Abstract
Objective To describe the burden of pneumococcal disease and associated risk factors in the Canadian adult population, delineate available pneumococcal vaccines and associated efficacy and effectiveness data, and review current pneumococcal vaccine recommendations and community-acquired pneumonia (CAP) prevention strategies in Canada.
Quality of evidence Pneumococcal vaccination guidelines from the Canadian National Advisory Committee on Immunization in 2013 and 2016 constitute level III evidence for CAP prevention in the Canadian adult population.
Main message It is recommended that immunosuppressed adults of all ages receive the 13-valent pneumococcal conjugate vaccine (PCV13) (grades A and B recommendations). In 2016, the National Advisory Committee on Immunization also recommended that all adults aged 65 years and older receive PCV13 (grade A recommendation) on an individual basis, followed by the 23-valent pneumococcal polysaccharide vaccine (grade B recommendation). This update is based on a large clinical study that demonstrated PCV13 efficacy against vaccine-type CAP in this population.
Conclusion Physicians should focus on improving pneumococcal vaccination rates among adults, which remain low. Vaccination with PCV13 should also be considered for adults with chronic conditions, whose baseline risk is often higher than that for healthy individuals aged 65 years and older.
Case description
A 65-year-old woman visits your office to discuss possible new treatment options for her high blood pressure. As her family physician, you review her vaccination history and discover that she has received influenza, shingles, and tetanus, diphtheria, and acellular pertussis vaccinations over the past 3 years. What is missing?
Lower respiratory tract infections, including pneumonia, represented the fourth leading cause of death worldwide in 2016.1 Similarly, in Canada, chronic lower respiratory diseases were ranked fifth, while influenza and pneumonia were ranked sixth, as causes of death in 2017.2 Community-acquired pneumonia (CAP) in Canada is additionally associated with high hospitalization rates (50% to 77% for patients aged ≥ 60 years),3 high intensive care unit (ICU) admission rates (18%), and high mortality rates (11.4% within 30 days).4 It is important to note that patients with CAP are at increased risk of cardiovascular complications (eg, cardiovascular disease, heart failure)5–7—one study showed that within 30 days after hospitalization for pneumonia, patients had a more than 4-fold risk of developing cardiovascular complications compared with healthy controls7—and there is an association with increased mortality in the short term.8 Although no randomized clinical studies have reported effects of pneumococcal vaccination on cardiovascular disease, a meta-analysis of 8 observational studies found a significant reduction in acute coronary syndrome events among elderly patients who received pneumococcal polysaccharide vaccination (odds ratio [OR] of 0.83; 95% CI 0.71 to 0.97).9 However, it is important to note that such observational studies might be confounded by the “healthy user effect,” wherein patients seeking preventive therapy, such as vaccination, are also more likely to practise healthier habits in general.10
Streptococcus pneumoniae is the most frequently isolated bacterial pathogen in CAP11 and is a leading cause of CAP, meningitis, and bacteremia.12 It was the most common pathogen causing CAP in all sites of care (out-patients, hospitalized non-ICU patients, and hospitalized ICU patients) across multiple studies13 and was the most frequently identified pathogen among 3 of 4 sources of culture-positive specimens from Canadian CAP patients admitted to the ICU (2000 to 2002).14 Approximately 75% of pneumococcal pneumonia events are nonbacteremic,15 but noninvasive disease might become invasive (eg, pneumonia accompanied by bacteremia).12 In addition to invasiveness, which is more often associated with certain pneumococcal serotypes,16 antimicrobial resistance in S pneumoniae is an important problem in Canada that highlights the need for CAP prevention. Penicillin resistance among S pneumoniae isolates increased dramatically from 1988 to 200917 but decreased from 2011 (12%) to 2014 (9%).18 Serogroup 19 (19A, 19F), which is common across all age groups in Canada,19 particularly demonstrates a multidrug-resistant pattern.20,21
Community-acquired pneumonia has many established risk factors. For instance, patients 60 years of age or older have much higher incidence rates than other individuals22 and account for most cases and hospitalizations.23,24 Symptoms in older adults are often more subtle, potentially delaying diagnosis and treatment.25 Patients aged 65 or older hospitalized for CAP have a higher 1-year mortality rate than the general population or individuals hospitalized for other reasons.26 Frailty, a related CAP risk factor, is associated with higher 1-year mortality resulting from CAP27 and impaired immune responses to pneumococcal conjugate vaccines (PCVs).28 Behavioral factors (including cigarette smoking,29–31 second-hand smoke exposure in non-smokers aged older than 65 years,32 and high alcohol consumption32,33) and environmental factors (such as living in long-term care facilities34 and homelessness29) also increase CAP risk. Comorbidities (eg, heart disease, diabetes, chronic respiratory disease) also increase the risk of adult pneumococcal pneumonia.30,33 Finally, multiple underlying conditions30,31,35,36 or immunocom-promising conditions30 further increase risk. For example, compared with similarly aged healthy individuals, risk of CAP is approximately 3-fold higher in the at-risk (high-risk using terminology from the Canadian National Advisory Committee on Immunization [NACI]) population and 4- to 6-fold higher in immunosuppressed individuals (Table 1).30,37 Individuals with certain comorbidities, such as chronic lung disease, show baseline risk exceeding that of healthy individuals aged 65 years or older or some immunosuppressed individuals.
Quality of evidence
Pneumococcal vaccination guidelines from NACI are based on level III evidence (ie, opinions or statements of expert authorities); these guidelines were updated in June 2016 regarding adults aged 65 years or older.38
Main message
Pneumococcal vaccines available in Canada.
Two pneumococcal vaccines are recommended for adults in Canada37: the 23-valent pneumococcal polysaccharide vaccine (PPSV23), which is $30.00 to $34.58 per dose,39–41 with antigens of serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F42; and the 13-valent PCV (PCV13), which is $110.00 to $125.00 per dose,39–41,43 containing antigens of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F conjugated to nontoxic diphtheria CRM197 protein.44 In Canada, 26% and 38% of cases of invasive pneumococcal disease (IPD) in 2014 were caused by PCV13 and PPSV23 serotypes, respectively.45 On average, between 7.0% and 14.8% of CAP cases in hospitalized patients in Canada were caused by PCV13 serotypes, depending on the number of diagnostic tests performed.46
Effectiveness of PPSV23.
Inconclusive evidence for PPSV23 vaccine efficacy against noninvasive (nonbacteremic) pneumococcal pneumonia in older adults has been acknowledged by regulatory and public health agencies, including the US Centers for Disease Control and Prevention47 and the European Medicines Agency.48 Table 2 summarizes findings from recent systematic reviews and meta-analyses, which are commonly regarded as providing the highest level of evidence, assessing PPSV23 effectiveness against IPD, pneumococcal CAP, and all-cause CAP.49–54
Three meta-analyses included in 2 different studies all found statistically significant effectiveness of PPSV23 against IPD.49,50 However, 2 of these were characterized by significant statistical heterogeneity, which indicates greater variation in study outcomes than can be attributed to chance alone, likely as a result of differences in the study parameters (eg, participant age, comorbidities, etc).55 For this reason, pooled results should be interpreted cautiously.
For pneumococcal CAP, 2 studies with significant statistical heterogeneity found that PPSV23 had no proven effectiveness for this outcome.51,52 Another study without heterogeneity concerns demonstrated significant effectiveness of PPSV23 against pneumococcal CAP (OR = 0.26; 95% CI 0.15 to 0.46), which was notably similar to findings for IPD (OR = 0.26; 95% CI 0.14 to 0.45), likely reflecting substantial overlap between the 2 analyses.50
Finally, there were 5 meta-analyses that included 3 studies evaluating PPSV23 effectiveness against all-cause CAP.49,50,52,53 Of these 5 meta-analyses, 3 (2 with significant statistical heterogeneity) found no effectiveness.49,53 The most recent Cochrane meta-analysis found that PPSV23 significantly reduced all-cause CAP (OR = 0.72; 95% CI 0.56 to 0.93), with pneumonia occurring in 4.32% of the vaccinated group compared with 6.17% of the placebo group.50 However, heterogeneity of the included studies was very high (85%), indicating that the pooled results are unreliable. Finally, a fifth study found a modest reduction in all-cause pneumonia (relative risk of 0.87; 95% CI 0.76 to 0.98), with those aged 65 years and older and those aged younger than 65 years who were at high risk showing particular benefit (relative risk of 0.72; 95% CI 0.69 to 0.94).52 Taken together, the results of these meta-analyses indicate that although PPSV23 is effective for IPD, there is inconclusive evidence of its effectiveness against pneumococcal or all-cause CAP.
Effectiveness of PCV13.
Pneumococcal conjugate vaccines have demonstrated effectiveness since their introduction in 2001.56 Specifically in Canada, hospitalization for all-cause and pneumococcal pneumonia has significantly declined in adults aged 65 years of age and older (P < .001), likely at least partially because of herd effects from the pediatric pneumococcal immunization program (which achieved 79.2% national coverage with 3 doses in 201357).22 More recently, the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), which randomized 84 496 vaccine-naïve subjects aged 65 years and older in the Netherlands to receive PCV13 or placebo, demonstrated PCV13 efficacy in preventing first episodes of pneumococcal CAP as well as vaccine-type pneumococcal CAP.58 In the modified intent-to-treat analysis, vaccine efficacy for PCV13 against first episodes of pneumococcal CAP was 22.4% (95% CI 2.3% to 38.5%), with incidence rates of 0.32% for PCV13 and 0.41% for placebo over a mean follow-up duration of approximately 4 years. Efficacy against first episodes of all-cause CAP (5.1%; 95% CI −5.1% to 14.2%; respective incidence rates of 1.77% and 1.86%) was not significant.58
The overall adverse event profile was consistent with findings of previous adult studies.58 Serious adverse events (the primary safety end point) occurred with similar frequencies across groups within both 1 month (all participants) and 6 months (safety subgroup) of vaccination; the frequencies of newly diagnosed chronic medical conditions (safety subgroup) and deaths (all participants) were also comparable across groups. The higher frequency of adverse events within 1 month of vaccination in the PCV13 group compared with the placebo group (18.7% vs 14.3% [safety subgroup]) was attributable to injection-site reactions and muscular pain.
The protective efficacy of PCV13 extended throughout the 4-year study. A recent report estimated that, based on data from this study, the number needed to vaccinate to prevent 1 case of all-cause CAP in those aged 65 years and older over 5 years was 234; it is important to note that this estimate used vaccine efficacy estimates for vaccine-type CAP in the per-protocol population (45.0%; 95.2% CI 14.2% to 65.3%) and the proportion of CAP caused by PCV13 serotypes as input parameters.58,59 Additionally, results from a post hoc analysis of CAPiTA data found that using additional screening to detect missed end points greatly reduced the calculated number need to vaccinate against vaccine-type CAP (from 1007 to 634)60; this overestimation likely relates to all study outcomes. Based on results from the CAPiTA trial, in July 2015, Health Canada approved PCV13 for active immunization of adults aged 18 years and older for preventing pneumonia and IPD caused by the PCV13 serotypes.61,62
Serotype replacement.
Widespread implementation of PCVs in pediatric vaccination programs, including in Canada, has led to increases in the prevalence of nonvaccine serotypes.19,63–65 In Canada, the proportion of IPD caused by PCV13 serotypes declined from 55% in 2010 (the year PCV13 was introduced) to 43% in 2012, but the proportion of nonvaccine types concomitantly increased from 20% to 25%.19 This phenomenon, termed serotype replacement, underscores the importance of monitoring changes in all-cause CAP and all-serotype IPD in both observational and interventional studies, as it is possible for vaccine-type CAP or IPD to decrease while morbidity and mortality remain unchanged owing to increasing prevalence of other serotypes or pathogens. For PCV13 in particular, it is important to note that serotype distributions following PCV13 introduction have been associated with statistically significant decreases in both invasiveness and antimicrobial resistance.63,66
Pneumococcal vaccination recommendations for select groups.
Pneumococcal vaccination guidelines in Canada have evolved over time. In 2013, NACI recommended PCV13 followed by PPSV23 8 or more weeks later for immunocompromised individuals.67 In 2016, NACI recommended PCV13 followed by PPSV23 for preventing CAP and IPD caused by PCV13 serotypes “on an individual basis” in immunocompetent pneumococcal vaccine-naïve individuals aged 65 or older (NACI recommendation grade A).38 Pneumococcal vaccination guidelines for individuals aged 65 years and older are illustrated in Figure 1.37,38,67,68 Immunocompetent individuals younger than 65 years of age with underlying medical conditions are generally recommended to receive PPSV23 alone.37 All individuals who received PPSV23 before age 65 should be revaccinated at age 65 years or older68; revaccination is also recommended for those of all ages at highest risk.37 Table 3 summarizes current NACI recommendations for pneumococcal vaccination by age and risk group.37,38,67,68
Improving vaccination rates in adults.
Vaccination with PPSV23 in Canada is cost-effective,69 and implementing a schedule of PCV13 followed by PPSV23 for all currently recommended adult groups is predicted to be cost-effective.70 Currently, most Canadian provinces at least partially cover PCV13 for the highest-risk patients,71–83 and PPSV23 is covered for all indicated groups.84 However, pneumococcal vaccination rates are low, with individuals aged 65 years and older and 18 to 64 years with chronic conditions (other than asthma) having respective estimated PPSV23 vaccination rates of only 37% and 17% in 2014, respectively.85 A series of studies between 2010 and 2013 identified barriers to vaccination in both patients and practitioners and made appropriate recommendations for diminishing the effects of these barriers (Box 1).86–91
Barriers to vaccination and recommendations for diminishing their effects
Barriers to vaccination
Lack of awareness of invasive pneumococcal disease or pneumococcal disease86
Infrequent well-visit vaccination opportunities89
Lack of strong endorsement or recommendation by health care providers87
Views that vaccines without public funding are less important (personal observation)
Concerns about safety of newer vaccines (personal observation)
Beliefs that vaccine refusal is the healthiest choice (personal observation)
Recommendations
Vaccination campaigns88
Use of physician extenders (eg, nurse-led vaccination programs)90
Patient outreach including reminder cards tied to nonmedical events (eg, 65th birthday)87,90
Administering pneumococcal vaccines during the annual influenza vaccine visit87,91
Administering recommended vaccines at sick visits in addition to well visits87,89
Case resolution
Based on current evidence, our recommendation for your patient is that she should be offered PCV13 followed by PPSV23 at least 8 weeks later to maximize potential protection against both CAP and IPD.
Conclusion
Recent NACI recommendations advise using PCV13 followed by PPSV23 8 or more weeks later for all immunocompromised adults and immunocompetent adults aged 65 years and older. Revaccination with PPSV23 is recommended after 5 years for all adults at highest risk.38 Efforts should be intensified by family physicians and other health care providers to increase coverage in these groups.
The most recent PCV13 recommendations do not target certain adults at elevated CAP and IPD risk, such as those with chronic illnesses, smokers, and the homeless. It is currently recommended that high-risk individuals receive PPSV23, the cost of which remains covered across all indicated groups,84 despite inconclusive evidence of PPSV23 effectiveness against CAP. There is demonstrated efficacy of PPSV23 against IPD50; thus, PPSV23 use should continue for IPD prevention because it targets more serotypes than PCV13,38 especially given ongoing serotype replacement induced by widespread PCV13 vaccination.19,63–65 However, high-risk individuals often have a higher risk of pneumonia than healthy individuals aged 65 and older (Table 1)30,37 and have CAP episodes that are more costly to the health care system in both direct and, potentially, indirect medical costs.92,93 We therefore recommend consideration of PCV13 vaccination for high-risk individuals based on superior PCV immunogenicity compared with PPSV23 in these populations.94,95 Individuals with chronic lung disease have the highest risk of all-cause and pneumococcal pneumonia among those with chronic at-risk conditions (Table 1)30,37; vaccination is thus especially critical in this group. We also stress the importance of identifying patients with increased CAP risk based on the presence of specific comorbidities, lifestyle, and environmental factors. In general, prevention of CAP also decreases the need for antibiotic use and in turn slows the progression of antibiotic resistance.
The most recent NACI recommendations outline directions for future research, which include assessing risks of concomitant PCV13 and PPSV23 administration, determining PCV13 booster efficacy and effectiveness in the immunocompetent population aged 65 years of age and older, and conducting nationwide CAP and IPD surveillance by age and serotype.38
Acknowledgments
Editorial support for development of this manuscript was provided by Dr Judith Kandel at Complete Healthcare Communications, LLC, in West Chester, Pa, and was funded by Pfizer.
Notes
Editor’s key points
▸ In 2016, the Canadian National Advisory Committee on Immunization updated guidelines to recommend the 13-valent pneumococcal conjugate vaccine (PCV13) for adults 65 years of age and older, based on efficacy data against community-acquired pneumonia from a large clinical study. These new guidelines suggest that vaccine-naïve adults aged 65 and older should receive PCV13 on an individual basis, followed by the 23-valent pneumococcal polysaccharide vaccine, which offers broader serotype coverage. Additionally, PCV13 continues to be recommended for all adults aged 18 years or older with immunocompromising conditions.
▸ While not recommended in the current guidelines, the authors suggest that PCV13 and the 23-valent vaccine should also be considered in adults younger than 65 who are at increased risk of pneumococcal disease owing to medical, lifestyle, or environmental factors, as the risk of community-acquired pneumonia in this population might exceed that in the healthy elderly population.
▸ While the effectiveness data are mixed, pneumococcal vaccination rates among Canadian adults remain low. Physicians should engage in shared decision making with patients on an individual basis.
Points de repère du rédacteur
▸ En 2016, le Comité consultatif national de l’immunisation du Canada a mis à jour sa déclaration pour recommander le vaccin conjugué antipneumococcique 13-valent (PCV13) chez les adultes de 65 ans et plus, en se fondant sur des données étayant son efficacité contre la pneumonie d’origine communautaire, tirées d’une étude clinique d’envergure. Cette nouvelle déclaration préconise que les adultes de 65 ans et plus non vaccinés reçoivent le PCV13 sur une base individuelle, qui sera suivi du vaccin polysaccharidique 23-valent contre le pneumocoque, ce dernier offrant une protection plus large contre d’autres stéréotypes. De plus, le PCV13 continue d’être recommandé pour tous les adultes de 18 ans et plus qui sont immunodéprimés.
▸ Même si les lignes directrices actuelles n’en font pas la recommandation, les auteurs suggèrent d’envisager le PCV13 et le vaccin 23-valent chez les adultes de moins de 65 ans qui sont à risque accru d’infections à pneumocoque en raison de facteurs médicaux, environnementaux ou liés au mode de vie, puisque le risque d’une pneumonie d’origine communautaire au sein de cette population pourrait être supérieur à celui chez les personnes plus âgées en santé.
▸ Si les données sur l’efficacité sont mitigées, les taux de vaccination contre le pneumocoque au Canada restent faibles. Les médecins devraient s’engager dans une prise de décision partagée avec leurs patients sur une base individuelle.
Footnotes
Contributors
All authors contributed to the literature review and interpretation, and to preparing the manuscript for submission.
Competing interests
This review was sponsored by Pfizer. Dr Kaplan reports support from AstraZeneca, Becton Dickinson, Boehringer Ingelheim, CanniMed, GlaxoSmithKline, Grifols, Meda, Merck Frosst, Pfizer, Purdue, Johnson & Johnson, Novartis, Novo Nordisk, Trudell, Sanofi, and Teva. Dr Arsenault has served on advisory boards for Amgen, Lundbeck, Novo Nordisk, and Purdue, and has served as a speaker in meetings sponsored by Purdue, Astra, and Merck. Dr Aw reports continuing medical education (CME) sponsorships from Merck, Sanofi, and Pfizer. Dr Brown reports participation on advisory boards for Pfizer, Merck, GlaxoSmithKline, and Amgen, and on speakers bureaus for Pfizer, Merck, Amgen, and Valneva. Dr Fox reports receiving honoraria or hospitality from Actelion, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche. Dr Grossman reports support from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Merck, GlaxoSmithKline, and Bayer Schering Pharma.Dr Jadavji reports receiving honoraria from Pfizer, Novartis, and Merck. Dr Laferrière was an employee of Pfizer Canada Inc. Dr Levitz has received support from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, and Novartis. Dr Loeb reports support from Sanofi, Seqirus, and Pfizer. Dr McIvor has served on advisory boards for and received honoraria for CME from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, and Trudell Medical, and is an employee of McMaster University and St Joseph’s Healthcare. Dr Mody has received speakers honoraria from Pfizer and was a site principal investigator for a clinical trial sponsored by Aradigm for which he received no personal compensation. Dr Poulin has served as a speaker for Pfizer. Dr Shapiro has served on advisory boards for Pfizer, Merck, GlaxoSmithKline, and Amgen, and has served on speakers bureaus for Merck, Pfizer, Amgen, and Novo Nordisk. Dr Tessier has served as a speaker for and received honoraria from Pfizer, Merck, Sanofi Pasteur, and Valneva. Dr Théorêt has received honoraria from Pfizer, Novartis, Knight, Merck, AstraZeneca, and Boehringer Ingelheim. Dr Weiss has received research funds and served on advisory boards for Pfizer. Dr Yaremko has received CME sponsorship from Merck, Pfizer, Sanofi, and Shire. Dr Zhanel has received research funding from Achaogen, Astellas, Basilea, Merck, Paratek, Pfizer, Sunovion, The Medicines Company, Tetraphase, and Zoetis.
This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
- Copyright© the College of Family Physicians of Canada
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