Controversial Immune Booster for Asthma in the Works

Ingrid Hein

June 13, 2019

LISBON, Portugal — Bacterial lysate, a cocktail of 21 bacterial species, reduces asthma exacerbations in schoolchildren and wheezing in preschool children when taken regularly, two meta-analyses show.

"School-age children who took bacterial lysates cut their asthma exacerbations in half," said investigator Geertje de Boer, PhD, from Franciscus Gasthuis in Rotterdam, the Netherlands. "That sounds promising."

Recent interest in the microbiome and the understanding that good bacteria can strengthen the immune system have shone a spotlight on a drug already approved for the treatment or prevention of respiratory tract infections, wheeze, and asthma in several European Union countries.

The oral cocktail, known as Broncho Vaxom, is taken for 10 consecutive days in each of 3 consecutive months. The drug has not been approved in the United States.

Until now, bacterial lysate "was seen as an alternative medicine. Not everyone took it seriously," de Boer told Medscape Medical News.

But results from the two meta-analyses — one from the Netherlands and the other from Poland — show that bacterial lysate has a significant preventative effect on respiratory disease in children. Both studies were presented here at the European Academy of Allergy and Clinical Immunology 2019 Congress.

Airway Pathogens

Bacterial lysate is a collection of inactive extracts from pathogenic respiratory bacteria. The bacteria are heated up to break down the cellular structure but not the protein. Once in the gut, the bacteria activate dendritic cells, which increases immune modulation, stimulates antibody production, and shows evidence of Th1/Th2 cytokine balance, ultimately providing protection against airway pathogens.

"I'm already prescribing this as an immunobooster on a regular basis when I do not detect any serious immune deficiency in a child," said investigator Wojciech Feleszko, MD, PhD, from the Medical University of Warsaw in Poland.

"I don't believe it's a magic bullet," he told Medscape Medical News, but "it causes an immunoregulatory effect and a dampened allergic response."

In the 6 years Feleszko has been prescribing bacterial lysate, he has seen no adverse effects. And "young asthmatics taking these products show lower exacerbations" consistently, he reported.

We think the results in children are very promising.

In the Dutch meta-analysis, de Boer and her colleagues identified 24 studies that reported the effectiveness of the drug as an add-on therapy for the prevention of respiratory tract infections after a systematic literature review in English.

They found that asthma exacerbations were significantly lower in youth 6 to 18 years of age after treatment with bacterial lysate than with placebo (mean difference, –0.86; P < .00001). In addition, there was a 23% reduction in COPD exacerbations in the study cohort (relative risk [RR], 0.77; P = .0002).

"We think the results in children are very promising, and it could also be very effective for COPD," de Boer said.

The team also determined that bacterial lysate decreases human interleukin (IL)-4 and increases serum IL-10, IFN gamma, and NKT CD4+ cells, all of which are immunologically beneficial for respiratory disease.

Most studies of bacterial lysate are underpowered, but all show that it improves the incidence of respiratory events, de Boer pointed out.

Her team is currently recruiting patients for a trial to look at how bacterial lysate can help adults with respiratory disease, and they plan to monitor microbiome data. "This would be the first study with more insight into adult asthma," she said.

In the Polish meta-analysis, wheezing in preschool children was reduced by about half.

"Preschool children had nearly one less wheezing episode during the year," said investigator Jakub Żółkiewicz, a PhD candidate at the University of Warsaw, who presented the findings.

"Each episode changes the structure of the airways, and it's irreversible," so reducing the number of episodes is beneficial, he told Medscape Medical News. "When you combine the reduction in wheezing and the safety of bacterial lysates, we have a good rationale for using them in children."

The quality of many of the studies they looked at were weak, in some cases were difficult to compare, and it was not clear whether exacerbation reductions were related to immunomodulatory changes or a reduction in respiratory tract infections. However, there is significant evidence that it works.

"We think it shapes our mucosal immunity, preventing viral infection that causes asthma," Żółkiewicz explained.

American Trial Underway

Researchers in the field understand that robust, well-designed studies of bacterial lysate are warranted and are looking forward to results from the Oral Bacterial Extract for the Prevention of Wheezing Lower Respiratory Tract Illness — or ORBEX — trial (NCT02148796) currently happening in the United States.

In modern society, 30% of children experience wheezing in their first year of life and are getting viral infections that should be "completely innocuous," said Fernando Martinez, MD, from the University of Arizona in Tucson, who is the lead ORBEX investigator.

And, he noted, "80 million people have taken this product and there's no evidence of a side effects."

Unless the immune system is stimulated in early life, it doesn't learn the appropriate response to distinguish between dangerous and nondangerous signals, he told Medscape Medical News.

"It's really a problem of microbial exposure; we need to be exposed. Yes, it carries with it a risk, but the immune system needs to train appropriately to environmental factors," he explained.

A previous study of Amish communities that Martinez was involved in showed that living "like a peasant" offers a good training ground for the immune system (Am J Respir Crit Care Med. 2018;197:573-579).

In isolated large family communities free of modern amenities, where contact with farming and farm animals is constant, children did not present with wheezing. "The Amish have practically no asthma," he explained. "Their immune systems are strong."

Because living like a peasant is not a realistic option for everyone, we need a way to get bacteria into our immune system to offer the same protection as the natural environment. Bacteria lysates might be part of the solution, he said.

"It's not a probiotic," he emphasized. "What we're trying to do is activate the immune system."

ORBEX has recruited about half of the nearly 1000 babies needed for the 36-month parallel-group, double-blind trial of Broncho-Vaxom 3.5 mg or placebo taken each month for 10 days over a 2-year period, he reported.

The primary outcome will be time to the first wheezing lower respiratory infection after the 2-year intervention.

The elimination of bacteria that make us sick in the last century might have been overkill. Now, children's bodies don't know what's bad for them, he added.

Not a Vaccine

Bacterial lysate was the subject of a recent review by the European Medicines Agency (EMA) to see if it offered protection from pneumococcal virus, which is part of the bacterial cocktail, and might one day replace vaccines.

That's not the case. "You don't get antibodies against bacteria effective like a vaccine. It's not a vaccine," Martinez explained.

But, he said, most bacteria share the same metabolites. "When you offer this bacterial product, you stimulate the intestine to grow in the right way, and that could decrease asthma."

Martinez said he grew up in Italy, where many doctors prescribed bacterial lysate and even took it themselves "because they know it's not voodoo or magic. At this point, we know it has a very specific effect on the immune system," but the literature "is not strong."

"I decided I had to do this study," he explained. "If we can publish in a major journal showing this is effective to prevent wheezing in babies, it will be very strong" and provide an inexpensive way boost the immune system in children.

de Boer, Zólkiewicz, and Martinez have disclosed no relevant financial relationships. Feleszko is on the speaker's bureau for Vifor.

European Academy of Allergy and Clinical Immunology (EAACI) 2019 Congress: Abstract TP0797 (de Boer) presented June 2; abstract TP1537 (Zólkiewicz), presented June 4, 2019.

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