Attempts to elucidate the global burden of pneumococcal disease have been frustrated by a lack of sensitivity of current diagnostic methods. As pneumococcal pneumonia is the main contributor to the global burden of pneumococcal disease mortality, its diagnosis is key to measure that burden. Diagnosis may be made in adults by microscopy or culture of good-quality sputum specimens, but children with pneumonia rarely produce purulent sputum. Blood culture is a highly specific diagnostic method but is positive only in a small fraction of presumed pneumococcal pneumonia cases in children. Attempts to culture the lungs themselves are invasive and rarely performed. There is also a paucity of diagnostic laboratories in developing countries and a lack of utilization of the meagre resources available in those countries [5
]. The millennium development goal 4, which aims to reduce the infant mortality rate (IMR) by two-thirds to under 40 deaths per thousand live births globally by 2015, is dependent on interventions to reduce pneumonia deaths, as the fraction of pneumonia deaths increases with increasing IMR [1
], but the contribution of the pneumococcus to that burden cannot be determined because of the insensitivity of these current diagnostic tests.
The contribution of the pneumococcus to the pneumonia fraction of the IMR has recently been elucidated by observations from three pivotal clinical trials in Africa and Asia, which showed that PCV can reduce chest radiograph-confirmed pneumonia [8
]. Based on these clinical trials and the distribution of pneumococcal serotypes globally, it has been possible to better define the global burden of pneumococcal mortality. This study emphasizes the burden of disease in Africa, but also the significant number of pneumococcal deaths in highly populated countries such as India and China [2
Figure 1. Pneumococcal deaths in children less than 5 years of age .
These trials also demonstrated that the burden of hospitalized lower respiratory tract infection extends beyond alveolar consolidation on X-ray [11
] to include clinical pneumonias that do not have wheezing, but have a raised C-reactive protein [12
]. Extension of these data from efficacy trials to the demonstration of PCV effectiveness in the prevention of pneumonia in countries where vaccination has been part of routine childhood immunization has been a challenge. Although pneumonia is considered to be the leading cause of childhood deaths globally [1
], there are few, if any, systematic population-based pneumonia surveillance programmes even in developed countries, let alone the poorest developing countries in which most of the pneumonia deaths occur. In the USA, surveillance based on rates of hospitalizations, which are coded in the International Statistical Classification of Diseases and Related Health Problems, v. 9 (ICD9), has been used to show a significant reduction in ICD9 code 481, which includes pneumococcal pneumonia and lobar pneumonia in children less than 2 years of age, since the introduction of PCV7 [13
]. The direct effect on pneumonia has been confirmed by review of records in children less than 1 year of age in one group health setting in Washington State [14
]. Long-term trends from Quebec have also confirmed a significant reduction in lobar pneumonia in infants following the introduction of PCV7 in that Canadian province [15
]. A similar impact has been demonstrated in Australia in children [16
]. A recent long-term analysis of more than a million hospitalizations in 24 per cent of the US population has demonstrated a 47 per cent reduction (95% CI 38–54%) by 2006 in the rate of pneumococcal or lobar pneumonia coded as ICD9 481, among children less than 2 years of age, compared with a pre-PCV7 baseline of 1997–1999 [17
Other insights from the conjugate pneumococcal vaccine trials include the significant contribution of pneumococcal disease to the hospitalization of HIV-infected children and the potential of vaccination to reduce that burden [9
]. Over 90 per cent of the pneumococcal disease burden of pneumonia and meningitis associated with HIV is in Africa [2
], which makes the case for the introduction of vaccination into this at risk group particularly compelling. There are also data from a recent randomized trial in adults showing that conjugate vaccination may be protective against vaccine-type invasive pneumococcal disease (IPD) among HIV-infected adults in Malawi [18
A further insight from vaccination into the clinical spectrum of pneumococcal disease is the identification of the role played by the pneumococcus in the aetiology of culture-negative empyema in the antibiotic era. It has been observed that the increase in invasive disease owing to pneumococcal serotypes not included in PCV7 has been temporally associated with an increase in culture-negative empyema [19
]. Where there has been extensive use of the polymerase chain reaction to detect pneumococcal DNA in empyema specimens, the role of these non-vaccine types as the leading cause of culture-negative empyema has been clearly established [20
The randomized trial of a 9-valent PCV in The Gambia [8
] showed that rural children with less access to care have a greater burden of pneumococcal-attributed pneumonia than children from urban [9
] or peri-urban settings [10
]. The Gambian study also demonstrated a 16 per cent reduction in all-cause mortality among recipients of the conjugate vaccine, which reduced IPD by 45 per cent [8
], suggesting that the true contribution of the pneumococcus to mortality may be in excess of 30 per cent in that community.