Influenza and pneumococcal vaccinations for patients with chronic obstructive pulmonary disease (COPD): an evidence-based review

Abstract

Objective: The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.

Influenza Disease: Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20^th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.

Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.

Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.

Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.

Streptococcal Pneumonia: Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.

People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.

Trivalent Influenza Vaccines in Canada: In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza^®) is formulated for intradermal use.

The 4 vaccines for intramuscular use are:

1. Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;

2. Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;

3. Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and

4. Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.

FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.

Pneumococcal Vaccine: Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:

1. Pneumovax 23^® (Merck & Co Inc. Whitehouse Station, NJ, USA), and

2. Pneumo 23^® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.

Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.

Research Questions:

1. What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?

2. What is the safety of these 2 vaccines in COPD patients?

3. What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?

Search Strategy: A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.

Inclusion Criteria:

1. studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;

2. randomized controlled trials published between January 1, 2000 and January 31, 2011;

3. studies including patients with COPD only;

4. studies investigating the efficacy of types of vaccines approved by Health Canada;

5. English language studies.

Exclusion Criteria:

1. non-randomized controlled trials;

2. studies investigating vaccines for other diseases;

3. studies comparing different variations of vaccines;

4. studies in which patients received 2 or more types of vaccines;

5. studies comparing different routes of administering vaccines;

6. studies not reporting clinical efficacy of the vaccine or reporting immune response only;

7. studies investigating the efficacy of vaccines not approved by Health Canada.

Outcomes of Interest: Primary Outcomes

Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.

Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.

Secondary Outcomes

1. rate of hospitalization and mechanical ventilation

2. mortality rate

3. adverse events

Quality of Evidence: The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:

[Table: see text]

Clinical Effectiveness: The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:

1. All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).

2. Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV₁] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).

3. Patients with moderate airflow obstruction (FEV₁ 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).

4. Patients with mild airflow obstruction (FEV₁ ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).

The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.

With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.

Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.

safety: Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).

With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV₁, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.

There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).

Clinical Effectiveness: The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).

With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).

Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.

Subgroup Analysis

The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV₁ < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV₁ less than 40% predicted (log-rank test 3.85; P = 0.0498).

Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV₁ less than 40% predicted and FEV₁ greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV₁ < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).

Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).

safety: No patients reported any local or systemic adverse reactions to the vaccine.