Patient input and consideration by the GP Recommendations for good medical practice are guiding as support and guidance when making diagnostic or therapeutic decisions in general practice. They summarize for the general practitioner what is scientifically the best policy for the average patient. In addition, there is the agenda of the patient, who is an equal partner in decision-making. Therefore, through clear communication, the patient's question must be clear to the general practitioner and the general practitioner must inform the patient sufficiently about all aspects of the various policy options. It is therefore possible that the general practitioner and patient together make a different best choice in a responsible and reasoned manner. For practical reasons, this principle is not addressed repeatedly in the recommendations, but is explicitly stated here.

Introduction

Since 1995, the 23-valent polysaccharide pneumococcal vaccine has been registered in Belgium. However, the use of this vaccine remains limited in our country. For the indication age above 60 years, a vaccination rate of 22% in Flanders and 32% in Wallonia was proposed in 2000 (1) .

To date, few studies have been conducted investigating the effect of the vaccine on reducing morbidity and mortality caused by pneumococcal infections, in particular pneumococcal pneumonia, in the elderly and at-risk groups for whom the vaccine is classically recommended (2) .

In 2000, the results of the 'Kaiser Permanente Efficacy Trial' were published, a Randomised Controlled Trial (RCT) to determine the effectiveness of a 7-valent conjugated pneumococcal vaccine in preventing pneumococcal infections in children (3) . This 7-valent conjugated vaccine was specifically developed for use in young children (4) , given their high risk of invasive pneumococcal infections and the lack of effectiveness of the polysaccharide pneumococcal vaccine.

Discussion of this new vaccine and vaccination in young children is beyond the scope of this recommendation.

The pneumococcus

Epidemiology of pneumococcal infections

Streptococcus pneumoniae is the most important etiologic agent of community-acquired pneumonia, accounting for 30-40% (5) and is a major cause of invasive infections (6) . In the United States, the annual incidence of invasive pneumococcal infections is estimated at 15 to 30 per 100,000 persons in the community. These incidence rates are two and a half times higher for those over 65 (50 to 83 per 100,000 per year) and almost ten times higher in children under 2 years of age (160 per 100,000 per year) (7) .

The incidence figures for pneumococcal pneumonia are unreliable. This is partly due to the problem of diagnosis, especially in the case of a non-bacteraemic form (8) . In the Netherlands, the figures for pneumococcal pneumonia fluctuate between 1 and 12 per thousand persons per year (9) . In Flanders, the diagnosis of pneumonia is made in general practice almost 5 times per thousand patients per year (10) . For the age group over 60 years, the incidence figures for pneumonia are assumed to be 25 per thousand per year, of which 30 to 40% is caused by pneumococci (11) .

The mortality related to pneumococcal pneumonia and pneumococcal bacteraemia is 5 to

10% and 15 to 20% respectively. The mortality of invasive pneumococcal infections in elderly patients and patients with chronic diseases increases to 30-50% (12) .

The number of invasive infections in people over 65 years of age in our country is estimated at 1,000 to 1,200 per year (13) .

Risk factors for pneumococcal infections

A high risk of pneumococcal infection is defined as an increased chance and/or a more severe course of pneumococcal infection in a group of individuals, compared to the general population. Pneumococcal infections are more common in individuals with reduced resistance to infections. Pneumococcal infections also occur more easily in certain clinical pictures or have a worse prognosis.

Pneumococcal infections are more common in infants, young children and persons over 60 years of age. They also have a poorer prognosis in these groups. Persons with asplenia, sickle cell disease, CSF leakage and HIV infection have a greatly increased risk of infection. Other risk groups include patients with Hodgkin's disease, chronic lymphocytic leukaemia, multiple myeloma, renal disease, autoimmune diseases, persons who have had an organ transplant and are on immunosuppressive therapy (14) . Persons with alcoholism, chronic heart failure, COPD (no asthma) also have an increased incidence or worse course of infection. Patients with diabetes mellitus are often mentioned as a risk group, although there is no evidence of an increased risk of pneumococcal infections, unless associated with one of the above risk factors (15) .

Antimicrobial resistance

The reduced sensitivity of pneumococci to antibiotics is a fact. Every year in Belgium, a progressive increase in resistance to penicillins, tetracyclines and erythromycins is reported. For 2002, there was a certain stabilisation (respectively 15.1%, 30.7% and 36.1%) (16) . Depending on the capsule type, there are also differences in the resistance profiles. The most common capsule types that cause invasive infections are those that show the most resistance to the mentioned antibiotics.

Motivation for the recommendation

From the epidemiological data we can deduce that pneumococcal infections, especially pneumococcal pneumonia, are frequent and that every general practitioner sees them often. Furthermore, during influenza epidemics, a mortality is observed that is usually attributed to pulmonary causes.

The polysaccharide pneumococcal vaccine could be useful if it protects well. We want to know:

• whether the vaccine is useful in reducing pneumococcal infections, how useful it is and for whom?
• whether there is an additive effect of the pneumococcal vaccine in reducing pulmonary complications of influenza in the risk groups?
• which vaccines are available, how they should be administered and what is their safety profile?
• What strategies are we going to use to reach the target groups?

Efficacy in preventing pneumococcal infections

If we compare the guidelines of other associations or authorities (17) , we can conclude that there is no unanimity regarding the target groups (18) .

Only a few RCTs have been conducted to investigate the effectiveness of the pneumococcal vaccine (19) . Moreover, these studies were conducted under very different circumstances: different population groups and continents, with varying valences of the vaccine and over a very wide period (1946-1999). Some RCTs were even conducted with such small groups that the effect of the intervention is difficult to demonstrate.

Eight meta-analyses have been published on the efficacy of pneumococcal vaccine in adults (20) . From the studies with the highest level of evidence, we can conclude the following (21) :

• The efficacy of the vaccine could not be demonstrated in high-risk patients and the elderly for the outcomes pneumococcal pneumonia and pneumonia-specific mortality (22 , 23) .
• The two most recent meta-analyses suggest an effect of the vaccine in the prevention of invasive pneumococcal infections in adults and the elderly (24 , 25) .
• The efficacy of the vaccine could not be demonstrated in patients with COPD or bronchial carcinoma for clinical endpoints such as pneumonia, pneumococcal pneumonia and invasive pneumococcal infections (26) .
• Some meta-analyses find an effect of the vaccine in low-risk groups for the outcomes pneumococcal pneumonia (27) , invasive pneumococcal disease (28) , and pneumonia-specific mortality (29) . However, these results were based on very old study data or data from studies that were not conducted under comparable conditions.

Observational studies (30) have also been conducted to demonstrate the usefulness of the vaccine (31) . From these we can conclude that:

• it is plausible that the vaccine is effective in preventing invasive pneumococcal infections in:
  • patients with anatomical asplenia, with an effectiveness of 77% (95% CI 14-95) (32) ;
  • patients with cardiovascular disease, with an effectiveness of 69% (95% CI 17-88) (33) ;
  • patients with chronic lung diseases (including asthma), with an effectiveness of 65% (95% CI 26-83) (34) ;
  • patients with alcohol abuse, with an effectiveness of 61% (95% CI 47-72) (35) ;
  • patients over 65 years of age, with an effectiveness of 44% (95% CI 7-67) (36) .
• the vaccine has not been shown to be effective in preventing invasive pneumococcal disease in immunocompromised patients (37 , 38) .

A large retrospective cohort study concludes that the vaccine is not effective in preventing community-acquired pneumonia in people aged 65 and over (39) .

Additive effect in the prevention of influenza-induced pulmonary complications

For this we can refer to three recent studies that have investigated this: one pseudorandomized study in people aged 65 and over (40) , one prospective cohort study in elderly patients with COPD (41) and one large prospective cohort study in people aged 65 and over (42) .

These studies show that patients vaccinated with both vaccines indeed have a reduced chance of being admitted to hospital for the diagnosis of influenza and pneumonia. However, this does not allow us to conclude that the effect is additive, due to the known effectiveness of the influenza vaccine against these outcomes.

Decision and recommendation

Meta-analyses, RCTs and observational studies could not demonstrate that the polysaccharide pneumococcal vaccine is effective in preventing pneumococcal pneumonia in high-risk patients and the elderly. The most recent meta-analyses did indicate a protective effect of the vaccine in preventing invasive pneumococcal infections in the elderly (see box).

Observational studies also indicate that the vaccine is effective in preventing invasive infections in the elderly and some risk groups. Whether the vaccine has an additive protective effect on pulmonary complications of influenza has not yet been proven.

Recommendation Based on the current state of knowledge about the effectiveness of the vaccine, we recommend that Flemish general practitioners: Despite the limited evidence of the efficacy of the vaccine, vaccinate patients at greatly increased risk of fulminant pneumococcal infections (evidence level 3) . This group includes patients with functional or anatomical asplenia. In elective splenectomy, the patient is vaccinated two weeks before the procedure; in non-elective (traumatic) splenectomy, the vaccine is administered within two weeks of the procedure. to discuss the appropriateness of vaccination with immunocompetent adult patients who are at increased risk of invasive pneumococcal disease. This group includes patients aged 50 years and older with chronic cardiovascular disease, chronic pulmonary disease (not asthma), alcohol abuse and patients aged 65 years and older. This discussion may take place at the time of the annual influenza vaccination or another vaccination status check. Topics to be discussed include: increased incidence, lack of evidence of vaccine efficacy in preventing pneumococcal pneumonia, evidence of vaccine efficacy in preventing invasive pneumococcal disease, vaccine safety, cost, side effects and revaccination (level of evidence 1) . to provide appropriate information about the vaccine to patients who ask questions (level of evidence 3) .

Levels of evidence Level 1 For level 1, the condition is that there are at least two independently conducted studies of good quality with similar results: RCT, independent blind comparison of diagnostic test with reference test or prospective cohort study. Systematic reviews or meta-analyses of this type of research with a high degree of consistency are also sufficient to achieve this level of evidence. Level 2 For level 2, the condition is that there are at least two independently conducted studies of moderate quality with similar results: RCT, independent blind comparison of diagnostic test with reference test, retrospective cohort study or case-control study. Systematic reviews or meta-analyses of this type of research with a high degree of consistency are also sufficient to achieve this level of evidence. Level 3 Level 3 is awarded if good quality comparative studies (RCTs) are lacking or if the results of RCTs and meta-analyses are contradictory. This level also includes expert opinions and consensus within the author group. (See also: Van Royen P. Levels of evidence. Huisarts Nu 2002;31:54-7.)

Carrying out the vaccination

Pneumococcal vaccines

Since October 2004, two types of pneumococcal vaccines have been available on the Belgian market: the 23-valent polysaccharide pneumococcal vaccine (Pneumo 23®) and the 7-valent conjugated pneumococcal vaccine (Prevenar®).

The polysaccharide pneumococcal vaccine

The currently available polysaccharide vaccine (Pneumo 23®) contains 23 purified capsular polysaccharide antigens of Streptococcus Pneumoniae. According to figures from the national reference laboratory, the vaccine contains 95% of the serotypes isolated in 2002 as the cause of invasive pneumococcal infections. The vaccine contains the serotypes that show the greatest resistance to antibiotics. After vaccination, type-specific antibodies appear. The immune response is not equally strong for each capsular type. Polysaccharide vaccines are not immunogenic in children under two years of age (see below). They are also less immunogenic in individuals with impaired immune systems (43) .

The pneumococcal conjugate vaccine

Recently, the conjugated pneumococcal vaccine (Prevenar®) has become available, which is immunogenic in infants and young children. It is a vaccine that conjugates the pneumococcal antigen to a protein carrier. This vaccine currently contains seven serotypes that are frequently found in infants and young children. Due to the physical properties of these protein conjugates, it is not possible to compose a high-strength vaccine with more than ten serotypes. Discussion of the use of this vaccine falls outside the scope of this recommendation.

Reaching the target groups

To reach patients with asplenia, a proactive intervention by the general practitioner is necessary. The presence of this risk factor must be noted in the medical file. The general practitioner is made aware of the indication for the vaccine (44) , either when opening the electronic medical file (EMD) or by riders placed on the paper patient files. He can invite the patient if necessary.

In elective splenectomy, vaccination is given fourteen days preoperatively. In non-elective surgery, the vaccine should be given as soon as possible after splenectomy (45) . Administration in hospital upon discharge of the patient is recommended.

The risk groups that overlap with the indications for the annual influenza vaccine are identified using the strategies as described in the recommendation Prevention of influenza (46) . The GP can use this vaccination moment or another consultation moment to discuss the opportunity for vaccination against pneumococci.

Information for the patient

The GP informs the patient who belongs to the risk groups about the increased risk of serious pneumococcal infections (47) . He states that the vaccine has no proven effect in preventing pneumococcal pneumonia. The usefulness of the vaccine is therefore aimed at the prevention of invasive pneumococcal infections for which it is plausible that the vaccine provides approximately 50% protection. The GP also discusses the safety of the vaccine, possible side effects, cost and frequency of vaccination.

Administration, precautions and contraindications

The vaccine is administered subcutaneously (SC) or intramuscularly (IM). This can be done together with other vaccines, but of course at a different injection site.

The safety of the vaccine in pregnant women has not been established. However, there is little reason to expect that vaccination in the first trimester of pregnancy will affect fetal development (48) .

There are no contraindications to pneumococcal vaccination other than a known severe hypersensitivity reaction to a previous dose or to any of the components of the vaccine (49) .

A booster vaccination is contraindicated in persons who had a severe reaction to the first dose (anaphylaxis and Arthus reaction) (50) .

Side effects are limited to a tender spot at the injection site and occur in 3% after the first vaccination and in 11% after a booster vaccination (51) . After a too early booster vaccination (less than three years interval) a more pronounced local reaction may occur. Serious or systemic side effects are rare.

The administration of the vaccine is recorded in the medical file and on the patient's vaccination card. The vaccination card is mainly used to avoid over- and under-vaccination (52) .

Revaccination

We recommend that patients with functional and anatomical asplenia be revaccinated once after five years (53) . In addition, it is advised to revaccinate elderly people over 65 years once if at least five years have elapsed since the first administration (54) . For the other risk groups, routine revaccination is not necessary (55) .

Creation

Departure point

Every year, a sensitive search strategy is used in Medline and the Cochrane Library to find publications related to the key messages of the recommendations.

According to the follow-up procedure of the recommendations, in addition to this annual update, a complete revision is required after five years. This is done in accordance with the procedures for the composition of the group of authors, literature research, review by experts and general practitioners, consensus meetings and validation.

Comparison guidelines

The first step in the literature search is the comparison of existing guidelines on the subject and of the commentaries on the original studies, meta-analyses and systematic reviews that have been published on the subject.

For the recommendation on the use of the polysaccharide pneumococcal vaccine in adults, several recommendations and commentaries were found. The search was conducted via the website of the Project Farmaka and of the 'National Guidelines Clearinghouse'. Among others, the guideline of the Superior Health Council, 'Centers for Disease Control and Prevention', 'Canadian Medical Association', SIGN and 'Australian Prescriber' discuss this subject. Commentaries were found in:

• Govaerts F. Pneumococcal vaccination in general practice. Huisarts Nu (Minerva) 1999;28:244-7.
• van Driel M. Pneumococcal vaccination. Huisarts Nu (Minerva) 2000;29:366-9.
• Clinical Evidence 2002;8:1546-57.
• Revue Prescrire 1997;17(176).
• Revue Prescrire 1999;19(201).
• messages VRGT 1999;9(1).
• Folia pharmacotherapeutica, June 2001
• Folia pharmacotherapeutica, August 2003
• Medicines letter 1997;4(1).

Additional literature research

After comparing the existing guidelines, the literature was searched for original studies and meta-analyses published to date on the effectiveness of the vaccine in risk groups. The following medical databases were consulted: Pubmed, Cochrane library, SumSearch in the period October November 2003 with the keywords “Pneumococcal Vaccine” AND “Clinical Trial” AND “RCT” AND “Practice Guideline”, with the limit “review after 1995”. After the first search, two more publications were added that appeared to be relevant to the subject, namely one meta-analysis and one large cohort study. For reaching the target groups, reference is made to the text and associated literature and search strategy of the recommendation Prevention of influenza (56) .

Assessment

After reading the literature based on checklists for critical reading, the first text was written and discussed with the co-authors. The first discussion took place on 20 January 2004. This happened again in the steering group Recommendations of the Scientific Association of Flemish General Practitioners on 29 January 2004. The comments were incorporated into the text.

The experts were then sent the text for review. This review formed part of the recommendation Prevention of influenza (57) . During a consensus meeting on 6 July 2004, the comments of the experts were discussed, and the text was subsequently amended on a number of points (58) . The experts were informed of the manner in which and the extent to which their comments were incorporated into the recommendation text.

In the various consensus meetings, there appeared to be uncertainty about the extent to which GPs would actually put specific tasks from the recommendation into practice. The most important questions that arose were included in the review by GPs.

A general request via e-mail to LOK groups to discuss the text did not yield any response. The full text and four specific questions (questionnaire) were therefore offered to 37 interested GPs. The questionnaire itself was discussed on 7 September 2004. We processed sixteen completed response forms. Even after this, there remained great uncertainty about one issue: the feasibility of the recommendation by doctors who do not use a computer file. This sticking point was briefly discussed at a refresher evening. Based on the answers, the text was further nuanced.

On 18 November 2004, the steering group Recommendations gave its approval to submit the recommendation for validation to CEBAM. At the same time, it was submitted for discussion to the editorial staff of Huisarts Nu.

Authors and experts

The authors of this recommendation are: Dr. Nathalie Van de Vyver (scientific employee of the Scientific Association of Flemish General Practitioners, theme responsible for vaccinations), Dr. Frans Govaerts (first author of the recommendation Prevention of Influenza) and Dr. Ann Pilaet (responsible for the practical project Pneumo-coccal vaccination).

The experts involved were: Prof. Dr. W. Peetermans (Head of the Department of Internal Medicine, University Hospital Gasthuisberg), Prof. Dr. K. Hoppenbrouwers (Senior Lecturer Faculty of Medicine, Department of Public Health, Catholic University of Leuven), Dr. K. De Schrijver (Provincial Health Inspectorate Antwerp), Prof. J. Verhaegen (Pneumococcal Reference Laboratory, University Hospital Gasthuisberg) and Prof. R. Peleman (Chief Physician University Hospital Ghent).

The experts and authors have no ties to the pharmaceutical industry or other interest groups.

This recommendation was developed with the support of the Flemish Community. This has in no way attempted to influence the content of the recommendation.

This recommendation was developed under the coordination of the Steering Committee on Recommendations of the Scientific Association of Flemish General Practitioners (Prof. Dr. Paul Van Royen, Dr. An De Sutter, Dr. Jan Michels, Dr. Samuel Coenen, Dr. Lieve Peremans, Dr. Hilde Philips, Dr. Frans Govaerts, Dr. Nathalie Van de Vyver and Cil Leytens) and with the support of the Flemish Community.

Footnotes

1

Bossuyt N, Van Casteren V. Pneumococcal vaccination in the elderly by the general practitioner. Epidemiological Bulletin 2002;42.

2

www.health.fgov.be/CSH_HGR/Nederlands/Brochures/nl2002_pneumokoken.pdf

3 

Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-95.

4 

Depending on age, other serotypes are responsible for pneumococcal infections. The 7-valences included in the conjugate vaccine are those most responsible for infections in children. In principle, this vaccine has no place for use in adults.

5 

Jonkers RE, Boersma WG. Pneumococcal vaccination of adults. Ned Tijdschr Geneeskd 2003;147:437-41.

6 

Invasive infections are when the germ is isolated from a normally sterile fluid of the body. In 90% of cases this is a bacteremia.

7

Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-8):1-24.

8 

Ten to 25% of pneumococcal pneumonias are complicated by bacteremia.

9 

Hak E, Van Essen GA, Grobbee DE. How effective is pneumococcal vaccination in general practice. Huisarts Wet 1998;10:470-5.

10

Diagnosis R81 pneumonia (registration period 1999-2003); www.intego.be (consulted on 23 June 2005).

11 

Fedson D, Henrichsen J, Makela PH, et al. Immunization of elderly people with polyvalent pneumococcal vaccine. Infection 1989;17:437-41.

12 

Peetermans W. Arguments for pneumococcal vaccination in everyone over 65 years of age. Tijdschr Geneeskd 2000;56:1318-24.

13 

The national reference laboratory receives isolates from more than one hundred laboratories, and the population reached is estimated at more than 50% of the Belgian population. For 2002, 641 samples were received for the age group of 60+ (bacteremia, pleurisy and meningitis). This age group is responsible for almost 50% of invasive pneumococcal infections. From this, an annual incidence of 54 per hundred thousand can be calculated, which is in line with the international literature.

• Verhaegen J. Surveillance of pneumococcal infections in Belgium. [Report] Leuven: UZ Gasthuisberg, 2002.

14 

Bruyn GAW, van Furth R. Pneumococcal polysaccharide vaccines: indications, efficacy and recommendations. Eur J Clin Microbiol Infect Dis 1991;10:897-910.

15 

Lipsky BA, Boyko EJ, Inui TS, et al. Risk factors for acquiring pneumococcal infections. Arch Intern Med 1986;146:2179-85.

16 

Verhaegen J. Surveillance of pneumococcal infections in Belgium. [Report] Leuven: UZ Gasthuisberg, 2002.

17 

• Canadian Immunization Guide. Health Canada, Population and Public Health Branch, 2002;177-84. www.ahrq.gov/clinic/2ndcps/adultimm.pdf

• Guidelines of the Dutch Health Council: www.gr.nl

The guideline of the Superior Health Council (SHC) for the use of pneumococcal vaccine was formulated in 1993. There is no reference to scientific literature. There is no mention of the level of evidence or the strength of the recommendation per target group. The guideline was ratified in 1996 by the Belgian pneumococcal vaccine working group in a consensus report. In 1999, an update of the consensus report was made with references to the literature: Peleman RA, Peetermans WE, Van Laethem Y, Bachez PG, et al. Prevention of pneumococcal disease: an update on the Belgian consensus report. Acta Clinica Belgica 1999;54:321-8.

• www.health.fgov.be/CSH_HGR/Nederlands/Brochures/nl2002_pneumokoken.pdf

• SIGN: Scottish Intercollegiate Guidelines Network: www.sign.ac.uk/guidelines/fulltext/59/section9.html

• Canadian Task Force on Preventive Health Care: www.ctfphc.org

• US Centers of Disease Control and Prevention; Recommendations of the Advisory Committee on Immunization Practices: Pneumococcal Polysaccharide: www.cdc.gov/nip/publications/acip-list.htm

• WHO position paper on pneumococcal vaccination: www.who.int/docstore/wer/pdf/1999/wer7423.pdf

18 

The vaccine is recommended for the over-65s in most guidelines, but not by the Canadian Task Force on Preventive Health Care and the Dutch Health Council, who refer to a meta-analysis by the Dutch Cochrane Centre. Most recommendations state the strength of the recommendation for each target group and also the level of evidence of the supporting scientific literature. For the target group of the over-65s, the strength of the recommendation in the international guidelines is 'medium'. The motivation for recommending the vaccine for the elderly is mainly based on observational retrospective research showing that it is plausible that the vaccine is effective in reducing the number of invasive pneumococcal infections in this target group.

19 

• Kaufman P. Pneumonia in old age: active immunization against pneumonia with pneumococcus polysaccharide - results of a 6 years study. Arch Intern Med 1947;79:518-31.

• Mac Leod CM, Hodges RG, Heidelberg M, et al. Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J Exp Med 1945;82:445-65.

• Austrian R, Douglas RM, Schiffman G, et al. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Phys 1976;89:184-94.

• Smit P, Oberholzer D, Hayden-Smith S, et al. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 1977;238:2613-6.

• Riley ID, Tarr PI, Andrews M, et al. Immunization with a polyvalent pneumococcal vaccine. Lancet 1977;1:1338-41.

• Austrian R. Surveillance of pneumococcal infection for field trials of polyvalent pneumococcal vaccines. Bethesda, Md: National Institute of Allergy and Infectious Diseases, 1980:1-59. National Institutes of Health publication DAB-VDP-12-84;Contract N01 A13257.

• Davis AL, Aranda CP, Schiffman G, et al. Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease. A pilot study. Chest 1987;92:204-12.

• Leech JA, Gervais A, Ruben FL. Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease. CMAJ 1987;136:361-5.

• Gaillat J, Zmirou D, Mallaret MR, et al. Clinical antipneumococcal vaccine clinic for the personal survival of the institution. Rev Epidemiol Santé Publique 1985;33:437-44.

• Klastersky J, Mommen P, Cantraine F, et al. Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma. Eur J Cancer Clin Oncol 1986;22:807-13.

• Simberkoff MS, Cross AP, Al IM, Geiseler PJ, et al. Efficacy of pneumococcal vaccine in high risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;315:1318-27.

• Ortqvist A, Hedlund J, Burman LA, et al. Randomized trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998;351:399-403.

• Koivula I, Sten M, Leinonen M, et al. Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997;103:281-90.

• Honkanen PO, Keistinen T, Miettinen L, et al. Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 1999;17:2493-500.