A national clinical trial led by researchers at the University of Arizona College of Medicine – Tucson found that treating young children with an oral bacterial extract did not reduce the risk of severe wheezing and respiratory illnesses that can precede asthma. 

The results of the large-scale, multiyear study, known as the ORBEX trial, were published Monday in The Lancet. Launched in 2017, ORBEX evaluated the preventive potential of a treatment called OM-85, commonly known by its brand name, Broncho-Vaxom®. Dr. Fernando Martinez, director of the university's Asthma and Airway Disease Research Center, and co-investigator Dr. Wayne Morgan, professor of pediatrics and physiology, led the study team at the U of A.

The findings add new evidence that may prompt researchers to rethink aspects of the hygiene hypothesis, a longstanding framework linking early-life microbial exposure to immune health.

Developed in England, the hygiene hypothesis suggests that reduced microbial exposure in modern sanitized environments may contribute to increased allergic and asthmatic diseases. Researchers at the Asthma and Airway Disease Research Center advanced the hypothesis, studying exposures in early life – such as daycare and dogs – that may reduce the risk of asthma, consistent with the concept.

Martinez, Morgan and their collaborators – a national team including pediatricians, immunologists and biostatisticians – put the hygiene hypothesis to the test with ORBEX. Earlier studies suggested OM-85 could train the immune system and reduce respiratory illnesses, raising the possibility that it could mimic the microbial exposure thought to protect against asthma.

"But we found no significant difference between the treatment and placebo groups," Martinez said. "We need to rethink what we have thought until now. That's my real conclusion. There's no easy solution for these complex diseases that are part of our time."

These findings point to new directions for preventing asthma, a priority for Martinez in the absence of treatments that can avert wheezing or stop the disease from developing.  Wheezing lower respiratory illnesses are a major concern in preschool children and a leading cause of hospitalization. Children under 5 are more likely than other age groups to go to the emergency department because of asthma, according to the U.S. Department of Health and Human Services.

Interpreting years of data

The double-blind study enrolled 822 children ages 6 to 18 months at high risk for asthma due to family history or eczema, an allergic skin condition associated with an increased risk of developing asthma. At 11 U.S. locations, including two Arizona sites, participants randomly received either OM-85 or a placebo 10 days a month for two years. With parents' help, researchers then tracked the children after treatment ended. This observation period was originally planned for one year but was extended to three years because the COVID-19 pandemic had temporarily suppressed common respiratory viruses.

"We had a very committed group of parents. Without five years of patience on their part, we would never have been able to complete the study," Morgan said.

The research team sought to determine if a two-year course of the medication could permanently train the immune system, preventing severe wheezing illnesses – defined as breathing issues serious enough to require multiple rescue treatments or prescription of oral corticosteroids – in the three years after treatment ended and ultimately stopping the development of asthma by age 6.

The primary prevention trial's main metric was the time it took for a child to experience their first severe wheezing episode. No meaningful difference between the time to first illness between the OM-85 and placebo groups was found. Over the three-year observation period, 21% of the children taking OM-85 experienced this type of episode, compared to 18% of the placebo group. Similarly, the rates of children diagnosed with clinical asthma by age 6 were identical between the two groups, at 21%.

Turning insights into next steps

One interpretation of why ORBEX's results differ from those of earlier, successful studies could be that those smaller trials involved children who already suffered from frequent wheezing, Morgan said, rather than those classified as at risk. The researchers suspect the medication may only work as a treatment once asthma pathways are active, not as a preventive measure. Future research will test this theory and explore alternative delivery methods like nasal sprays.

In addition to guiding future asthma prevention investigations, the ORBEX study's findings prompt further exploration of complex factors shaping immune development that go beyond the hygiene hypothesis, Martinez said. 

Rather than simply asking which bacteria might protect against asthma, Martinez believes it's time to look deeper: What factors make some children more susceptible to asthma than others? The answer could involve differences that begin before birth, including epigenetic factors – changes that influence how genes are turned on or off without altering the underlying DNA sequence. These changes can arise during pregnancy in response to environmental influences and may affect how the immune system develops and functions.

Exploring these prenatal factors builds on Martinez's decades of research into the origins of asthma. He and his collaborators are preparing to pursue these new leads, while recognizing the scope of the work ahead.

"We are left with a big challenge – even greater than before," Martinez said. "This is what science is all about. I still think we will find a way to prevent asthma, but it will take much more understanding."

Funding for the ORBEX trial was provided by the National Heart, Lung, and Blood Institute, with supplemental funding from OM Pharma, which also provided the study drug and placebo.