JPediatr(RioJ).2015;91(4):315---317
www.jped.com.br
EDITORIAL
The
pertussis
problem:
classical
epidemiology
and
strain
characterization
should
go
hand
in
hand
夽
,
夽夽
O
problema
da
coqueluche:
a
caracterizac
¸ão
da
epidemiologia
clássica
e
da
cepa
deve
ser
feita
por
todos
Frits
R.
Mooi
∗,
Anne
Zeddeman,
Marjolein
van
Gent
CentreforInfectiousDiseaseControl,NationalInstituteforPublicHealthandtheEnvironment,Bilthoven,Netherlands
In thisissue of Jornal de Pediatria,Torres etal.1 present astudy ontheincidence,clinical features,mortality, and vaccinationstatusof patientswithwhooping coughin the state of Paraná,in theperiod of2007 to2013. They also providegenotypicdataontheB.pertussisstrainsisolated. ThestudyshowsthatpertussisinParanáisontheincrease, andthatmostseveresymptomsanddeathsoccurinchildren youngerthan2monthsofage.Thecombinationofclassical epidemiology--- which focusesonincidences,age distribu-tion,andclinicalfeatures---withstraincharacterizationis animportantaspectofthispaper,asonlythiscombination allowsustofullyunderstandthecausesfortheresurgence ofpertussis.
Pertussis is on the increase across the world and, as theauthorsnote,partofthisincrease isduetoenhanced awarenessamongcliniciansandimproveddetectionthrough theintroductionofpolymerasechainreaction(PCR).These twofactors have resulted in a more accurateassessment of thediseaseburden, which hastended tobe underesti-mated. The increased accuracy of pertussis diagnosis has led some authors to suggest that the resurgence of
per-DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2014.09.004
夽 Pleasecitethisarticleas:MooiFR,ZeddemanA,vanGentM.
Thepertussisproblem:classicalepidemiologyandstrain character-izationshouldgohandinhand.JPediatr(RioJ).2015;91:315---7.
夽夽
SeepaperbyTorresetal.inpages333---8. ∗Correspondingauthor.
E-mail:frits.mooi@rivm.nl(F.R.Mooi).
tussisisan artifact.However,current knowledgesupports the assumptionthat there is a real increase in pertussis, mainlycaused by twofactors: waning of vaccine-induced immunityandadaptation ofthepathogenby mutationsin itsDNA.Thetwofactorsarenotindependent,aspathogen adaptationreducestheperiodinwhichvaccinesare effec-tive andthereby increases the speed in which protective immunitywanes(seebelow).Hence,waningimmunityand pathogenadaptationaretwosidesofthesamecoin.2Recent studies indicatethat the switchfrom whole cellvaccines (WCVs) to acellular vaccines (ACVs) has also contributed tothe resurgenceof pertussis,becauseimmunityinduced by ACVs is of shorter duration compared to WCVs.3,4 It should be noted, however, that resurgence of pertussis is also observed in countries which have retained WCVs, underliningagain, thatmultiple factors areinvolved (this study).5,6
Pathogensdonotonly becomeresistant against antibi-otics,butalsoagainstvaccines.However,thelatterprocess issubtler,becausevaccineresistanceaccruesinsmallsteps andmaytherefore(initially)gounnoticed.Further,vaccine resistanceisnot absoluteanddoes notimply thatB. per-tussisisabletocausediseaseinahighlyimmunehost.The effectislesspronounced,inthatadaptedstrainsareableto infecthostsatahigherlevelofimmunity(i.e.earlierafter vaccination) comparedto non-adapted strains. Obviously, thisresultsinanincreaseinsusceptiblepersonsandthusin pathogencirculation.
Althoughstudiesinmicehaveshownthatpathogen adap-tationaffectsvaccineefficacy,sucheffectsaredifficultto establishin humanpopulations,astheyrequirelong-term
http://dx.doi.org/10.1016/j.jped.2015.02.001
316 MooiFRetal.
studies withlarge populations.Therefore, it is important toanalyzethenature ofthe geneticadaptationsin order toassessiftheyareexpectedtoaffectvaccineefficacy.In generalthis is the case withB. pertussis.The first adap-tations in B. pertussis involved relatively small changes insurface proteins knowntoinduce protective immunity: pertussistoxin (Ptx),pertactin(Prn), andfimbriae.2Later, changesingeneregulationwerefound,whichresultedinan increasedproductionofseveralvirulencefactorsincluding Ptxandproteinsinvolvedincomplementresistance.7,8Such changes may resultin increasedimmune suppressionand immuneevasion.Thestrainsshowingincreasedproduction ofvirulence factorsbelong tothe so-called P3(or ptxP3) lineage,whichhasrecentlyspreadworldwideand predom-inatesinmanyvaccinatedpopulations.9,10 Increasesinthe prevalenceofP3strainshavebeenassociatedwithincreased notification in the Netherlands and Australia.7,11 A study, usingpulsed-fieldgelelectrophoresis(PFGE)totype Brazil-ianstrains,identifiedtwoprofileswhicharefoundamongP3 strainscirculatingintheUS,12,13 suggestingthatP3strains arealsopresentinBrazil.Indeed,thegenomesequenceof aBrazilianP3strainhasrecentlybeenpublished.14
ThemostrecentadaptationofB.pertussisinvolvesthe lossofthe productionof Prn,a componentof mostACVs. Prn-deficientstrainspredominateinanumberofcountries inwhichACVshavebeenusedformanyyears.15,16 Interest-ingly,Prn-deficientstrainshavenotbeenobservedinPoland, whichusesaWCV.17 Thissuggeststhattheintroductionof ACVshas selectedfor Prn-deficientstrains,and thattheir emergencecanbepreventedbytheuseofvaccineswhich provideabroadimmunity.Itwouldbeinterestingto deter-mineifPrn-deficientstrainscirculateinBrazil.
How could the study performed by Torres et al.1 be improved?Itmustberealizedthattherewillalwaysbelocal constraints such aslack of funds, equipment,and exper-tise.Thus,thisisnotacriticism,but anattempt topaint theidealpicture.Onesuggestionistouseatypingmethod whichallowsfor internationalcomparisons.Bysequencing polymorphicregionsinthegenesforthePtxAsubunit,the Ptxpromoter(ptxP),Prn,andFim3,important characteris-ticsofcurrent strainscanbedetermined.18 Ofcourse,the vaccinestrainshouldbeincludedtodeterminetheextent ofdivergence withcirculating strains.PFGE is alsouseful to type strains, but requires careful standardization and doesnotalways revealtrue geneticrelationships.19 Single nucleotidepolymorphism (SNP) typing has the discrimina-torypowerofPFGE,isunequivocal,andrevealstruegenetic relationships.We haverecentlydevelopedan economical, high-throughputSNPtypingmethod.20
Tosolvethepertussisproblem,itisnecessaryto distin-guishbetweenshort-termandlong-termapproaches.Inthe longterm,weneedtodeveloppertussisvaccinesthatinduce longer-lastingimmunity.Intheshortterm,introductionof maternalvaccinationcan substantiallydecreasemorbidity and mortality. Studies in the UK have shown that mater-nalvaccinationisveryeffective(estimatedvaccineefficacy 90%)andsafeformotherandchild.21,22Asmanystudieshave shown, including the study by Torres et al., most severe pertussis and mortality occurs in infants younger than 2-3 months. If this category can be protected by maternal vaccinationuntiltheprimaryserieshavestarted,themost significant part of the pertussis problem may be solved.
Thequestionthatshouldthenbeaddressediswhetherthe pertussisburden inadolescents,adults,andtheelderly is severeenoughtomeritusinglimitedresourcesinorderto developbetterpertussisvaccines.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
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