cortisol to creatinine at an increased dose of inhaled glucocorticoids. "And that could be significant in terms of side effects," Israel said.

No notable interactions emerged with respect to the percentage of African ancestry and the primary composite outcome or any of the individual outcomes.

The mechanisms behind the differential response in young children are unknown, "but there might be different expression of the genes at different ages or environmental factors that may result in differences with age," Wechsler said. "As well, the pathophysiology of asthma may be different in children than adults and different in black kids than black adults."

Although the study assessed genetic markers of African ancestry, it did not closely analyze specific genetic factors or biomarkers predictive of treatment response. Genetic mapping to identify subgroups by response are now underway, Wechsler said.

Socioeconomic factors driving the differences would likely be similar for children, adolescents, and adults in the two groups, Wechsler noted. Although socioeconomic factors do influence health, "when studies have corrected for socioeconomic status, they've still found differences in response between blacks and nonblacks," he said.

Offering her perspective on the research, Bridgette L. Jones, MD, an allergist/immunologist at Mercy Children's Hospital in Kansas City, Missouri, observed that pediatricians and subspecialists recognize the heterogeneity of disease and response to treatment among asthma patients. In her view, extrinsic factors such as social determinants of health ― racism, for example ― may lead to biological changes that could affect disease phenotype and treatment response.

But, added Christie Sadreameli, MD, MPH, an assistant professor of pediatrics and a pediatric pulmonologist at Johns Hopkins University School of Medicine in Baltimore, Maryland, "[a]lthough inner-city residence, poverty, and environmental exposures such as indoor exposure to mice are risk factors that we know affect some black children, these factors do not fully explain the differences in asthma severity and risk."

According to Sadreameli, who was not a participant in the present study, the data reinforce what is already known about differential response in children and, specifically, black children. "[T]he data are not surprising, and we do see this in practice," she said. "This study adds to the principle that we should consider different treatment approaches for our patients and make changes when the patient is not responding."

Jones stressed the need for new, inclusive clinical trials and translational research to address those disproportionately affected by a disease. "Although further studies should be conducted to confirm these findings, these data should be considered when treating children and adolescents with asthma," she said.

According to Israel, the next logical step is to perform a simpler, more direct study of treatment in a larger number of black patients. "And because there's been some concern about the safety of salmeterol in black patients, that should be tested in larger groups, too," Wechsler added.

The overarching message of the findings is that treatment recommendations cannot be automatically extrapolated from one population to another. "We need to think about subpopulations when we formulate guidelines and ensure that guidelines are fine-tuned to most affected subpopulations," Israel said. "In the context of what we found, we need to reexamine what is considered best practice in add-on therapy for asthma that is uncontrolled."

Added Jones: "We may be using medications in these children daily that is not the most effective for them or may not be effective at all. We have got to do better for all children."

The study was funded by the National Heart, Lung, and Blood Institute. Wechsler has reported multiple ties to companies, including AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Mylan, Novartis, Regeneron, resTORbio, Sanofi, Genzyme, and others. Several coauthors have also disclosed various relationships with industry. Commentators Jones and Sadreameli have disclosed no relevant financial relationships.

N Engl J Med. Published online September 25, 2019. Abstract

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