title: Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. COPD is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non-typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis.
  
  
  OBJECTIVE
  To assess the effectiveness of an oral, whole-cell, non-typeable H. influenzae (NTHi) vaccine in protecting against recurrent episodes of acute exacerbations of chronic bronchitis and COPD in adults. To assess the effectiveness of NTHi vaccine in reducing NTHi colonising the respiratory tract during recurrent episodes of acute exacerbations of COPD.
  
  
  METHODS
  We searched the following databases: CENTRAL (2014, Issue 6), MEDLINE (1946 to July week 3, 2014), EMBASE (1974 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014) and Web of Science (1955 to July 2014). We also searched trials registries and contacted authors of trials requesting unpublished data.
  
  
  METHODS
  We included randomised controlled trials comparing the effects of an oral monobacterial NTHi vaccine in adults with recurrent acute exacerbations of chronic bronchitis or COPD when there was overt matching of the vaccine and placebo groups on clinical grounds. The selection criteria considered populations aged less than 65 years and those older than 65 years.
  
  
  METHODS
  Two authors independently assessed trial quality and extracted data from original records and publications for incidence and severity of bronchitis episodes and carriage rate of NTHi measured in the upper respiratory tract, as well as data relevant to other primary and secondary outcomes.
  
  
  RESULTS
  We identified six placebo-controlled randomised controlled trials with a total of 557 participants. They investigated the efficacy of enteric-coated, killed preparations of H. influenzae in populations prone to recurrent acute exacerbations of chronic bronchitis or COPD. The vaccine preparation and immunisation regime in all trials consisted of at least three courses of formalin-killed H. influenzae in enteric-coated tablets taken at intervals (for example, days 0, 28 and 56). Each course generally consisted of two tablets taken after breakfast over three consecutive days. In all cases the placebo groups took enteric-coated tablets containing glucose. Risk of bias was moderate across the studies, namely due to the lack of information provided about methods and inadequate presentation of results.Meta-analysis of the oral NTHi vaccine showed a small, non-statistically significant reduction in the incidence of acute exacerbations of chronic bronchitis or COPD by 2.048% (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.84 to 1.12, P value = 0.68). There was no significant difference in mortality rate between the vaccine and placebo groups (odds ratio (OR) 1.62, 95% CI 0.63 to 4.12, P value = 0.31).We were unable to meta-analyse the carriage levels of NTHi in participants as each trial reported this result using different units and tools of measurement. Four trials showed no significant difference in carriage levels, while two trials showed a significant decrease in carriage levels in the vaccinated group compared with placebo.Four trials assessed severity of exacerbations measured by requirement for antibiotics. Three of these trials were comparable and when meta-analysed showed a statistically significant 80% increase in antibiotic courses per person in the placebo group (RR 1.81, 95% CI 1.35 to 2.44, P value < 0.0001). There was no significant difference between the groups with regards to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04, P value = 0.97). Adverse events were reported in all six trials with a point estimate suggestive that they occurred more frequently in the vaccine group, however, this result was not statistically significant (RR 1.43, 95% CI 0.70 to 2.92, P value = 0.87). Quality of life was not meta-analysed but was reported in two trials, with results at six months showing an improvement in quality of life in the vaccinated group (scoring at least two points better than placebo).
  
  
  CONCLUSIONS
  Analyses demonstrate that NTHi oral vaccination of patients with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence is mixed and the individual trials that show a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD.
authors.affiliation: Faculty of Health Sciences and Medicine, Bond University, University Drive, Gold Coast, Queensland, Australia, 4229.
authors.forename: Edward
authors.initials: E
authors.lastname: Teo
authors.forename: Hugh
authors.initials: H
authors.lastname: House
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lockhart
authors.forename: Sai Navya
authors.initials: SN
authors.lastname: Purchuri
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pushparajah
authors.forename: Allan W
authors.initials: AW
authors.lastname: Cripps
authors.forename: Mieke L
authors.initials: ML
authors.lastname: van Driel
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D029481:Bronchitis, Chronic / Q000517:prevention & control*; D018450:Disease Progression; D018073:Haemophilus Vaccines / Q000008:administration & dosage*; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D055502:Secondary Prevention
chemical_list: D000900:Anti-Bacterial Agents; D018073:Haemophilus Vaccines