Beek, D

Bijlsma, M

Brouwer, M

Dias, S

Ende, A

English

Repositório do Centro Hospitalar de Lisboa Central, EPE

Journal of Infection (2016) 73, 616e627www.elsevierhealth.com/journals/jinfLETTERS TO THE EDITORTable 1 Capsular pneumococcal serotypes from 447 menand 481 women with pneumococcal meningitis.Sex-based differences in pneumococcalserotype distribution in adults withpneumococcal meningitisSerotype Men e no. (%) Women e no. (%) p-Value7F 54 (12) 56 (12) 0.823 59 (13) 47 (10) 0.108 43 (10) 35 (7) 0.1922F 27 (6) 41 (9) 0.1523F 21 (5) 23 (5) 1.0019A 17 (4) 23 (5) 0.4719F 15 (3) 19 (4) 0.6410A 12 (3) 18 (4) 0.3723B 15 (3) 15 (3) 0.824 13 (3) 15 (3) 0.8612F 11 (2) 16 (3) 0.446B 11 (2) 14 (3) 0.681 8 (2) 15 (3) 0.2014 8 (2) 15 (3) 0.2018C 9 (2) 14 (3) 0.399N 8 (2) 13 (3) 0.3511A 11 (2) 9 (2) 0.5323A 10 (2) 10 (2) 0.8628 other serotypesa 95 (21) 83 (17) ePCV7 typesb 89 (20) 104 (22) 0.54PCV10 typesc 152 (34) 177 (37) 0.40PPV23 typesd 362 (81) 401 (83) 0.42Totale 447 481Individual serotypes are presented in descending order of fre-quency. Abbreviations: PCV7, heptavalent conjugate vaccine;PCV10, 10-valent conjugate vaccine; PPV23, 23-valent polysac-charide vaccine.a Other serotypes were as follows: 6A in eight males and tenfemales; 24F in seven male and nine females patients; 33F innine men and eight women; 9V in 12 men and four women;15B in four males and 11 females; 6C in seven male and five fe-male patients; 16F in four men and six women; 35F in sevenmales and three females; 15A and 17F in five male and three fe-male patients each; 28 in three males and three females; 31 inthree men and two women; 15C in four males and two females;20 in four males; 37 in four females; 18B in one male and threefemales; 5 in one male and two females; 34 and 35B both in twomales and one female; 22A in two males; 10B, 13, 25A, 28F and7B in one male each; 27, 24B and 7A in one female each.b 4, 6B, 9V, 14, 18C, 19F and 23F.c 1, 5 and 7F þ PCV7 types.d 2, 3, 9N, 10A, 11A, 12F, 15B, 17F, 19A 20, 22F and 33Fþ PCV10types.e Percentages may not add up to 100% due to rounding.We read with interest the study by Gounder et al., onthe epidemiology of bacterial meningitis in the NorthAmerican Arctic following the introduction of paediatricconjugate vaccines, which was published recently in thisjournal.1 Widespread use of paediatric conjugate vaccineshas changed the epidemiological landscape of bacterialmeningitis; however, it remains a serious health problemworldwide.2 In the Netherlands, there has been a signifi-cant decrease in the incidence of adult bacterial meningitissince their inclusion in childhood immunisation schedules,most sharply among Streptococcus pneumoniae capsular se-rotypes included in the seven-valent (PCV7) and ten-valent(PCV10) pneumococcal conjugate vaccines.3 These wereintroduced in the Netherlands in 2006 and 2011, respec-tively; a 23-valent polysaccharide vaccine (PPV23) is alsoavailable and recommended for certain risk groups.4 Simi-larly to what Gounder and colleagues reported, S. pneumo-niae is currently the leading cause of bacterial meningitis inthe Dutch population.3 As pneumococcal vaccines targetonly a limited set of the over 90 known serotypes,5 emer-gence of non-conjugate vaccine type (NVT) disease remainsa concern.6Pneumococcal serotypes have been associated withdifferences in invasiveness potential and outcome,4 makingknowledge of factors affecting serotype distribution impor-tant. A patient’s sex is a key determinant of infectious dis-eases, influencing susceptibility to illness and response tovaccination, while social and behavioural factors may alsoplay a role.7 Data regarding sex-based differences in pneu-mococcal serotype distribution, however, are limited,8e10and the impact of patient sex on serotype distribution inpneumococcal meningitis remains unclear. To investigatethis, we analysed serotype distribution and post-vaccination incidence trends in adult men and womenwith community-acquired pneumococcal meningitis in aprospective nationwide cohort study.We included all patients with pneumococcal meningitis,identified through the Netherlands Reference Laboratoryfor Bacterial Meningitis between March 2006 and June2014, for whom capsular serotype was available. Allparticipants or their legally authorized representativesprovided informed consent. Pneumococcal meningitiswas defined as a positive cerebrospinal fluid culture forLetters to the Editor 617S. pneumoniae, and isolates were serotyped by Quellungreaction using specific antisera. Individual serotypeswere grouped into vaccine types (i.e. those included inPCV7, PCV10 and PPV23) and NVT for analyses andcompared between sexes using the Chi-Square or Fisherexact test (as appropriate), with Bonferroni correctionfor multiple testing. Incidence rates in men and womenwere calculated as the number of cases per 100,000male or female population>16 years-old, respectively,per epidemiological year from July 2007 onward, as dueto pending ethical approval in several centres this wasthe first year in which all Dutch hospitals participated inthe study. Incidence rate ratios (IRR) and 95% confidenceFigure 1 Total incidence of pneumococcal meningitis (solid line)to serotypes included in the PCV7 and PCV10 conjugate vaccinespending ethical approval in several, not all patients could be inclufrom July 2007 onward were considered.intervals (CI) were used to assess differences in incidencerates between men and women. Analyses were performedusing IBM SPSS Statistics software (version 22.0), with two-tailed p-values below 0.05 considered statistically signifi-cant. Detailed methods of the MeninGene Study havebeen described previously.3We identified 997 episodes of pneumococcal meningitis.Serotype was available in 928 (93%), of which 447 (48%)were male, and 46 distinct capsular types were identified(Table 1). Serotypes 3, 7F and 8, in that order, were themost commonly found in men, while 7F, 3 and 22F werethe most frequent in women. After correcting for multipletesting, we found no differences between sexes in serotypewith 95% confidence intervals (dotted lines) and incidence due(bars) in men (A) and women (B) from 2007 to 2013. Due toded in the first months of the study, and therefore only cases618 Letters to the Editordistribution, neither individually nor using serotype 7F as areference (data not shown). We also found no differencesbetween men and women in the proportion of episodesdue to serotypes included in the PCV7, PCV10 or PPV23vaccines.Overall incidence of pneumococcal meningitis was 0.78/100,000 male and 0.85/100,000 female patients, with anIRR of 0.92 (95% CI 0.80e1.06). There was a markeddecrease over the study period (Fig. 1), mainly driven bya reduction in the incidence of PCV7 serotypes in both sexes(from 0.37 in 2007 to 0.02 in 2013). Incidence of diseasecaused by PPV23-exclusive serotypes remained largely un-changed throughout the study period (from 0.41 in 2007to 0.36 in 2013), with no difference between sexes. Therewas no absolute increase in the incidence of non-PCV10types in either sex, although the proportion of cases causedby these types did rise, from 58% (37 of 64 cases) in 2007 to91% (40 of 44 cases) in 2013 in men (p < 0.001) and 42% (36of 86 cases) in 2007 to 87% (34 of 39 cases) in 2013 in women(p < 0.001).In the Netherlands, coverage rates for conjugate vac-cines in infants are around 95%, while adults are notroutinely vaccinated.4 As a result, sex-based differencesin response to pneumococcal vaccination are unlikely tohave influenced our results, as evidenced by the relativestability of disease caused by serotypes exclusive to thePPV23 during the study period. These findings are, there-fore, best explained as a result of herd protection.Parents are thought to often acquire pneumococci fromtheir children, who are the primary community reservoir,and increased NVT carriage rates have been reported inparents of PCV7-vaccinated children.10 In many societies,women are more active in childcare than men, which couldfavour acquisition of pneumococci, specifically NVT. How-ever, although the female to male ratio in pneumococcalmeningitis in our cohort was slightly higher when comparedwith non-pneumococcal cases, this was not statistically sig-nificant,3 and there was no female preference for NVTdisease.We also found no significant sex-based differences in thedistribution of individual serotypes. Literature on this topicis scarce, and studies have yielded varying results.Rodrıguez et al., reported serotype 8 (not included inpneumococcal vaccines) to be more common in men, and1 and 7F (both included in the PCV10) in women withinvasive pneumococcal disease (IPD),9 while van Mens andcolleagues found increased serotype 1 IPD prevalence inyoung women10; a pre-vaccination study by Scott et al.,described a female preference for serogroup 14 and 23IPD.8 It is possible these findings are the result of chance,natural fluctuation in serotypes, differences in methodol-ogy or publication bias. Furthermore, none of these studiesspecifically investigated meningitis, and potentially the in-fluence of sex on serotype distribution may differ betweenmeningitis and other types of IPD.Funding informationThis work was supported by grants from the EuropeanResearch Council [ERC Starting Grant #281156, DvdB]; theNational Institute of Public Health and the Environment;the European Union’s seventh framework program[#279185, EUCLIDS]; Academic Medical Center (AMC Fellow-ship to DvdB); and the Netherlands Organization for HealthResearch and Development [Vidi grant number 016.116.358to DvdB, Veni grant 2012 number 916.13.078 to MCB]. Thesponsor of the study had no role in study design, datacollection, analysis, or interpretation or writing of thereport.Conflicts of interestNone.AcknowledgementsWe thank many physicians in the Netherlands for theircooperation and acknowledge the ESCMID Study Group forInfectious Diseases of the Brain (ESGIB) for thiscollaboration.References1. Gounder PP, Zulz T, Desai S, Stenz F, Rudolph K, Tsang R, et al.Epidemiology of bacterial meningitis in the North AmericanArctic, 2000-2010. J Infect 2015;71(2):179e87.2. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advancesin treatment of bacterial meningitis. Lancet 2012;380(9854):1693e702.3. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT,Lucas MJ, Tanck MW, et al. Community-acquired bacterialmeningitis in adults in the Netherlands, 2006-14: a prospectivecohort study. Lancet Infect Dis 2015;16(3):339e47.4. Jansen AG, Rodenburg GD, van der Ende A, van Alphen L,Veenhoven RH, Spanjaard L, et al. Invasive pneumococcal dis-ease among adults: associations among serotypes, disease char-acteristics, and outcome. Clin Infect Dis 2009;49(2):e23e9.5. Geno KA, Gilbert GL, Song JY, Skovsted IC, Klugman KP,Jones C, et al. Pneumococcal capsules and their types:past, present, and future. Clin Microbiol Rev 2015;28(3):871e99.6. Weinberger DM, Malley R, Lipsitch M. Serotype replacement indisease after pneumococcal vaccination. Lancet 2011;378(9807):1962e73.7. Fish EN. The X-files in immunity: sex-based differences pre-dispose immune responses. Nat Rev Immunol 2008;8(9):737e44.8. Scott JA, Hall AJ, Dagan R, Dixon JM, Eykyn SJ, Fenoll A,et al. Serogroup-specific epidemiology of Streptococcuspneumoniae: associations with age, sex, and geography in7,000 episodes of invasive disease. Clin Infect Dis 1996;22(6):973e81.9. Rodrıguez MA, Gonzalez AV, Gavın MA, Martınez FM, Marın NG,Blazquez BR, et al. Invasive pneumococcal disease: associationbetween serotype, clinical presentation and lethality. Vaccine2011;29(34):5740e6.10. van Mens SP, van Deursen AM, Meijvis SC, Vlaminckx BJ,Sanders EA, de Melker HE, et al. Increased incidence ofserotype-1 invasive pneumococcal disease in young femaleadults in The Netherlands. Epidemiol Infect 2014;142(9):1996e9.Sara P. DiasDepartment of Neurology, Center of Infection andImmunity Amsterdam (CINIMA), Academic Medical Center,Letters to the Editor 619University of Amsterdam, P.O. Box 22660, 1100 DDAmsterdam, The NetherlandsDepartment of Neurology, Hospital de Santo Antonio dosCapuchos, Centro Hospitalar de Lisboa Central, Alamedade Santo Antonio dos Capuchos, 1169-050 Lisbon, PortugalMatthijs C. BrouwerMerijn W. BijlsmaDepartment of Neurology, Center of Infection andImmunity Amsterdam (CINIMA), Academic Medical Center,University of Amsterdam, P.O. Box 22660, 1100 DDAmsterdam, The NetherlandsArie van der EndeDepartment of Medical Microbiology, Center of Infectionand Immunity Amsterdam (CINIMA), Academic MedicalCenter, University of Amsterdam, P.O. Box 22660, 1100 DDAmsterdam, The NetherlandsThe Netherlands Reference Laboratory for BacterialMeningitis, Academic Medical Center, P.O. Box 22660, 1100DD Amsterdam, The NetherlandsDiederik van de Beek*Department of Neurology, Center of Infection andImmunity Amsterdam (CINIMA), Academic Medical Center,University of Amsterdam, P.O. Box 22660, 1100 DDAmsterdam, The Netherlands*Corresponding author. Fax: þ31 205669374.E-mail address: d.vandebeek@amc.uva.nl (D. van de Beek)Accepted 18 August 2016http://dx.doi.org/10.1016/j.jinf.2016.08.009ª 2016 The British Infection Association. Published by Elsevier Ltd.All rights reserved.Simplification to a dual regimen withdarunavir/ritonavir plus lamivudine oremtricitabine in virologically-suppressedHIV-infected patientsDear Editor,In this Journal, Buteel and colleagues explored theemergence of drug resistant HIV variants at virologicalfailure (VF) of 3-drugs combinations (HAART) containingefavirenz, tenofovir and lamivudine or emtricitabine.1Recently, strategies of treatment switch to a dual therapywith atazanavir/ritonavir or lopinavir/ritonavir plus lamivu-dine in virologically-suppressed HIV-infected patients haveshown promising results with low risk of virological failureand emergence of resistance.2e4 However, few data areavailable for the darunavir/ritonavir þ lamivudine or emtri-citabine combination.5We performed a multicenter, retrospective, observa-tional study including patients on HAART, with HIV-RNA< 50 copies/mL and CD4> 200 cells/mL switching duringroutine clinical practice to darunavir/ritonavir 800/100 mgplus lamivudine300mgor emtricitabine 200mgoncedaily forintolerance to nucleoside reverse transcriptase inhibitors(NRTI) or to prevent NRTI toxicity. We excluded patients withpositive HBsAg, pregnancy or genotypic resistance to dar-unavir or lamivudine/emtricitabine. All patients providedinformed consent to be included in observational studies,approved by the institutional Ethics Committees.Patients were followed from darunavir/ritonavir þlamivudine or emtricitabine initiation (baseline) to treat-ment discontinuation/switch (TD, defined as any modifica-tion or discontinuation of the dual regimen) or to the lastavailable visit.The primary endpoint was to estimate the time to TDand to explore its predictors using KaplaneMeier curves andCox regression models. Secondary endpoints included theevaluation of time to VF (defined as HIV-RNA > 50 copies/mL in two consecutive determinations or >1000 copies/mLin a single determination) and of CD4, lipid parameters andrenal function evolution over time.A total of 194 patients were included [145 (76.1%) males,median age 49 years (interquartile range, IQR 40e55), 33(17%)HCV-coinfected, 45 (23.2%)with previous AIDS-definingevents, median CD4 nadir 223 cells/mL (IQR 94e324), medianbaseline CD4 626 cells/mL (IQR 482e786), median time withHIV-RNA < 50 copies/mL 41 months (IQR 21e75)]. PreviousHAART regimens were protease inhibitor (PI)-, non-nucleoside reverse transcriptase inhibitor (NNRTI)- or inte-grase inhibitor (InSTI)-based in 125 (64.4%), 33 (17%) or 25(12.9%) patients, respectively. The NRTI backbone includedtenofovir in 78.4% (Supplementary Table 1).At baseline, 186 (96%) and 8 (4%) patients simplifiedtreatment to darunavir/ritonavir þ lamivudine and daru-navir/ritonavir þ emtricitabine, respectively. The medianfollow-up after baseline was 8.8 months (IQR 4.8e19.8).VF was observed in 7 (3.6%) patients with an incidence of3.7 per 100 person years of follow-up (PYFU). Five of them(2.6%) switched treatment with subsequent virologicalcontrol. The remaining 2 patients (1.0%) remained on dualtherapy with spontaneous virological re-suppression. Gen-otyping testing at VF, available for 1/7 patients, did notdemonstrate any resistance mutation.Overall, TD occurred in 44 (22.7%) patients with anincidence of 23 per 100 PYFU. Main reasons of TD were:adverseevents [nZ22 (11.3%), incidence11.5 per 100PYFU],simplification to PI monotherapy or single tablet regimens[nZ 6 (3.1%), incidence 3.1 per 100 PYFU], virological failure[n Z 5 (2.6%), incidence 2.6 per 100 PYFU], inadequateadherence [n Z 4 (2.1%), incidence 2.1 per 100 PYFU]. Mainadverse events leading to TD were dyslipidemia (n Z 10,5.2%) and gastrointestinal intolerance (nZ 6, 3.1%).The estimated probabilities of VF and TD were 5.6% and18.7% at 12 months, respectively (Fig. 1a and b). A higherprobability of TD was observed for patients switchingfrom InSTI-based (40.3%) when compared to PI-based(13.9%) and NNRTI-based regimens (12.6%) (p Z 0.004);this difference was mainly driven by TD for adverse events(Fig. 1c and d). Exploring predictors of TD, pre-switch InSTI-based regimens [adjusted hazard ratio (aHR) 2.63, 95%

Sex-Based Differences in Pneumococcal Serotype Distribution in Adults with Pneumococcal Meningitis

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Sex-Based Differences in Pneumococcal Serotype Distribution in Adults with Pneumococcal Meningitis

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Repositório do Centro Hospitalar de Lisboa Central, EPE