Pneumococcal capsular serotypes and lung infection.

Streptococcus pneumoniae is second only to Mycobacterium tuberculosis as a bacterial cause of worldwide mortality. Unlike M tuberculosis, S pneumoniae remains a major cause of death in the developed world, with a standardised mortality rate of 25 per 100 000 in the UK. S pneumoniae is the commonest pathogen causing community acquired pneumonia (CAP), and the majority of serious S pneumoniae infections are cases of CAP in infants and older people. S pneumoniae is also an important cause of septicaemia, meningitis and infective exacerbations of chronic obstructive pulmonary disease and bronchiectasis. S pneumoniae is surrounded by an extracellular layer of polysaccharide called the capsule which promotes immune evasion and is an essential virulence factor. The structure of the capsule differs between S pneumoniae strains, with 93 variants identifiable by serotyping. Serotype prevalence is unequal, with the majority of disease caused by around 20 common serotypes. Which serotypes are predominant varies with age, geography and site of infection (eg, the nasopharynx, pleural space or the blood). In the paper by Bewick et al, technical advances in microbiology have been used to identify which S pneumoniae capsular serotypes are the commonest causes of CAP in a UK centre. Why do these rather technical data matter to a clinician, and how could they affect future developments in the management of S pneumoniae lung infection? First, the ability to identify which serotypes are causing CAP is in itself a major advance. Previously, capsular serotyping required cultured bacteria and was therefore biased towards serotypes that cause septicaemia as respiratory cultures have such low sensitivity in CAP. For example, in Bewick et al’s paper only 58 of 366 cases of S pneumoniae CAP had positive cultures, mainly from blood. By using urine samples for a highly sensitive multiplex immunoassay based on xMAP bead technology, Bewick et al were able to identify S pneumoniae capsular serotype in culture negative cases of CAP, providing for the first time a largely unbiased assessment of which serotypes cause CAP. At present the multiplex serotype immunoassay is restricted to only 14 serotypes, the pneumococcal conjugate vaccine (PCV13) serotypes and serotype 8, and this limitation is probably why no serotype was identified for one-third of their patients with S pneumoniae CAP. Future technical developments are likely to increase the numbers of serotypes that can be detected and partially overcome this problem. Interestingly, the multiplex immunoassay increased the sensitivity of microbiological confirmation of S pneumoniae CAP, identifying 144 cases in which the established urinary antigen test (Binax NOW, Portland, Maine, USA) was negative. This provides a potential justification for using this technology independent of the possible advantages in identifying serotype. Second, capsular serotype could identify patients at risk of specific complications of CAP. Serotype affects S pneumoniae resistance to complement, phagocytosis, adhesion to epithelial cells and virulence in mouse models. Probably related to these biological effects of serotype, in human disease duration of S pneumoniae colonisation, the number of episodes of invasive disease per colonisation event, mortality and ability to cause empyema are all linked to serotype. For example, before the introduction of infant vaccination the top five capsular serotypes causing S pneumoniae septicaemia and meningitis were 14, 19F, 6B, 23F and 18C, yet 80e90% of cases of S pneumoniae empyema are caused by serotypes 1, 3, 7F and 19A. Until now it was not clear whether the serotypes commonly causing empyema simply reflected their dominance as serotypes causing CAP or a specific affinity for invading the pleural space. Bewick et al found that only one of the three commonest CAP serotypes frequently causes empyema, and overall only 40% of cases of CAP were caused by serotypes associated with empyema. Similarly a recent Spanish study which used a multiplex PCR to identify S pneumoniae serotypes in culture-positive patients with CAP showed serotypes 4, 5 and 8 are more likely and serotypes 19F and 6B less likely to cause an associated septicaemia. In addition, infection with serotype 3 is clearly associated with increased mortality. These data demonstrate specific S pneumoniae serotypes are associated with important complications of CAP such as empyema, septicaemia and death. Identifying infecting serotype could therefore help risk stratify patients with S pneumoniae CAP, and identify those who might benefit from earlier intervention such as drainage of pleural effusions. Furthermore, comparing the biology of serotypes associated with specific disease phenotypes will help characterise the bacterial and host factors involved in the pathogenesis of infection at different sites. Third, Bewick et al have provided additional data suggesting that S pneumoniae infection in younger patients is largely restricted to a limited number of highly invasive serotypes. As discussed above, serotype affects the ability of S pneumoniae to cause invasive disease with attack rates (number of cases of meningitis or septicaemia per colonisation episode) ranging from 0 to 75 for different serotypes. Bewick et al found a direct correlation between increasing age and comorbidities and infection with less invasive serotypes, supporting the hypothesis that advancing age allows less aggressive S pneumoniae serotypes to cause disease. The increasing incidence of less invasive serotypes with age and comorbidity (both markers for increased mortality) may also explain the seemingly paradoxical observation that infection with more invasive serotypes has a lower mortality than infection with less invasive serotypes. One caveat to these data is that the exclusion of serotype 14 and 19A strains from the invasive serotype group by Bewick et al could be challenged as both serotypes have high attack rates; including these serotypes in the invasive group could have altered the statistically significant association of less invasive serotypes with increasing age and comorbidities. The final reasons why data on S pneumoniae serotypes causing adult lung infection are important are the implications for prevention by vaccination. Although most of the serious S pneumoniae infections occurring in adults are CAP, the adult S pneumoniae vaccine (PPV, based on pneumococcal capsular polysaccharide from the commonest 23 serotypes) only prevents S pneumoniae septicaemia and meningitis and has little efficacy against lung infection. The childhood PCV vaccine also uses capsular antigen but Correspondence to Centre for Respiratory Research, Department of Medicine, University College Medical School, Rayne Institute, London WC1E 6JJ, UK; [email protected]