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Redefining risk categories for pneumococcal disease in adults: critical analysis of the evidence

Open AccessPublished:May 18, 2015DOI:https://doi.org/10.1016/j.ijid.2015.05.003

      Highlights

      • Multimorbidity is defined as any co-occurrence of two or more chronic or acute diseases and medical conditions within one person.
      • The prevalence of multimorbidity among adult patients aged <65 years and ≥65 years was found to range from approximately 15% to 60% and from approximately 20% to >90%, respectively.
      • Risk factors associated with pneumococcal disease (PD) such us diabetes, chronic heart disease, and chronic obstructive pulmonary disease are the most frequent comorbidities described in patients with multimorbidity.
      • The odds ratios (OR) for PD of patients with two or more comorbidities are similar to the ORs for PD described in the literature for immunocompromised patients currently classified as high risk.

      Summary

      Objective

      To analyze the available published data (2005–2014) describing the prevalence of multimorbidity in adult patients with pneumococcal disease, with a focus on the comorbidities considered by the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention to increase the risk of pneumococcal disease in adults (immunocompetent persons with chronic medical conditions (at risk) and immunocompromised or immunosuppressed persons (high risk)). An analysis of case–control and population-based surveillance studies that have evaluated risk factors for community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) was also performed in order to estimate the importance of risk stacking.

      Methods

      Studies that established the enrolment procedure for patients and reported the incidence of multimorbidity and risk factors for CAP and/or IPD were included. In order to obtain a risk stacking value based on the at-risk comorbidity odds ratios (OR), the multiplicative method described by Campbell was used.

      Results

      Thirty-eight articles were selected, 19 for multimorbidity and 19 for risk factors for CAP/IPD. With regard to multimorbidity, the prevalence among adults aged ≥65 years ranged from 23% to 98.7% for two or more comorbidities and from 18% to 89.7% for three or more comorbidities. Diabetes (DBT), chronic heart disease (CHD), and chronic obstructive pulmonary disease (COPD) were the three most frequent comorbidities described (7.6–28.5%, 6.9–25.8%, and 3.8–15.4%, respectively). With regard to risk factors, based on the multiplicative method, the hypothetical scenario of concurrence of the three most frequent at-risk conditions (DBT + CHD + COPD) showed an OR of ≥7.5. In this group of patients, the addition of smoking, another common at-risk factor for CAP (stacking four concurrent conditions) increased the OR from 8.5 to >40. These ORs were generally similar to rates described by other authors in persons with a high risk.

      Conclusions

      The ORs for CAP and IPD of patients with two or more comorbidities, with or without smoking, were found to be similar to the ORs for CAP and IPD described in the literature for patients currently classified as high risk. The potential impact of multiple, stacking comorbidities is underestimated and there is a need for the risk categories for pneumococcal disease to be redefined.

      Keywords

      1. Introduction

      Streptococcus pneumoniae (pneumococcus) remains a leading cause of serious illness among adults worldwide.
      • Fung H.B.
      • Monteagudo-Chu M.O.
      Community-acquired pneumonia in the elderly.
      In fact, S. pneumoniae is the etiological agent of 30–50% of community-acquired pneumonia (CAP), the most common clinical presentation of pneumococcal disease (PD) in this type of patient.
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      Acute community-acquired pneumonia in adults: guidelines for initial antimicrobial therapy based on local evidence from a South American Working Group (ConsenSur).
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      • Arango A.
      • Bavestrello L.
      • et al.
      Updated acute community-acquired pneumonia in adults: guidelines for initial antimicrobial therapy based on local evidence from the South American Working Group (ConsenSur II).
      Invasive pneumococcal disease (IPD) is defined as an infection confirmed by the isolation of pneumococcus from a normally sterile site (e.g., blood). Blood cultures are positive in only 10–15% of CAP cases.
      • Ruiz L.A.
      • Zalacain R.
      • Capelastegui A.
      • Bilbao A.
      • Gomez A.
      • Uranga A.
      • et al.
      Bacteremic pneumococcal pneumonia in elderly and very elderly patients: host- and pathogen-related factors, process of care, and outcome.
      The risk profiles for PD have been defined by the presence of medical conditions for which the Advisory Committee on Immunization Practices (ACIP) currently recommends pneumococcal vaccination.
      • Centers for Disease Control
      • Prevention (CDC)
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      Immunocompetent persons with one or more of the chronic medical conditions identified by the ACIP are classified as at risk. Immunocompromised or immunosuppressed persons and those with a cochlear implant are classified as high risk (Table 1).
      • Centers for Disease Control
      • Prevention (CDC)
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      However, in terms of the probability of suffering PD, some authors have recently reported that rates in immunocompetent persons with two or more at-risk conditions (defined as multimorbidity) are generally similar to those in persons with high risk conditions, and rates in persons with three or more at-risk conditions are similar or higher than rates in persons with high-risk conditions (risk stacking).
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      • Zell E.
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      Epidemiology of invasive pneumococcal disease among high-risk adults since the introduction of pneumococcal conjugate vaccine for children.
      Table 1Risk groups for pneumococcal disease—Advisory Committee on Immunization Practices (ACIP)
      • Centers for Disease Control
      • Prevention (CDC)
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      Pneumococcal disease groupDescription
      At riskChronic heart or lung disease, trisomy 21, chronic liver disease, alcoholism, smoking, neuromuscular disorders, prematurity/small gestational age, asthma (mild, moderate, severe), and diabetes (insulin-dependent, non-insulin-dependent)
      High riskImmunodeficiency, anatomical or functional asplenia, cochlear implant, nephrotic syndrome, chronic renal failure, malignancy, and treatment with immunosuppressive or radiation therapy
      This review summarizes the available published data from 2005 through 20134 describing the prevalence of multimorbidity in adult patients, with a focus on the co-morbidities included by the ACIP in the ‘at risk’ group. An analysis of case–control and population-based surveillance studies that have evaluated risk factors for CAP and IPD was also performed in order to estimate the importance of risk stacking.

      2. Methods

      The data presented here are part of a larger global literature search performed in PubMed (filters activated: published in the last 10 years, humans, adult 19+ years) to identify studies assessing the prevalence of multimorbidity (“multimorbidity” AND “prevalence” OR “frequency”) and risk factors for CAP and/or IPD ((“risk factor”) OR “comorbidity”) AND “pneumococcal infections”) OR “pneumococcal infection”) OR “pneumococcal pneumonia”). To ensure the retrieval of relevant articles, the search was performed by exploring and combining medical subject headings (MeSH) and free search terms.
      At a minimum, studies had to establish the enrolment procedure used for patient recruitment and report the incidence of multimorbidity and risk factors for CAP of their entire cohort. The methodological quality of articles was evaluated by three independent reviewers. Pairs of independent researchers screened titles and abstracts of the citations identified. They categorized the articles as either eligible or excluded. Studies with a focus on case series (defined as studies with ≤100 participants), articles without original data, vaccine and/or antibiotic efficacy trials, and studies that included pediatric patients were excluded. Furthermore, publications that reported modeling or health economics studies without a focus on prevalence, investigations in patients with CAP and IPD and studies for which the denominator was unknown were also excluded.
      The multiplicative method described by Campbell was used to obtain a risk stacking value based on the at-risk factors odds ratios (OR) for CAP and IPD published in the selected articles.
      • Campbell M.J.
      Teaching logistic regression.
      Because of the limited number of studies available, these analyses are presented in a descriptive format only.

      3. Results and discussion

      The search strategy yielded 1197 articles for review. A flow summary of the selection process is given in Figure 1. Table 2, Table 3 present a summarized description of the 38 articles finally selected (19 for multimorbidity and 19 for risk factors for CAP).
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      • Meisinger C.
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      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • Marengoni A.
      • Winblad B.
      • Karp A.
      • Fratiglioni L.
      Prevalence of chronic diseases and multimorbidity among the elderly population in Sweden.
      • Noël P.H.
      • Parchman M.L.
      • Williams Jr., J.W.
      • Cornell J.E.
      • Shuko L.
      • Zeber J.E.
      • et al.
      The challenges of multimorbidity from the patient perspective.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
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      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Fortin M.
      • Bravo G.
      • Hudon C.
      • Vanasse A.
      • Lapointe L.
      Prevalence of multimorbidity among adults seen in family practice.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      • García-Olmos L1
      • Salvador C.H.
      • Alberquilla Á.
      • Lora D.
      • Carmona M.
      • García-Sagredo P.
      • et al.
      Comorbidity patterns in patients with chronic diseases in general practice.
      • Steinman M.A.
      • Lee S.J.
      • John Boscardin W.
      • Miao Y.
      • Fung K.Z.
      • Moore K.L.
      • et al.
      Patterns of multimorbidity in elderly veterans.
      • Prados-Torres A.
      • Poblador-Plou B.
      • Calderón-Larrañaga A.
      • Gimeno-Feliu L.A.
      • González-Rubio F.
      • Poncel-Falcó A.
      • et al.
      Multimorbidity patterns in primary care: interactions among chronic diseases using factor analysis.
      • O’Kelly S.
      • Smith S.M.
      • Lane S.
      • Teljeur C.
      • O’Dowd T.
      Chronic respiratory disease and multimorbidity: prevalence and impact in a general practice setting.
      • Glynn L.G.
      • Valderas J.M.
      • Healy P.
      • Burke E.
      • Newell J.
      • Gillespie P.
      • et al.
      The prevalence of multimorbidity in primary care and its effect on health care utilization and cost.
      • Rizza A.
      • Kaplan V.
      • Senn O.
      • Rosemann T.
      • Bhend H.
      • Tandjung R.
      • et al.
      Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Agborsangaya C.B.
      • Ngwakongnwi E.
      • Lahtinen M.
      • Cooke T.
      • Johnson J.A.
      Multimorbidity prevalence in the general population: the role of obesity in chronic disease clustering.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • Farkouh R.A.
      • Strutton D.R.
      • Pelton S.I.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      • Kyaw M.H.
      • Rose Jr., C.E.
      • Fry A.M.
      • Singleton J.A.
      • Moore Z.
      • et al.
      The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults.
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Raga-Luria X.
      • Gomez-Bertomeu F.
      EPIVAC Study Group
      Epidemiology of community-acquired pneumonia in older adults: a population-based study.
      • Thomsen R.W.
      • Hundborg H.H.
      • Lervang H.H.
      • Johnsen S.P.
      • Schønheyder H.C.
      • Sørensen H.T.
      Risk of community-acquired pneumococcal bacteremia in patients with diabetes: a population-based case–control study.
      • Talbot T.R.
      • Hartert T.V.
      • Mitchel E.
      • Halasa N.B.
      • Arbogast P.G.
      • Poehling K.A.
      • et al.
      Asthma as a risk factor for invasive pneumococcal disease.
      • Skull S.A.
      • Andrews R.M.
      • Byrnes G.B.
      • Campbell D.A.
      • Kelly H.A.
      • Brown G.V.
      • et al.
      Hospitalized community-acquired pneumonia in the elderly: an Australian case-cohort study.
      • Rodriguez-Barradas M.C.
      • Goulet J.
      • Brown S.
      • Goetz M.B.
      • Rimland D.
      • Simberkoff M.S.
      • et al.
      Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study.
      • Müllerova H1
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      • Hagan G.W.
      • Woodhead M.A.
      • Miravitlles M.
      • Davis K.J.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • Ollgren J.
      • Kaijalainen T.
      • Leinonen M.
      • et al.
      Risk of invasive pneumococcal infections among working age adults with asthma.
      • Jung J.A.
      • Kita H.
      • Yawn B.P.
      • Boyce T.G.
      • Yoo K.H.
      • McGree M.E.
      • et al.
      Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma.
      • Jacups S.P.
      • Cheng A.
      The epidemiology of community acquired bacteremic pneumonia, due to Streptococcus pneumoniae, in the Top End of the Northern Territory, Australia—over 22 years.
      • Jackson M.L.
      • Nelson J.C.
      • Jackson L.A.
      Risk factors for community-acquired pneumonia in immunocompetent seniors.
      • Jackson M.L.
      • Neuzil K.M.
      • Thompson W.W.
      • Shay D.K.
      • Yu O.
      • Hanson C.A.
      • et al.
      The burden of community-acquired pneumonia in seniors: results of a population-based study.
      • Gau JT1
      • Acharya U.
      • Khan S.
      • Heh V.
      • Mody L.
      • Kao T.C.
      Pharmacotherapy and the risk for community-acquired pneumonia.
      • Flory J.H.
      • Joffe M.
      • Fishman N.O.
      • Edelstein P.H.
      • Metlay J.P.
      Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
      • Farr B.M.
      • Bartlett C.L.
      • Wadsworth J.
      • Miller D.L.
      Risk factors for community-acquired pneumonia diagnosed upon hospital admission. British Thoracic Society Pneumonia Study Group.
      • de Roux A.
      • Cavalcanti M.
      • Marcos M.A.
      • Garcia E.
      • Ewig S.
      • Mensa J.
      • et al.
      Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia.
      • Almirall J.
      • Bolíbar I.
      • Serra-Prat M.
      • Roig J.
      • Hospital I.
      • Carandell E.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      • Almirall J.
      • González C.A.
      • Balanzó X.
      • Bolíbar I.
      Proportion of community-acquired pneumonia cases attributable to tobacco smoking.
      Figure thumbnail gr1
      Figure 1Summary of the literature search and screening.
      Table 2Data on multimorbidity
      ReferenceCountry, data collection yearsData source, number of casesPrevalence of multimorbidity by age-group
      Kirchberger et al.
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      Germany, 1984–2001Patient survey, n = 412765–94 years, 58.6%
      Two or more chronic conditions.
      Marengoni et al.
      • Marengoni A.
      • Winblad B.
      • Karp A.
      • Fratiglioni L.
      Prevalence of chronic diseases and multimorbidity among the elderly population in Sweden.
      Sweden, 1987–2000Patient database, n = 109977–84 years, 51.6%
      Two or more chronic conditions.
      ≥85 years, 58.5%
      Two or more chronic conditions.
      Noël et al.
      • Noël P.H.
      • Parchman M.L.
      • Williams Jr., J.W.
      • Cornell J.E.
      • Shuko L.
      • Zeber J.E.
      • et al.
      The challenges of multimorbidity from the patient perspective.
      USA, 1997–2001Patient survey, n = 422>50 years, 53%
      Two or more chronic conditions.
      Taylor et al.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      Australia, 2000–2003Patient interview, n = 165140–59 years, 32.1%
      Two or more chronic conditions.
      >65 years, 57.9%
      Two or more chronic conditions.
      van Oostrom et al.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      Netherlands, 2002–2008Electronic database, n = 52 01455–64 years, 22.7%
      Two or more chronic conditions.
      65–74 years, 39.1%
      Two or more chronic conditions.
      ≥74 years, 59.2%
      Two or more chronic conditions.
      Fortin et al.
      • Fortin M.
      • Bravo G.
      • Hudon C.
      • Vanasse A.
      • Lapointe L.
      Prevalence of multimorbidity among adults seen in family practice.
      Canada, 2003Patient records, n = 98045–64 years, 92.8%
      Two or more chronic conditions.
      >65 years, 98.7%
      Two or more chronic conditions.
      van den Bussche et al.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      Germany, 2004Health insurance data, n = 123 224>65 years, 73%
      Two or more chronic conditions.
      >65 years, 62.1%
      Three or more chronic conditions.
      Britt et al.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      Australia, 2005Patient survey, n = 915645–64 years, 46.5%
      Two or more chronic conditions.
      65–74 years, 74.6%
      Two or more chronic conditions.
      >75 years, 83.2%
      Two or more chronic conditions.
      45–64 years, 22.7%
      Three or more chronic conditions.
      65–74 years, 46.0%
      Three or more chronic conditions.
      >75 years, 58.2%
      Three or more chronic conditions.
      Violán et al.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      Spain, 2006Electronic database, n = 1 597 25845–64 years, 52.9%
      Two or more chronic conditions.
      65–74 years, 79.8%
      Two or more chronic conditions.
      ≥75 years, 87.2%
      Two or more chronic conditions.
      Barnett et al.
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      Scotland, 2007Electronic database, n = 1 751 84145–64 years, 30.4%
      Two or more chronic conditions.
      65–84 years, 64.9%
      Two or more chronic conditions.
      ≥85 years, 81.5%
      Two or more chronic conditions.
      García-Olmos et al.
      • García-Olmos L1
      • Salvador C.H.
      • Alberquilla Á.
      • Lora D.
      • Carmona M.
      • García-Sagredo P.
      • et al.
      Comorbidity patterns in patients with chronic diseases in general practice.
      Spain, 2007Electronic database, n = 19 867>14 years, 24.5%
      Two or more chronic conditions.
      Steinman et al.
      • Steinman M.A.
      • Lee S.J.
      • John Boscardin W.
      • Miao Y.
      • Fung K.Z.
      • Moore K.L.
      • et al.
      Patterns of multimorbidity in elderly veterans.
      USA, 2007–2008Hospital database, n = 2 002 693>65 years, 89.7%
      Three or more chronic conditions.
      Prados-Torres et al.
      • Prados-Torres A.
      • Poblador-Plou B.
      • Calderón-Larrañaga A.
      • Gimeno-Feliu L.A.
      • González-Rubio F.
      • Poncel-Falcó A.
      • et al.
      Multimorbidity patterns in primary care: interactions among chronic diseases using factor analysis.
      Spain, 2008Electronic database, n = 275 68245–64 years, 21%
      Two or more chronic conditions.
      >65 years, 23%
      Two or more chronic conditions.
      45–64 years, 12%
      Three or more chronic conditions.
      >65 years, 18%
      Three or more chronic conditions.
      O’Kelly et al.
      • O’Kelly S.
      • Smith S.M.
      • Lane S.
      • Teljeur C.
      • O’Dowd T.
      Chronic respiratory disease and multimorbidity: prevalence and impact in a general practice setting.
      Ireland, 2008–2009Patient records, n = 65365–94 years, 60%
      Two or more chronic conditions.
      Glynn et al.
      • Glynn L.G.
      • Valderas J.M.
      • Healy P.
      • Burke E.
      • Newell J.
      • Gillespie P.
      • et al.
      The prevalence of multimorbidity in primary care and its effect on health care utilization and cost.
      Ireland, 2009Patient records, n = 3309>50 years, 66.2%
      Two or more chronic conditions.
      Rizza et al.
      • Rizza A.
      • Kaplan V.
      • Senn O.
      • Rosemann T.
      • Bhend H.
      • Tandjung R.
      • et al.
      Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
      Switzerland, 2009–2011Electronic database, n = 66 21250–59 years, 15.7%
      Two or more chronic conditions.
      60–69 years, 25.8%
      Two or more chronic conditions.
      70–79 years, 33.6%
      Two or more chronic conditions.
      50–59 years, 6.82%
      Three or more chronic conditions.
      60–69 years, 13.0%
      Three or more chronic conditions.
      70–79 years, 20.0%
      Three or more chronic conditions.
      Ornstein et al.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      USA, 2011Electronic database, n = 667 37955–64 years, 61%
      Two or more chronic conditions.
      65–74 years, 74.3%
      Two or more chronic conditions.
      75–84 years, 81%
      Two or more chronic conditions.
      55–64 years, 72%
      Three or more chronic conditions.
      65–74 years, 57.3%
      Three or more chronic conditions.
      75–84 years, 67.5%
      Three or more chronic conditions.
      Agborsangaya et al.
      • Agborsangaya C.B.
      • Ngwakongnwi E.
      • Lahtinen M.
      • Cooke T.
      • Johnson J.A.
      Multimorbidity prevalence in the general population: the role of obesity in chronic disease clustering.
      Canada, 2012Patient survey, n = 4803>64 years, 63.8%
      Two or more chronic conditions.
      Formiga et al.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      Spain, NDPatient interview, n = 328>85 years, 77.1%
      Three or more chronic conditions.
      ND, not deternmined.
      a Two or more chronic conditions.
      b Three or more chronic conditions.
      Table 3Risk factors for pneumococcal disease: publications analyzed
      ReferenceCountry, yearType of study, number of casesObjectiveMeasure of association
      Shea et al.
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • Farkouh R.A.
      • Strutton D.R.
      • Pelton S.I.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      USA, 2006–2010Population-based adult cases, 26 362 865Risk factors IPD and CAPRR
      Kyaw et al.
      • Kyaw M.H.
      • Rose Jr., C.E.
      • Fry A.M.
      • Singleton J.A.
      • Moore Z.
      • et al.
      The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults.
      USA, 1999–2000Case–control study, 1570:2765Risk factors IPDRR
      Vila-Córcoles et al.
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Raga-Luria X.
      • Gomez-Bertomeu F.
      EPIVAC Study Group
      Epidemiology of community-acquired pneumonia in older adults: a population-based study.
      Spain, 2002–2005Population-based adult cases, 11 241Risk factors CAPOR
      Thomsen et al.
      • Thomsen R.W.
      • Hundborg H.H.
      • Lervang H.H.
      • Johnsen S.P.
      • Schønheyder H.C.
      • Sørensen H.T.
      Risk of community-acquired pneumococcal bacteremia in patients with diabetes: a population-based case–control study.
      Denmark, 1992–2001Case–control study, 598:5980DBT for bacteremic CAPOR
      Talbot et al.
      • Talbot T.R.
      • Hartert T.V.
      • Mitchel E.
      • Halasa N.B.
      • Arbogast P.G.
      • Poehling K.A.
      • et al.
      Asthma as a risk factor for invasive pneumococcal disease.
      USA, 1995–2002Case–control study, 635:6350Asthma for IPDOR
      Skull et al.
      • Skull S.A.
      • Andrews R.M.
      • Byrnes G.B.
      • Campbell D.A.
      • Kelly H.A.
      • Brown G.V.
      • et al.
      Hospitalized community-acquired pneumonia in the elderly: an Australian case-cohort study.
      Australia, 2000–2002Case–control study, 1952:2927Risk factors for CAPRR
      Rodriguez-Barradas et al.
      • Rodriguez-Barradas M.C.
      • Goulet J.
      • Brown S.
      • Goetz M.B.
      • Rimland D.
      • Simberkoff M.S.
      • et al.
      Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study.
      USA, 2001–2002Population-based adult cases, 1628Risk factors for CAPHR
      Müllerova et al.
      • Müllerova H1
      • Chigbo C.
      • Hagan G.W.
      • Woodhead M.A.
      • Miravitlles M.
      • Davis K.J.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      UK, 1996–2005Case–control study, 1469:7345COPD for CAPOR
      Klemets et al.
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • Ollgren J.
      • Kaijalainen T.
      • Leinonen M.
      • et al.
      Risk of invasive pneumococcal infections among working age adults with asthma.
      Finland, 1995–2002Case–control study, 1282:12 785Risk factors for IPDOR
      Jung et al.
      • Jung J.A.
      • Kita H.
      • Yawn B.P.
      • Boyce T.G.
      • Yoo K.H.
      • McGree M.E.
      • et al.
      Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma.
      USA, 1964–1983Case–control study, 348:174Asthma for IPDOR
      Jacups and Cheng
      • Jacups S.P.
      • Cheng A.
      The epidemiology of community acquired bacteremic pneumonia, due to Streptococcus pneumoniae, in the Top End of the Northern Territory, Australia—over 22 years.
      Australia, 1987–2008Population-based adult cases, 204Risk factors for bacteremic CAPRR
      Jackson et al.
      • Jackson M.L.
      • Nelson J.C.
      • Jackson L.A.
      Risk factors for community-acquired pneumonia in immunocompetent seniors.
      USA, 2000–2002Case–control study, 2346:1173Risk factors for CAPOR
      Jackson et al.
      • Jackson M.L.
      • Neuzil K.M.
      • Thompson W.W.
      • Shay D.K.
      • Yu O.
      • Hanson C.A.
      • et al.
      The burden of community-acquired pneumonia in seniors: results of a population-based study.
      USA, 1998–2001Population-based adult cases, 2979Risk factors for CAPHR
      Gau et al.
      • Gau JT1
      • Acharya U.
      • Khan S.
      • Heh V.
      • Mody L.
      • Kao T.C.
      Pharmacotherapy and the risk for community-acquired pneumonia.
      USA, 2004–2006Case–control study, 194:952Risk factors for CAPOR
      Flory et al.
      • Flory J.H.
      • Joffe M.
      • Fishman N.O.
      • Edelstein P.H.
      • Metlay J.P.
      Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
      USA, 2002–2004Population-based adult cases, 609Risk factors for CAPOR
      Farr et al.
      • Farr B.M.
      • Bartlett C.L.
      • Wadsworth J.
      • Miller D.L.
      Risk factors for community-acquired pneumonia diagnosed upon hospital admission. British Thoracic Society Pneumonia Study Group.
      USA, 1982–1983Population-based, case–control, 178:385Risk factors for CAPOR
      de Roux et al.
      • de Roux A.
      • Cavalcanti M.
      • Marcos M.A.
      • Garcia E.
      • Ewig S.
      • Mensa J.
      • et al.
      Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia.
      Spain, 1997–2001Population-based adult cases, 128:1165Alcohol for CAPOR
      Almirall et al.
      • Almirall J.
      • Bolíbar I.
      • Serra-Prat M.
      • Roig J.
      • Hospital I.
      • Carandell E.
      • et al.
      New evidence of risk factors for community-acquired pneumonia: a population-based study.
      Spain, 1993–1995Population-based, case–control, 205:475Tobacco for CAPOR
      Almirall et al.
      • Almirall J.
      • González C.A.
      • Balanzó X.
      • Bolíbar I.
      Proportion of community-acquired pneumonia cases attributable to tobacco smoking.
      Spain, 1999–2000Population-based, case–control, 1336:1326Risk factors for CAPOR
      IPD, invasive pneumococcal disease; CAP, community-acquired pneumonia; RR, relative risk; OR, odds ratio; DBT, diabetes; HR, hazard risk; COPD, chronic obstructive pulmonary disease.

      3.1 Multimorbidity

      The prevalence of multimorbidity among adult patients aged ≥65 years was reported in 14 of the 19 articles (74%), and ranged from 23% to 98.7% in the presence of two or more comorbidities and from 18% to 89.7% in the presence of three or more comorbidities.
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • Noël P.H.
      • Parchman M.L.
      • Williams Jr., J.W.
      • Cornell J.E.
      • Shuko L.
      • Zeber J.E.
      • et al.
      The challenges of multimorbidity from the patient perspective.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Fortin M.
      • Bravo G.
      • Hudon C.
      • Vanasse A.
      • Lapointe L.
      Prevalence of multimorbidity among adults seen in family practice.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      • Glynn L.G.
      • Valderas J.M.
      • Healy P.
      • Burke E.
      • Newell J.
      • Gillespie P.
      • et al.
      The prevalence of multimorbidity in primary care and its effect on health care utilization and cost.
      • Rizza A.
      • Kaplan V.
      • Senn O.
      • Rosemann T.
      • Bhend H.
      • Tandjung R.
      • et al.
      Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Agborsangaya C.B.
      • Ngwakongnwi E.
      • Lahtinen M.
      • Cooke T.
      • Johnson J.A.
      Multimorbidity prevalence in the general population: the role of obesity in chronic disease clustering.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      The prevalence in those aged <65 years (described in only eight of the 19 articles – 42%) ranged from 15.7% to 61% among subjects with two or more comorbidities and from 6.8% to 72% in those who presented three or more risk conditions.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      • Prados-Torres A.
      • Poblador-Plou B.
      • Calderón-Larrañaga A.
      • Gimeno-Feliu L.A.
      • González-Rubio F.
      • Poncel-Falcó A.
      • et al.
      Multimorbidity patterns in primary care: interactions among chronic diseases using factor analysis.
      • Rizza A.
      • Kaplan V.
      • Senn O.
      • Rosemann T.
      • Bhend H.
      • Tandjung R.
      • et al.
      Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      Only five of 19 articles (26.3%) provided a detailed list and frequency of occurrence of the different comorbidities (in two additional papers the comorbidities considered were only listed).
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      Although, the comorbid conditions covered a broad spectrum of diseases, the defined at-risk conditions diabetes (DBT), chronic heart disease (CHD), and chronic obstructive pulmonary disease (COPD) were the three most frequent comorbidities described (ranging from 7.6% to 28.5%, 6.9% to 25.8%, and 3.8% to 15.4%, respectively) (Figure 2).
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      Figure thumbnail gr2
      Figure 2Multimorbidity in adults patients: prevalence of the most common at-risk conditions (DBT, diabetes; CHD, chronic heart disease; COPD, chronic obstructive pulmonary disease); 1Ref.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      ; 2Ref.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      ; 3Ref.
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      ; 4Ref.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      ; 5Ref.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      .
      Specific disease combinations (co-occurrence) were also studied in seven of 19 articles (37%).
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • García-Olmos L1
      • Salvador C.H.
      • Alberquilla Á.
      • Lora D.
      • Carmona M.
      • García-Sagredo P.
      • et al.
      Comorbidity patterns in patients with chronic diseases in general practice.
      • Steinman M.A.
      • Lee S.J.
      • John Boscardin W.
      • Miao Y.
      • Fung K.Z.
      • Moore K.L.
      • et al.
      Patterns of multimorbidity in elderly veterans.
      • Prados-Torres A.
      • Poblador-Plou B.
      • Calderón-Larrañaga A.
      • Gimeno-Feliu L.A.
      • González-Rubio F.
      • Poncel-Falcó A.
      • et al.
      Multimorbidity patterns in primary care: interactions among chronic diseases using factor analysis.
      • O’Kelly S.
      • Smith S.M.
      • Lane S.
      • Teljeur C.
      • O’Dowd T.
      Chronic respiratory disease and multimorbidity: prevalence and impact in a general practice setting.
      Individuals aged ≥55 years had DBT, CHD, and COPD as a unique comorbidity in only 27%, 20%, and 16% of cases.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      In this population, the co-occurrence of DBT (as the index disease) + CHD (with or without hypertension), DBT (as the index disease) + COPD, COPD (as the index disease) + DBT, and COPD (as the index disease) + CHD (with or without hypertension), were described in 20.4–30%, 11–17.2%, 13–25.8%, and 14–27.4%, respectively.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • Steinman M.A.
      • Lee S.J.
      • John Boscardin W.
      • Miao Y.
      • Fung K.Z.
      • Moore K.L.
      • et al.
      Patterns of multimorbidity in elderly veterans.

      3.2 Risk factors

      The ORs for the most frequent at-risk factors for CAP and IPD (DBT, CHD, and COPD) were described in 9/19 (47%) and 1/19 (5%) articles, respectively.
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Raga-Luria X.
      • Gomez-Bertomeu F.
      EPIVAC Study Group
      Epidemiology of community-acquired pneumonia in older adults: a population-based study.
      • Skull S.A.
      • Andrews R.M.
      • Byrnes G.B.
      • Campbell D.A.
      • Kelly H.A.
      • Brown G.V.
      • et al.
      Hospitalized community-acquired pneumonia in the elderly: an Australian case-cohort study.
      • Rodriguez-Barradas M.C.
      • Goulet J.
      • Brown S.
      • Goetz M.B.
      • Rimland D.
      • Simberkoff M.S.
      • et al.
      Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study.
      • Müllerova H1
      • Chigbo C.
      • Hagan G.W.
      • Woodhead M.A.
      • Miravitlles M.
      • Davis K.J.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • Ollgren J.
      • Kaijalainen T.
      • Leinonen M.
      • et al.
      Risk of invasive pneumococcal infections among working age adults with asthma.
      • Jackson M.L.
      • Nelson J.C.
      • Jackson L.A.
      Risk factors for community-acquired pneumonia in immunocompetent seniors.
      • Jackson M.L.
      • Neuzil K.M.
      • Thompson W.W.
      • Shay D.K.
      • Yu O.
      • Hanson C.A.
      • et al.
      The burden of community-acquired pneumonia in seniors: results of a population-based study.
      • Gau JT1
      • Acharya U.
      • Khan S.
      • Heh V.
      • Mody L.
      • Kao T.C.
      Pharmacotherapy and the risk for community-acquired pneumonia.
      • Farr B.M.
      • Bartlett C.L.
      • Wadsworth J.
      • Miller D.L.
      Risk factors for community-acquired pneumonia diagnosed upon hospital admission. British Thoracic Society Pneumonia Study Group.
      • Almirall J.
      • González C.A.
      • Balanzó X.
      • Bolíbar I.
      Proportion of community-acquired pneumonia cases attributable to tobacco smoking.
      Table 4 gives a summary of the ORs analyzed as well as the risk stacking OR values for different scenarios of multimorbidity based on the algebra described by Campbell.
      • Campbell M.J.
      Teaching logistic regression.
      The hypothetical scenario of the concurrence of the three conditions DBT + CHD + COPD showed an OR of ≥7.5 in four of the seven articles (57%) and an OR of ≤4.5 in three of the seven articles (43%) for which this co-occurrence in CAP could be analyzed. In these groups of patients, the addition of another common at-risk factor for CAP such as smoking (four concurrent conditions) increased the OR calculated (2 to >40).
      Table 4Scenarios of odds ratio stacked considering four common at-risk conditions for community-acquired pneumonia and invasive pneumococcal disease
      CAPIPD
      Type of studyPopulation-basedCase–controlPopulation-basedCase–controlCase–controlPopulation-basedCase–controlCase–controlCase–controlCase–control
      Number11 2411952:292716281469:73451173:23462979194:952178:3851336:13261282:12 785
      CountrySpainAustraliaUSAUKUSAUSAUSAUSASpainFinland
      Ref.
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Raga-Luria X.
      • Gomez-Bertomeu F.
      EPIVAC Study Group
      Epidemiology of community-acquired pneumonia in older adults: a population-based study.
      Ref.
      • Skull S.A.
      • Andrews R.M.
      • Byrnes G.B.
      • Campbell D.A.
      • Kelly H.A.
      • Brown G.V.
      • et al.
      Hospitalized community-acquired pneumonia in the elderly: an Australian case-cohort study.
      Ref.
      • Rodriguez-Barradas M.C.
      • Goulet J.
      • Brown S.
      • Goetz M.B.
      • Rimland D.
      • Simberkoff M.S.
      • et al.
      Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study.
      Ref.
      • Müllerova H1
      • Chigbo C.
      • Hagan G.W.
      • Woodhead M.A.
      • Miravitlles M.
      • Davis K.J.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      Ref.
      • Jackson M.L.
      • Nelson J.C.
      • Jackson L.A.
      Risk factors for community-acquired pneumonia in immunocompetent seniors.
      Ref.
      • Jackson M.L.
      • Neuzil K.M.
      • Thompson W.W.
      • Shay D.K.
      • Yu O.
      • Hanson C.A.
      • et al.
      The burden of community-acquired pneumonia in seniors: results of a population-based study.
      Ref.
      • Gau JT1
      • Acharya U.
      • Khan S.
      • Heh V.
      • Mody L.
      • Kao T.C.
      Pharmacotherapy and the risk for community-acquired pneumonia.
      Ref.
      • Farr B.M.
      • Bartlett C.L.
      • Wadsworth J.
      • Miller D.L.
      Risk factors for community-acquired pneumonia diagnosed upon hospital admission. British Thoracic Society Pneumonia Study Group.
      Ref.
      • Almirall J.
      • González C.A.
      • Balanzó X.
      • Bolíbar I.
      Proportion of community-acquired pneumonia cases attributable to tobacco smoking.
      Ref.
      • Klemets P.
      • Lyytikäinen O.
      • Ruutu P.
      • Ollgren J.
      • Kaijalainen T.
      • Leinonen M.
      • et al.
      Risk of invasive pneumococcal infections among working age adults with asthma.
      OROROROROROROROROROR
      At-risk conditions
       DBT2.91

      (2.35–3.61)
      1.22

      (1.05–1.42)
      1.45

      (0.88–2.39)
      1.07

      (0.89–1.28)
      1.3

      (1.00–1.5)
      1.13

      (1.01–1.27)
      ND1.89

      (0.62–5.70)
      1.43

      (1.11–1.92)
      2.3

      (1.6–3.5)
       CHD1.46

      (1.16–1.84)
      ND1.78

      (0.98–3.23)
      1.37

      (1.20–1.57)
      5.2

      (3.8–7.1)
      1.48

      (1.33–1.65)
      1.80

      (1.28–2.52)
      3.24

      (1.41–7.46)
      1.81

      (1.33–2.49)
      2.8

      (1.0–8.2)
       COPD1.82

      (1.14–2.89)
      2.41

      (2.10–2.77)
      1.66

      (1.01–2.72)
      1.35

      (1.11–1.63)
      2.5

      (1.9–3.3)
      1.21

      (1.07–1.36)
      3.84

      (2.77–5.32)
      4.40

      (2.76–7.00)
      2.96

      (2.26–3.87)
      ND
      Scenario, two conditions
       DBT + COPD5.29

      (2.67–10.43)
      2.94

      (2.20–3.93)
      2.4

      (0.88–6.5)
      1.45

      (0.98–2.08)
      3.25

      (1.9–4.5)
      1.36

      (1.08–1.72)
      ND8.3

      (1.71–39.9)
      4.2

      (2.50–7.43)
      ND
       CHD + COPD2.65

      (1.32–5.31)
      ND2.95

      (0.99–8.78)
      1.85

      (1.33–2.55)
      13

      (7.2–23.43)
      1.8

      (1.42–2.24)
      6.9

      (3.54–13.4)
      14.2

      (3.89–52.22)
      5.4

      (3.00–9.63)
      ND
       DBT + CHD4.2

      (2.72–6.64)
      ND2.6

      (0.86–7.71)
      1.5

      (1.06–2.00)
      6.8

      (3.8–10.65)
      1.7

      (1.34–2.09)
      ND6.1

      (0.87–45.52)
      2.6

      (1.47–4.78)
      6.5

      (1.6–28.7)
      Scenario, three conditions
       DBT + CHD + COPD7.73

      (3.10–19.1)
      ND4.2

      (0.87–21)
      1.98

      (1.18–3.27)
      16.9

      (7.22–35.14)
      2.02

      (1.43–2.84)
      ND26.9

      (2.41–297.65)
      7.66

      (3.33–18.50)
      ND
      Scenario, four conditions
       Smoker1.12

      (0.83–1.49)
      ND1.48

      (0.97–2.26)
      0.99

      (0.86–1.14)
      2.5

      (2.0–3.2)
      1.31

      (1.17–1.46)
      2.06

      (1.29–3.29)
      1.84

      (1.20–2.83)
      1.34

      (1.11–1.62)
      ND
       DBT + CHD + COPD + smoker8.66

      (2.57–28.4)
      ND6.3

      (0.84–47.46)
      1.96

      (1.01–3.72)
      42.25

      (14.44–112.4)
      2.65

      (1.67–4.14)
      14.2

      (4.56–44.08)
      49.5

      (2.89–842.34)
      10.26

      (3.69–29.97)
      ND
      CAP, community-acquired pneumonia; IPD, invasive pneumococcal disease; OR, odds ratio; DBT, diabetes; CHD, chronic heart disease; COPD, chronic obstructive pulmonary disease; ND, not determined.

      3.3 Conclusions

      Because of the aging of the population and the association of chronic diseases with advanced age, multimorbidity is expected to become a common problem in adult populations (those aged >50 years).
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • Marengoni A.
      • Winblad B.
      • Karp A.
      • Fratiglioni L.
      Prevalence of chronic diseases and multimorbidity among the elderly population in Sweden.
      • Noël P.H.
      • Parchman M.L.
      • Williams Jr., J.W.
      • Cornell J.E.
      • Shuko L.
      • Zeber J.E.
      • et al.
      The challenges of multimorbidity from the patient perspective.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      In this review, the prevalence of multimorbidity among adult patients aged <65 years and ≥65 years ranged from approximately 15% to 60% and from approximately 20% to >90%, respectively.
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      • Noël P.H.
      • Parchman M.L.
      • Williams Jr., J.W.
      • Cornell J.E.
      • Shuko L.
      • Zeber J.E.
      • et al.
      The challenges of multimorbidity from the patient perspective.
      • Taylor A.W.
      • Price K.
      • Gill T.K.
      • Adams R.
      • Pilkington R.
      • Carrangis N.
      • et al.
      Multimorbidity—not just an older person's issue. Results from an Australian biomedical study.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Fortin M.
      • Bravo G.
      • Hudon C.
      • Vanasse A.
      • Lapointe L.
      Prevalence of multimorbidity among adults seen in family practice.
      • van den Bussche H.
      • Koller D.
      • Kolonko T.
      • Hansen H.
      • Wegscheider K.
      • Glaeske G.
      • et al.
      Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • Violán C.
      • Foguet-Boreu Q.
      • Hermosilla-Pérez E.
      • Valderas J.M.
      • Bolíbar B.
      • Fàbregas-Escurriola M.
      • et al.
      Comparison of the information provided by electronic health records data and a population health survey to estimate prevalence of selected health conditions and multimorbidity.
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      • Glynn L.G.
      • Valderas J.M.
      • Healy P.
      • Burke E.
      • Newell J.
      • Gillespie P.
      • et al.
      The prevalence of multimorbidity in primary care and its effect on health care utilization and cost.
      • Rizza A.
      • Kaplan V.
      • Senn O.
      • Rosemann T.
      • Bhend H.
      • Tandjung R.
      • et al.
      Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
      • Ornstein S.M.
      • Nietert P.J.
      • Jenkins R.G.
      • Litvin C.B.
      The prevalence of chronic diseases and multimorbidity in primary care practice: a PPRNet report.
      • Agborsangaya C.B.
      • Ngwakongnwi E.
      • Lahtinen M.
      • Cooke T.
      • Johnson J.A.
      Multimorbidity prevalence in the general population: the role of obesity in chronic disease clustering.
      • Formiga F.
      • Ferrer A.
      • Sanz H.
      • Marengoni A.
      • Alburquerque J.
      • Pujol R.
      • et al.
      Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study.
      Not surprisingly, a number of negative impacts of multimorbidity have been identified, associated with reduced health outcomes including functioning and quality of life, more complex clinical management, specific health care needs, and increased health care costs.
      • Kirchberger I.
      • Meisinger C.
      • Heier M.
      • Zimmermann A.K.
      • Thorand B.
      • Autenrieth C.S.
      • et al.
      Patterns of multimorbidity in the aged population. Results from the KORA-Age study.
      The most common disease clusters in older adults with multimorbidity include several comorbidities defined by the ACIP as ‘at risk’ conditions significantly associated with CAP and IPD (i.e. DBT, CHD, and COPD). The relationship between multimorbidity and the rates of all-cause CAP, pneumococcal CAP, and IPD among adults have been analyzed by Shea et al.
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • Farkouh R.A.
      • Strutton D.R.
      • Pelton S.I.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      using three large health care databases in the USA. The authors found that in adults aged 50–64 years, 19.6% had one at-risk condition, 4.4% had two, and 1.2% had three or more; the most common conditions were DBT (49%), CHD (30%), and smoking (13%). In adults ≥65 years of age, 26.4% had one at-risk condition, 9.5% had two, and 3.1% had three or more; the most common conditions were CHD (52%), DBT (50%), and COPD (20%).
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • Farkouh R.A.
      • Strutton D.R.
      • Pelton S.I.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      In line with the publication of Shea et al.,
      • Shea K.M.
      • Edelsberg J.
      • Weycker D.
      • Farkouh R.A.
      • Strutton D.R.
      • Pelton S.I.
      Rates of pneumococcal disease in adults with chronic medical conditions.
      in the present review, the most common comorbid conditions defined by the ACIP as ‘at risk’ conditions of CAP/IPD were found to be DBT, CHD, and COPD. In that regard, it was found that individuals aged ≥55 years have DBT, CHD, and COPD as a unique comorbidity in less than 30% of cases.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      The co-occurrence of these three comorbid conditions (15–30% of cases) might reflect a pathophysiological association among these risk factors.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      • Britt H.C.
      • Harrison C.M.
      • Miller G.C.
      • Knox S.A.
      Prevalence and patterns of multimorbidity in Australia.
      • Steinman M.A.
      • Lee S.J.
      • John Boscardin W.
      • Miao Y.
      • Fung K.Z.
      • Moore K.L.
      • et al.
      Patterns of multimorbidity in elderly veterans.
      In fact, the combinations of CHD + DBT, CHD + COPD, CHD + DBT, COPD has been the most common cluster found by Weycker in patients aged 50–54 years and ≥65 years with CAP or IPD.
      • Weycker D.
      • Farkouh R.
      • Shea K.
      • Strutton D.
      • Edelsberg J.
      • Pelton S.I.
      Excess risk of invasive pneumococcal disease and pneumonia in persons with asthma or diabetes.
      It is well-established that these types of comorbid condition may occur together by chance in older people. The impact of this co-occurrence on the risk of suffering certain illnesses (e.g. CAP) is sometimes greater than the sum of the impacts of the individual diseases.
      • van Oostrom S.H.
      • Picavet H.S.
      • van Gelder B.M.
      • Lemmens L.C.
      • Hoeymans N.
      • van Dijk C.E.
      • et al.
      Multimorbidity and comorbidity in the Dutch population—data from general practices.
      Stacking the individual ORs for each condition in the same patient allows an estimation of the real probability of suffering CAP or IPD (risk stacking).
      The mathematical approach suggested by Campbell seems to be the baseline value of the OR stacked.
      • Campbell M.J.
      Teaching logistic regression.
      The classic model to calculate the OR is described in terms of the log; what is additive on the log scale is multiplicative on the linear scale. Thus if being in a particular group increases the risk of PD three times for DBT and being a smoker increases the risk by a factor of two, then if the two risk factors are independent, someone in this group will have a risk of 2 × 3 = 6 times that of someone without those risk factors.
      • Campbell M.J.
      Teaching logistic regression.
      This algebra is limited by the lack of adjustment related to the potential interaction among the different conditions. This is a consequence of the model if the two factors are independent. However, from a clinical point of view, the association of conditions such as DBT, CHD, and COPD suggests a strong synergistic effect in terms of CAP and also IPD. The scenarios of risk stacking taking into account the at-risk conditions for CAP and IPD (DBT, CHD, and COPD, with or without another frequent risk factor (i.e. smoking)), show similar ORs, mainly for CAP, to those observed in subjects classified as high risk (5–10 to >40).
      Limitations of this review result from the selection of studies, heterogeneous nature of the subjects across studies, methods of study analysis, interpretation of heterogeneity, and generalization and application of the results. However, the conclusions on the prevalence of multimorbidity in older patients and the impact of risk stacking on the CAP/IPD incidence have the potential advantage of being based on most existing evidence from relevant studies.
      In conclusion, the high prevalence of multimorbidity together with the potential impact of the OR stacked on the probability of suffering CAP and IPD are the reasons why the current classification for high-risk patients based only on the immune status of the patient needs to be redefined.
      Conflict of interest: The authors are employed by Pfizer, Inc.

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