Introduction Invasive pneumococcal disease due to serotype 19A has become a major concern, particularly in the USA and Asia. We describe the characteristics of pneumococcal serotype 19A related empyema and changes in its incidence in the UK.
Methods Data from paediatric empyema patients between September 2006 and March 2011 were collected from 17 respiratory centres in the UK. Pneumococcal serotypes were identified as part of the Health Protection Agency enhanced paediatric empyema surveillance programme.
Results Four serotypes accounted for over 80% of 136 cases (Serotype 1 : 43%, 3 : 21%, 7 : 11% and 19A:10%). The incidence of empyema due to serotype 19A quadrupled from 0.48 (0.16–1.13) cases per million children in 2006/2007 to 2.02 (1.25–3.09) in 2010/2011. Severity of disease was significantly increased in children with 19A infection when compared to other serotypes.
Conclusions The incidence of empyema due to pneumococcal serotype 19A infection has increased significantly and is associated with substantial morbidity.
- Infectious Diseases
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Streptococcus pneumoniae is the leading cause of bacterial pneumonia in children worldwide, and is responsible for an estimated 700 000 to one million deaths annually in children under 5 years of age.1 There are over 90 recognised serotypes of S pneumoniae, but not all are commonly associated with human disease.1 Conjugated pneumococcal vaccines currently provide protection against a limited number of serotypes with the seven-valent conjugate vaccine (PCV-7) providing protection against seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) and the 13-valent vaccine (PCV-13), which was recently introduced in the UK, active against an additional six serotypes (1, 3, 5, 6A, 7F and 19A).
The range of pneumococcal serotypes causing invasive disease is changing. In particular, the incidence of serotype 19A (Spn19A) has increased substantially in some countries, notably the USA, Spain and South Korea.1 In the USA, Spn19A was present in only 2.5% of isolates from children under 5 years of age prior to the introduction of PCV-7 in 1998–1999 but was identified in 47.2% of isolates 6 years later and prior to the introduction of PCV-13 became the leading cause of invasive pneumococcal disease in children in that country.1 In England and Wales, a recent report from the Health Protection Agency (HPA) has highlighted the emergence of Spn19A as a cause of invasive pneumococcal disease.2
Historically, Spn19A has not been a recognised cause of paediatric empyema in the UK3 ,4 but it has been linked to the rise in incidence of empyema in the USA.1 Complication rates in paediatric empyema have been shown to vary between pneumococcal serotypes but Spn19A has not been previously highlighted as a concern.4 In light of the increasing importance of Spn19A in pneumococcal disease we describe changes in the incidence of Spn19A infection in empyema in England and evaluate the resulting changes in disease severity.
Pneumococcal serotype surveillance
From September 2006, culture negative pleural fluid samples from children (0–16 years) with empyema were forwarded to the HPA from microbiology laboratories across England as part of the programme of enhanced surveillance of pneumococcal empyema in UK children (UK-ESPE). Samples were tested with a pneumococcal PCR (pneumolysin and autolysin) and positive samples underwent serotyping. Serotyping involved a non-culture multiplex polysaccharide antigen detection assay that has been described previously.5 Serotyping of culture negative pleural fluid was used as the source of pneumococcal serotyping data as in the majority of cases (127 of the 136 (93%) UK-ESPE cases included) pleural fluid in children with pneumococcal empyema was sterile at the point of testing, presumably because of antibiotic use prior to referral.5
Detailed clinical data on children (0–16 years) with empyema requiring pleural drainage between September 2006 and March 2011 were collected from 17 collaborating UK-ESPE centres. A secure web-accessed proforma was completed on each patient by the clinical team at the relevant collaborating centre. These data were then matched to the national serotyping surveillance data (n=137). Additional patients from Scottish centres collaborating with the UK-ESPE study were added where serotyping results were available. Caldicott approval for the collection of clinical data was obtained.
Incidence calculations were based on total numbers of patients identified by the PCR based culture negative surveillance carried out by the HPA in England from 2006 onwards. The denominator was the child population of England estimated by the UK Office for National Statistics. Clinical characteristics were analysed using Kruskal-Wallis and Fisher's exact tests for continuous and categorical variables respectively. Cox's proportional hazard models were used for length of stay analysis. All analyses were carried out using the R statistical package (V.11.2).
Cases of complicated pneumonia and empyema due to Spn19A in England increased from 5 in 2006/2007 (the year following the introduction of PCV-7) to 21 cases in 2010/11 which was the year following the replacement of PCV-7 with PCV-13. The incidence increased from 0.48 cases per million children (95% CI 0.16 to 1.13) in 2006/2007 to 2.02 (95% CI 1.25 to 3.09) in 2010/2011, giving an incidence rate ratio of 4.17 (95% CI 1.53 to 14.2).
Of the 136 UK-ESPE cases (134 from England and 2 from Scotland) where a pneumococcal serotype was identified and clinical details were available, 14 (10%) were serotype 19A. Serotypes 1, 3 and 7 (43%, 20.6% and 11%) were the other common serotypes detected. Of Spn19A cases, five (36%) had a positive blood culture and all but one had culture negative pleural fluid (7%). One isolate was resistant to Penicillin, Tetracycline and Clindamycin but sensitive to Cephalosporins on standard testing. No evidence of antibiotic resistance was reported in any of the other isolates. Characteristics of children with Spn19A infection and those with other pneumococcal serotypes are shown in table 1. Four of five children with Spn19A infection who developed complications had culture positive disease. Duration of hospital admission was increased by 50% in patients with 19A disease compared to all other serotypes (adjusting for age and sex—Hazard: 0.52, 95% CI 0.28 to 0.95, p=0.034). Survivorship curves are shown in the figure 1.
The incidence of empyema due to Spn19A infection has increased dramatically in UK children. It is unclear exactly what has driven this change in incidence but vaccine induced serotype replacement, antibiotic pressure, existing secular trends and introduction of new clones are all potentially relevant factors.1 ,2 In the absence of molecular epidemiological and prevaccine data it is impossible to be certain which of these factors are relevant.
The most striking finding from our data was the severity of disease. Children with Spn19A related empyema stayed longer in hospital. They were significantly more likely to require intensive care and had higher complication rates when compared to children with empyema due to other pneumococcal serotypes. There were no differences in comorbidity, prehospital antibiotic usage and surgical intervention rate suggesting that the increased severity was serotype related rather than due to patient or treatment factors. Furthermore, Picazo and colleagues found similar high rates of intensive care admission (63.6%) and complications (27.3%) in Spanish children with empyema due to Spn19A.6 The pneumococcal capsule is an important virulence factor, and hence differences in disease severity between serotypes are well described.1 However, this level of disease severity is in marked contrast to the traditional clinical picture in paediatric empyema and is of significant concern.4
We found only limited evidence of antibiotic resistance within the Spn19A isolates, although molecular testing for resistance for example, by use of pbp2b PCR assay was not available. These findings are in contrast to the experience in the USA and Asia where Spn19A isolates are frequently resistant to multiple antibiotics, possibly as a consequence of excess antibiotic usage in the community.1
Miller and colleagues have previously demonstrated that the epidemiology of invasive pneumococcal disease is changing both in children and in adults in the UK.2 Spn19A related empyema has increased in UK children and this change may have been driven by vaccine related serotype replacement disease following the introduction of PCV-7. PCV-13 introduced in 2010 in the UK contains antigen for 19A. This is likely to lead to a significant reduction in Spn19A disease but given the PCV-7 experience, further changes in the clinical profile of pneumococcal disease are possible. Continued surveillance will be required to monitor for further evolutionary changes in this group of organisms.
Pneumococcal 19A infection has become the commonest cause of invasive disease in children in the USA but has not been a significant problem in the UK.
There are differences in the disease severity caused by infection with different pneumococcal serotypes.
The incidence of paediatric empyema due to pneumococcal serotype 19A has increased in the UK.
Serotype 19A related empyema is associated with significantly higher levels of morbidity than empyema related to other pneumococcal serotypes.
The authors would also like acknowledge S Beaton, Glasgow University for his support of the web-based data collection, T Harrison, Health Protection Agency and all those at the UK-ESPE collaborating centres study: C Wallis, V Rasiah, R Thursfield, Great Ormond Street Hospital, London; C Murray, J Mercy, Royal Manchester Children's Hospital, Manchester; C Pao, Royal London Hospital, London; R Ross-Russell, Addenbrooke's Hospital, Cambridge; J Bhatt, R Radcliffe, K Ward, Nottingham Children's Hospital; A Thomson, Children's Hospital, Oxford; I Balfour-Lynn, Royal Brompton Hospital, London; W Lenney, University Hospital of North Staffordshire, Stoke-on-Trent; J Clarke, I Brookes, Birmingham Children's Hospital, Birmingham; R Primhak, Sheffield Children's Hospital, Sheffield; E Carroll, J Clark, Alder Hey Children's Hospital, Liverpool; T Hilliard, Bristol Royal Hospital for Children, Bristol; A Cade, Derriford Hospital, Plymouth; A Prendiville, H Soloman, Royal Cornwall Hospital, Truro; S Cunningham, Royal Hospital for Sick Children, Edinburgh.
Contributors MFT: study design, data collection, analysed data and drafted final manuscript. CLS, MG, MPES and RCG: pneumococcal surveillance, serotyping and analysis and contributed to final manuscript. RG, JEC and SPR: analysed data and contributed to final manuscript. CLS, DC, MAE: data collection and contributed to final manuscript. JYP and DAS: devised the study, analysed data and contributed to final manuscript.
Funding The UK-ESPE study has been supported by unrestricted grants from GSK and Pfizer to DAS. GSK and Pfizer had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Competing interests CLS has received support from Pfizer to attend overseas conferences. MPES is a member of advisory boards of GSK and Pfizer has received funding to her institution from GSK and Pfizer for investigation of multiple pneumococcal serotype carriage using DNA microarray, been an invited speaker at scientific meetings organised by GSK and Pfizer and has received support from both companies to attend conferences. RCG received funding to his institution from GSK and Pfizer for pneumococcal diagnostics and characterisation studies. He also received support from GSK and Pfizer Inc to attend overseas conferences. JEC has received pneumonia research funding from Pfizer.
Ethics approval R&D and Caldicott approval granted for all participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.
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