By Concepta Merry, MB, BCh, BAO, BA

Associate Professor, Global Health, School of Medicine, Trinity College Dublin

Dr. Merry reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • There is growing interest in the possible roles of the gastrointestinal microbiota and probiotics in immune mediated disorders such as asthma.
  • This aim of this study was to see if free probiotics could reduce winter infections and associated antibiotic prescribing in asthmatics over the age of 5.
  • The study failed to show any benefit of free probiotics in this patient population in terms of respiratory health or antibiotic prescribing.

SYNOPSIS: A randomized, controlled trial of recommendations that asthmatics (5 years of age and older) take free daily probiotics over a winter season failed to show any benefits in terms of antibiotic usage or overall respiratory health.

SOURCE: Smith TD, Watt H, Gunn L, et al. Recommending oral probiotics to reduce winter antibiotic prescriptions in people with asthma: A pragmatic randomized controlled trial. Ann Fam Med 2016;14:422-430.

Resistance to antimicrobial agents is considered a major threat to global health security.1,2 Antimicrobial resistance has been described as a “problem without borders” and has been identified as a key health priorities in the United States.3 Ongoing efforts to stem the emergence of antimicrobial resistance include antimicrobial stewardship, new regulatory approaches, enhanced antimicrobial surveillance, increased research funding, and the elimination of non-judicious use of antibiotics in animals, plants, and marine life.4 Little, if anything, has been said about looking at integrative health approaches to reducing antibiotic prescribing. Respiratory tract infections account for the vast majority of antibiotics prescribed in the primary healthcare setting.5 People with asthma are particularly susceptible to viral respiratory tract infections and receive a disproportionate number of unnecessary antibiotics.6

Smith et al sought to determine whether access to free probiotics could reduce winter respiratory tract infections and antibiotic use in people with asthma older than age 5 years. The rationale for the use of probiotics was twofold. First, a 2011 Cochrane review suggested that probiotic use can reduce upper respiratory tract infections and antibiotic use.7 The Cochrane review focused on children younger than 8 years of age and did not select out children with asthma. Second, a small pilot study that looked at acupuncture plus probiotics showed a reduction in the rates of respiratory tract infections in people with asthma.8 The pilot study was underpowered and the differences in infection rates were not statistically significant.

The science behind the use of probiotics in asthma relates to a growing interest in a possible role for intestinal microbiota in the development of immune-mediated disorders such as asthma.9 The working hypothesis is that the gut microbiota influence immune stimulation and tolerance. U.K. researchers conducted a community-based study in a semi-urban practice caring for 23,000 patients that examined the use of probiotics alone for reducing antibiotic use in asthmatics over a single winter between October 2013 and March 2014. Patients attending the Ashfields Primary Care Centre who were 5 years of age and who had a current diagnosis of asthma were included. All practice patients who met the study inclusion criteria were enrolled in the study and were randomly allocated to a control or intervention arm.

All U.K.-based asthmatic patients are entitled to receive the annual influenza vaccine. In this study, all patients received an invitation to come in for the seasonal influenza vaccine along with other helpful wellness tips via the U.K. postal service. This pragmatic study design essentially piggybacked onto the existing clinical care and randomized study participants to either receive standard of care clinical practice or to receive an additional leaflet offering them free probiotics to try to reduce winter respiratory infections and antibiotic use.

Households in the intervention arm received information about probiotics and three tokens, each of which entitled the households to receive a two-month supply of a patented probiotic free of charge. The probiotic contained 2.5 billion colony-forming units per capsule (containing two different strains of Lactobacillus acidophilus plus Bifidobacterium bifidum and Bifidobacterium animals). The probiotic used is a commercially available patented brand; none of the investigators disclosed any conflict of interest. The participants were instructed to take one capsule daily. The study did not have a placebo comparison arm.

The primary outcome for the study was the proportion of patients who received antibiotics for respiratory tract infections over the course of the winter. The secondary outcome for the study was overall respiratory health as defined by consultations for respiratory tract infections, exacerbations of asthma, and the number and cost of antibiotic courses prescribed during the six-month intervention period.

Both intention-to-treat and per-protocol analyses were carried out with an anticipated 20% loss of outcome data and a 5% contamination rate in the control group. A total of 1,270 study participants were enrolled in the study. The probiotic was accessed by 121 (19%) participants in the intervention group at least once. This means that 19% of households in the study used the token to get free probiotic capsules. The study design did not factor in any assessment of compliance, specifically whether the household member with asthma actually took the probiotics. There was a supplement to the study, which mentioned that one patient who was randomized to the intervention arm contacted the study team to request probiotics for her daughter.

The results of the study showed that there was no significant difference in the primary outcome measure. Smith et al reported 27.7% of children in the intervention group received antibiotics compared to 26.9% of children in the control group in the intent-to-treat analysis (odds ratio, 1.04; 95% confidence interval [CI], 0.82-1.34) or the per-protocol analysis (adjusted odds ratio, 1.08; 95% CI, 0.69-1.69). There was no evidence of any effect on respiratory tract infections or asthma exacerbations. There was no significant difference in serious adverse events between the intervention and control groups.

Commentary

The results of this study do not support the use of leaflets and free access to probiotics to reduce antibiotic prescriptions or improve respiratory tract health in asthmatics older than 5 years of age. These results differ from the 2011 Cochrane review, which showed that probiotics reduce the risk of antibiotic use for acute upper respiratory tract infections.

To try to reconcile the apparent contradictory results between the British study and the Cochrane review, it is worth noting the key differences between the study designs. The British study focused on people with asthma aged 5 years or older. The authors of the British study suggested that the younger age of the children included in the Cochrane review may have affected the results, as younger children may be more sensitive to the immunological changes in the gastrointestinal tract triggered by taking probiotics. Additionally, the probiotic strains and formulation used in the British study were different from the ones included in the Cochrane review. Specifically, the British study used intact probiotic capsules rather than a liquid formulation. It is unclear whether probiotics prevent respiratory tract infections via local effects in the mucosa of the upper respiratory tract, in which case liquids may be superior to capsules.

In summary, free probiotics were not effective in preventing winter antibiotic prescribing, upper respiratory tract infections, lower respiratory tract infections, or asthma exacerbation rates in patients older than 5 years of age. This study provides real-world data, which show that free probiotics cannot be recommended to prevent winter infections and reduce antibiotic use in older children and adults with asthma.

Given the limitations of the study, including the lack of a placebo control arm and the inability to ascertain who (if anyone) within the household took probiotics, it is not possible to extrapolate from this study to make any generalizations about probiotics in asthma. Although this study failed to show any benefit of probiotics at either the individual patient level or at the public health level in terms of global antibiotic consumption, the investigators get top marks for the trial design and innovative integrative health style approach to address the growing concern about antimicrobial resistance.

REFERENCES

  1. Institute of Medicine. Antimicrobial Resistance: A Problem Without Borders. Washington, DC: National Academies Press Oct. 13, 2014.
  2. World Health Organization. Antibiotic resistance — a threat to global health security. Available at: http://www.who.int/drugresistance/activities/wha66_side_event/en/. Accessed Feb. 10, 2017.
  3. Centers for Disease Control and Prevention. Antimicrobial Resistance — A Global Imperative. Available at: https://blogs.cdc.gov/global/2015/11/16/antimicrobial-resistance-a-global-imperative/. Accessed Feb. 10, 2017.
  4. Infectious Diseases Society of America (IDSA); Spellberg B, Blaser M, Guidos RJ, et al. Combating antimicrobial resistance: Policy recommendations to save lives. Clin Infect Dis 2011;52(Suppl 5):S397-428.
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  6. Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet 2010;376:826-834.
  7. Hao Q, Lu Z, Dong BR, et al. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev 2011;(9):CD006895. doi: 10.1002/14651858.CD006895.pub2. Review. Update in: Cochrane Database Syst Rev 2015;2:CD006895.
  8. Stockert K, Schneider B, Porenta G, et al. Laser acupuncture and probiotics in school age children with asthma: A randomized, placebo-controlled pilot study of therapy guided by principles of Traditional Chinese Medicine. Pediatr Allergy Immunol 2007;18:160-166.
  9. Penders J, Stobberingh EE, van den Brandt PA, Thijs C. The role of the intestinal microbiota in the development of atopic disorders. Allergy 2007;62:1223-1236.