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In England and Wales, replacement of childhood 7-valent pneumococcal conjugate vaccine (PCV7) with a 13-valent vaccine (PCV13) in 2010 was associated with a significant reduction in PCV13-serotype invasive pneumococcal disease (IPD), with a small increase in IPD due to non-vaccine serotypes. Here, we describe the clinical presentation, comorbidity prevalence, serotype distribution and outcomes of childhood IPD during the first 6 years after PCV13 introduction.Public Health England conducts enhanced IPD surveillance in England and Wales, with detailed information requested from general practitioners for all cases in children <5 years of age. Invasive isolates are routinely serotyped at the Public Health England reference laboratory.From April 2010 to March 2016, 1280 IPD episodes were confirmed in 1255 children 3–59 months of age; 84.3% (1059/1255) isolates were serotyped. Clinical presentation with meningitis was most prevalent in 3- to 11-month olds (45.8%, 209/456) and lower respiratory tract infection in 24- to 59-month olds (46.7%, 133/285). Overall, 259 (20.6%) children had 292 comorbidities, particularly immunosuppression (31.6%, 92/292). Twenty-one children (1.8%) had recurrent IPD. The case fatality rate was 5.1% (64/1255; 95% confidence interval [CI]: 3.9%–6.5%) and independently associated with meningitis (aOR 3.53; 95% CI: 1.62–7.70) and presence of comorbidity (aOR, 2.41; 95% CI: 1.25–4.64). In 2015/2016, PCV13 serotypes were responsible for 10.8% (25/232) of serotyped cases; the most prevalent non-PCV13 serotypes were 12F (18%), 10A (12%), 23B (10%), 33F (10%), 15B/C (10%) and 8 (8%).Most childhood IPD cases are now due to non-PCV13 serotypes. A higher proportion of children with IPD have underlying comorbidity, but, reassuringly, the risk of recurrent IPD or death remains low.