Scolaris Content Display Scolaris Content Display

Inclusion of trials flow diagram.
Figures and Tables -
Figure 1

Inclusion of trials flow diagram.

Forest plot of comparison: 1 Primary outcomes, outcome: 1.1 Exacerbations (number of exacerbations/person/year).Refer to for Overall rate estimates of acute exacerbations across included studies.
Figures and Tables -
Figure 2

Forest plot of comparison: 1 Primary outcomes, outcome: 1.1 Exacerbations (number of exacerbations/person/year).

Refer to Table 1 for Overall rate estimates of acute exacerbations across included studies.

Forest plot of comparison: 1 Primary outcomes, outcome: 1.2 Mortality (deaths during trial period).
Figures and Tables -
Figure 3

Forest plot of comparison: 1 Primary outcomes, outcome: 1.2 Mortality (deaths during trial period).

Forest plot of comparison: 2 Secondary outcomes, outcome: 2.1 Prescriptions (number of courses/person/year).Refer to for Overall rate estimates of antibiotic prescriptions across included studies.
Figures and Tables -
Figure 4

Forest plot of comparison: 2 Secondary outcomes, outcome: 2.1 Prescriptions (number of courses/person/year).

Refer to Table 2 for Overall rate estimates of antibiotic prescriptions across included studies.

Forest plot of comparison: 2 Secondary outcomes, outcome: 2.3 Adverse events (number of adverse events/person/year).Refer to for Overall rate estimates of adverse events across included studies.
Figures and Tables -
Figure 5

Forest plot of comparison: 2 Secondary outcomes, outcome: 2.3 Adverse events (number of adverse events/person/year).

Refer to Table 3 for Overall rate estimates of adverse events across included studies.

Comparison 1 Primary outcomes, Outcome 1 Exacerbations (number of exacerbations/person).
Figures and Tables -
Analysis 1.1

Comparison 1 Primary outcomes, Outcome 1 Exacerbations (number of exacerbations/person).

Comparison 1 Primary outcomes, Outcome 2 Mortality (deaths during trial period).
Figures and Tables -
Analysis 1.2

Comparison 1 Primary outcomes, Outcome 2 Mortality (deaths during trial period).

Comparison 2 Secondary outcomes, Outcome 1 Prescriptions (number of courses/person/year).
Figures and Tables -
Analysis 2.1

Comparison 2 Secondary outcomes, Outcome 1 Prescriptions (number of courses/person/year).

Comparison 2 Secondary outcomes, Outcome 2 Adverse events (number of adverse events/person).
Figures and Tables -
Analysis 2.2

Comparison 2 Secondary outcomes, Outcome 2 Adverse events (number of adverse events/person).

Summary of findings for the main comparison. Haemophilus influenzae oral vaccination for prevention of acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD)

Haemophilus influenzae oral vaccination for prevention of acute exacerbations of chronic bronchitis and COPD

Patient or population: adults (> 18 years of age) with either COPD or recurrent acute exacerbations of chronic bronchitis

Settings: community and outpatients

Intervention: oral monobacterial vaccination with killed NTHi

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Not vaccinated

Corresponding risk

NTHi oral vaccinated

Acute exacerbations

(number of exacerbations/person/year)

2.111 exacerbations per person/year

1.668 exacerbations
per person/year

RR 0.79

(0.57 to 1.10)

557
(6)

⊕⊕⊝⊝
low1

Despite an absolute estimated decrease in the rate of exacerbations in the vaccinated group, the result is negligible (95% CI crosses 1.00) and not statistically significant (P = 0.16)

Mortality

(deaths during trial period)

23 per 1000

37 per 1000
(15 to 88)

OR 1.62

(0.63 to 4.12)

518
(5)

⊕⊝⊝⊝
very low2

Despite more absolute deaths occurring in the vaccinated group, the result is negligible (95% CI crosses 1.00) and not statistically significant (P = 0.31). Deaths were not necessarily attributed to the use of the vaccine

Carriage of NTHi

Not meta‐analysed

N/A

N/A

N/A

N/A

⊕⊝⊝⊝
very low6

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. 4 trials showed no significant difference in carriage levels, while 2 trials showed a significant decrease in carriage levels in the vaccinated group compared with the placebo group

Antibiotic prescriptions

(number of courses/person/year)

**Corticosteroids not meta‐analysed

5.723
prescriptions
per person/year

3.162
prescriptions
per person/year

RR 1.81

(1.35 to 2.44)

142
(3)

⊕⊕⊝⊝
low3

Courses of antibiotics were found to be prescribed in the placebo group at a rate approximately 80% greater than in the vaccinated group (P < 0.001)

(Note that a RR > 1.0 here indicates more antibiotics being prescribed to participants in the placebo group, i.e. RR 1.81 corresponds to an approximately 80% increased rate of antibiotic prescriptions when not receiving the vaccine. The placebo group is being compared to the vaccine group in this instance to attempt to demonstrate how many more antibiotics are required in those not vaccinated)

**2studies reported corticosteroid use, however due to differences in units of measurement, these results could not be meta‐analysed

Hospital admissions

(number of participants hospitalised during trial period)

N/A

N/A

N/A

N/A

⊕⊕⊕⊝
moderate4

Hospital admissions was not meta‐analysed due to differing units of measurement by the 2 trials that reported this finding. Notwithstanding that pooling the data for the 2 trials would have yielded high heterogeneity. Hospital admissions were not necessarily attributable to the vaccine

Adverse events

(number of adverse events/person/year)

0.319
adverse events
per person/year

0.456
adverse events
per person/year

RR 1.43

(0.70 to 2.92)

484
(5)

⊕⊕⊝⊝
low5

Despite an estimated absolute increased rate of adverse events in the vaccinated group, the result is negligible (95% CI crosses 1.00) and not statistically significant (P = 0.61). Adverse events were not necessarily attributable to the vaccine

Quality of life

Not meta‐analysed

N/A

N/A

N/A

N/A

⊕⊝⊝⊝
very low6

Quality of life was not meta‐analysed due to differing units of measurement, but was reported in 2 trials, which showed an improvement at 6 months in the vaccine group (scoring at least 2 points better than the placebo group; significance unknown)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval (CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; N/A: not applicable; NTHi: non‐typeable Haemophilus influenzae; OR: odds ratio; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1One study had marked heterogeneity; most studies had a low number of participants; one study had significant attrition.
2Mortality was not formally measured; five studies reported on deaths but none attributed to vaccine.
3Only three studies recorded information on prescriptions; studies had a low number of participants; method of allocation concealment and randomisation was unclear in two of the studies.
4Only two studies recorded information on hospitalisations; one study was significantly larger than the other.
5Most studies had a low number of participants; one study may have had attrition bias; two studies had high risk of bias for randomisation and allocation concealment.
6Meta‐analysis was not performed; inconsistent units of measurement used by studies, therefore not comparable.

Figures and Tables -
Summary of findings for the main comparison. Haemophilus influenzae oral vaccination for prevention of acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD)
Table 1. Rate estimates of acute exacerbations across included studies

Study

Vaccinated

Placebo

*Absolute rate difference

Clancy 1985

0.256

0.272

0.016 (‐)

Clancy 1990

1.000

1.700

0.700 (‐)

Clancy 2016

0.717

0.767

0.050 (‐)

Lehmann 1991

0.800

1.210

0.410 (‐)

Tandon 1991

3.355

4.364

1.009 (‐)

Tandon 2010

3.667

4.350

0.683 (‐)

Overall mean

1.633

2.111

0.478 (‐)

*Estimated rate of exacerbation calculated as number of exacerbations per person per year.

Refer to Analysis 1.1: Forest plot comparison and rate ratios for exacerbations.

Figures and Tables -
Table 1. Rate estimates of acute exacerbations across included studies
Table 2. Rate estimates of antibiotic prescriptions across included studies

Study

Vaccinated

Placebo

*Absolute rate difference

Clancy 1990

0.500

1.200

0.700 (‐)

Tandon 1991

5.806

10.194

4.388 (‐)

Tandon 2010

3.180

7.200

4.020 (‐)

Overall mean

3.162

6.198

3.036 (‐)

*Estimated rate of antibiotic prescriptions calculated as number of antibiotic courses per person per year.

Refer to Analysis 2.1: Forest plot comparison and rate ratios for antibiotic prescriptions.

Figures and Tables -
Table 2. Rate estimates of antibiotic prescriptions across included studies
Table 3. Rate estimates of adverse events across included studies

Study

Vaccinated

Placebo

*Absolute rate difference

Clancy 2016

0.008

0.025

0.017 (‐)

Lehmann 1991

0.067

0.031

0.036 (+)

Tandon 1991

1.032

1.212

0.180 (‐)

Tandon 2010

0.167

0.450

0.283 (‐)

Overall mean

0.319

0.430

0.111 (‐)

*Estimated rate of adverse events calculated as number of adverse events per person per year.

Refer to Analysis 2.2: Forest plot comparison and rate ratios for adverse events.

Figures and Tables -
Table 3. Rate estimates of adverse events across included studies
Comparison 1. Primary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations (number of exacerbations/person) Show forest plot

6

557

Rate Ratio (Random, 95% CI)

0.79 [0.57, 1.10]

2 Mortality (deaths during trial period) Show forest plot

5

518

Odds Ratio (M‐H, Fixed, 95% CI)

1.62 [0.63, 4.12]

Figures and Tables -
Comparison 1. Primary outcomes
Comparison 2. Secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Prescriptions (number of courses/person/year) Show forest plot

3

142

Rate Ratio (Fixed, 95% CI)

1.81 [1.35, 2.44]

2 Adverse events (number of adverse events/person) Show forest plot

4

484

Rate Ratio (Fixed, 95% CI)

1.43 [0.70, 2.92]

Figures and Tables -
Comparison 2. Secondary outcomes