Incidence and etiology of community-acquired pneumonia in the elderly in a prospective population-based study.

Scandinavian Journal of Infectious Diseases, 2014; 46: 250–259

ORIGINAL ARTICLE

Scand J Infect Dis Downloaded from informahealthcare.com by University of Maastricht on 07/03/14 For personal use only.

Incidence and etiology of community-acquired pneumonia in the elderly in a prospective population-based study

ARTO A. PALMU1,2, ANNIKA SAUKKORIIPI1, MARJA SNELLMAN1, JUKKA JOKINEN1, PÄIVI TORKKO1, THEDI ZIEGLER1, TARJA KAIJALAINEN1, WILLIAM P. HAUSDORFF3, VINCENT VERLANT3 & TERHI M. KILPI1 From the1National Institute for Health and Welfare, Helsinki, Finland, 2University of Tampere, School of Public Health, Tampere, Finland, and 3GlaxoSmithKline Vaccines, Wavre, Belgium

Abstract Background: We conducted a prospective population-based epidemiological study to prepare a setting for documentation of the efficacy of novel vaccines against pneumococcal (Pnc) community-acquired pneumonia (CAP) in the elderly. Specific objectives were to demonstrate setting feasibility, to construct a case definition for Pnc CAP, and to estimate its incidence. Methods: We prospectively enrolled patients with clinical and radiological findings compatible with CAP at municipal on-call clinics serving an elderly population (age ⱖ 65 y) of approximately 29,500. Sputum, urine, nasopharyngeal swab (NPS), and blood samples were analyzed using diverse methods for the identification of Pnc (culture, PCR, antigen tests, serology) and of other pathogens. The following case definition for Pnc CAP was derived: encapsulated Pnc in blood culture or in high-quality sputum culture or at least 2 of the following: positive urine Pnc antigen; ⱖ 2-fold increase in serum anti-PsaA or anti-CbpA antibodies; encapsulated Pnc culture or LytA PCR in either sputum or NPS. Results: We enrolled 490 clinical CAP patients during the 2-y follow-up, 53% of all clinical CAP patients in the source population; 323 were radiologically confirmed. The incidence of radiologically confirmed CAP was 5.5/1000 person-y (95% confidence interval (CI) 4.9–6.1) and 10.5/1000 person-y when adjusted for non-captured patients. The proportion of radiologically confirmed CAP caused by Pnc was estimated at 17%; i.e. 0.95/1000 person-y (95% CI 0.7–1.2) and 1.8 when adjusted for non-captured patients. Conclusions: We developed and documented a feasible methodology for capturing endpoints in a vaccine trial for the prevention of pneumonia. CAP incidence in the elderly population remains considerable and Streptococcus pneumoniae was one of the most commonly detected causative agents.

Keywords: Pneumonia, Streptococcus pneumoniae, incidence, etiology, population-based, elderly

Introduction Pneumonia remains a significant disease, especially in the elderly with underlying comorbidities and who are frail. The incidence of pneumonia increases with age in adults [1,2]. Only a few population-based prospective studies are available. In a study conducted in Finland in the 1980s, the incidence of communityacquired pneumonia (CAP) was 19.9 per 1000 person-y in the elderly aged ⱖ 60 y [1]. Koivula et al. [3] reported an incidence of 12.3 in the same age group. Outside Finland, the population-based estimates for the incidence of all CAP in the elderly (individuals aged ⱖ 65 y) have varied widely from 28.4 per 1000 person-y in the USA [4] to 3.2 per 1000 person-y in

Spain [5]. For hospitalized CAP, incidence estimates from 10 to 11 [6,7] up to 18.3 hospitalizations/1000 person-y [8] in the elderly aged ⱖ 65 y have been reported. Numerous pathogens are important in CAP, but Streptococcus pneumoniae (pneumococcus; Pnc) has been reported as the leading etiologic agent in the elderly [9–13]. The prevention of pneumococcal pneumonia in elderly individuals has proven difficult. The effectiveness of the pneumococcal polysaccharide vaccine has not been documented against nonbacteremic pneumococcal pneumonia in clinical trial settings [3,14–16]. Furthermore, the effectiveness estimates for all-cause clinical pneumonia have been

Correspondence: A. A. Palmu, National Institute for Health and Welfare (THL), Finn-Medi I, Biokatu 6, 33520 Tampere, Finland. Tel: ⫹ 358 29 524 7910. Fax: ⫹ 358 32 532 390. E-mail: [email protected] (Received 5 September 2013 ; accepted 26 November 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.876509


Community-acquired pneumonia in the elderly negative in these studies. Therefore, better vaccines or other prevention measures are needed. Recently, infant pneumococcal conjugate vaccination programs have also decreased the detected invasive pneumococcal disease burden in the elderly through indirect protection [17,18], but the impact on pneumonia remains unknown [19,20]. No data for the direct effectiveness of conjugate vaccines in adults or the elderly have been reported. The definition of pneumococcal pneumonia is problematic [21] as a sensitive and specific assay for the detection of pneumococcal pneumonia is lacking. The objectives of the Finnish Community-Acquired Pneumonia Epidemiological study (FinCAP Epi) were to document the feasibility of capturing CAP cases and obtaining samples, to define the optimal radiological and microbiological case definitions of all-cause and pneumococcal pneumonia, and to estimate their incidences for the evaluation of sample size for a vaccine trial. We also enrolled various groups of patients without pneumonia for comparison, in order to explore the performances of the assays in non-pneumonia patients.

Materials and methods Patient groups The FinCAP Epi study was a prospective observational study conducted from May 17, 2005 to May 17, 2007 in the city of Tampere, Finland. At that time, influenza vaccination was recommended and available free of charge through the National Vaccination Program (NVP) for individuals ⱖ 65 y of age or belonging to risk-groups. The estimated coverage of influenza vaccinations in the elderly was around 45–53% in the study area during the influenza seasons 2005 to 2007. Pneumococcal polysaccharide vaccine was not included in the NVP. Pneumococcal conjugate vaccine was commercially available, but not included in the infant NVP. The use of both vaccines was low. A specific study clinic with physicians and nurses was established. Subjects were enrolled at the municipal city hospital on-call clinic and at the nearby Tampere University Hospital (TAUH) emergency department and from the in-patient wards of both hospitals. Non-institutionalized, non-immunosuppressed elderly patients aged ⱖ 65 y not treated in hospital within 1 week prior to the visit and living permanently in Tampere (source population 29,500) were eligible. Patients visiting the 2 hospitals with acute symptoms suggestive of pneumonia and radiological findings consistent with pneumonia as judged by the study physician were enrolled as clinical CAP patients. Chest X-rays (CXR) had to be taken within 48 h of hospital admission.

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For radiological confirmation of the CAP diagnosis in the enrolled patients, previous baseline, current acute, and follow-up visit (when available) CXRs were reviewed retrospectively by 2 radiologists from TAUH and by 1 international reviewer. An enrolled clinical CAP patient was considered to have radiologically confirmed CAP (CXR-CAP) if at least 2 of the 3 reviewers classified the case as probable or definite pneumonia. Radiologically definite pneumonia was defined as any opacity compatible with pneumonia seen on the acute visit CXR that diminished or disappeared during follow-up. Radiologically probable pneumonia was defined as acute visit CXR with any opacity compatible with pneumonia. A CXR-CAP episode starting at least 30 days after the start of the previous episode was regarded as a new episode. Clinical CAP patients not classified as CXR-CAP were designated as rejected CAP cases. Subjects with a final diagnosis of acute respiratory infection (ARI) without signs of pneumonia on CXR as judged by the study physician were enrolled as a comparison group (ARI patients). It was further required that ARI patients were not diagnosed with pneumonia within 30 days preceding and 30 days following enrolment in the study. A second comparison group, chronic lung disease (CLD) patients, was enrolled during the second year of the study from patients with an International Classification of Diseases 10th revision (ICD-10) discharge diagnosis of chronic bronchitis (J42), lung emphysema (J43), or chronic obstructive pulmonary disease (COPD, J42) at the TAUH pulmonary clinic. The CLD patients underwent spirometry and were in a stable condition without concurrent exacerbation. Informed consent was obtained from all subjects or their next of kin/guardians prior to any study procedure. The study protocol was approved by the TAUH ethics review board and the institutional review board of the National Institute for Health and Welfare, Finland (THL). Microbiological samples CAP and ARI patients were sampled at the acute visit for aerobic and anaerobic blood cultures, a venous blood sample with a paired convalescent sample 4–8 weeks later, urine, nasopharyngeal swab (NPS), and sputum. CLD patients were sampled for urine, NPS, and sputum. Detection of Streptococcus pneumoniae The following assays were performed for the detection of Pnc: culture of blood, sputum, and NPS; quantitative real-time PCR on sputum and NPS, including the following target genes: pneumolysin


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(ply), Pnc surface adhesin A (psaA, for first year samples only), and autolysin A (lytA); antigen detection in urine by Streptococcus pneumoniae NOW and in sputum by latex agglutination and Quellung; serology for PsaA and CbpA (choline-binding protein A) antigens with paired sera. Pnc CAP was defined by a combination algorithm developed using latent class analysis (LCA [22–24]) and the following data from different assays in several comparison groups (see Results). For culture of blood, 1 sample of at least 8 ml of blood for both aerobic and anaerobic cultures was tested by automated commercial culture methods. A spontaneously produced or induced sputum sample, using an NaCl nebulizer, was obtained. The purulent looking part of the sputum sample was spread on a glass microscope slide, air-dried, and stored at room temperature before transportation to the bacteriology laboratory. Part of the sample was stored for viral analyses and the left-over sputum was treated with sputolysin (DTT, dithiothreitol) and spread on a microscope slide, as above, for the determination of purulence. The sputolysin-treated sample was then plated undiluted and at a 1/100 dilution on chocolate, blood, and gentamicin blood–agar plates and incubated at 37°C for 24 h. The incubated plates were sent overnight to the bacteriology laboratory. Sputolysin-treated sputum was also transferred into plastic tubes (200 μl per tube) for DNA isolation for bacterial PCRs and for pneumococcal antigen detection and direct Quellung. All tubes were stored at ⫺ 70°C. The sputum quality was assessed by microscopy of the glass slide after Gram-stain. The quality was rated high if the ratio of leukocytes/epithelial cells was ⬎ 1 per low-power field [25]. Irrespective of the quality assessment, all samples were processed and assayed as planned. From the culture plates, Pnc, Haemophilus influenzae, and Moraxella catarrhalis were identified according to standard methods. A part of the homogenized sputum was mixed with pneumococcal omniserum and observed microscopically for the Quellung reaction, and a second part of the sputum was used for S. pneumoniae antigen detection (Remel Wellcogen polyvalent latex test; Thermo Scientific, Lenexa, KS, USA). For PCR analyses, DNA was extracted with commercial kits using a MagNaPure LC instrument (Roche Diagnostics, Germany). S. pneumoniae was detected by quantitative real-time PCRs targeted at ply; the method was modified by adding a melting curve analysis, lytA and psaA [26–28]. A value of 10 S. pneumoniae genomes/μl of sample was used as a cutoff for positivity in all 3 PCRs. Deep NPS samples were collected with a calcium alginate swab, as recommended by the World Health

Organization (WHO) [29]. The swabs were stored in STGG (skim milk, tryptone, glucose, and glycerol) medium at ⫺ 70°C or lower. The presence and quantity of Pnc was assessed by direct culture and by PCR as described above. Pneumococcal isolates were serotyped as described previously [30]. For urine, the Binax NOW antigen tests for S. pneumoniae (Inverness Medical Innovations, Cranfield, UK) were performed in accordance with the manufacturer’s instructions by the study nurses. Serology for PsaA and CbpA was performed with the methods developed at GSK Vaccines. Detection of other respiratory pathogens H. influenzae and M. catarrhalis were identified by a positive culture result in high-quality sputum for the entire duration of the study. During the first year of the study, other pathogens were also assayed for CAP patients. Chlamydia pneumoniae (a ⱖ 4-fold rise of IgG or IgA antibodies in paired sera) and Mycoplasma pneumoniae (a positive result in the follow-up serum (an enzyme immunoassay unit (EIU) value ⬎ 45 for IgG and EIU ⬎ 12 for IgA) and at least 1.5-fold or 1.3-fold EIU increase in paired sera, depending on the EIU values in the acute sera) were detected by serology using commercially available diagnostic kits. For C. pneumoniae, the microimmunofluorescence (MIF) method was used, and for M. pneumoniae, an enzyme-linked immunosorbent assay (ELISA) was used; both were supplied by Ani Labsystems Ltd, Vantaa, Finland. Influenza virus types A and B and respiratory syncytial virus (RSV) were detected by a nested-type, multiplex reverse-transcription PCR (RT-PCR) assay performed on sputum samples. The nucleotide sequences for the primers have been published previously [31], and the multiplex format has been adapted from the work published by Walsh et al. [32]. Parainfluenza virus types 1 and 3 were detected in sputum samples by a real-time RT-PCR assay [33]. Influenza serology was done by standard hemagglutination inhibition test in accordance with the WHO recommendations. Antibodies to RSV were determined by an in-house enzyme immunoassay using a glycine–NaOH extract of RSV-infected cultured cells as antigen. Legionella pneumophila antigen detection in urine was performed with the commercial Binax NOW Legionella antigen test (Inverness Medical Innovations). Collection of additional data CAP and ARI patients were interviewed for comorbidities and potential risk factors. Study physicians performed a clinical examination, and

Community-acquired pneumonia in the elderly clinical laboratory assays were performed. We also collected patient records at the follow-up visit to obtain data on patient care and resources used. Furthermore, all clinical CAP ICD-10 diagnoses were collected during the entire study period from the records of the 2 hospitals, and the patient records were reviewed retrospectively for study inclusion and exclusion criteria.


Case definition for pneumococcal CAP By applying LCA [23] we adopted the following case definition for pneumococcal CAP in the elderly: (1) encapsulated Pnc cultured from blood, or (2) encapsulated Pnc cultured from high-quality sputum, or (3) at least 2 of the following: (a) urine Pnc antigen positive; (b) at least 2-fold increase in serum antiPsaA and/or anti-CbpA antibodies; (c) detection of Pnc from sputum of any quality or from NPS by either culture (encapsulated Pnc) or lytA PCR.

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Incidence of CAP irrespective of etiology According to the retrospective register data collection and chart review, we captured 53% (490 of 930) of the clinical CAP cases diagnosed at the 2 hospitals during the study period. Including those verified in registers, the incidence of clinical CAP was 15.8/1000 person-y (95% confidence interval (CI) 14.8–16.8) during the study period (Figure 1). The incidence of enrolled CXR-CAP was 5.5/1000 person-y (95% CI 4.9–6.1). When taking into consideration the non-captured CAP patients, the adjusted incidence was 10.5/1000 person-y. The unadjusted incidence of CXR-CAP by gender and age group is shown in the (Supplementary Figure 1 available online at http://informahealthcare. com/doi/abs/10.3109/00365548.2013.876509). The incidence rate ratio for males compared to females was 1.7 (95% CI 1.4–2.1).

Etiology of CAP Data analysis Incidences were calculated using population denominator data by age group and gender at the end of each calendar year, excluding subjects living permanently in institutions. Incidence figures were adjusted based on the proportion of clinical CAP patients enrolled in the study out of all clinical CAP cases identified from the hospital register data verified as eligible to participate in the study. Results Enrolment of patients A total of 490 clinical CAP cases in 462 subjects were included in the study. Altogether 323/490 (66%) episodes in 305 subjects were CXR-CAP cases. There were 2 episodes in 12 subjects and 3 episodes in 3 subjects.The remaining 167 clinical CAP patients were classified as rejected CAP cases. In addition, 101 ARI patients were enrolled at their acute visit. Of these, 18 were rejected after retrospective assessment because they were not eligible according to the protocol. Of the 127 stable CLD patients enrolled, 106 had the diagnosis of COPD confirmed by spirometry (FEV1/FVC or VC ⬍ 0.70). For 16 patients, the COPD diagnosis was not confirmed. Their clinical diagnoses included chronic bronchitis, bronchiectasis, and emphysema. For 5 patients spirometry was not performed. The background characteristics and prognostic factors for the different patient groups are presented in Table I.

Samples obtained and the proportions of positive results of pneumococcal assays for available samples are shown in Table II. None of the assays alone showed a high yield of positivity with presumed high specificity when compared to the other patient groups. High-quality sputum with encapsulated Pnc culture showed moderate prevalence in the CAP cases, with substantially lower prevalences in the comparison groups. However, such a sample was only available for roughly half of the subjects (Table II). The case definition created using the LCA yielded a 17% prevalence of pneumococcal CXRCAP. With this case definition, the incidence estimate for CXR-confirmed Pnc CAP was 0.95/1000 person-y (95% CI 0.7–1.2). Assuming the same proportion of CXR-confirmed Pnc CAP among the non-captured CAP patients, the estimated incidence of CXR-confirmed Pnc CAP in the elderly would be 1.80/1000 person-y. The incidence rate ratio for males compared to females was 2.4 (95% CI 1.4–4.1),(Supplementary Figure 2 available online at http://informahealthcare.com/doi/abs/10.3109/00 365548.2013.876509). The CURB-65 score distribution was similar in Pnc CAP and non-Pnc CAP. The most common pneumococcal serotypes detected in blood, sputum, and NPS are shown in Table III. Coverages for the available 10-, 13-, and 23-valent vaccines were highest in blood (67–89%), intermediate in sputum (45–63%), and lowest in NPS (38–59%). The etiological findings of the CXR-CAP cases and rejected CAP cases including all respiratory pathogens assayed are shown in Table IV. The 2 patient groups differed in the detected frequency of 2 organisms: Pnc

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Age, y, median (range) Gender, % male Current smoker, % Antimicrobial exposure within 2 weeks before enrolment, % Previous pneumococcal vaccination, % Influenza vaccination within 1 y, % Comorbidities, % Cardiac illness Cerebrovascular illness Dementia Diabetes or impaired glucose tolerance Malignant disease Chronic pulmonary disease Renal insufficiency Prognostic factors Hospitalized, % Length of stay in hospitalized, days, median CURB-65 score 1, % CURB-65 score 2, % CURB-65 score 3–5, % 30-day mortality, %

Radiologically confirmed CAP (n ⫽ 323)a

Rejected CAP (n ⫽ 167)

ARI (n ⫽ 83)

Stable CLD (n ⫽ 127)

79 (65–97) 50 9 39 5 64

80 (65–94) 50 13 31 3 56

78 (65–99) 41 13 25 5 64

72 (65–86) 68 25 2 6 76

60 18 13 19 15 39 10

54 23 16 22 18 30 6

51 14 6 20 7 33 10

85 9 34 40 25 5

80 10 36 45 19 1

47 8 NA NA NA 1

45 11 3 17 13 100 6 0 NA NA NA NA 0

CAP, community-acquired pneumonia; ARI, acute respiratory infection; CLD, chronic lung disease; CURB-65 ⫽ Confusion, Urea ⬎ 7 mmol/l, Respiratory rate ⱖ 30/min, low Blood pressure (systolic ⬍ 90 mmHg or diastolic ⱕ 60 mmHg), age ⱖ 65 y [34]; NA, not asked/not applicable. aSubjects with missing data vary for different factors.

was detected strikingly more often in the CXR-CAP cases and influenza A in the rejected cases.

and February 2007). Pnc CAP showed minor seasonal variation and peaks were seen in December 2005 and 2006 before the yearly influenza epidemics.

Seasonal variation There was a marked seasonal variation in the monthly incidence of CAP (Figure 2). The incidence peaks did not clearly coincide with the influenza epidemics in the hospital district of the study area (March 2006

Discussion Our study showed that CAP causes a considerable disease burden in the elderly, requires hospitalization in most cases, and has a high associated mortality of

80 70 Incidence per 1000 person years


Table I. Baseline characteristics and prognostic factors of the different patient groups.

60

Males Females

50 40 30 20 10 0 65-74

75-84

85+

Age, years Figure 1. Incidence of clinical community-acquired pneumonia (CAP) by gender and age. Includes enrolled and non-enrolled cases found in the register and chart review.

Community-acquired pneumonia in the elderly

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Table II. Results of different pneumococcal assays in the different patient groups for the available samples.


Radiologically confirmed CAP n (%) Cases Blood culture samples Encapsulated Pnc Urine samples Binax antigen Sputum sample (any) Culture, any Pnc Culture, encapsulated Pnc ply PCR psaA PCRb lytA PCR Latex antigen Quellung Sputum sample (HQ) Culture, encapsulated Pnc Nasopharyngeal swab Culture, any Pnc Culture, encapsulated Pnc ply PCR psaA PCRb lytA PCR Paired sera 2-fold increase in PsaA Ab 2-fold increase in CbpA Ab 2-fold increase in either Bacteriological Pnc CAP definition criteria fulfilled

323 319 9 281 27 226 50 40 89 23 50 41 42 170 35 306 37 32 38 20 25 264 29 34 43 56

(99)a (3) (87)a (10) (70)a (22) (18) (39) (27) (22) (18) (19) (53)a (21) (95)a (12) (10) (12) (13) (8) (82)a (11) (13) (16) (17)a

Rejected CAP n (%) 167 166 0 140 5 107 12 6 30 2 3 7 10 74 3 157 10 7 8 4 6 134 8 2 9 5

(99)a (84)a (4) (64)a (11) (6) (28) (6) (3) (7) (9) (44)a (4) (94)a (6) (4) (5) (5) (4) (80)a (6) (1) (7) (3)a

ARI n (%) 83 83 0 73 2 65 10 2 17 3 2 4 5 49 2 80 6 2 3 2 1 73 0 1 1 2

(100)a (88)a (3) (78)a (15) (3) (26) (11) (3) (6) (8) (59)a (4) (96)a (8) (3) (4) (4) (1) (88)a (1) (1) (2)a

Stable CLD n (%) 127 0a NA 125 (98)a 3 (2) 103 (81)a 6 (6) 3 (3) 44 (43) NA 10 (10) 5 (5) 3 (3) 65 (51)a 3 (5) 121 (95)a 7 (6) 3 (2) 3 (2) NA 1 (1) 0a NA NA NA 3 (2)a

CAP, community-acquired pneumonia; ARI, acute respiratory infection; CLD, chronic lung disease; Pnc, pneumococcus; HQ, high-quality sputum defined as ⬎ 1 leukocytes per epithelial cell per low-power field [25]; PsaA, Pnc surface adhesin A, CbpA, choline binding protein A; Ab, antibodies; NA, not available. aPercentages are % of cases (the rest are % of obtained samples). bpsaA PCR taken during the first study year only.

5%. S. pneumoniae was among the most common pathogens, with a prevalence of 17% according to our case definition. The estimated incidence of CXR-CAP in the whole source population (10.5/1000 person-y) was lower than that reported from previous Finnish studies (19.9 and 12.3/1000 person-y) in the elderly aged ⱖ 60 y [1,3], but our estimate of the hospitalized CAP incidence is in concordance with the estimates reported from the USA [6–8]. We found at least 1 potential etiological pathogen in 58% of the episodes, similar to recent reports on CAP etiology in adults [11–13,35]. Also, our estimate for the Pnc CAP prevalence was similar to those of recent studies (17% prevalence of all episodes; 32% of all episodes with at least 1 pathogen detected), although the yields of blood culture and urine antigen tests were lower compared to many previous results. Comparison to previous studies is hampered by the fact that nearly all adult studies reporting etiological results have included subjects aged ⱖ 18 y, mostly in tertiary care hospitals. Although half of the cases are usually elderly, the results specific to them are difficult to extract.

In addition to S. pneumoniae, H. influenzae and M. pneumoniae were also common bacterial findings in CXR-CAP. RSV was the most common virus detected in CXR-CAP cases. In previous studies, influenza A virus [11,12] or parainfluenza viruses [13,35,36] have been the most common viruses detected in pneumonia patients. In the current study, influenza A was found in less than 6% of the cases fulfilling the criteria of CXR-CAP, but was somewhat surprisingly found in more than 20% of the clinically suspected CAP cases that were rejected in the final CXR review. The influenza epidemics were relatively mild in Finland during the study period. Pnc was found far more often in the CXR-CAP group compared to the other subject groups in several assays performed. It is probable that the true prevalence was higher in CXR-CAP compared to the other subject groups, but it is also possible that the sensitivity of the tests may be higher in more severe disease. The estimated prevalences of the specific etiologic agents are likely to be underestimates of the true proportions, as factors such as low assay sensitivity,

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Table III. Number of pneumococcal serotypes in radiologically confirmed community-acquired pneumonia in the elderly.


Serotype 1b 3c 4b 6Ac 6Bb 7C 7Fb 9Nd 9Vb 10Ad 11Ad 14b 15Bd 15C 19Ac 19C 19Fb 21 22Fd 23A 23Fb 35B 35F NC Total NC of total Proportion PCV10 Proportion PCV13 Proportion PPV23

Blood

1 2

1 1

Sputum 1a 3a 2 2 3 1 1 2 1

1 1 1

1 3 1 1 1 1 9 1 1 1 3

0 9 0% 67% 78% 89%

2 10 51 20% 45% 57% 63%

1

NPS

3 2 2 0 1 1

1 1 4 1 1 1 1 5 1 1 2 1 3 5 37 14% 38% 54% 59%

NC, non-encapsulated; NPS, nasopharyngeal swab; PCV, pneumococcal conjugate vaccine; PPV, pneumococcal polysaccharide vaccine. aDuplicate finding in 1 sample. bPCV10 serotypes; cadditional PCV13 serotypes; dadditional PPV23 serotypes (serotype 6A not in PPV23).

missing samples and incomplete testing, antimicrobial treatment, suboptimal sampling and specimen processing, and different patient characteristics may decrease the yields. Access to care early during the disease process may reduce the sensitivities of the assays, especially in the frail elderly whose coping is compromised early in the disease process. Furthermore, obtaining adequate sputum samples may be especially difficult in elderly individuals. However, we were able to obtain the samples in high proportions with clear standard operating procedures and specifically trained and motivated study personnel. Antimicrobial exposure prior to the visit and sampling was common in our study population, but comparable to other similar studies. Antimicrobial exposure is difficult to avoid in this kind of prospective epidemiological study. Exclusion of these patients would probably have biased the results. Poor assay specificity may bias the prevalence estimates upwards. We explored the pathogen

prevalences in non-pneumonia patients as one way to evaluate the specificity of the assays. Also, previous nasopharyngeal carriage data from healthy elderly were available for comparison [37]. By definition, these groups did not have pneumococcal pneumonia, yet some groups, especially rejected CAP and ARI, probably had cases of non-CAP respiratory disease of pneumococcal etiology. An assay that was similarly positive in all patient groups, like ply-PCR, would hardly be a specific indicator of pneumococcal etiology in CXR-CAP. On the other hand, an assay giving the expected prevalence in CXR-CAP but lower prevalences in other patient groups would suggest that the assay positivity is associated with the disease process. The most accurate comparison group would have been non-pneumococcal pneumonia, but this was not available in the absence of a gold standard for Pnc CAP. Due to the pitfalls listed above we used statistical modeling to develop the case definition for Pnc CAP [23], which was optimized to result in the highest possible vaccine efficacy estimate with as low a sample size as possible in a vaccine trial. Thus, high specificity was particularly important, with less emphasis on high sensitivity of the case definition. Therefore, in the absence of positive blood culture or high-quality sputum culture of encapsulated pneumococcus, which alone are considered specific enough, our case definition required a combination of 2 positive results for the remaining Pnc assays. Our prevalence estimate is, however, an underestimation of the true Pnc CAP; the LCA modeling suggested a true Pnc CAP prevalence of 24% [23]. This was a population-based study with reliable estimates for the source population. The whole source population is served by 2 public municipal hospitals. There are no private hospitals treating elderly pneumonia patients, yet there are multiple private medical offices where pneumonia may be diagnosed and treated in outpatients. We may have missed some ambulatory patients, but the number of missed chest X-ray-confirmed ambulatory patients treated in private offices was probably low, because pneumonia is usually a severe disease in the elderly as indicated by the high hospitalization rate. We estimated the total incidences of CAP from the proportion of clinical patients enrolled out of all clinical CAP cases identified in the registers and verified using the chart review. This may result in biased estimates for the CXR-CAP and Pnc CAP if the populations of enrolled and non-enrolled patients were different. Based on the register and enrolment data, the proportion enrolled was similar in the different sex and age groups. However, there was a higher proportion of non-enrolled subjects at the university hospital clinic, with probably more


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Table IV. Positive results for all the pathogens in radiologically confirmed and rejected CAP patients in the FinCAP Epi study. Radiologically confirmed CAP (n ⫽ 323) Pathogen

Sample and method

Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis

Combination, see case definition High-quality sputum culture High-quality sputum culture


Influenza B virus Respiratory syncytial virus Parainfluenza 1 virus Parainfluenza 2 virus Parainfluenza 3 virus Any of the above positive

Number positive

Number, sample availablea

% positive

Number positive

Number, sample availablea

% positive

56

323

17

5

167

3

39

226

17

13

104

13

14

226

6

5

104

5

Radiologically confirmed CAP (n ⫽ 164)

First-year results only for the following Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila Influenza A virus



Paired serology

26

137

19

12

66

18

Paired serology

5

137

4

1

66

2

Urine antigen

1

142

1

0

61

0

Sputum PCR or serology Sputum PCR or serology Sputum PCR or serology Sputum PCR Sputum PCR Sputum PCR All above during the first year

9

153

6

16

74

22

1

153

1

0

74

0

16

153

10

9

74

12

2 2 3 95

112 112 112 164

2 2 3 58

3 0 1 40

46 46 46 77

7 0 2 52

CAP, community-acquired pneumonia. least 1 sample result available in case of ⬎ 1 assay in the definition.

aAt

severe patients with complex underlying diseases treated there. We found our prospective study methodology to be feasible and suitable for case detection in clinical

vaccine trials. However, further efforts will be needed to capture a higher proportion of CAP cases in a study setting, although it will be easier to detect cases in the closed prospectively enrolled population of a vaccine

70 Clinical CAP, adjusted CXR-confirmed CAP, adjusted

60

CXR-confirmed PncCAP, adjusted Influenza A and B reports of the study area in the National infectious diseases register

50

40

30

20

10

0 5 2005

6

7

8

9

10 11 12

1

2006

2

3

4

5

6

7

8

9

10 11 12

1

2

3

4

5

2007 Year and month

Figure 2. Numbers of community-acquired pneumonia (CAP) cases and register-based influenza cases by month of study. Adjusted for clinical cases found in the register and chart review.

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A. A. Palmu et al.

trial compared to the current open population-based approach. Pneumococcal pneumonia remains a considerable public health problem with a high proportion of hospitalization and a mortality of 5%; better prevention methods need to be pursued. Some reduction of the disease burden is expected due to infant vaccination programs, but the serotype coverage of even the 10- and 13-valent pneumococcal conjugate vaccines may not be adequate.


Acknowledgements We are indebted to the Tampere city and Tampere University Hospital administration and personnel for their collaboration. We sincerely thank all the elderly participating subjects for consenting to the study during an acute illness. Other members of the Finnish Community-Acquired Pneumonia Study Group are the following: THL steering group members: Helena Käyhty, Pirjo H. Mäkelä, Maija Leinonen; study physicians: Sirkka-Liisa Kaistinen, Ritva Syrjänen, Stiina Zitting; study nurses: Päivi Siren, Mervi Mannila, Eija Lahtinen, Seija Nieminen, Nina Pere, Maiju Välimaa; bacteriology: Leena Erkkilä, Paula Asumaniemi, Katariina Autio, Aili Hökkä, Eeva-Liisa Korhonen, Leena Kuisma, Katja Nummilinna, Anu Ojala, Marika Vainio; virology: Titta Koivula, Esa Rönkkö; immunology: Merja Väkeväinen; data management: M. Grönholm, E. Koskenniemi, E. Ruokokoski; secretariat: Ulla Johansson, Merja Martenson; radiologists: reviewers Tiina Kauppinen and Tuula Vierikko, Finland and Charles White, USA. GSK Finland: Markku Pulkkinen; GSK Belgium: Jeanne-Marie Devaster, Isabelle Henckaerts, Thierry Pascal, Jan Poolman, Pierre Vandepapeliere. This study was conducted in collaboration with GlaxoSmithKline Vaccines, which supported the study process and participated in the design, interpretation, and writing of the manuscript. Declaration of interest: The FinCAP Epi study was funded by GlaxoSmithKline. AAP has received travel expenses and honoraria from GlaxoSmithKline to attend expert group meetings and has had travel paid for by Merck to attend expert group meetings. He is the head of the Clinical Research Unit at the National Institute for Health and Welfare, which has received research funding from GlaxoSmithKline. JJ is the head of the Vaccine Research Unit at the National Institute for Health and Welfare, which has received research funding from GlaxoSmithKline. TM is director of the Department of Vaccination and Immune Protection at the National Institute for Health and Welfare, which has received research funding from GlaxoSmithKline. WPH and VV are

shareholders and employees of GlaxoSmithKline. AS, MS, PT, TZ, TK: no conflicts of interest.

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