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Community-acquired pneumonia in adults: Highlighting missed opportunities for vaccination

Published:October 15, 2016DOI:https://doi.org/10.1016/j.ejim.2016.09.024

      Highlights

      • Pneumococcal pneumonia represents a significant disease burden in adults.
      • Awareness of pneumococcal vaccination is low among patients and vaccinators.
      • Identifying eligible patients for vaccination is critical.

      Abstract

      Pneumococcal pneumonia remains a clear unmet medical need for adults worldwide. Despite advances in vaccine technology, vaccination coverage remains low, putting many people at risk of significant morbidity and mortality. The herd effect seen with paediatric vaccination is not enough to protect all older and vulnerable people in the community, and more needs to be done to increase the uptake of pneumococcal vaccination in adults. Several key groups are at increased risk of contracting pneumococcal pneumonia, and eligible patients are being missed in clinical practice. At present, community-acquired pneumonia costs over €10 billion annually in Europe alone. Pneumococcal conjugate vaccination could translate into preventing 200,000 cases of community-acquired pneumonia every year in Europe alone.
      This group calls on governments and decision makers to implement consistent age-based vaccination strategies, and for healthcare professionals in daily clinical practice to identify eligible patients who would benefit from vaccination strategies.

      Keywords

      1. Introduction

      Despite technological advances in pneumococcal vaccination in recent years, pneumococcal pneumonia still represents a considerable disease burden in adults worldwide. Pneumonia is the most common pneumococcal disease in adults, and has a short incubation period of 1–3 days, with fast onset of fever and chills accompanied by chest pain, cough, dyspnea, tachypnea, hypoxia, tachycardia and general malaise and weakness [
      ]. Streptococcus pneumoniae, a bacterial pathogen commonly carried in the nasopharynx, is the leading cause of a range of diseases including community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD). S. pneumoniae is found in almost half of all pneumonia cases [
      • Welte T.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ,
      • Lode H.M.
      Managing community-acquired pneumonia: a European perspective.
      ,
      • Cillóniz C.
      • Ewig S.
      • Polverino E.
      • et al.
      Microbial aetiology of community-acquired pneumonia and its relation to severity.
      ], and results in a more severe episode of pneumonia than any other causative pathogen [
      • Cillóniz C.
      • Ewig S.
      • Polverino E.
      • et al.
      Microbial aetiology of community-acquired pneumonia and its relation to severity.
      ]. Lower respiratory tract infections are reported to be the fourth-leading cause of death worldwide [
      • World Health Organization
      The top 10 causes of death in the world, 2000 and 2012.
      ], and up to one-third of these infections are caused by pneumococcal pneumonia [
      • Naghavi M.
      • Wang H.
      • Lozano R.
      • et al.
      Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the global burden of disease study 2013.
      ,
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • et al.
      Global and regional mortality from 235 causes for death of 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010.
      ]. Additionally, pneumonia can be associated with serious cardiac and respiratory complications and in 2010 across the globe almost 1.5 million deaths were attributed to the disease [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • et al.
      Global and regional mortality from 235 causes for death of 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010.
      ]. IPD predominantly presents as pneumococcal meningitis, bacteraemic pneumococcal pneumonia and pneumococcal bacteraemia with incidence rates of 11 to 27 per 100, 000 in Europe [
      • Drijkoningen J.
      • Rohde G.G.U.
      Pneumococcal infection in adults: burden of disease.
      ]. IPD is particularly prevalent in people aged >65 years [
      • The European Centre for Disease Prevention and Control
      ].
      Despite these dramatic figures pneumococcal disease is a vaccine-preventable disease, and pneumococcal conjugate vaccines (PCV7, PCV10 and PCV13) and pneumococcal polysaccharide vaccines (PPV23) have been available for routine use for many years. Data collected after the introduction of the 7-valent PCV into paediatric national immunisation programmes suggest that there is a herd effect achieved from high vaccine coverage in children that also works to protect adults through a reduction in carriage and a decline in disease-causing vaccine serotypes [
      • Waight P.A.
      • Andrews N.J.
      • Ladhani S.N.
      • et al.
      Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study.
      ,
      • Rodrigo C.
      • Bewick T.
      • Sheppard C.
      • et al.
      Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.
      ]. However, the herd effect alone is not enough to adequately protect entire adult populations against all pneumococcal diseases [
      • Rodrigo C.
      • Bewick T.
      • Sheppard C.
      • et al.
      Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.
      ] – particularly patients with comorbidities or older people. Therefore, despite a protective herd effect from paediatric vaccination, unvaccinated adults are likely to have a residual burden of pneumococcal disease [
      • Rodrigo C.
      • Bewick T.
      • Sheppard C.
      • et al.
      Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.
      ]. There has been a lack of consistent results demonstrating the ability of pneumococcal polysaccharide vaccines to prevent in particular non-bacteremic pneumococcal pneumonia [
      • Isturiz R.
      • Webber C.
      Prevention of adult pneumococcal pneumonia with the 13-valent pneumococcal conjugate vaccine: CAPiTA, the community-acquired pneumonia immunization trial in adults.
      ]. Vaccination rates also show that only 75% of adults aged over 65 years are receiving their vaccination, contributing further to the increase in pneumococcal disease in adults []. Due to the difficulty in distinguishing between S. pneumoniae that simply colonises the upper respiratory tract and that which causes pneumonia, accurate diagnosis of CAP remains a challenge along with assessing the efficacy of the vaccinations available [
      • Song J.Y.
      • Eun B.W.
      • Nahm M.H.
      Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward.
      ]. The medical community and regulatory agencies worldwide have identified this as a clear and important unmet medical need [
      • Isturiz R.
      • Webber C.
      Prevention of adult pneumococcal pneumonia with the 13-valent pneumococcal conjugate vaccine: CAPiTA, the community-acquired pneumonia immunization trial in adults.
      ,
      • European Medicines Agency
      CHMP variation assessment report type II variation EMEA/H/C/001104/II/0028.
      , ,
      • World Health Organization
      Pneumococcal vaccines: WHO position paper – 2012.
      ].
      Age-based vaccination strategies for pneumococcal vaccines are being introduced in an effort to combat pneumococcal pneumonia in adults, but currently these strategies show wide variation between different continents, countries and regions and the uptake in terms of vaccination coverage is generally low [,
      • Poethko-Müller C.
      • Schmitz R.
      Vaccination coverage in German adults: results of the German health interview and examination survey for adults (DEGS1).
      ,
      • Australian Institute of Health and Welfare
      2009 adult vaccination survey: summary results.
      ,
      • Naito T.
      • Matsuda N.
      • Tanei M.
      • et al.
      Relationship between public subsidies and vaccination rates with the 23-valent pneumococcal vaccine in elderly persons, including the influence of the free vaccination campaign after the great East Japan earthquake.
      ,
      • Castiglia P.
      Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
      ]. For example, coverage with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults aged between 65 and 79 is less than one-third of the population in Germany [
      • Poethko-Müller C.
      • Schmitz R.
      Vaccination coverage in German adults: results of the German health interview and examination survey for adults (DEGS1).
      ], and even in Australia where the vaccine has been provided free of charge under government-funded initiatives or by employers still only just over half of target adults have received it [
      • Australian Institute of Health and Welfare
      2009 adult vaccination survey: summary results.
      ]. These statistics are further reflected in the UK where it is advised that the PPV23 immunisation programme should continue for those aged 65 and over and for adults in a clinical risk group [], however the proportion of adults aged 65 and over vaccinated up to and including March 2015 stands at only 35.1% []. The most common barriers cited for the non-acceptance of adult pneumococcal vaccination at a healthcare professional and patient level are a perception of non-efficacy, a lack of resources (unfunded vaccination), patient refusal, organisational problems or simple lack of time [
      • Gavazzi G.
      • Wazieres B.
      • Lejeune B.
      • et al.
      Influenza and pneumococcal vaccine coverages in geriatric health care settings in France.
      ,
      • Zimmerman R.K.
      • Nowalk M.P.
      • Terry M.A.
      • et al.
      Assessing disparities in adult vaccination using multimodal approaches in primary care offices: methodology.
      ].
      The content of this paper is based on a series of presentations given by the authors at a meeting held in October 2015 in Vienna, Austria. At the meeting, three-quarters of attending healthcare professionals reported that it is difficult to implement adult vaccination in everyday clinical practice, and that current awareness of the burden of pneumococcal disease is low among vaccinators. This report aims to improve awareness and understanding of pneumococcal pneumonia in adults, and to raise the profile of adult vaccination.

      2. Burden of cap in adults

      In adults, pneumococcal disease most frequently manifests as pneumonia, with 25% of cases classified as IPD [
      • Said M.A.
      • Johnson H.L.
      • Nonyane B.A.S.
      • et al.
      Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques.
      ]. CAP incidence estimates in Europe range from 1.6–11.6 per 1000 population [
      • Drijkoningen J.
      • Rohde G.G.U.
      Pneumococcal infection in adults: burden of disease.
      ]. Cases of CAP are two-fold higher in winter than summer [
      • Ochoa-Gondar O.
      • Vila-Corcoles A.
      • de Diego C.
      • et al.
      The burden of community-acquired pneumonia in the elderly: the Spanish EVAN-65 study.
      ], and frequently follow outbreaks of influenza. Observational studies have assessed the epidemiological burden and found up to 74% of the serotypes causing CAP are included in PCV13 and 83% in PPV23 [
      • Amaro R.
      • Liapikou A.
      • Cilloniz
      • et al.
      Predictive and prognostic factors in patients with blood-culture-positive community-acquired pneumococcal pneumonia.
      ]. Further studies of IPD have reported 67% of cases attributed to a PPV23 serotype and 33% attributed to a PCV13 serotype [
      • The European Centre for Disease Prevention and Control
      ].
      It is widely accepted that paediatric vaccination with PCVs has resulted in reduced nasopharyngeal carriage of vaccine serotypes and lower rates of pneumococcal disease, including CAP, in both vaccinated and unvaccinated children [
      • Waight P.A.
      • Andrews N.J.
      • Ladhani S.N.
      • et al.
      Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study.
      ,
      • Rodrigues F.
      • Foster D.
      • Caramelo F.
      • et al.
      Progressive changes in pneumococcal carriage in children attending daycare in Portugal after 6 years of gradual conjugate vaccine introduction show falls in most residual vaccine serotypes but no net replacement or trends in diversity.
      ,
      • Flasche S.
      • Van Hoek A.J.
      • Sheasby E.
      • et al.
      Effect of pneumococcal conjugate vaccination on serotype-specific carriage and invasive disease in England: a cross-sectional study.
      ,
      • Griffin M.R.
      • Mitchel E.
      • Moore M.R.
      • et al.
      Declines in pneumonia hospitalizations of children aged <2 years associated with the use of pneumococcal conjugate vaccines – Tennessee, 1998–2012.
      ,
      • Angoulvant F.
      • Levy C.
      • Grimpel E.
      • et al.
      Early impact of 13-valent pneumococcal conjugate vaccines on community-acquired pneumonia in children.
      ,
      • Van Hoek A.J.
      • Sheppard C.L.
      • Andrews N.J.
      • et al.
      Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England.
      ], with hospitalisation rates for pneumonia in children under the age of 2 years decreasing by over 20% since the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) [
      • Simonsen L.
      • Taylor R.J.
      • Schuck-Paim C.
      • et al.
      Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis.
      ]. The herd effect associated with high levels of paediatric vaccine coverage has brought about a decrease in cases of invasive pneumococcal disease in adults over the time period since PCV7 was introduced [
      • Waight P.A.
      • Andrews N.J.
      • Ladhani S.N.
      • et al.
      Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study.
      ,
      • Simonsen L.
      • Taylor R.J.
      • Schuck-Paim C.
      • et al.
      Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis.
      ]. However, despite these impressive reductions, the herd effect alone is not enough to protect all older adults in the community [
      • Rodrigo C.
      • Bewick T.
      • Sheppard C.
      • et al.
      Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.
      ,
      • Prato R.
      • Fortunato F.
      • Martinelli D.
      Pneumococcal pneumonia prevention among adults: is the herd effect of pneumococcal conjugate vaccination in children as good a way as the active immunization of the elderly?.
      ], which is a concern given that the incidence and severity of CAP typically increases with age [
      • Ochoa-Gondar O.
      • Vila-Corcoles A.
      • de Diego C.
      • et al.
      The burden of community-acquired pneumonia in the elderly: the Spanish EVAN-65 study.
      ,
      • Bewick T.
      • Sheppard C.
      • Greenwood S.
      • et al.
      Serotype prevalence in adults hospitalised with pneumococcal non-invasive community-acquired pneumonia.
      ]. A study in Spain found that the CAP incidence rate in people over the age of 85 is almost three-times that of the 65–74-year age bracket [
      • Ochoa-Gondar O.
      • Vila-Corcoles A.
      • de Diego C.
      • et al.
      The burden of community-acquired pneumonia in the elderly: the Spanish EVAN-65 study.
      ]. Additionally, serotypes traditionally classified as less invasive are increasingly able to cause disease in older people and those with comorbidities [
      • Bewick T.
      • Sheppard C.
      • Greenwood S.
      • et al.
      Serotype prevalence in adults hospitalised with pneumococcal non-invasive community-acquired pneumonia.
      ]. For people with chronic medical conditions and complications – or those with previous episodes of pneumonia who contract CAP – S. pneumoniae is the most frequently isolated pathogen [
      • Sicras-Mainar A.
      • Ibanez-Nolla J.
      • Cifuenetes I.
      • et al.
      Retrospective epidemiological study for the characterization of community- acquired pneumonia and pneumococcal pneumonia in adults in a well-defined area of Badalona (Barcelona, Spain).
      ,
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ,
      • Almirall J.
      • Serra-Prat M.
      • Bolibar I.
      Risk factors for community-acquired pneumonia in adults: recommendations for its prevention.
      ].
      This has serious implications for our global ageing population, as well as for healthcare funding: as many as three-quarters of pneumococcal CAP cases require hospitalisation, with an average stay of 10–12 days [
      • Ochoa-Gondar O.
      • Vila-Corcoles A.
      • de Diego C.
      • et al.
      The burden of community-acquired pneumonia in the elderly: the Spanish EVAN-65 study.
      ,
      • Jokinen C.
      • Heiskanen L.
      • Juvonen H.
      • et al.
      Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland.
      ,
      • Almirall J.
      • Bolíbar I.
      • Vidal J.
      • et al.
      Epidemiology of community-acquired pneumonia in adults: a population-based study.
      ,
      • Lim W.S.
      • Baudouin S.V.
      • George R.C.
      • et al.
      British Thoracic Society guidelines for the management of community acquired pneumonia in adults: update 2009.
      ,
      • Nelson J.C.
      • Jackson M.
      • Yu O.
      • et al.
      Impact of the pneumococcal conjugate vaccine on rates of community acquired pneumonia in children and adults.
      ]. Full recovery takes close to a month on average, but can be up to seven weeks in some patients [
      • Sicras-Mainar A.
      • Ibanez-Nolla J.
      • Cifuenetes I.
      • et al.
      Retrospective epidemiological study for the characterization of community- acquired pneumonia and pneumococcal pneumonia in adults in a well-defined area of Badalona (Barcelona, Spain).
      ]. Clearly, CAP places a significant burden on resources – both medical and financial [
      • Ostermann H.
      • Garau J.
      • Medina J.
      • Pascual E.
      • McBride K.
      • Blasi F.
      • et al.
      Resource use by patients hospitalized with community-acquired pneumonia in Europe: analysis of the REACH study.
      ]. It also has many indirect socioeconomic costs [
      • Lode H.M.
      Managing community-acquired pneumonia: a European perspective.
      ]. Typically, pneumonia patients over the age of 65 accrue the majority of direct medical costs associated with all pneumococcal diseases in all groups, whilst the indirect costs arising from lost productivity and work absences are significant in those aged 18–50 [
      • Huang S.S.
      • Johnson K.M.
      • Ray G.T.
      • et al.
      Healthcare utilization and cost of pneumococcal disease in the United States.
      ].
      CAP is a severe disease. Of those patients who require hospitalisation 2–14% will die as an in-patient [
      • Bewick T.
      • Sheppard C.
      • Greenwood S.
      • et al.
      Serotype prevalence in adults hospitalised with pneumococcal non-invasive community-acquired pneumonia.
      ,
      • Ewig S.
      • Birkner N.
      • Strauss R.
      • et al.
      New perspectives on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement programme in healthcare quality.
      ,
      • Jain S.
      • Self W.H.
      • Wunderink R.G.
      • et al.
      Community-acquired pneumonia requiring hospitalization among U.S. adults.
      ], and 12% will require readmission within 30 days of discharge [
      • Klausen H.H.
      • Petersen J.
      • Lindhardt T.
      • et al.
      Outcomes in elderly Danish citizens admitted with community-acquired pneumonia. Regional differences, in a public healthcare system.
      ]. Even those who recover and are discharged with no readmission will have reduced odds for both short- and long-term survival [
      • Lim W.S.
      • Baudouin S.V.
      • George R.C.
      • et al.
      British Thoracic Society guidelines for the management of community acquired pneumonia in adults: update 2009.
      ,
      • Sandvall B.
      • Rueda A.M.
      • Musher D.M.
      Long-term survival following pneumococcal pneumonia.
      ], with a case-fatality rate of 39% reported at 5 years [
      • Lim W.S.
      • Baudouin S.V.
      • George R.C.
      • et al.
      British Thoracic Society guidelines for the management of community acquired pneumonia in adults: update 2009.
      ] and an overall difference in survival seen as far out as 10 years between pneumonia survivors and age- and sex-matched peers. This may be due to underlying inflammation or predisposing host or environmental factors, although to date the precise mechanism is unclear [
      • Sandvall B.
      • Rueda A.M.
      • Musher D.M.
      Long-term survival following pneumococcal pneumonia.
      ].
      In addition to a reduction in long-term survival and an increased risk of repeat episodes, CAP may cause worsening of pre-existing comorbidities [
      • Wyrwich K.W.
      • Yu H.
      • Sato R.
      • et al.
      Community-acquired pneumonia: symptoms and burden of illness at diagnosis among US adults aged 50 years and older.
      ], and patients may be at an increased risk of suffering from major cardiac adverse events such as myocardial infarction, serious arrhythmia or chronic heart failure [
      • Musher D.M.
      • Rueda A.M.
      • Kaka A.S.
      • et al.
      The association between pneumococcal pneumonia and acute cardiac events.
      ]. There may also be an impact on patients with chronic obstructive pulmonary disease (COPD), with an increase in exacerbations and a decrease in quality of life [
      • Schnoor M.
      • Schoefer Y.
      • Henrich G.
      • et al.
      General and health-related life satisfaction of patients with community-acquired pneumonia.
      ,
      • Huerta A.
      • Domingo R.
      • Soler N.
      EPOC y neumonía.
      ]. In patients with COPD, return to baseline health is not achieved until at least 2 months after the CAP episode [
      • Wyrwich K.W.
      • Yu H.
      • Sato R.
      • Powers J.H.
      Observational longitudinal study of symptom burden and time for recovery from community-acquired pneumonia reported by older adults surveyed nationwide using the CACAP burden of illness questionnaire.
      ].
      Alongside the clinical burden of CAP, the economic burden also has implications with pneumonia costs in Europe standing at approximately €10.1 billion per annum. Of these costs, inpatient care, outpatient care and drugs account for 64% with indirect costs of lost work days amounting to 36% [
      • Welte A.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ]. Treatment of patients with CAP places a high burden on hospital resources, with patients with pre-existing comorbidities and of an older age shown to further increase costs [
      • Khan M.
      • Naqvi S.
      • Shafiq Y.
      • et al.
      Direct cost of treatment in hospitalized community-acquired pneumonia patients.
      ]. Antibiotic resistance seen in pathogens associated with CAP and the rise in antibiotic-resistant strains has led to further increasing the cost of treatment through use of more expensive classes of antibiotics or longer hospitalisation required [
      • Welte A.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ].
      It is therefore clear that the burden of CAP is much broader and has more far-reaching effects than the isolated pneumonia episode itself.

      3. Benefits of vaccines for the prevention of pneumonia

      Pneumococcal vaccination can reduce the burden of disease. There are currently two types of vaccines available: PCV13 and PPV23. These vary not only in the serotype antigens they carry, but also in their structural composition and mechanism of action. Vaccines work very differently in adults and children. Conjugated vaccines offer benefits in children over traditional polysaccharide formulations as the conjugates elicit higher antibody responses and can generate an immune memory. They can also work at the mucosal surfaces to prevent nasopharyngeal colonisation and carriage, which PPV23 is unable to do [
      • Siegrist C.A.
      Vaccine immunology.
      ,
      • Pollard A.J.
      • Perrett K.P.
      • Beverley P.C.
      Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines.
      ]. PCVs work in all adult age groups, and PCV13 has been shown to be effective in preventing episodes of vaccine-type pneumococcal CAP, with a recorded vaccine efficacy of 45%, and IPD in older adults, with a recorded vaccine efficacy of 75% [
      Prevenar 13 SPC.
      ,
      • Bonten M.J.M.
      • Huijts S.M.
      • Bolkenbaas M.
      • et al.
      Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.
      ]. Based on current figures, we have calculated that this rate of prevention of pneumonia could translate into preventing 200,000 cases of community-acquired pneumonia every year in Europe alone [
      • Bonten M.J.M.
      • Huijts S.M.
      • Bolkenbaas M.
      • et al.
      Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.
      ,
      • European Respiratory Society (ERS)
      ]. In contrast, the efficacy of PPV23 is uncertain [
      • World Health Organization
      Pneumococcal vaccines: WHO position paper – 2012.
      ,
      • Moberley S.
      • Holden J.
      • Tatham D.P.
      • Andrews R.M.
      Vaccines for preventing pneumococcal infection in adults (review).
      ,
      • Huss A.
      • Scott P.
      • Stuck A.E.
      • et al.
      Efficacy of pneumococcal vaccination in adults: a meta-analysis.
      ].
      Pneumococcal vaccines may be administered sequentially, but it is recommended that PCV13 be given before PPV23 as prior doses of PPV23 may diminish the response to PCV13, although the same is not seen in reverse [
      • Greenberg R.N.
      • Gurtman A.
      • Frenck R.W.
      • et al.
      Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults 60–64 years of age.
      ,
      • Jackson L.A.
      • Gurtman A.
      • Rice K.
      • et al.
      Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine.
      ]. Studies have shown that PCV13 can be co-administered with the trivalent influenza vaccine (TIV) with no significant impact on immunogenicity or safety [
      Prevenar 13 SPC.
      ,
      • Schwarz T.F.
      • Flamaing J.
      • Rümke H.C.
      • et al.
      A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years.
      ,
      • Frenck R.W.
      • Gurtman A.
      • Rubino J.
      • et al.
      Randomized, controlled trial of a 13-valent pneumococcal conjugate vaccine administered concomitantly with an influenza vaccine in healthy adults.
      ]. This concomitant administration of PCV13 and TIV may help to reduce the disease burden on vaccinators in everyday clinical practice by allowing multiple vaccines to be given at the same clinic appointment [
      • Frenck R.W.
      • Gurtman A.
      • Rubino J.
      • et al.
      Randomized, controlled trial of a 13-valent pneumococcal conjugate vaccine administered concomitantly with an influenza vaccine in healthy adults.
      ].

      4. Identifying eligible patients to improve vaccination uptake

      Being able to identify eligible patients who would benefit from vaccination is critical for reducing the disease burden of CAP and IPD in adult populations. In the past, isolating S. pneumoniae cultures from normally sterile body fluids was the gold standard used to identify and diagnose pneumococcal disease; however, this was not always practical in the clinic – not least because the results can take several days. Clinicians now have access to urinary antigen detection (UAD) tests, which represent a major advance. UAD has a specificity of up to 99.7% in adults and a sensitivity of 79–97% for both bacteremic and non-bacteremic pneumococcal pneumonia [
      • Song J.Y.
      • Eun B.W.
      • Nahm M.H.
      Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward.
      ,
      • Molinos L.
      • Zalacain R.
      • Menéndez R.
      • et al.
      Sensitivity, specificity, and positivity predictors of the pneumococcal urinary antigen test in community-acquired pneumonia.
      ]. As well as allowing tailoring of antibiotic treatment, a positive diagnosis of pneumococcal pneumonia can identify those patients who should receive vaccination on disease resolution or discharge from hospital. It is important to understand that an episode of CAP does not prime the immune system against future infection; in fact, individuals previously diagnosed with pneumococcal pneumonia are at a clear increased risk of a subsequent episode for at least 2 years, independent of comorbidities or other risk factors [
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • et al.
      Epidemiology of community-acquired pneumonia in older adults: a population-based study.
      ]. With this in mind, routine vaccination with PCV13 on discharge from hospital following an episode of pneumococcal pneumonia should be advocated in all healthcare systems.
      In addition to positively diagnosing and identifying current cases of CAP, there is a need to identify those people in the community who may be at increased risk of infection. For example, some people may be at increased risk of contracting pneumococcal pneumonia due to inherent environmental factors in their living or working arrangements. Typically only 5–10% of healthy adults without children carry pneumococci in their nasopharynx. These figures increase dramatically for adults in families with pre-school age children or grandchildren, as well as for adults living or working in communal institutions such as schools, hospitals, military bases and nursing homes – and asymptomatic carriage may be found in as many as 70% of adults in these groups [
      ]. Vaccination rates for other pathogens such as influenza are high in some areas – 68% of older adults in the US and 45% in the EU have routinely received a ‘flu vaccination’, while only 60% in the US and 10% in the EU have been vaccinated against pneumococcus [
      • National Immunization Survey-Flu (NIS-Flu)
      • Behavioral Risk Factor Surveillance System (BRFSS)
      Flu vaccination coverage, United States, 2014–15 influenza season.
      ,

      MMWR Vaccination Coverage Among Adults, Excluding Influenza Vaccination—2013.

      ,
      • European Centre for Disease Prevention and Control
      Seasonal influenza vaccination in Europe — overview of vaccination recommendations and coverage rates in the EU member states for the 2012–13 influenza season.
      ,
      • European Centre for Disease Prevention and Control
      National seasonal influenza vaccination survey, March 2014.
      ,

      European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe, 2012. Stockholm: ECDC; 2015.

      ].
      The risk of pneumococcal infection is influenced by host as well as environmental factors. This extends beyond age, and many conditions may increase susceptibility – particularly those that lower a person's innate immunity or require immunosuppressive treatment [
      • Castiglia P.
      Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
      ,
      • Musher D.M.
      Streptococcus pneumoniae.
      ,
      • Van Hoek A.J.
      • Andrews N.
      • Waight P.A.
      • et al.
      The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England.
      ,
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • et al.
      Invasive pneumococcal infections among persons with and without underlying medical conditions: implications for prevention strategies.
      ]. As such, CAP represents a heavy disease burden in particular groups, with higher infection and case fatality rates seen in high-risk and immunocompromised patients [
      • Van Hoek A.J.
      • Andrews N.
      • Waight P.A.
      • et al.
      The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England.
      ]. There are also significantly higher incidence rates seen in men and those aged over 65 years. Being underweight can be a factor, possibly due to nutritional deficiencies limiting the efficiency of the immune system [
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ]. Lifestyle choices such as being a current or past smoker or frequent alcohol user also confer a significantly increased risk in all adult age groups [
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • et al.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      ]. Even a passive exposure to tobacco smoke can increase a person's risk of developing CAP [
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ]. Encouragingly, these elevated risks do decrease for ex-smokers after 4 years [
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ] – even in those with HIV [
      • Bénard A.
      • Mercié P.
      • Alioum A.
      • et al.
      Bacterial pneumonia among HIV-infected patients: decreased risk after tobacco smoking cessation. ARNS CO3 Aquitaine cohort, 2000–2007.
      ]. As such, patients should be counselled on the risks and offered smoking cessation programmes.
      Common underlying medical conditions increase the risk of pneumococcal pneumonia in adults [
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • et al.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      ]. At-risk definitions include people with chronic or immunocompromising conditions such as asthma, diabetes and COPD. These conditions have been found to increase the risk of CAP many times over – particularly in patients with COPD with fold increases of between 1.3 and 13.5 for CAP and 1.3 and 16.8 for IPD for those patients with COPD [
      • Drijkoningen J.
      • Rohde G.G.U.
      Pneumococcal infection in adults: burden of disease.
      ,
      • Almirall J.
      • Bolibar I.
      • Serra-Prat M.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      ,
      • Huss A.
      • Scott P.
      • Stuck A.E.
      • et al.
      Efficacy of pneumococcal vaccination in adults: a meta-analysis.
      ,
      • Bénard A.
      • Mercié P.
      • Alioum A.
      • et al.
      Bacterial pneumonia among HIV-infected patients: decreased risk after tobacco smoking cessation. ARNS CO3 Aquitaine cohort, 2000–2007.
      ,
      • Torres A.
      • Peetermans W.E.
      • Viegi G.
      • et al.
      Risk factors for community-acquired pneumonia in adults in Europe: a literature review.
      ,
      • Rodriguez L.A.G.
      • Ruigómez A.
      • Wallander M.-A.
      • et al.
      Acid-suppressive drugs and community-acquired pneumonia.
      ,
      • Müllerova H.
      • Chigbo C.
      • Hagan G.W.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      ,
      • Torres A.
      • Blasi F.
      • Dartois N.
      • et al.
      Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease.
      ]. High-risk patients include those with sickle-cell anaemia, an immunodeficiency or people taking immunosuppressive drugs [
      • Castiglia P.
      Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
      ,
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • et al.
      Invasive pneumococcal infections among persons with and without underlying medical conditions: implications for prevention strategies.
      ] (Table 1).
      Table 1Traditional risk definitions for CAP
      • Castiglia P.
      Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
      ,
      • Mitteilung der Ständigen Impfkommission am Robert Koch-Institut (RKI)
      Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch-Institut/stand.
      ,
      • Bedeschi E.
      Aggiornamento delle indicazioni sulle vaccinazioni per la prevenzione delle malattie invasive batteriche nelle persone con patologie o condizioni di rischio.
      ,
      • Haut Conseil de la Sante Publique
      Infections invasives à pneumocoque: recommandations vaccinales pour les personnes à risqué.
      ,
      • Department of Health
      .
      At riskHigh risk
      Metabolic diseases (diabetes mellitus)Immunodeficiency (B or T cell deficiency)
      Chronic respiratory disease

      (asthma, COPD, interstitial lung diseases)
      Cerebrospinal fluid leakage, skull fracture, cochlear implant
      Chronic heart, liver, renal diseasesFunctional asplenia or splenectomy
      Chronic alcoholismSickle-cell anaemia
      SmokingNephrotic syndrome
      Patients living within an institutionTransplantation (organ or bone marrow)
      People with a history of (pneumococcal)

      pulmonary infection
      Immunosuppressive therapy
      Leukaemia, lymphoma, multiple myeloma
      Neoplastic disease
      HIV infection
      Autoimmune diseases
      A study in Germany found that 22% of patients with CAP also had pulmonary diseases (including COPD), 19% had cardiac comorbidities, 14% had disorders of the central nervous system and 9% had diabetes [
      • Ewig S.
      • Birkner N.
      • Strauss R.
      • et al.
      New perspectives on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement programme in healthcare quality.
      ]. In a large cohort looking at COPD patients, 8% experienced an episode of CAP over the 10-year observation period; this was strongly associated with age, COPD severity and a history of previous pneumonia [
      • Müllerova H.
      • Chigbo C.
      • Hagan G.W.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      ]. A critical consideration in assessing the factors for an individual patient is that multiple underlying conditions have a cumulative effect, with the risk for a person with two conditions being similar to someone officially classified as ‘high risk’, and those with three or more conditions being much greater [
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • et al.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      ]. A study of a German database for quality in healthcare found increased case fatality rates for hospitalised CAP in patients with at least one comorbidity (17.4%) compared to overall hospital deaths in CAP patients of 13.7 and 14.4% across 2 years [
      • Ewig S.
      • Birkner N.
      • Strauss R.
      • et al.
      New perspectives on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement programme in healthcare quality.
      ].
      The ability to identify eligible patients in clinical practice therefore has a huge impact on prevention strategies. Currently, recommendations vary widely in whether they are based on age or risk, and how schemes are funded and implemented [
      • Castiglia P.
      Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
      ]. Overall, pneumococcal vaccination rates in adults are low, especially compared to other routine preventative vaccines; for example, vaccine rates for influenza in adults in France are four-times higher than those achieved for pneumococcal vaccination [
      • Gavazzi G.
      • Wazieres B.
      • Lejeune B.
      • et al.
      Influenza and pneumococcal vaccine coverages in geriatric health care settings in France.
      ].
      To ensure that the most is made of the available vaccines the value of adult pneumococcal vaccination must be promoted for eligible patients through both cost-effectiveness analysis and working to overcome vaccine hesitancy. PCV13 has been shown to be cost-saving in high-risk adults aged 65–74 years of age and cost-effective for those deemed at medium-risk in the same age group [
      • Mangen M.J.
      • et al.
      With these cost-savings possible, encouraging vaccination uptake through education and improved infrastructure to overcome vaccine hesitancy is imperative.
      ]. With these cost-savings possible, encouraging vaccination uptake through education and improved infrastructure to overcome vaccine hesitancy is imperative [
      • MacDougall D.M.
      • et al.
      The challenge of vaccinating adults: attitudes and beliefs of the Canadian public and healthcare providers.
      ].
      Eligible patients are easy to recognise (Box 1), and should be targeted for long-term monitoring and management [
      • Müllerova H.
      • Chigbo C.
      • Hagan G.W.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      ]. People with increased age, or those with environmental or host risk factors should be proactively offered pneumococcal vaccination in order to reduce the burden of pneumococcal disease and prevent unnecessary morbidity and mortality, as well as to reduce healthcare spend. Incidence and case fatality rate are increased in people over the age of 65, and this should influence the development of age-based recommendations for vaccination.
      Eligible patients: identifying key risks for adults in the general population [
      • Müllerova H.
      • Chigbo C.
      • Hagan G.W.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      ,
      • Grau I.
      • et al.
      Smoking and alcohol abuse are the most preventable risk factors for invasive pneumonia and other pneumococcal infections.
      ,
      • Maruyama T.
      • et al.
      Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial.
      .
      • Age over 65
      • Current or past smoker
      • High alcohol intake
      • Under- or overweight
      • Living or working in institutions such as schools, hospitals, prisons or care homes
      • Comorbidities such as diabetes, asthma or COPD
      • Previous pneumococcal infection
      • Chronic immunosuppressive disease

      5. Learning points

      • Pneumonia is a vaccine-preventable disease and PCV13 has been shown to be effective in preventing vaccine-type pneumococcal non IPD CAP and IPD in older adults [
        • Bonten M.J.M.
        • Huijts S.M.
        • Bolkenbaas M.
        • et al.
        Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.
        ].
      • PCV13 should be considered for co-administration alongside the influenza vaccine in adults [
        Prevenar 13 SPC.
        ,
        • Bonten M.J.M.
        • Huijts S.M.
        • Bolkenbaas M.
        • et al.
        Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.
        ].
      • Lifestyle changes could help to lower the risk of CAP [
        • Shea K.M.
        • Edelsberg J.
        • Weycker D.
        • et al.
        Rates of pneumococcal disease in adults with chronic medical conditions.
        ].
      • PCV13 should be given to all people diagnosed with CAP on discharge from hospital or resolution of infection in order to prevent further episodes [
        • Almirall J.
        • Bolibar I.
        • Serra-Prat M.
        • et al.
        New evidence of risk factors for community-acquired pneumonia: a population-based study.
        ,
        • Vila-Corcoles A.
        • Ochoa-Gondar O.
        • Rodriguez-Blanco T.
        • et al.
        Epidemiology of community-acquired pneumonia in older adults: a population-based study.
        ].
      • Age-based recommendations are needed for PCV13 vaccination.

      6. Summary

      Pneumococcal pneumonia is a major health problem in adults. General awareness of the disease burden and severity of pneumococcal disease remains low, despite significant advances in vaccination technology in recent years and many local and national recommendations and society guidelines []. Regulatory agencies have suggested that there is a clear unmet medical need in this area [
      • European Medicines Agency
      CHMP variation assessment report type II variation EMEA/H/C/001104/II/0028.
      ]. Given that data do exist to support the use of PCV13 in adult populations, it is critical that consistent age-based strategies are put in place to increase the uptake of preventative vaccination and reduce the significant disease burden of pneumococcal pneumonia on medical resources and funding.
      Currently, many opportunities for vaccination are being missed. The most common barriers to acceptance of adult vaccination are a perception of non-efficacy, a lack of resources, organisation or time, or simply patient refusal [
      • Gavazzi G.
      • Wazieres B.
      • Lejeune B.
      • et al.
      Influenza and pneumococcal vaccine coverages in geriatric health care settings in France.
      ,
      • Zimmerman R.K.
      • Nowalk M.P.
      • Terry M.A.
      • et al.
      Assessing disparities in adult vaccination using multimodal approaches in primary care offices: methodology.
      ], but these are not insurmountable issues, and can be overcome with education and improved awareness. Vaccination against other pathogens is well-recognised, and has a significantly higher uptake. Pneumococcal vaccination should be seen as an important part of promoting a healthy lifestyle for children and adults alike.

      Contributors

      All authors were involved in drafting, review and final approval of the manuscript.

      Funding

      The development and preparation of this manuscript and the meeting it is based on was supported by funding from Pfizer. Pfizer was involved in the design, data collection, interpretation, writing of the manuscript, and the decision to submit the paper for publication.

      Conflicts of interest

      • Francesco Blasi has received in the last three years speaker or consultant honoraria or research funding from: Almirall, AstraZeneca, Boeringher Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Lab. Guidotti e Malesci, Menarini, Mundipharma, Novartis, Pfizer, Teva,Valeas and Zambon.
      • Murat Akova has received in the last three years speaker or consultant honoraria or research funding from: Astellas, Gilead, MSD, Pfizer, Sanofi Pasteur.
      • Paolo Bonanni has received in the last three years speaker or consultant honoraria or research funding from: Pfizer, GSK, Novartis Vaccines, Sanofi Pasteur MSD, Sequiros.
      • Nathalie Dartois is a Pfizer employee, and holds stock in Pfizer.
      • Evelyne Sauty is a Pfizer employee, and holds stock in Pfizer.
      • Chris Webber is a Pfizer employee, and holds stock in Pfizer.
      • Antoni Torres received in the last three years speaker or consultant honoraria or research funding from Astra-Zeneca, Bayer, Cardeas, GlaxoSmithKline, Pfizer and Roche.

      Acknowledgments

      Organisational and editorial support was provided by Marie Farrow at Synergy Medical Communications Ltd.

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