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Pneumococcal respiratory disease and vaccines 

Pneumococcal respiratory disease and vaccines
Chapter:
Pneumococcal respiratory disease and vaccines
Author(s):

Thomas Bewick

and Wei Shen Lim

DOI:
10.1093/med/9780199588084.003.0008
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Key points

  • Streptococcus pneumoniae is the predominant bacterial pathogen implicated in all lower respiratory tract infections

  • The organism's pathogenicity is to a large extent due to its polysaccharide capsule, which also enables classification into different serotypes/serogroups

  • Risk factors associated with pneumococcal pneumonia include HIV infection, defects in humoral immunity, asplenia, diabetes mellitus, cancer, high alcohol intake, smoking and the extremes of age

  • Pneumococcal urinary antigen detection kits enable a rapid and accurate diagnosis of pneumococcal infection

  • Adult pneumococcal vaccination with polysaccharide vaccine does not reduce the incidence of community-acquired pneumonia, but may attenuate its severity

  • Childhood pneumococcal vaccination with conjugate vaccine is highly effective at reducing all pneumococcal disease in children and may also provide beneficial effects in unvaccinated children and adults as a result of herd protection

8.1Introduction

Streptococcus pneumoniae (the ‘pneumococcus’) is a Gram positive diplococcus responsible for the majority of bacterial respiratory infections worldwide. It is the principle cause of community-acquired pneumonia (CAP), otitis media (OM), and non-pneumonic lower respiratory tract infection (LRTI) (Table 8.1). It is also the cause of invasive disease such as bacterial meningitis (especially in the very young and old), septicaemia, and endocarditis.

Table 8.1 The proportion of disease thought to be attributable to S. pneumoniae in different medical conditions

Medical condition

Proportion of disease caused by S. pneumoniae

All lower respiratory tract infections (LRTIs)

17–30%

Non-pneumonic LRTI

8–14%

Community acquired pneumonia

> 50%

Otitis media

28–55%

8.2 From carriage to infection

8.2.1 Nasopharyngeal carriage

Streptococcus pneumoniae can normally be found as part of the nasopharyngeal mucous membrane microflora. Such colonization usually does not result in any symptoms. However, carriers act as a reservoir for transmission to others and it is generally thought that pneumococci in the nasopharynx are the source of pneumococcal infection in the same individual. The prevalence of pneumococcal nasopharyngeal carriage is strongly associated with the age and contact with pneumococcal carriers. In developing countries, newborns may become colonised with pneumococci within days following birth. Nasopharyngeal carriage rates in young children (especially infants) range between 50% to 90%. Beyond 10 years of age, carriage rates drop below 10%. In affluent countries, pneumococcal colonisation is often delayed till a few months after birth and prevalence rates at 2 years of age are around 40% to 50% and start to drop by age 5 years of age. From the few data available, carriage rates in the elderly are thought to be very low. Transmission from person to person is via contact with respiratory secretions from carriers.

8.2.2 athogenesis

Streptococcus pneumoniae causes disease when it encounters an area of the body where it is not a commensal organism, such as the alveolus or middle ear. The mechanism of transition from commensal to pathogen is not fully understood. Conditions such as immune suppression or co-existent viral infection appear to promote this transition. In the lungs, resident alveolar macrophages can phagocytose low levels of bacteria, but failure to adequately clear the bacteria results in activation of the other arms of the host innate immune response, resulting in cytokine release, activation of the complement cascade, and attraction of neutrophils to the site of infection. Subsequently bacteria may enter the blood stream and seed to other sites such as the heart valves, meninges or joints.

The pneumococcus has a polysaccharide-containing capsule surrounding the cell wall, which helps to protect the bacterium from immunological attack, particularly by preventing opsonisation by immunoglobulins and complement and subsequent phagocytosis. Capsular variation is responsible for different patterns of disease and virulence, and allows characterization of S. pneumoniae into over 90 serotypes/serogroups. The spleen contains macrophages that are key to removing opsonized pneumococci; hence asplenic patients are at particular risk of pneumococcal disease. Other recognized risk factors associated with pneumococcal pneumonia include HIV infection, abnormal humoural immunity (defects in complement or immunoglobulin), diabetes mellitus, cancer, high alcohol intake, smoking and the extremes of age.

8.2.3Clinical disease

Characteristic features of pneumococcal pneumonia that have been described include an abrupt onset of illness, pleuritic chest pain, and rust-coloured or blood-tinged sputum. However, these features are not specific for pneumococcal infection and it is generally acknowledged that pneumococcal lower respiratory tract infections cannot be reliably distinguished clinically from similar infections caused by other respiratory pathogens. Importantly, the clinical presentation of pneumococcal pneumonia caused by penicillin-sensitive and resistant strains does not appear to differ significantly. In contrast, some differences according to serotype have been described. For instance, serotype 1 has been associated with childhood pneumoccoal empyema in the United States and United Kingdom.

Occasionally, patients present with only extra-pulmonary symptoms, such as meningitis, severe sepsis or endocarditis. Rarer manifestations of pneumococcal disease include pericarditis and peritonitis. Austrian's triad refers to the concurrence of bacteremic pneumococcal pneumonia, meningitis, and endocarditis; a rare and virulent presentation of invasive pneumococcal disease named after Dr Robert Austrian––a major figure in pneumococcal research who described the syndrome. Patients with HIV have a higher rate of invasive disease compared to immunocompetent individuals.

8.3Diagnosis

Invasive pneumococcal disease (IPD) may be detected by blood culture. However, this test is insensitive as a means of detection of pneumococcal infections; in routine practice, it is positive in only about 5% of all cases of CAP. Sputum culture and Gram stain are useful when an adequate sputum sample is obtained for analysis (ideally <10 epithelial cells and >25 white blood cells per low-power field magnification, x 10). Unfortunately, a substantial proportion of patients with lower respiratory tract infection either do not cough up sputum, or are unable to produce adequate samples. In addition, prior antibiotic use greatly reduces the diagnostic rate. Even a single oral dose of penicillin can render subsequent blood and sputum cultures negative.

A diagnostic test for S. pneumoniae with reasonable sensitivity (65–75%) and good specificity (94–100%) is an immunochromatographic assay which detects fragments of pneumococcal capsular polysaccharide. Although this assay has primarily been validated on urine samples, it has also been used successfully on pleural fluid. When applied to patients with CAP, it can increase the proportion of patients in whom a diagnosis of pneumococcal infection is made (over and above sputum and blood cultures) by >25%. A further advantage is that unlike other microbiological methods that depend on bacterial culture, antigen detection is less affected by prior antibiotic use. The assay is commercially marketed as a ‘bedside’ diagnostic kit with results obtainable in 15 minutes.

8.4Pneumococcal polysaccharide vaccine

Pneumococcal vaccines work by inducing protective antibody responses to the capsular polysaccharide antigens, and are typically defined by the number of different serotypes covered (their ‘valency’). The first pneumococcal vaccine introduced in 1977 for adults was 14-valent. This was replaced by a 23-valent polysaccharide vaccine (PPV-23; Pneumovax®) which has been used in the UK since 1983. The 23 capsular polysaccharide components of PPV represent the commonest pneumococcal serotypes which together account for 88% of worldwide invasive pneumococcal disease in adults. Vaccine coverage includes those serotypes implicated in most invasive disease or in antibiotic resistance (Table 8.2). The breadth of protection is further improved by cross-reactivity of some serotypes contained within the vaccine with others that are not (for example, 6A and 6B). This increases vaccine coverage by an additional 8%.

Table 8.2 Pneumococcal vaccine serotype coverage. PPV; pneumococcal polysaccharide vaccine. PCV; pneumococcal conjugate vaccine

Vaccine

Serotypes covered

PPV-23

1, 2, 3, 4, 5, 6B, 7F, 8, 9N,

9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F

PCV-7

4, 6B, 9V, 14, 18C, 19F, 23F

PCV-10

1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F

PCV-13

1,3,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F

8.4.1Target groups

In many countries, vaccination with PPV-23 is offered to younger adults who are at-risk of pneumococcal disease (Box 8.1) and to older adults (≥65 years of age) without specific risk factors. It is not appropriate for use in children aged less than 2 years due to their relatively immature immune system. In the immunocompetent adult, the vaccine only needs to be given once and protection should last at least 5 years. In some immunocompromised adults a second dose may be given 5 years after the initial vaccination.

8.4.2Efficacy

Polysaccharides, as contained in PPV-23, are poorly immunogenic when compared with proteins, and only induce a T cell-independent response. Between 75% and 85% of healthy adults will mount a good antibody response to vaccination. However, the elderly, those with severe co-morbidity, patients with HIV and patients who are functionally hyposplenic produce far lower responses. In addition, the relationship between antibody levels and protection from IPD is not certain. PPV-23 has not been conclusively shown to prevent CAP, either on an outpatient basis or as measured by admissions to hospital, and has not been shown to reduce mortality from CAP. Nevertheless, it has an efficacy of between 30% and 45% in reducing the incidence of invasive pneumococcal disease. Some data also suggest that PPV-23 vaccinated individuals who develop CAP have less severe disease as measured by reduced admission rates to critical care.

8.4.3HIV infection

The immune responses generated by PPV-23 are attenuated in the HIV- infected population, especially in patients with lower CD4 cell counts. Patients on anti-retroviral therapy appear to gain more protection from vaccination although the response remains sub-optimal, even after re-vaccination. Current guidelines recommend the use of PPV-23 in HIV-infected patients with CD4 counts of >200 cells/µl, and recommend consideration of the vaccine in those with CD4 counts <200 cells/µl, though the evidence for benefit is not certain.

8.4.4Re-vaccination

Antibody levels fall after 5–10 years in the healthy adult, but it is not known whether vaccine efficacy decreases with time. As it induces a T cell-independent response, it is not possible to produce a ‘booster’ effect by administering a repeat vaccination. Re-vaccination results in lower antibody rises than following the first vaccination, and a higher rate of local side effects. Repeat vaccination may also reduce additional responses to antigen challenge (‘hyporesponsiveness’). Consequently re-vaccination should never be offered within 3 years of first vaccination, and is usually only considered in later years in patients at high risk of pneumococcal disease.

8.5Pneumococcal conjugate vaccine

Conjugate vaccines involve the combination (conjugation) of pneumococcal capsular polysaccharides with an immunogenic protein (e.g. derived from diphtheria). This provokes a T cell-dependent response, inducing immunological memory and therefore theoretically conferring greater protection. A 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced to the childhood immunization schedule in the US in 2000 and to the UK in September 2006. In 2010, both countries switched to a 13-valent vaccine (PCV-13) which includes the original 7 serotypes in PCV-7 plus 6 additional serotypes. At least a further 24 countries offer PCV as part of a routine childhood immunization schedule. Most regimens comprise 3 vaccinations at 2, 4 and 13 months of age, taking advantage of the ‘booster effect’ that immunological memory confers. The 13-valent PCV offers coverage of the 13 serotypes representing the majority of childhood pneumococcal disease globally. (Table 8.3) These serotypes include those associated with the majority of pneumococcal penicillin resistance.

Table 8.3 Approximate proportions of IPD in children <5 years of age due to serotypes in PCV-13. (data from Johnson HL et al. Plos Med 2010 Oct 5;7(10). pii: e1000348.)

Region

Childhood IPD due to PCV-13 serotypes (%)

Africa

76

Asia

74

Europe

88

Latin America and Caribbean

83

North America

88

Oceania

80

Global

75

8.5.1Efficacy and herd protection

PCV generates antibody responses in between 60% and 100% of infants vaccinated. In contrast to PPV, PCV has been shown to reduce the incidence not only of childhood invasive pneumococcal disease (90% reduction of vaccine-type), but also childhood CAP (25–37% reduction). PCV-7 also induces stronger IgA responses than PPV, accounting for a 6–7% reduction in otitis media.

Anti-pneumococcal IgA serves to reduce nasopharyngeal carriage of serotypes covered by the vaccine. This is thought to promote herd protection with consequent reduction in the burden of pneumococcal disease in non-vaccinated children and adults. For instance, childhood vaccination has been shown to reduce carriage within non-vaccinated adults in the same household, and since the introduction of childhood PCV vaccination in the US, rates of adult IPD have also fallen significantly.

8.6Future vaccine developments

The 13-valent PCV is currently being evaluated for use in older adults, where it is hoped that the improved immunogenicity of PCV will enhance the prevention of IPD and CAP in this age group. Fifteen valent vaccines have also been developed to further extend serotype coverage. However, manufacturing difficulties limit the number of valencies that can be reasonably incorportated into a single vaccine.

As the use of PCVs increase, serotype replacement may occur as the prevalence of non-vaccine serotypes increase. Close monitoring of prevailing serotypes is therefore necessary.

Other vaccine developments involve targeting non-capsular protein-based antigens which would in theory provide protection against all pneumococcal serotypes, and the adjuvant stimulation of innate immune responses to improve host defences.

Further reading

1 Braido F., Bellotti M., Maria A., et al. (2008) The role of pneumococcal vaccine. Pulm Pharmacol Ther 21: 608–15.Find this resource:

2 Grijalva C.G., Nuorti J.P., Arbogast P.G., Martin S.W., Edwards K.M., Griffin M.R. (2007) Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 369(9568): 1179–86.Find this resource:

3 Huss A., Scott P., Stuck A.E., Trotter C., Egger M. (2009) Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ 180(1): 48–58.Find this resource:

4 Johnson H.L., Deloria-Knoll M., Levine O.S., et al. (2010) Systemic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project. PLoS Med 7(10). pii:e1000348.Find this resource:

5 van der Poll T., Opal S.M. (2009) Pathogenesis, treatment and prevention of pneumococcal pneumonia. Lancet 374: 1543–56.Find this resource: