G Oligbu

Pneumococcal conjugate vaccine failure in children: A systematic review of the literature

BACKGROUND Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing pneumococcal invasive disease (IPD) due to serotypes included in the vaccines. The risk of vaccine-type IPD in immunised children (i.e. vaccine failure) has not been systematically assessed in countries with established PCV programmes. METHODS We undertook a systematic review of the English literature published from January 2000 to April 2016 to evaluate the vaccine schedule, risk factors, serotype distribution, clinical presentation and outcomes of vaccine failure in children vaccinated with the 7-valent (PCV7), 10-valent (PCV10), and 13-valent (PCV13) vaccines. Data sources included MEDLINE, EMBASE, Cochrane library, and references within identified articles. RESULTS We identified 1742 potential studies and included 20 publications involving 7584 participants in children aged ⩽5year-olds: 5202 received 2 doses followed by a booster in 10 studies, (68.6%), 64 (0.8%) received 3 doses without a booster in 2 studies, and 2318 received a 3+1 schedule (30.6%) in 8 studies. A total of 159 vaccine failure cases were identified, representing 2.1% [95% CI: 1.8-2.4%] of the reported IPD cases. Most studies did not report clinical characteristics or outcomes. Among eight studies reporting comorbidities, 33/77 patients (42.9%) had an underlying condition. The main serotypes associated with vaccine failure were 19F (51/128 cases with known serotype; 39.8%), 6B (33/128; 25.8%), and 4 (10/128; 7.8%). Only five studies reported patient outcomes, with a crude case fatality rate of 2.4% (2/85; 95%CI: 0.3-8.5%). CONCLUSION Pneumococcal conjugate vaccines have been implemented in national immunisation programmes for more than a decade, yet there are only a few studies reporting vaccine failure. PCV failure is rare, irrespective of vaccine or schedule. Co-morbidity prevalence was high amongst vaccine failure cases but case fatality rate was relatively low. There is a need for more systematic reporting vaccine failure cases in countries with established pneumococcal vaccination programmes.

Risk of Invasive Pneumococcal Disease in Children with Sickle Cell Disease in England: A National Observational Cohort Study, 2010–2015

Objective To describe the clinical presentation, risk factors, serotype distribution and outcomes of invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in the UK. Design Prospective national newborn screening for SCD and enhanced national IPD surveillance. Participants Children with SCD born in England between 1 September 2010 and 31 August 2014 who developed laboratory-confirmed IPD by 31 December 2015. Main outcomes and measures Risk of IPD in children with SCD compared with children without SCD during the surveillance period. Results Eleven children homozygote for haemoglobin S (HbSS) and one double heterozygote for haemoglobin S and C (HbSC) developed IPD. Septicaemia (n=7) and lower respiratory tract infection (n=4) were the main clinical presentations, and serogroup 15 (not present in PCV13) was responsible for 73% (8/11) of cases. Three children with HbSS (27%) died compared with <5% nationally. Children with HbSS had a 49-fold (95% CI 27 to 89, P<0.001) higher risk of IPD compared with their peers without SCD. Conclusions Children with SCD remain at increased risk of IPD despite national newborn screening, early penicillin prophylaxis and high pneumococcal vaccine uptake. They are also more likely to die of their infection compared with their peers without SCD. Most IPD cases are now due to serotypes not covered by PCV13. Healthcare professionals need to work more closely with families with SCD and local communities to emphasise the importance of penicillin prophylaxis, explore barriers, allay misguided beliefs and facilitate rapid access to healthcare.

Characteristics and Serotype Distribution of Childhood Cases of Invasive Pneumococcal Disease Following Pneumococcal Conjugate Vaccination in England and Wales, 2006–2014

Background The 7-valent and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes. Vaccine failure (vaccine-type IPD after age-appropriate immunization) is rare. Little is known about the risk, clinical characteristics, or outcomes of PCV13 compared to PCV7 vaccine failure. Methods Public Health England conducts IPD surveillance and provides a national reference service for serotyping pneumococcal isolates in England and Wales. We compared the epidemiology, rates, risk factors, serotype distribution, clinical characteristics, and outcomes of IPD in children with PCV13 and PCV7 vaccine failure. Results A total of 163 episodes of PCV failure were confirmed in 161 children over 8 years (4 September 2006 to 3 September 2014) in 10 birth cohorts. After 3 vaccine doses, PCV7 and PCV13 failure rates were 0.19/100000 (95% confidence interval [CI], .10-.33 [57 cases]) and 0.66/100000 (95% CI, .44-.95 [104 cases]) vaccinated person-years, respectively. Children with PCV13 failure were more likely to be healthy (87/105 [82.9%] vs 37/56 [66.1%]; P = .02), present with bacteremic lower respiratory tract infection (LRTI) (61/105 [58.1%] vs 11/56 [19.6%]; P < .001), and develop empyema (41/61 [67.2%] vs 1/11 [9.1%]; P < .001) compared to PCV7 failures. Serotypes 3 (n = 38 [36.2%]) and 19A (n = 30 [28.6%]) were responsible for most PCV13 failures. Six children died (4% [95% CI, 1%-8%]), including 5 with comorbidities. Conclusions PCV failure is rare and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause bacteremic LRTI and empyema in healthy vaccinated children.

Childhood Deaths Attributable to Invasive Pneumococcal Disease in England and Wales, 2006–2014

Background Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal disease (IPD), but deaths due to IPD still occur. We aimed to describe children who died of IPD since PCV introduction in England and Wales. Methods Public Health England conducts enhanced IPD surveillance in England and Wales. IPD cases in PCV-eligible children aged <5 years (born since 4 September 2004 and diagnosed between 4 September 2006 and 3 September 2014) were actively followed up by postal questionnaires and, for fatal cases, detailed information was requested prospectively from multiple sources. Results During the 8-year period, there were 3146 IPD cases and 150 IPD-related deaths (case fatality rate, 4.8%). Overall, 132 isolates from fatal cases were serotyped (88%) and 35 distinct serotypes were identified, with no serotype predominance. Most deaths occurred in children aged <1 year (88/150 [59%]) and 1-year-olds (36/150 [24%]). One-third (53/150 [35%]) had a known risk factor for IPD. Clinical presentation varied with age but not by serotypes in the different conjugate vaccines. Meningitis was diagnosed in nearly half the fatal cases (71/150 [47%]). The IPD-related mortality rate declined after 7-valent PCV introduction from 1.25/100000 children in 2006-2007 to 0.60/100000 in 2009-2010, with a further reduction following 13-valent PCV introduction from April 2010 to 0.39/100000 in 2013-2014 (14 deaths; incidence rate ratio, 0.31 [95% confidence interval, .16-.61]; P = .0003), when most deaths were due to nonvaccine serotypes or in neonates. Conclusions Most fatal IPD cases are currently not vaccine-preventable. Additional strategies will be required to reduce childhood pneumococcal deaths in countries with established pneumococcal vaccination programs.

G328(P) Risk of transverse myelitis following zika virus infection

Introduction Transverse myelitis (TM) is a neurological disorder causing acute cord injury as a result of acute inflammation, and it is often associated with infectious or autoimmune disease. 20% of all cases of TM occur in children. Since 2015, an outbreak of Zika Virus infection (ZiKV) has been reported in over 30 countries. Emerging evidence suggest ZikV causes a spectrum of neurologic diseases. However, its association with TM, especially in children, is not well described. Methods We undertook a systematic review of the English literature published from 1947 to August 2017 to evaluate the risk factors, distribution, pathogenesis, clinical presentation, management and outcomes of TM following Zika virus infection. Data sources included MEDLINE, EMBASE, Cochrane library, and references within identified articles. We also searched the papers using the ISI web of knowledge, to identify relevant articles and conference proceedings. Results We identified 102 potential studies, of which 9 were duplicates and 89 were excluded on the basis of title and abstracts. Of the 4 eligible studies [5–8], there were 6275 with suspected ZiKV in all age groups. 695 cases were confirmed ZiKV either by RT-PCR in plasma, CSF and urine, ELIZA or MRI while excluding other aetiologies. There were 11 (1.6%) cases of TM. Among 3 studies reporting clinical characteristics and outcome, the mean age was 23 years (Range 15–43) and 63% (n=5/8) of cases were male. 40% (n=4/10) required admission to the ITU, with no reported case fatality. Conclusions and clinical implications Complications from ZiKV, although uncommon, may be severe. With international spread, clinicians need to be aware that ZiKV may be associated with TM. As only 10% of cases were children, standardising the collection and reporting for individual cases across regions and countries would further allow meaningful analysis of the data collected, enabling monitoring of trends over time.

G54 Impact of pneumococcal conjugate vaccines on pneumococcal meningitis in england and wales, 2000 – 2016

Introduction The introduction of pneumococcal conjugate vaccines (PCV) was associated with reduction in incidence of invasive pneumococcal disease (IPD) especially IPD caused by the vaccine serotypes. Its impact on meningitis in the United Kingdom has not been assessed. Methods Public Health England conducts enhanced surveillance for IPD and provides a national reference service for serotyping pneumococcal isolates in England and Wales. Data were extracted for isolates from confirmed IPD cases between 1 st July 2000 and 30th June 2016, covering the 2000/01 to 2015/16 epidemiological years. Incidence rate ratio (IRR) and case fatality rate (CFR) were calculated. Multivariable logistic regression was used to calculate the odds of meningitis and assessed its association with death. Results There were 80 313 laboratory-confirmed IPD cases over the 16 year surveillance period, including 4160 cases (4.9%) with meningitis. Of the 4108 with reported age, 1611 (39.2%) cases were reported in children aged <5 y, 1729 (42.1%) in 5–64 year-olds and 768 (18.7%) cases in 65+year olds. This compares with 8324 (10.5%), 32 297 (40.6%) and 38 999 (49.0%) of 79 620 non-meningitis cases during the same period, respectively (p<0.001). PCV7 introduction in September 2006 had no impact on the overall incidence of pneumococcal meningitis (0.55/100,00 during 2000/01–2005/06 vs 0.56/100,000 during 2008/09–2009/10) because of serotype replacement disease. PCV7 replacement with PCV13 in April 2010, however, led to a 48% (95% CI: 38%–62%) reduction in pneumococcal meningitis incidence by 2015/16, whilst meningitis cases due to non-PCV13 serotypes remained static. The overall CFR was 17.5% (631/3,611, increasing from 10.7% (150/1408) in <5 y to 17.3% (262/1517) in 5–64 y and 31.9% (219/686) in 65+year olds. This compared with 3.6% (254/716), 10.8% (3,235/30,090) and 30.6% (11,292/36,907) for non-meningitis for the same age groups, respectively. CFR for meningitis due to PCV7 serotypes (130/916, 14.2%) compared to PCV13 (143/793, 18.0%) or non-PCV13 serotypes (290/1,534, 18.9%). Among meningitis cases, serotype 8 was associated with increased odds of death (aOR, 2.91; 95% CI: 1.79 to 4.71; p<0.0001) Conclusions The impact of PCV on pneumococcal meningitis has been less prominent than for other IPD presentations and case fatality remains high; a different strategy is, therefore, required to reduce the burden and outcomes of pneumococcal meningitis.

G61(P) Efficacy of antibiotics in the management of granuloma annulare in children: a systematic review of the literature

Introduction Granuloma anulare (GA) is a benign inflammatory dermatosis of unknown cause. The Generalised granuloma annulare (GGA) is a subtype of which tends to be resistant to treatment. Various antibiotics have been proposed as a potential therapy for GGA, the most recent being combination therapy with Rifampicin, Ofloxacin and Minocycline (ROM). Aims This study aim to explore the efficacy of antibiotics in treating GGA, and whether antibiotics may be useful in Children. Methods We undertook a systematic review of English literature published from August 1947 to July 2017 to evaluate the efficacy of antibiotics in treating GGA and extract relevant data in children less than 18 years. Data sources included MEDLINE, EMBASE, Cochrane library, and references of identified articles. Results We identified 790 potential studies, of which 229 were duplicates. 541 were excluded on the basis of title and abstracts. Of the 20 eligible studies included in the final analysis. Studies were from USA (40%, n=8), Europe (35%, n=7), Asia (25%, n=5). Majority were case studies (65%, n=13), case series (10%, n=2), cohort studies (10%, n=2) and Open label prospective studies (15%, n=3; 2 on ROM therapy and 1 of dapsone). There were 113 treated patients, 60% (n=68) were female. Children constitute 14% (n=16/113), with age range 2–18 years, treated with antibiotics, of which 3 were GGA and 13 Non-GGA (i.e 8 Localised GA, 2 perforating GA, and 3 subcutaneous GA). Main antibiotic treatments reported were either the monthly combination therapy given as ROM, or single therapy of dapsone or doxycycline/Minocycline. There was a good response in Non-GGA in Children with only 15% recurrence rate while only 33% achieve remission in the GGA. Unlike adults, no side effects reported in Children. Strength and limitations Our results highlight the strengths of combining outcomes of rare events. The lack randomised controlled trials, however, was a significant limitation. In addition, none of the literature looking at ROM combination therapy were in Children. Conclusion There is paucity of evidence to support the use of antibiotics in the treatment of GGA in children. Although, recently ROM as shown promising results in adults, more studies are needed to validate this findings. References . Garg S, Baveja S. Monthly rifampicin, ofloxacin, and minocycline therapy for generalised and localised granuloma annulare. Indian J Dermatol Venereol Leprol2015;81(1):35–39. . Simpson B, Foster S, Ku JH, Simpson EL, Ehst BD. Triple antibiotic combination therapy may improve but not resolve granuloma annulare. Dermatologic Therapy2014;27(6):343–347. . Mahmood T, Mansouri B, Menter A. Successful treatment of generalised granuloma annulare with adalimumab. Clin Exp Dermatol2015;40(5):537–539. . Garg S, Baveja S. Generalised granuloma annulare treated with monthly rifampicin, ofloxacin, and minocycline combination therapy. Indian J Dermatol2013;58(3):197–199. . Successful treatment of recalcitrant disseminated granuloma annulare with minocycline, ofloxacin, and rifampin combination therapy. Journal of the American Academy of Dermatology2013;68(4):AB64. http://dx.doi.org/10.1016/j.jaad.2012.12.268 Accessed 8/20/2017 3:18:52 PM. . Marcus DV, Mahmoud BH, Hamzavi IH. Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol2009;145(7):787–789. . Steiner A, Pehamberger H, Wolff K. Sulfone treatment of granuloma annulare. Journal of the American Academy of Dermatology1985;13(6):1004–1008. http://dx.doi.org/10.1016/S0190-9622(85)70253-8 [Accessed: 8/19/2017, 11:06:43 AM] . Boyd AS. Granuloma annulare responsive to oral calcitriol. Int J Dermatol2012;51(1):120–122. . Martín-Sáez E, Fernández-Guarino M, Carrillo-Gijón R, Muñoz-Zato E, Jaén-Olasolo P. Efficacy of dapsone in disseminated granuloma annulare: A case report and review of the literature. Actas Dermo-Sifiliográficas (English ed.) 2008;99(1):64–68. http://dx.doi.org/10.1016/S1578-2190(08)70196-3 [Accessed: 8/16/2017 1:20:39 PM]. . Gualco F, Zaccaria E, Drago F, Rebora A. Interstitial granuloma annulare and borreliosis: A new case. Journal of the European Academy of Dermatology and Venereology 2007;21(8):1117–1118. . Kiremitci U, Karagulle S, Topcu E, et al.Generalised granuloma annulare resolving to anetoderma. Dermatol Online J 2006;12(7):16. . Altomare GF, Frigerio E, Capella GL. Disseminated granuloma annulare: Effectiveness of sulphone treatment. G Ital Dermatol Venereol 2003;138(5):419–424. . Saied N, Schwartz RA, Estes SA. Treatment of generalised granuloma annulare with dapsone. Arch Dermatol 1980;116(12):1345–1346. . Cheng Y, Tsai W, Chuang F, et al. A retrospective analysis of 44 patients with granuloma annulare during an 11-year period from a tertiary medical centre in south Taiwan. Dermatologica Sinica 2016;34(3):121–125. Accessed 8/20/2017 3:19:30 PM. doi: http://dx.doi.org/10.1016/j.dsi.2015.11.002. . Yun JH, Lee JY, Kim MK, et al. Clinical and pathological features of generalised granuloma annulare with their correlation: A retrospective multicenter study in Korea. Ann Dermatol 2009;21(2):113–119. . Kozic H, Webster GF. Treatment of widespread granuloma annulare with adalimumab: A case report. J Clin Aesthet Dermatol 2011;4(11):42–43. . Duarte A, Mota A, Pereira M, Baudrier T, Azevedo F. Generalised granuloma annulare: Response to doxycycline. Journal of the European Academy of Dermatology and Venereology 2009;23(1):84–85. . Kovich O, Burgin S. Generalised granuloma annulare. Dermatology Online Journal 2005;11(4). . Ashida M, Katayama I, Kamo T. Oral minocycline improved generalised granuloma annulare possibly triggered by spider-bite (arachnidism). Nishi Nihon Hifuka 2004;66(3):246–250. . Successful treatment of generalised granuloma annulare with amoxicillin/clavulanic acid. J Am Acad Dermatol 74(5):AB73.

G337(P) Gender, ethnicity and social disadvantage patterns in ed attendance – not such a simple story

Background There are well established gender, ethnicity and socio-economic differences in the incidence and prevalence of epilepsy, autism and allergy sensitisation.1,2,3,4 Less is known about these differences within an ED setting. Simons et al. noted a gender disparity with more boys presenting to ED with sickness, head injury and falls than girls,5 but this was not statistically significant. Aim To establish the role of gender, ethnicity, and social deprivation as factors associated with presentation to ED in children under 5. Methods Study design: A retrospective study was conducted on a routine operational data set of basic demographic data collected from a large district general hospital. Sample: Paediatric ED data 01/04/2015–31/03/2016 for children below 5 years. Levels of deprivation: 2015 Index of Multiple Deprivation.6 Office for National Statistics (ONS) mid-year data used for denominator. Analysis: Descriptive analysis. Rate ratios were calculated for each age. Deciles were obtained for each postcode using 2015 Index of Multiple Deprivation data. Results Of the 19 267 under 16 year-olds paediatric attendances, 10 925 (56.7%) were less than 5 years of age. Of these, 6227 (57%) were male; M:F ratio in ED 1.33 cf. 1.05 local population. The proportion of the population attending ED decreased with age. Presentation rate was consistently higher in males than in females, but the gender gap decreased with age. Ethnicity was recorded for 89.9% of attendances. The gender difference in presentations was greatest for the black population (622 males vs 392 females, M:F ratio 1.59 cf. 1.01 population). At extremes of IMD, the rates of presentation were lowest (4.8% decile 1, 7.3% decile 10) and gender gap is least pronounced (male:female rate ratio 1.13 decile 1, 1.26 decile 10, greatest 1.39 decile 4. Conclusions and clinical implications More males attend ED than females in all ages and ethnic groups, with greatest gender disparity in the black population. In addition, it appears that the least and most deprived are least likely to present to ED. This study emphasises the utility of operational data for epidemiological research at local level and supports the need to further explore clinical and sociological reasons for differences in gender related attendances. References . Levine R, Kilbourne B, Rust G, Langston M, Husaini B, Gittner L, Sanderson M, Hennekens C. Social determinants and the classification of disease: Descriptive epiidemiology of selected socially mediated disease constellations. PLoS One 2014;9(11). . Retico AG Alessia, Tancredi R, Cosenza A, Apicella F, Narzisi A, Biagi L, Tosetti M, Muratori F, Calderoni S. The effect of gender on the neuroanatomy of children with autism spectrum disorders: A support vector machine case-control study. Mol Autism2016;7(5). . Pickrell W, Lacey A, Bodger O, Demmler J, Thomas R, Lyons R, Smith P, Rees M, Kerr M. Epilepsy and deprivation, a data linkage study. Epilepsia2015;56(4):585–91. . Joseph C, Zoratti E, Ownby D, Havstad D, Nicholas C, Nageotte C, Misiak R Enbeg, Ezell R, Johnson C. Exploring racial differences in IgE- mediated food allergy in the WHEALS birth cohort. Ann Allergy Asthma Immunol2016;116(3):219- 224. . Simons J. Young children in A&E: A local review. Paediatric Nursing1999;24(7). . Department for Communities and Local Government. The English indices of deprivation 2015;2015.

P2 Pneumococcal conjugate vaccine failure in children younger than 5 years old in England and Wales, 2006–14

Introduction and aims The 7-valent (PCV7) and 13-valent (PCV13) pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes and vaccine failure (vaccine-type IPD after age-appropriate immunisation) is rare. Although a number of studies have described children with PCV7 failure, little is known about PCV13 failure. Here, we describe the vaccination status, serotype distribution, risk factors, clinical characteristics and outcomes of children younger than 5 years with PCV7 and PCV13 failure over an eight-year period. Methods Public Health England conducts enhanced surveillance for IPD and provides a national reference service for serotyping pneumococcal isolates in England and Wales. General practitioners are routinely contacted to complete surveillance questionnaires for children aged <5 years with laboratory-confirmed IPD.Abstract P2 Figure 1 Serotype distribution of clinical presentation Results A total of 163 episodes of PCV failure were confirmed in 161 children aged <5 years over eight years (During 04 September 2006 to 03 September 2014) in ten birth cohorts (04 September 2004 to 03 September 2014), with an overall vaccine failure rate of 0.82 (0.70–0.96) per 100,000 vaccinated person-years. Of the 161 children, one third (n = 56, 35%) were exclusively PCV7 failures and 105 (65%) had received 1 PCV13 dose. Children with PCV13 failure were more likely to be healthy (87/105 [83%] vs. 37/56 [66%]; P = 0.016), present with lower respiratory tract infection (61/105 [58%] vs. 11/56 [20%]; P < 0.001) and develop empyema (41/61 [67%] vs. 1/11 [9%]; P < 0.001) compared to PCV7 failures. Children with co-morbidity were likely to be older (median age, 80.9 (IQR, 58.7–100.5) vs. 66.3 (48.8–83.4); P = 0.018) and present with septicaemia (P < 0.001). The case fatality rate was 3.1% (n = 5); four children had underlying co-morbidity (4/37 [10.8%] vs. 1/123 [0.81%); P = 002).Abstract P2 Table 1 Distribution of vaccine failure serotypes compared to the pre-vaccine baseline Conclusions PCV failure is rare in young children and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause LRTI and empyema in healthy vaccinated children, but most children recover without sequelae. Given that most IPD cases in countries with established PCV13 programmes are currently due to non-PCV13 serotypes, there is an urgent need for serotype-independent subunit or whole-cell vaccines to control this devastating disease.