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RESURGENCE OF BORDETELLA PERTUSSIS

RESURGENCE OF BORDETELLA PERTUSSIS

IN AMERICAData from the acellular Pertussis acci!e trial "APERT# co!$ucte$ i! the US su%%est that the i!ci$e!ce of &ertussis i!fectio! "$efi!e$ serolo%icall'# i! a$olesce!ts a!$ a$ults is arou!$ 1( &er 'ear "ra!%e )*+, -*.(#* Si!ce mi$/-)110 a su1sta!tial rise i! &ertussis cases has 1ee! re&orte$ i! the state of 2ashi!%to!* I! res&o!se to this i!crease0 the 2ashi!%to! State Secretar' of 3ealth $eclare$ a &ertussis e&i$emic o! A&ril 40 -)1-* B' 5u!e 160 the re&orte$ !um1er of cases i! 2ashi!%to! i! -)1- ha$ reache$ -07-) "4.*7 cases &er 1))0))) resi$e!ts#0 a 104))( i!crease com/&are$ 8ith the same &erio$ i! -)11 a!$ the hi%hest !um1er of cases re&orte$ i! a!' 'ear si!ce 19+-* IN EUROPE/ The sur eilla!ce &ro:ect EU;AC/NET has recor$e$ a 117( i!crease i! i!ci$e!ce rates i! chil$re! a%e$ o er 1+ 'ears 1et8ee! 199< a!$ -))-* IN AUSTRALIA/ There 8ere 4+0+9) &ertussis !otificatio!s recei e$ 1' the Natio!al Notifia1le Diseases Sur eilla!ce S'stem "NNDS# i! -)1)0 the hi%hest recor$e$ si!ce 1991*Rece!tl'0 there has 1ee! a rise i! !otificatio! rates i! the -)/79 'ear ol$ a%e %rou&0 a!$ i! those o er the a%e of 6)0 i!creasi!% 1' 7.( a!$ 1.( res&ecti el' i! -)1)* IN NET3ERLAND/ I! the Netherla!$s0 $es&ite co!siste!tl' hi%h acci!atio! co era%e for $eca$es0 i!crease$ !um1ers of &ertussis !otificatio!s ha e 1ee! o1ser e$ si!ce 1996 8ith e&i$emic &ea=s e er' -,4 'ears* The Netherla!$s recor$e$ more tha! 60))) cases i! -))90 u& from 4) cases i! 19<)* IN INDIA/ I! I!$ia the total cases of 8hoo&i!% i! -))6 8as -)6))* I! -)). there 8ere -71-6 male0 1747) female0 +).-9 totals* I! the I!$ia0 case $efi!itio!s are 1ase$ o! cli!ical co!firmatio! $ue to limite$ access to la1orator' facilities* This ma=es case $efi!itio! $ifficult i! a$olesce!ts0 a!$ a$ults*

RESURGENCE OF BORDETELLA PERTUSSIS

INCIDENCE OF PERTUSSIS IN ADULT/

PERTUSSIS EPIDE>IC AND GENO>E >ODIFICATION/

INTRODUCTION/
Bordetella pertussis 8as first isolate$ i! &ure culture i! 19)6 1' Bor$et a!$ Ge!%ou* To$a'0 B
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RESURGENCE OF BORDETELLA PERTUSSIS

pertussis 1elo!%s to the %e!us Bordetella i! the famil' Alcali%e!aceae0 8hich co!tai!s se eral s&ecies of closel' relate$ 1acteria 8ith similar mor&holo%'* 2hile !i!e s&ecies of Bordetella ha e 1ee! i$e!tifie$ to $ate0 o!l' three a$$itio!al mem1ers0 B. bronchiseptica0 B. parapertussis0 a!$ B. holmesii0 ha e 1ee! associate$ 8ith res&irator' i!fectio!s i! huma!s a!$ other mammals* B. bronchiseptica i!fects a 8i$e ra!%e of hosts a!$ occasio!all' causes cou%h ill!esses i! huma!s? i! &articular0 se ere i!fectio!s ha e 1ee! !ote$ i! &erso!s 8ho are immu!ocom&romise$ such as &atie!ts 8ith AIDS* 3uma!/a$a&te$ B. parapertussis "B. parapertussishu# causes a mil$er &ertussis/li=e $isease a!$0 li=e B. pertussis0 lac=s a! e! iro!me!tal reser oir* B. holmesii0 the most rece!t of the Bordetella s&ecies associate$ 8ith huma! res&irator' tract i!fectio!0 has 1ee! fou!$ i! the 1loo$ of 'ou!% a$ults a!$ occasio!all' i! the s&utum Bordetella pertussis is a small "a&&ro@imatel' )*< Am 1' )*+ Am#0 ro$/sha&e$0 coccoi$0 or o oi$ %ram !e%ati e 1acterium that is e!ca&sulate$ a!$ $oes !ot &ro$uce s&ores* It is a strict aero1e* It is arra!%e$ si!%l' or i! small %rou&s a!$ is motile*

ELECTRON >ICROSCOPE OF BORDETELLA PERTUSSIS/

RESURGENCE OF BORDETELLA PERTUSSIS

VIRULENCE FACTORS OF BORDETELLA PERTUSSIS-

The bvg locus/


B % locus e!co$es &rotei!s that tra!smit e@tracellular si%!als to the cellular tra!scri&tio! machi!er'0 causi!% cha!%es i! %e!e e@&ressio!* 2ith the e@ce&tio! of tracheal c'toto@i!0 e@&ressio! of irule!ce factors is coor$i!atel' re%ulate$ 1' the &ro$ucts of the bvg locus* It occu&ies B7 =1 o! the total %e!ome a!$ co$es for B %A0 B %S a!$ a!other &rotei! $o8!stream0 B %R* Stu$ies o! this locus ha e re eale$ that its tra!scri&tio! is co!trolle$ 1' a 47) 1& DNA fra%me!t ha i!% four &romoters* Three of them0 P10 P- a!$ P4 are i! ol e$ i! the tra!scri&tio! of the bvg locus 8hile the fourth0 P+0 is i! ol e$ i! the s'!thesis of a! a!tise!se RNA* A!other &romoter PF3A0 locate$ !ear the bvg locus is res&o!si1le for the tra!scri&tio! of a irule!t a$hesio! factor "F3A0 $iscusse$ later#* U!$er !o!/i!$uci!% co!$itio!s0 the &romoter P - is acti e a!$ mai!tai!s a lo8 le el of the re%ulator' &rotei! B %A 8hich is !ot e!ou%h to acti ate the irule!ce %e!es* U!$er i!$uci!% co!$itio!s0 B %A is acti ate$ 1' &hos&hor'latio!0 follo8i!% 8hich it acti ates the &romoters P10 P-0 P40 P+0 PF3A0 a!$ other &romoters of the ;irule!ce Acti ate$ Ge!es
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RESURGENCE OF BORDETELLA PERTUSSIS

"vag#0 a class of loci i!clu$i!% %e!es e!co$i!% the a$hesi!s a!$ to@i!s* This re&rese!ts the Bvg+ &he!ot'&e* The a!tise!se RNA co$e$ from P+ &ositi el' re%ulates P10 P- a!$ P4 1' h'1ri$iCi!% to their 7D u!tra!slate$ re%io!s* 3'1ri$iCatio! i!hi1its the formatio! of seco!$ar' structure i! the mRNAs0 there1' fa ori!% their i!teractio! 8ith the ri1osome* This causes a 7)/fol$ i!crease i! the rate of tra!slatio!*

Fi%ure/ 4 The 1 % locus 8ith 1 % ASR %e!es a!$ the &romoters P10 P-0 P4 a!$ P+* The B %/ &hase is $efi!e$ 1' the a1se!ce of vag/e!co$e$ factors a!$ occurs 8he! the bvg locus is $elete$ or 8he! B %AS acti it' is su&&resse$ 1' mo$ulati!% co!$itio!s such as the &rese!ce of sulfate a!io!0 !icoti!ic aci$0 or re$uce$ tem&erature* It also i! ol es the e@&ressio! of a seco!$ class of bvg re%ulate$ %e!es $uri!% the mo$ulate$ &hase0 the ;irule!ce Re&resse$ Ge!es "vrg#* Namel' vrg6, vrg 18, vrg 24, vrg 53 a!$ vrg 73* The first four of the fi e vrg %e!es me!tio!e$ are re%ulate$ 1' bvg acti ate$ re&ressor molecule "B %R# throu%h a co!ser e$ re&ressor 1i!$i!% site* 2hile the bvg/re&resse$ %e!es of B. bronchiseptica a&&ear to 1e i! ol e$ i! sur i al outsi$e the host0 their fu!ctio! i! B. pertussis is relati el' u!=!o8!* 3o8e er it has 1ee! sho8! that B %R me$iate$ re%ulatio! of %e!e e@&ressio! co!tri1utes to res&irator' i!fectio! i! mice*

RESURGENCE OF BORDETELLA PERTUSSIS

The B % AS t8o com&o!e!t s'stem/


Bordetella pertussis em&lo's a t8o/com&o!e!t si%!al tra!s$uctio! s'stem com&risi!% B %S a!$ B %A0 to re%ulate cellular fu!ctio!s i! res&o!se to e! iro!me!tal co!$itio!s0 8hich are !ot &ro&erl' u!$erstoo$ so far* B %S is a 147 =Da &eri&lasmic se!sor histi$i!e =i!ase* It co!sists of a &eri&lasmic i!&ut $omai! a!$ se eral c'to&lasmic $omai!s0 the li!=er0 tra!smitter0 recei er a!$ the C/termi!us* The B %S &eri&lasmic $omai! se!ses e@ter!al stimuli "&erha&s ia $imeriCatio!# a!$ tri%%ers a series of &hos&hor'latio! ste&s starti!% 8ith auto&hos&hor'latio! i! the tra!smitter $omai! at a co!ser e$ histi$i!e resi$ue* This is follo8e$ 1' the tra!sfer of the &hos&hate %rou& to a co!ser e$ as&artic aci$ i! the recei er $omai! 8hich tra!sfers it to a histi$i!e at the C/termi!al $omai!*

Fi%ureE +
Pro&ose$ mo$el of the re%ulator' !et8or= of the 1 % locus* "a# No!/i!$uci!% co!$itio!s 'iel$ a lo8 amou!t of B %A0 8hich is i!acti e* "1# U!$er i!$uci!% co!$itio!s0 B %A is co! erte$ to a! acti e form "$e&icte$ as &hos&hor'late$# a!$ tra!sacti ates P10 P-0 P40 P+0 PF3A a!$ all other &romoters of the 1 % re%ulo!* "c# The acti e form of B %A is am&lifie$ 1' this &ositi e tra!scri&tio!al fee$1ac= at the 1 % locus* "$# Cha!%i!% to !o!/i!$uci!% co!$itio!s 8here B %A is &rese!t i! lar%e amou!ts 1ut i! a! i!acti e form.
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RESURGENCE OF BORDETELLA PERTUSSIS

B %A0 the res&o!se re%ulator0 is a -4/=Da c'to&lasmic &rotei! com&risi!% a N/termi!al recei er a!$ a C/termi!al out&ut $omai!0 8hich co!tai!s a heli@/tur!/heli@ "3T3# DNA 1i!$i!% motif* B %A is acti ate$ 1' the tra!sfer of the &hos&hate %rou& from the C/termi!al of B %S to a co!ser e$ as&artic aci$ i! the B %A N/termi!al recei er $omai!* U&o! &hos&hor'latio!0 B %A &ositi el' re%ulates the bvg ! a!$ other irule!ce factor &romoters 1' 1i!$i!% to the tar%et seFue!ce TTTCCTA* It has also 1ee! sho8! that B %A is a1le to $imeriCe i! solutio! as a &ossi1le mea!s to 1ri!% a1out its DNA 1i!$i!% &ro&ert'*

Fi%ure/7
>o$el for the t8o com&o!e!t si%!al tra!s$uctio! s'stem 1' the B %AS &rotei!s.

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RESURGENCE OF BORDETELLA PERTUSSIS

Se eral li!es of e i$e!ce su%%est that the mecha!ism of re%ulatio! 1' the bvg locus is $iffere!t for $iffere!t irule!ce loci* Althou%h B %A is ca! !ot $irectl' sufficie!t acti ate for tra!scri&tio! the acti atio! from of the "ha a!$ bvg &romoters0 the bvg locus

the pt# a!$ c$a &romoters "$etaile$ later#* This ca! 1e i!ter&rete$ i! terms of the lo8er 1i!$i!% affi!it' or hi%her le els of acti ate$ B %A reFuire$ to stimulate tra!scri&tio! at the pt#com&are$ to the "ha &romoter* Rece!t 8or= has also im&licate$ the reFuireme!t of a$$itio!al accessor' factors such as the rece!tl' i$e!tifie$ Baf &rotei! or the $iffere!tial effects of DNA to&olo%' for the selecti e acti atio! of some &romoters* Gi e! the arie$ as&ects of B %A me$iate$ tra!scri&tio!al acti atio!0 the bvg re%ulo! has &ro e$ to 1e a! e@celle!t s'stem for the stu$' of $iffere!tial a!$ timel' re%ulatio! of tar%et &romoters to o&timiCe the i!fectio! &rocess* FILA>ENTOUS 3AE>AGGLUTININ/ Filame!tous hema%%luti!i! is a lar%e "--) =Da# &rotei! that forms filame!tous structures o! the cell surface* F3A 1i!$s to %alactose resi$ues o! a sulfate$ %l'coli&i$ calle$ sulfati$e 8hich is er' commo! o! the surface of ciliate$ cells* >utatio!s i! the F3A structural %e!e re$uce the a1ilit' of the or%a!ism to colo!iCe0 a!$ a!ti1o$ies a%ai!st F3A &ro i$e &rotectio! a%ai!st i!fectio!* 3o8e er0 it is u!li=el' that F3A is the o!l' a$hesi! i! ol e$ i! colo!iCatio!* The structural %e!e for F3A has 1ee! clo!e$ a!$ e@&resse$ i! %. coli0 raisi!% the &ossi1ilit' of its &ro$uctio! for use i! a com&o!e!t acci!e*

FI>BRIAE/
B.pertussis fim1riae are su1microsco&ic &rotei!aceous a&&e!$a%es that &rotru$e from the cell surface* The' are com&rise$ of a ma:or a!$ a mi!or su1u!it a!$ are 1elie e$ to cause &ersiste!c' of i!fectio!* The mi!or su1u!it0 !ame$ FimD 1i!$s to the i!te%ri! ;la/70 locate$ o! mo!oc'tes* The ma:or su1u!it 1i!$s to sulfate$ su%ars li=e he&ara! sulfate0 cho!$roiti! sulfate a!$ $e@tra! sulfate 8hich are u1iFuitous i! the res&irator' tract* Stu$ies ha e sho8! that 1oth the $e%ree a!$ arra!%eme!t of sulfate %rou&s $etermi!es the affi!it' of the 1i!$i!% of fim1riae* It is i!teresti!% to !ote that these 1i!$i!% acti ities are also fou!$ i! fi1ro!ecti!0 a host &rotei! fou!$ i! the e@tracellular matri@0 a!$ that the ma:or su1u!it share co!si$era1le homolo%' 8ith fi1ro!ecti! 8ithi! re%io!s im&licate$ 8ith he&ari! 1i!$i!%* Thus B. pertussis fim1riae mimics !atural host li%a!$/rece&tor i!teractio!s to further its i!fectio! &rocess* Sulfate$ su%ars o! res&irator' tract cells

RESURGENCE OF BORDETELLA PERTUSSIS

are also reco%!iCe$ 1' F3A0 he!ce &rese!ce of fim1riae coul$ &ossi1l' 1e to $iffere!tiate 1et8ee! $iffere!t host cells a!$ tissues e@hi1iti!% ma!' $iffere!t co!fi%uratio!s of he&ara! sulfate* Bi!$i!% of fim1riae to mo!oc'tes results i! acti atio! of CR4 "com&leme!t rece&tor t'&e/4#0 the mo!oc'te rece&tor of F3A0 reflecti!% their s'!er%istic actio! $uri!% i!fectio!*

PERTACTIN/ Pertacti!0 a 69 =Da !o!fim1rial outer mem1ra!e &rotei!0 u!$er the co!trol of the bvg locus0 is &artl' res&o!si1le for the a$hesio! of the 1acteria to the host cells* It also fu!ctio!s as a &rotecti e a!ti%e! i! a!imal mo$els* The mature &rotei! has t8o Ar%i!i!e/Gl'ci!e/As&artic aci$ "RGD# seFue!ces0 at --7/--. a!$ 667/ 66.* These seFue!ces are also &rese!t o! other mammalia! a$hesio! &rotei!s li=e fi1ro!ecti!0 itro!ecti! a!$ fi1ri!o%e! a!$ 1i!$ s&ecificall' to the i!te%ri! famil' of &rotei!s0 locate$ o! the mammalia! cell surface*

ADENYLATE CYCLASE A$e!'late c'clase e!ters mammalia! cells "Bacillus anthracis &ro$uces a similar e!C'me0 EF#* This to@i! acts locall' to re$uce &ha%oc'tic acti it' a!$ &ro1a1l' hel&s the or%a!ism i!itiate i!fectio!* This to@i! is a +7 =Da &rotei! that ma' 1e cell/associate$ or release$ i!to the e! iro!me!t* >uta!ts of B. pertussis i! the a$e!'late c'clase %e!e ha e re$uce$ irule!ce i! mouse mo$els* The or%a!isms ca! still colo!iCe 1ut ca!!ot &ro$uce the lethal $isease* The a$e!'late c'clase to@i! is a si!%le &ol'&e&ti$e 8ith a! e!C'matic $omai! "i*e*0 a$e!'late c'clase acti it'# a!$ a 1i!$i!% $omai! that 8ill attach to host cell surfaces* The a$e!'late c'clase 8as ori%i!all' i$e!tifie$ as a hemol'si! 1ecause it 8ill l'se re$ 1loo$ cells* I! fact0 it is res&o!si1le for hemol'tic Co!es arou!$ colo!ies of Bordetella pertussis %ro8i!% o! 1loo$ a%ar* Pro1a1l' it i!serts i!to the er'throc'te mem1ra!e 8hich causes hemol'sis* A! i!teresti!% feature of the a$e!'late c'clase to@i! is that it is acti e o!l' i! the &rese!ce of a eu=ar'otic re%ulator' molecule calle$ calmo$uli!0 8hich u&/re%ulates the acti it' of the eu=ar'otic a$e!'late c'clase* The a$e!'late c'clase to@i! is o!l' acti e i! the eu=ar'otic cell si!ce !o similar re%ulator' molecule e@ists i! &rocar'otes* Thus0 the molecule seems

1)

RESURGENCE OF BORDETELLA PERTUSSIS

to ha e e ol e$ s&ecificall' to &arasitiCe eu=ar'otic cells* A!thra@ EF "e$ema factor# is also a calmo$uli!/$e&e!$e!t a$e!'late c'clase* DER>ATONECROTIC TOGIN/ It &ro$uces a hi%hl' lethal to@i! 8hich causes i!flammatio! a!$ local !ecrosis a$:ace!t to sites 8here B. pertussis is locate$* The lethal to@i! is a 1)- =Da &rotei! com&ose$ of four su1u!its0 t8o 8ith a m8 of -+=Da a!$ t8o 8ith m8 of 4) =Da* It causes !ecrotic s=i! lesio!s 8he! lo8 $oses are i!:ecte$ su1cuta!eosl' i! mice a!$ is lethal i! hi%h $oses* The role of the to@i! i! 8hoo&i!% cou%h is !ot =!o8!* TRAC3EAL CHTOTOGIN/ It &ro$uces a su1sta!ce calle$ the tracheal c'toto@i! 8hich is to@ic for ciliate$ res&irator' e&ithelium a!$ 8hich 8ill sto& the ciliate$ cells from 1eati!%* This su1sta!ce is !ot a classic 1acterial e@oto@i! si!ce it is !ot com&ose$ of &rotei!* The tracheal c'toto@i! is a &e&ti$o%l'ca! fra%me!t0 8hich a&&ears i! the e@tracellular flui$ 8here the 1acteria are acti el' %ro8i!%* The to@i! =ills ciliate$ cells a!$ causes their e@trusio! from the mucosa* It also stimulates release of c'to=i!e IL/10 a!$ so causes fe er* PERTUSSIS TOGIN/ A &rotei! that me$iates 1oth the colo!iCatio! a!$ to@emic sta%es of the $isease* PT@ is a t8o com&o!e!t0 AIB 1acterial e@oto@i!* The A su1u!it "S1# is a! ADP ri1os'l tra!sferase* The B com&o!e!t0 com&ose$ of fi e &ol'&e&ti$e su1u!its "S- throu%h S7#0 1i!$s to s&ecific car1oh'$rates o! cell surfaces* The role of PT@ i! i! asio! has alrea$' 1ee! $iscusse$* PT@ is tra!s&orte$ from the site of %ro8th of the Bor$etella to arious susce&ti1le cells a!$ tissues of the host* Follo8i!% 1i!$i!% of the B com&o!e!t to host cells0 the A su1u!it is i!serte$ throu%h the mem1ra!e a!$ release$ i!to the c'to&lasm i! a mecha!ism of $irect e!tr'* The A su1u!it %ai!s e!C'matic acti it' a!$ tra!sfers the ADP ri1os'l moiet' of NAD to the mem1ra!e/1ou!$ re%ulator' &rotei! Gi that !ormall' i!hi1its the eu=ar'otic a$e!'late c'clase* The Gi &rotei! is i!acti ate$ a!$ ca!!ot &erform its !ormal fu!ctio! to i!hi1it a$e!'late c'clase* The co! ersio! of ATP to c'clic A>P ca!!ot 1e sto&&e$ a!$ i!tracellular le els of cA>P i!crease* This has the effect to $isru&t cellular fu!ctio!0 a!$ i! the case of &ha%oc'tes0 to $ecrease their &ha%oc'tic acti ities such as chemota@is0
11

RESURGENCE OF BORDETELLA PERTUSSIS

e!%ulfme!t0 the o@i$ati e 1urst0 a!$ 1acteri$ci$al =illi!%* S'stemic effects of the to@i! i!clu$e l'm&hoc'tosis a!$ alteratio! of hormo!al acti ities that are re%ulate$ 1' cA>P0 such as i!crease$ i!suli! &ro$uctio! "resulti!% i! h'&o%l'cemia# a!$ i!crease$ se!siti it' to histami!e "resulti!% i! i!crease$ ca&illar' &ermea1ilit'0 h'&ote!sio! a!$ shoc=#* PT@ also affects the immu!e s'stem i! e@&erime!tal a!imals* B cells a!$ T cells that lea e the l'm&hatics sho8 a! i!a1ilit' to retur!* This alters 1oth A>I a!$ C>I res&o!ses a!$ ma' e@&lai! the hi%h freFe!c' of seco!$ar' i!fectio!s that accom&a!' &ertussis "the most freFue!t seco!$ar' i!fectio!s $uri!% 8hoo&i!% cou%h are &!eumomia a!$ otitis me$ia#* Althou%h the effects of the &ertussis to@i! are $e&e!$e!t o! ADP ri1os'latio!0 it has 1ee! sho8! that mere 1i!$i!% of the B oli%omer ca! elicit a res&o!se o! the cell surface such as l'm&hoc'te mito%e!icit'0 &latelet acti atio!0 a!$ &ro$uctio! of i!suli! effects* The &ertussis to@i! %e!e has 1ee! clo!e$ a!$ seFue!ce$ a!$ the su1u!its e@&resse$ i! %. coli* The to@i! ca! 1e i!acti ate$ a!$ co! erte$ to to@oi$ for use i! com&o!e!t acci!es* Com&ariso! 1et8ee! cholera to@i! a!$ &ertussis to@i! "&t@# i! their a1ilit' to i!terfere 8ith the re%ulatio! of the eucar'otic a$e!'late c'clase com&le@* Normal re%ulatio! of a$e!'late c'clase acti it' i! mammalia! cells is acti ate$ !ormall' 1' a stimulator' re%ulator' &rotei! "Gs# a!$ %ua!osi!e tri&hos&hate "GTP#? ho8e er the acti atio! is !ormall' 1rief 1ecause a! i!hi1itor' re%ulator' &rotei! "Gi# h'$rol'Ces the GTP* A$e!'late c'clase acti ate$ 1' cholera to@i!* The cholera to@i! A1 fra%me!t catal'Ces the attachme!t of ADP/Ri1ose "ADPR to the re%ulator' &rotei! Gs0 formi!% Gs/ADPR from 8hich GTP ca!!ot 1e h'$rol'Ce$* Si!ce GTP h'$rol'sis is the e e!t that i!acti ates a$e!'late c'clase "AC#0 the e!C'me remai!s co!ti!uall' acti ate$* A$e!'late c'clase acti ate$ 1' &ertussis to@i! "The &ertussis A su1u!it tra!sfers the ADP ri1os'l moiet' of NAD to the mem1ra!e/1ou!$ re%ulator' &rotei! Gi that !ormall' i!hi1its the eu=ar'otic a$e!'late c'clase* The Gi &rotei! is i!acti ate$ a!$ ca!!ot &erform its !ormal fu!ctio! to i!hi1it a$e!'late c'clase* The co! ersio! of ATP to c'clic A>P ca!!ot 1e sto&&e$* LIPOPOLYSACCHARIDEAs a Gram/!e%ati e 1acterium Bordetella pertussis &ossesses li&o&ol'sacchari$e "e!$oto@i!# i! its outer mem1ra!e0 1ut its LPS is u!usual* It is hetero%e!eous0 8ith t8o ma:or forms $ifferi!% i! the &hos&hate co!te!t of the li&i$ moiet'* The alter!ati e form of Li&i$ A is $esi%!ate$ Li&i$ G* The
1-

RESURGENCE OF BORDETELLA PERTUSSIS

u!fractio!ate$ material elicits the usual effects of LPS "i*e*0 i!$uctio! of IL/10 acti atio! of com&leme!t0 fe er0 h'&ote!sio!0 etc*#0 1ut the $istri1utio! of those acti ities is $iffere!t i! the t8o forms of LPS* For e@am&le0 Li&i$ G0 1ut !ot Li&i$ A0 is &'ro%e!ic0 a!$ its O/si$e chai! is a er' &o8erful immu!e a$:u a!t* Furthermore0 Bor$etella LPS is more &ote!t i! the limulus assa' tha! LPS from other Gram/!e%ati e 1acteria0 so it is !ot relia1le to a&&l' =!o8le$%e of the 1iolo%ical acti it' of LPS i! the %nterobacteriaceae to the LPS of Bordetella* The role of this u!usual LPS i! the &atho%e!esis of 8hoo&i!% cou%h has !ot 1ee! i! esti%ate$*

PAT3OP3HSIOLOGH/
The a%e!t of 8hoo&i!% cou%h is tra!smitte$ &rimaril' ia $ro&lets* I!fectio! results i! colo!iCatio! a!$ ra&i$ multi&licatio! of the 1acteria o! the mucous mem1ra!es of the res&irator' tract* Bacteremia $oes !ot occur* Electro! microsco&ic stu$ies ha e $emo!strate$ that &hase I strai!s of B pertussis a$here o!l' to the tuft of ciliate$ cells i! the mucosa of the huma! res&irator' tract? !o attachme!t to !o!ciliate$ cells 8as o1ser e$* Co! i!ci!% e@&erime!tal $ata i!$icate that the a$here!ce of B pertussis to huma! cilia is affecte$ 1' a s'!er%istic actio! of &ertussis to@i! a!$ filame!tous hema%%luti!i!0 each acti!% as a 1i ale!t 1ri$%e 1et8ee! the 1acterium a!$ the ciliar' rece&tor* COLONIJATION/ Stu$ies of B. pertussis a!$ its a$hesi!s ha e focuse$ o! culture$ mammalia! cells that lac= most of the features of ciliate$ e&ithelial cells* 3o8e er0 some %e!eralities ha e 1ee! $ra8!* The t8o most im&orta!t colo!iCatio! factors are the filame!tous hema%%luti!i! "F3A# a!$ the &ertussis to@i! "PT@#* Filame!tous hema%%luti!i! is a lar%e "--) =Da# &rotei! that forms filame!tous structures o! the cell surface* F3A 1i!$s to %alactose resi$ues o! a sulfate$ %l'coli&i$ calle$ sulfati$e 8hich is er' commo! o! the surface of ciliate$ cells* >utatio!s i! the F3A structural %e!e re$uce the a1ilit' of the or%a!ism to colo!iCe0 a!$ a!ti1o$ies a%ai!st F3A &ro i$e &rotectio! a%ai!st i!fectio!* 3o8e er0 it is u!li=el' that F3A is the o!l' a$hesi! i! ol e$ i! colo!iCatio!* The structural %e!e for F3A has 1ee! clo!e$ a!$ e@&resse$ i! %. coli0 raisi!% the &ossi1ilit' of its &ro$uctio! for use i! a com&o!e!t acci!e*

14

RESURGENCE OF BORDETELLA PERTUSSIS

O!e of the to@i!s of B. pertussis0 the &ertussis to@i! "PT@#0 is also i! ol e$ i! a$here!ce to the tracheal e&ithelium* Pertussis to@i! is a 1)7 =Da &rotei! com&ose$ of si@ su1u!itsE S10 S-0 S40 S+0 a!$ S7* The to@i! is 1oth secrete$ i!to the e@tracellular flui$ a!$ cell 1ou!$* Some com&o!e!ts of the cell/1ou!$ to@i! "S- a!$ S4# fu!ctio! as a$hesi!s0 a!$ a&&ear to 1i!$ the 1acteria to host cells* S- a!$ S4 utiliCe $iffere!t rece&tors o! host cells* S- 1i!$s s&ecificall' to a %l'coli&i$ calle$ lactos'lcerami$e0 8hich is fou!$ &rimaril' o! the ciliate$ e&ithelial cells* S4 1i!$s to a %l'co&rotei! fou!$ mai!l' o! &ha%oc'tic cells*

PAT3OGENESIS OF INFECTION/
Si!ce the S4 su1u!it of &ertussis to@i! is a1le to 1i!$ to the surface of &ha%oc'tes0 a!$ si!ce F3A 8ill attach to i!te%ri! CR4 o! &ha%oc'te surfaces "the rece&tor for com&leme!t C41#0 it has 1ee! s&eculate$ that the 1acterium mi%ht 1i!$ &refere!tiall' to &ha%oc'tes i! or$er to facilitate its o8! e!%ulfme!t* The role of such self/i!itiate$ &ha%oc'tosis is !ot clear* Bacteria ta=e! u& 1' this a1!ormal route ma' a oi$ stimulati!% the o@i$ati e 1urst that !ormall' accom&a!ies &ha%oc'tic u&ta=e of 1acterial cells 8hich are o&so!iCe$ 1' a!ti1o$ies or com&leme!t C41* O!ce i!si$e of cells the 1acteria mi%ht utiliCe other to@i!s "i*e* a$e!'late c'clase to@i!# to com&romise the 1acterici$al acti ities of &ha%oc'tes* I! a!' case0 there is some e i$e!ce that Bordetella pertussis ca! use this mecha!ism to %et i!to a!$ to &ersist i! &ha%oc'tes as a! i!tracellular &arasite* If B. pertussisis a! i!tracellular &arasite it 8oul$ e@&lai! 8h' immu!it' to &ertussis correlates 1etter 8ith the &rese!ce of s&ecific c'toto@ic T cells tha! it $oes 8ith the &rese!ce of a!ti1o$ies to 1acterial &ro$ucts* The to@i!s a!$ a$hesi!s are im&orta!t 1oth for their &ote!tial role i! &atho%e!esis of $isease a!$ for their use as a!ti%e!s i! acellular &ertussis acci!es* Filame!tous hema%%luti!i! "F3A#0 &ertacti!0 a!$ fim1riae are a$hesi!s that are com&o!e!ts of some of the acellular acci!es0 1ut all curre!tl' a aila1le acci!es i!clu$e &ertussis to@i! "PT#* I! a$$itio! to 1ei!% a! a$hesi!0 F3A has 1ee! sho8! to co!tai! a! RGD "ar%i!i!e/%l'ci!e/ as&ara%i!e,co!tai!i!% seFue!ce# site0 i!teract 8ith the i!te%ri! CD111KCD1< "also =!o8! as CR4 or >ac/1#0 a!$ mo$ulate the fu!ctio!s of cells i! the host immu!e s'stem* PT is a mem1er of the famil' of a$e!osi!e $i&hos&hate,ri1os'lati!% to@i!s that i!clu$es cholera to@i! a!$ $i&htheria to@i!0 a!$ it has as its i!tracellular tar%et se eral %ua!osi!e tri&hos&hate,

1+

RESURGENCE OF BORDETELLA PERTUSSIS

1i!$i!% &rotei!s such as GiL* PT@ is a t8o com&o!e!t0 AIB 1acterial e@oto@i!* a!$ release$ i!to the c'to&lasm i! a mecha!ism of $irect e!tr'* The A su1u!it %ai!s e!C'matic acti it' a!$ tra!sfers the ADP ri1os'l moiet' of NAD* The co! ersio! of ATP to c'clic A>P ca!!ot 1e sto&&e$ a!$ i!tracellular le els of cA>P i!crease* This has the effect to $isru&t cellular fu!ctio!0 a!$ i! the case of &ha%oc'tes0 to $ecrease their &ha%oc'tic acti ities such as chemota@is0 e!%ulfme!t0 the o@i$ati e 1urst0 a!$ 1acteri$ci$al =illi!%* S'stemic effects of the to@i! i!clu$e l'm&hoc'tosis a!$ alteratio! of hormo!al acti ities that are re%ulate$ 1' cA>P0 such as i!crease$ i!suli! &ro$uctio! "resulti!% i! h'&o%l'cemia# a!$ i!crease$ se!siti it' to histami!e "resulti!% i! i!crease$ ca&illar' &ermea1ilit'0 h'&ote!sio! a!$ shoc=#* PT@ also affects the immu!e s'stem i! e@&erime!tal a!imals* B cells a!$ T cells that lea e the l'm&hatics sho8 a! i!a1ilit' to retur!* This alters 1oth A>I a!$ C>I res&o!ses a!$ ma' e@&lai! the hi%h freFe!c' of seco!$ar' i!fectio!s that accom&a!' &ertussis "the most freFue!t seco!$ar' i!fectio!s $uri!% 8hoo&i!% cou%h are &!eumomia a!$ otitis me$ia#*

LIPOPOLHSACC3ARIDE/
As a Gram/!e%ati e 1acterium Bordetella pertussis &ossesses li&o&ol'sacchari$e "e!$oto@i!# i! its outer mem1ra!e0 1ut its LPS is u!usual* It is hetero%e!eous0 8ith t8o ma:or forms $ifferi!% i! the &hos&hate co!te!t of the li&i$ moiet'* The alter!ati e form of Li&i$ A is $esi%!ate$ Li&i$ G* The u!fractio!ate$ material elicits the usual effects of LPS "i*e*0 i!$uctio! of IL/10 acti atio! of com&leme!t0 fe er0 h'&ote!sio!0 etc*#

17

RESURGENCE OF BORDETELLA PERTUSSIS

P3ASE ;ARIATION AND P3ENOTHPIC >ODULATION/


Li=e ma!' other 1acterial &atho%e!s0 the e@&ressio! of the irule!ce %e!es are phase variation a!$ phenot$pic modulation* Phase ariatio! i!$icates a re ersi1le alteratio! i! the %e!ot'&e cause$ 1' frameshift mutatio!s i! 8hich the irule!t 1acteria simulta!eousl' lose the a1ilit' to s'!thesiCe to@i!s a!$ other factors associate$ 8ith &atho%e!icit'* Er'throm'ci! tolera!ce has 1ee! sho8! a &hase mar=er cause$ 1' e@te!si e alteratio!s i! the surface &ro&erties 1et8ee! the irule!t a!$ the a irule!t strai!s0 8hich co!fer susce&ti1ilit' to this a!ti1iotic* The !atural emer%e!ce of &hase aria!ts i! the later sta%es of i!fectio! im&lies that &hase cha!%e coul$ 1e a $efe!se mecha!ism to esca&e immu!e $etectio!0 li=e !almonella fla%ellar &hase ariatio! 8here the cha!%e of a!ti%e!ic t'&e hel&s the 1acteria to e a$e the immu!e s'stem. The other &he!ome!o! terme$ &he!ot'&ic mo$ulatio! 8as first o1ser e$ 1' Lace' i! 196)* It im&lies re&ressio! of the e@&ressio! of irule!ce factors e@ce&t the Tracheal c'toto@i! at lo8er tem&erature "-7)C# or i! the &rese!ce of i! itro mo$ulators li=e SO +-0 ClO+/ a!$ Nicoti!ic aci$* Usi!% tra!s&oso!al muta%e!esis0 a si!%le %e!e locus res&o!si1le for 1oth the &he!ome!a 8as i$e!tifie$* This 8as terme$ the bvg "Bordetella virule!ce ge!e# locus* The bvg %e!es share homolo%' 8ith a famil' of &ro=ar'otic re%ulator' &rotei!s that res&o!$ to e! iro!me!tal stimuli* irule!ce factors i! Bordetella pertussis is co!trolle$ 1' %ro8th co!$itio!s* T8o im&orta!t &he!ome!a i! the re%ulatio! of the

16

RESURGENCE OF BORDETELLA PERTUSSIS

CLINICAL FEATURE/ CATARRA3AL STAGE


Im&orta!tl'0 the s'm&toms that i!itiate the catarrhal &hase "rhi!orrhea0 i!crease$ lacrimatio!0 co!:u!cti al i!:ectio!0 a!$ sometimes lo8/%ra$e fe er# are !o!s&ecific a!$ !ot o!es that su%%est &ertussis0 e@ce&t i! the setti!% of a! o!%oi!% hos&ital or commu!it' out1rea=* This &hase0 8hich ca! last as little as a fe8 $a's or as lo!% as a 8ee=0 is ofte! associate$ 8ith the o!set of !o!&ro$ucti e cou%h*

PAROGHS>AL STAGE
This stri=i!% cou%h co!sists of a series of u!co!trolla1le e@&iratio!s0 follo8e$ 1' %as&i!% i!halatio!0 8hich $e&e!$i!% o! the air8a' a!atom'0 is res&o!si1le for the M8hoo&i!%N sou!$* 2hoo& is more freFue!t i! chil$re! tha! a$ults* It is !ot u!commo! for each e&iso$e of cou%hi!% to 1e associate$ 8ith c'a!osis a!$ e!$ 8ith %a%%i!% a!$ omiti!%* The &aro@'smal sta%e ca! last u& to + 8ee=s0 a!$ the $e elo&me!t of fe er or 8orse!i!% &ulmo!ar' fu!ctio! $uri!% this time shoul$ su%%est the &ossi1ilit' of seco!$ar' &!eumo!ia

CON;ALESCENT P3ASE/
Re$uctio! i! the freFue!c' a!$ se erit' of cou%hi!% attac=s mar=s the tra!sitio! to the co! alesce!t &hase0 8hich ca! last se eral mo!ths* It is $uri!% this time that a$ults &rese!t to the health care s'stem 8ith Mchro!ic cou%hN a!$ ma' 1e e aluate$ for co!$itio!s such as asthma0 tu1erculosis0 other chro!ic lu!% $iseases0 mali%!a!cies0 a!$ %astroeso&ha%eal reflu@* After the cou%hi!% s&ells ha e e!$e$0 &atie!ts ma' ha e retur! of the &aro@'smal cou%h i! co!:u!ctio! 8ith a! u!relate$ u&&er res&irator' ill!ess? this is ofte! i!correctl' i!ter&rete$ as recurre!ce of &ertussis* Ei%ht' &erce!t of a$ults 8ith &ertussis ha e a! ill!ess of at least 4 8ee=sD $uratio!0 a!$ -.( are still cou%hi!% after 9) $a's*

1.

RESURGENCE OF BORDETELLA PERTUSSIS

Length

Clinical Featu e!

Sta%e 1E Usuall' ./1) $a's? ra!%e of CharacteriCe$ 1'E Catarrhal +/-1 Cor'Ca Lo8/%ra$e fe er >il$0 occasio!al cou%h "8hich %ra$uall' 1ecomes more se ere# Sta%e -E Usuall' lasts 1/6 8ee=s0 1ut CharacteriCe$ 1'E Paro@'sma ma' &ersist for u& to 1) Paro@'sms of !umerous0 ra&i$ cou%hs l 8ee=s $ue to $ifficult' e@&elli!% thic= mucus from the tracheo1ro!chial tree* Lo!% as&irator' effort accom&a!ie$ 1' a hi%h/&itche$ O8hoo&O at the e!$ of the &aro@'sms C'a!osis ;omiti!% a!$ e@haustio! Paro@'smal attac=sE Occur freFue!tl' at !i%ht0 8ith a! a era%e of 17 attac=s &er -+ hours* I!crease i! freFue!c' $uri!% the first 1/8ee=s0 remai! at the same freFue!c' for -/4 8ee=s0 a!$ the! %ra$uall' $ecrease* Sta%e 4E Usuall' ./1) $a's? ra!%e of CharacteriCe$ 1'E Co! alesc +/-1 Gra$ual reco er' e!t Less &ersiste!t0 &aro@'smal cou%hs that $isa&&ear i! -/4 8ee=s Paro@'sms ofte! recur 8ith su1seFue!t res&irator' i!fectio!s for ma!' mo!ths after the o!set of &ertussis*

1<

RESURGENCE OF BORDETELLA PERTUSSIS

Classificatio! of cou%hi!% e&iso$es i! ol i!% &ertussis 1ase$ o! cultures0 serolo%'0 famil' e@&osure0 a!$ cli!ical s'm&toms/ Classificatio! a!$ criteria
Pertussis 1* B. pertussis isolate$ from the !aso&har'!@ -* At least o!e of the follo8i!% criteria fulfille$E a* Si%!ifica!t i!crease i! PT I%G 1* Si%!ifica!t i!crease i! F3A I%G 8ithout other criteria for &ara&ertussis c* Both PT I%G a!$ F3A I%G P60))) i! the same co! alesce!t serum $* Famil' mem1er 8ith &ertussis erifie$ 1' culture or serolo%' 4* Cli!ical &ertussis 8ith at least 4 8ee=s of &aro@'smal cou%h a!$ =!o8! e@&osure to &ertussis outsi$e the famil'? serum sam&les lac=i!% or su1o&timal timi!% i! relatio! to o!set of s'm&toms +* Q!o8! e@&osure to &ertussis 8ithi! or outsi$e the househol$? cli!ical s'm&toms !ot e alua1le 1ecause of earl' er'throm'ci! treatme!t

BORDETELLA PERTUSSIS IN ADULTSDuri!% the last t8o $eca$es0 a !um1er of stu$ies ha e i!$icate$ that B. pertussis i!fectio!s i! a$olesce!ts a!$ a$ults are commo!* There has also 1ee! a! i!crease i! the !um1er re&orte$ cases of &ertussis i! a$olesce!ts a!$ a$ults i! co!cert 8ith these stu$ies* All a$ults a!$ most a$olesce!ts 8ho ha e B. pertussis i!fectio!s ha e ha$ a &re ious B. pertussis i!fectio!0 ha e 1ee! acci!ate$0 or 1oth* Pre ious i!fectio! or &re ious immu!iCatio! te!$s to mo$if' ill!ess i! a$ults* Ne ertheless0 a$olesce!ts a!$ a$ults ca! ha e s'm&tomatic i!fectio!0 mil$ $isease0 or classic &ertussis* The results of se eral stu$ies su%%est that a$ults 8ho 8ere &rime$ 1' &re ious i!fectio! "as o&&ose$ to &rimi!% 1' immu!iCatio!# are more li=el' to ha e t'&ical &ertussis* I! a U*S* stu$' of -. a$olesce!ts a!$ a$ults0 the follo8i!% cli!ical fi!$i!%s 8ere !ote$E "i# the me$ia! $uratio! of cou%h 8as +- $a's0 8ith a ra!%e from -. to 66 $a's? "ii# all su1:ects ha$ &aro@'smal cou%h? "iii# -6( of the su1:ects ha$ 8hoo&i!%? "i # 76( ha$ &ost/tussi e omiti!%? a!$ " # 1))( ha$ &ost/tussi e %a%%i!%* Ei%ht' &erce!t or more of a$olesce!ts a!$ a$ults 8ith &ertussis
19

RESURGENCE OF BORDETELLA PERTUSSIS

ha e &aro@'smal cou%h0 1ut the freFue!c' of 8hoo& a!$ &ost/tussi e omiti!% i! this &o&ulatio! is Fuite aria1le* I! a$$itio!0 $uri!% the &aro@'smal sta%e0 a$ults e@&erie!ce s'm&toms !ot $escri1e$ i! chil$re!0 such as a scratch' throat0 other &har'!%eal s'm&toms0 a!$ e&iso$es of s8eati!%* I! a!other stu$'0 the atte!$i!% $octors faile$ to $ia%!ose &ertussis i! 41 u!i ersit' stu$e!ts 8ho sho8e$ la1orator' e i$e!ce of Bordetella i!fectio!* I!stea$0 their $ia%!oses i!clu$e$ u&&er res&irator' tract i!fectio! "49(#0 1ro!chitis "+<(#0 a!$ others "16(#* I! this %rou& of &atie!ts 8ith &ertussis0 the me$ia! $uratio! of cou%h ill!ess &rior to 1ei!% see! 8as -1 $a's? 9+( of &atie!ts ha$ o!e or more cou%hi!% e&iso$es &er hour0 a!$ 9)( of the cou%hi!% fits ha$ a staccato or &aro@'smal Fualit'* O!l' t8o fi!$i!%s i! this stu$' $iffere!tiate$ &atie!ts 8ith Bordetella i!fectio! from those 8ith cou%h ill!esses 8ithout e i$e!ce of Bordetella i!fectio!* Patie!ts 8ith &ertussis 8ere less li=el' to ha e a &ro$ucti e cou%h "4( ersus -1(# a!$ 8ere less li=el' to ha e a! a!ti1iotic &rescri1e$ at the time of the isit "49( ersus 6+(#* I! co!trast to the t8o U*S* stu$ies0 the fi!$i!%s i! t8o Germa! stu$ies !ote$ more t'&ical ill!ess* It shoul$ 1e !ote$ that most of the Germa! a$ults ha$ !ot 1ee! immu!iCe$ $uri!% chil$hoo$ 8hereas most of the a$olesce!ts a!$ a$ults i! the U*S* stu$ies ha$*

CO>PLICATIONS OF B&'(%)%** +%'),!!-!/


The most freFue!t com&licatio! o1ser e$ i! chil$re! is &!eumo!ia0 8hich occurs i! 6( of cases* Other com&licatio!s i!clu$e si!usitis0 otitis me$ia0 iral a!$ 1acterial su&eri!fectio!s0 !utritio!al $eficie!cies resulti!% from re&eate$ omiti!% a!$ !eurolo%ic com&licatio!s0 8hich are $ue mostl' to h'&o@ia $uri!% cou%hi!% s&ells a!$ a&!ea* The ris= of com&licatio!s is hi%her amo!% i!fa!ts a!$ a$ults tha! amo!% ol$er chil$re! a!$ a$olesce!ts* I! a &ros&ecti e case series i! Germa!'0 the rate of com&licatio!s amo!% i!fa!ts less tha! 6 mo!ths of a%e 8as -+(0 as com&are$ 8ith 7( amo!% ol$er chil$re!* I! the first - mo!ths of life0 &!eumo!ia0 seiCures a!$ e!ce&halo&ath' ha e 1ee! re&orte$ i! -7(0 4( a!$ 1( of cases0 res&ecti el'* Car$iac arrh'thmias a!$ e&iso$es of i!tracta1le h'&o%l'cemia ha e also 1ee! re&orte$* After chil$hoo$0 the ris= of com&licatio!s i!creases 8ith a%e* P!eumo!ia has 1ee! o1ser e$ i! -( of &atie!ts less tha! 4) 'ears of a%e0 as com&are$ 8ith 7(,9( of ol$er &atie!ts* S'!co&e0 uri!ar' i!co!ti!e!ce0 1ac= &ai!0 ri1 fracture a!$ her!ia ha e 1ee! also $escri1e$* Se ere

-)

RESURGENCE OF BORDETELLA PERTUSSIS

&aro@'sm0 &ost/tussi e c'a!osis0 8hoo&i!%0 &osttussi e omiti!%0 a&!ea0 &!eumo!ia a!$ seiCures are the most freFue!t reaso!s &atie!ts are a$mitte$ to hos&ital0 re%ar$less of a%e* I!fa!ts0 es&eciall' those 8ho ha e !ot 1ee! acci!ate$ or ha e 1ee! i!com&letel' acci!ate$0 are the most li=el' to reFuire hos&ital care* Birth 1efore 4. 8ee=sR %estatio! a!$ lo8 1irth 8ei%ht ha e 1ee! i!co!siste!tl' i!$icate$ as i!$e&e!$e!t ris= factors for hos&ital a$missio!* Death from &ertussis is i! ersel' relate$ to a%e0 8ith almost 9)( of re&orte$ $eaths occurri!% i! u! acci!ate$ i!fa!ts less tha! 1 'ear ol$0 8ho ha e a case/fatalit' rate of )*6(* 3i%h le els of leu=oc'tosis a!$ l'm&hoc'tosis ma' &re$ict a fatal outcome i! chil$re! a$mitte$ to hos&ital*

FRESUENCH OF SH>PTO>S IN ADULT PERTUSSIS/

-1

RESURGENCE OF BORDETELLA PERTUSSIS

DIAGNOSIS OF 23OOPING COUG3 .B&'(%)%** +%'),!!-!#/ CULTURE/


Culture is co!si$ere$ to 1e the %ol$ sta!$ar$0 ho8e er0 its se!siti it' $ecreases stee&l' if the s&ecime! is ta=e! more tha! - 8ee=s after o!set of cou%h a!$ is re$uce$ 1' &rior immu!it' from $isease or immu!isatio!* Three 8ee=s after comme!ceme!t of cou%h0 se!siti it' of culture is o!l' 1,4(0 e e! lo8er i! a$ults a!$ a$olesce!ts 8ho are more li=el' to &rese!t late* 3o8e er0 culture allo8s t'&i!% a!$ a!ti1iotic se!siti it' to 1e $etermi!e$* Results ca! 1e a aila1le i! .- h0 es&eciall' i! hi%h titre i!fectio!0 1ut - 8ee=s are reFuire$ 1efore culture ma' 1e $efi!iti el' re&orte$ as !e%ati e* The se!siti it' of culture is re$uce$ 1' the t'&e of s&ecime! collecte$ "8ith a !aso&har'!%eal s8a1 1etter tha! &er!asal#0 the metho$ of collectio! "&refera1l' i! 'ou!%er chil$re! a !aso&har'!%eal as&irate# a!$ the use of cotto! or ra'o! s8a1s0 8hich are i!hi1itor'

--

RESURGENCE OF BORDETELLA PERTUSSIS

DNA POLH>ERASE C3AIN REACTIONPol'merase chai! reactio! "PCR# metho$s e!ha!ce the &ro1a1ilit' of i$e!tificatio! of B. &ertussis* Co! e!tio!al/semi !este$ "Cs!PCR# a!$ real/time PCR "RtPCR# are t8o PCR tools em&lo'e$ for the $etectio! of B* &ertussis 8ith the former $etecti!% am&lifie$ tar%et %e!e &ro$ucts isualiCe$ 1' ultra iolet "U;# li%ht follo8i!% a%arose %el electro&horesis a!$ the latter mo!itori!% the fluoresce!ce emitte$ throu%hout PCR reactio! &hases i!$icati!% %e!e am&lificatio!* No el real/ time PCR assa's tar%eti!% the Bor$etella &ertussis i!sertio! seFue!ce IS+<10 the to@i! &romoter re%io! a!$ Bor$etella &ara&ertussis i!sertio! seFue!ce IS1))1 8ere $esi%!e$* PCR assa's 8ere ca&a1le of $etecti!% 1) co&ies of tar%et DNA &er reactio!0 8ith a! am&lificatio! efficie!c' of 9)(*Si!ce &ositi e results ma' 1e o1tai!e$ e e! 8he! the or%a!ism is !o lo!%er cultura1le* Se!siti it' a!$ s&ecificit' of PCR $e&e!$ o! the &rimers use$0 a!$ arious com1i!e$ tech!iFues ha e 1ee! re&orte$ to e!ha!ce the &erforma!ce of this metho$* 3o8e er0 the se!siti it' of PCR $ecreases 8ith the $uratio! of s'm&toms0 si!ce the metho$ is 1ase$ o! the $etectio! of the microor%a!ism*

DIRECT FLUOROSCENT ANTIBODH TEC3NISUE/9E


3istoricall'0 B. pertussis DFA testi!% 8as recomme!$e$ as a scree!i!% tool0 a!$ cli!icia!s relie$ o! this test 1ecause of its Fuic= tur!arou!$ time0 se!siti it' com&ara1le to that of culture0 a!$ re&orte$ s&ecificit'* It has limite$ se!siti it' $ue to the !um1er of or%a!isms !ecessar' for microsco&ic isualiCatio!* DFA also suffers from $ifficulties i! i!ter&retatio! a!$ aria1ilit'* O!e ma:or &ro1lem 8ith DFA is the hi%h &erce!ta%e of false &ositi es0 ra!%i!% from 6*. to +)(* >uch of this &ro1lem is $ue to aria1ilit' 1et8ee! tech!olo%ists i! i!ter&reti!% DFA test results0 as 8ell as to &oor/Fualit' sli$es a!$ !o!s&ecific rea%e!ts*

-4

RESURGENCE OF BORDETELLA PERTUSSIS

Ta1le 1E T'&ical course of &ertussis T e olutio! of s'm&toms0 relati e se!siti it' of $ia%!ostic

metho$s a!$ effect of a!ti1iotic thera&'0 1' &hase of &ertussis


;aria1le Catarrhal &hase"1,- 8=# S"#$t%# Cou%h Paro@'smal cou%h 2hoo&i!% cou%h ;omiti!% C'a!osis A&!ea Te!t !en!iti&it" Culture PCR Serolo%' S'm&toms alle iate$ II II ,KI II ,KI II II ,KI , II , , , , , II ,KI , III III III , III III III ,KI , II ,KI ,KI Paro@'smal &hase"4,6 8=# Co! alesce!t &hase"U 6 8=#

E''ect %' anti(i%tic the a$"

SEROLOGICAL >ET3ODS/
I!fectio! of 1or$etella &ertusis is follo8e$ 1' i!crease i! the co!ce!tratio!s i! serum of I%A0 I%G0 a!$ I%> a!ti1o$ies to s&ecific a!ti%e!s as 8ell as to &re&aratio!s of the 8hole or%a!ism* Prior to the $e elo&me!t of ELISA tech!iFues0 the mai! serolo%ic test for the $ia%!osis of &ertussis 8as the $emo!stratio! of a fourfol$ i!crease i! a%%luti!ati!%/a!ti1o$' titer* The a!ti1o$ies measure$ i! this test are $irecte$ a%ai!st FI>-K40 PRN0 a!$ LPS* E@&erie!ce su%%ests that this test ha$ reaso!a1l' %oo$ s&ecificit' 1ut lac=e$ se!siti it'* The mai!sta' of the serolo%ic $ia%!osis of &ertussis $uri!% the last 17 'ears has 1ee! ELISA0 usi!% s&ecific B. pertussis &rotei!s as a!ti%e!s* Sta!$ar$iCe$ tech!iFues ha e 1ee! $e elo&e$0 a!$ a!ti1o$ies are Fua!titate$ 1' the refere!ce li!e com&uter &ro%ramme a!$ refere!ce sera from the Ce!ter for Biolo%ics E aluatio! a!$ Research0 U*S* Foo$ a!$ Dru% A$mi!istratio!* The &recisio! of the test is such that i!tra/assa' coefficie!ts of ariatio! ha e 1ee! re$uce$ to V1)(0 8hich ma=es a t8ofol$ i!crease i! titer si%!ifica!t* I! co!trast to !atural i!fectio!0 the &rimar' immu!iCatio! of chil$re! i!$uces mai!l' I%> a!$ I%G a!ti1o$ies* Serolo%ic $ia%!osis of &ertussis ma' 1e sus&ecte$ 1' the $emo!stratio! of a! i!crease i! a%%luti!i! titer or the use of ELISA0 sho8i!% a! i!crease i! I%A or I%G a!ti1o$' titer to PT0 F3A0

-+

RESURGENCE OF BORDETELLA PERTUSSIS

PRN0 FI>0 or to so!icate$ 8hole or%a!isms i! t8o serum sam&les collecte$ - to + 8ee=s a&art* It is !o8 clear that a!ti1o$' res&o!ses to F3A a!$ PRN also occur follo8i!% other Bordetella i!fectio!s0 so that isolate$ i!creases i! titers of a!ti1o$' a%ai!st these a!ti%e!s are !ot s&ecific for B. pertussis i!fectio!* I! a$$itio!0 hi%h titers of a!ti1o$' to F3A ma' 1e the result of cross/reacti!% e&ito&es of !o!e!ca&sulate$ /.in"luen0ae0 1.pneumoniae0 2.pneumoniae0 a!$ &erha&s other 1acteria* Some culture/&ositi e &atie!ts0 &articularl' chil$re! 'ou!%er tha! 4 mo!ths0 fail to $e elo& measura1le a!ti1o$ies* The &rimar' &ro1lem i! the serolo%ic $ia%!osis of B. pertussis i!fectio! 1' ELISA is the $ela' i! o1tai!i!% the acute/&hase s&ecime!* I! &atie!ts 8ith rei!fectio!s0 a ra&i$ i!crease i! titer occurs0 so that 8ith a $ela'e$ acute/&hase sam&le0 the titer is li=el' to ha e alrea$' &ea=e$ a!$ further titer i!creases 1et8ee! the acute/&hase a!$ co! alesce!t/&hase sera ma' !ot 1e o1ser e$* 3o8e er0 for those !ot rece!tl' immu!iCe$0 this &ro1lem ca! 1e circum e!te$ 1' usi!% si!%le/serum ELISA* S&ecificall'0 &atie!ts 8ith ill!ess 8ill ha e ELISA titers that are si%!ifica!tl' hi%her tha! G>T* The %reatest se!siti it' a!$ s&ecificit' for the serolo%ical $ia%!osis of B. pertussis i!fectio! is achie e$ 1' ELISA a!$ measureme!t of I%G a!$ I%A a!ti1o$ies to PT* A si%!ifica!t rise i! titer "%reater tha! or eFual to t8ofol$# 1et8ee! acute/&hase a!$ co! alesce!t/&hase sera !ee$s to 1e $emo!strate$* I! a$olesce!ts a!$ a$ults0 si!%le hi%h alues of I%G or I%A a!ti1o$ies to PT also i!$icate i!fectio!* Althou%h I%A a!ti1o$' to PT is more i!$icati e of a rece!t a!ti1o$' res&o!se0 it is less co!siste!t tha! a PT I%G res&o!se*

Si!%le serum s&ecime!s T Si!%le/sam&le serolo%' tests for a!ti&ertussis to@i! I%G must 1e
collecte$ at least t8o 8ee=s after s'm&tom o!set* A hi%h a!ti1o$' titer more tha! t8o 'ears follo8i!% acci!atio! su&&orts the $ia%!osis of &ertussis* A solitar' a!ti1o$' co!ce!tratio! of I%G a!ti/PT %reater tha! 1))/1-7 EUKmL su%%ests rece!t B* &ertussis i!fectio! or e@&osure* A stu$' i! the Netherla!$s sho8e$ that a titer of 1)) EUKmL a%ai!st this a!ti%e! has a se!siti it' of .6 &erce!t a!$ s&ecificit' of 99 &erce!t for the $ia%!osis of acute &ertussis +

CRIETARIA FOR SEROLOGICAL DIAGNOSIS OF BORDETELLA PERTUSSIS


-7

RESURGENCE OF BORDETELLA PERTUSSIS

Si%!ifica!t i!crease i! ELISA $ia%!ostics 1* Co!troll serum i!terassa' ariatio! V1)( V17( U7)( U1))( Acute to co! alasce!t &hase i!crease i! AB

-* >INI>U> LE;EL FOR CON;ALESCENT SERU> A* + TI>ES >LD FOR ANTIBODIES TO PT B* 4- TI>ES >LD FOR ANTIBODIES TO F3A

-6

RESURGENCE OF BORDETELLA PERTUSSIS

>ANAGE>ENT OF BORDETELLA PERTUSSIS/


>ai!tai!i!% hi%h acci!atio! co era%e rates amo!% &reschool chil$re!0 a$olesce!ts0 a!$ a$ults a!$ mi!imiCi!% e@&osures of i!fa!ts a!$ &erso!s at hi%h ris= for &ertussis is the most effecti e 8a' to &re e!t &ertussis* A!ti1iotic treatme!t of &ertussis a!$ :u$icious use of a!timicro1ial a%e!ts for &oste@&osure &ro&h'la@is 8ill era$icate B. pertussis from the !aso&har'!@ of i!fecte$ &erso!s "s'm&tomatic or as'm&tomatic#* A macroli$e a$mi!istere$ earl' i! the course of ill!ess ca! re$uce the $uratio! a!$ se erit' of s'm&toms a!$ lesse! the &erio$ of commu!ica1ilit'* A&&ro@imatel' <)(, 9)( of &atie!ts 8ith u!treate$ &ertussis 8ill s&o!ta!eousl' clear B. pertussis from the !aso&har'!@ 8ithi! 4,+ 8ee=s from o!set of cou%h? 3o8e er0 u!treate$ a!$ u! acci!ate$ &erso! ca! remai! culture/&ositi e for U6 8ee=s* Close as'm&tomatic co!tacts ca! 1e a$mi!istere$ Er'throm'ci!0 a macroli$e a!ti1iotic0 has 1ee! the a!timicro1ial of choice for treatme!t or &oste@&osure &ro&h'la@is of &ertussis* It is usuall' a$mi!istere$ i! + $i i$e$ $ail' $oses for 1+ $a's* Althou%h effecti e for treatme!t a!$ &oste@&osure &ro&h'la@is0 er'throm'ci! is accom&a!ie$ 1' u!comforta1le to $istressi!% si$e effects that result i! &oor a$here!ce to the treatme!t re%ime!* Duri!% the last $eca$e0 i! itro stu$ies ha e $emo!strate$ the effecti e!ess a%ai!st B. pertussis of t8o other macroli$e a%e!ts "aCithrom'ci! a!$ clarithrom'ci!#* Results from i! itro stu$ies are !ot al8a's re&licate$ i! cli!ical stu$ies a!$ &ractice*

Ge!eral Pri!ci&les Treatme!t/


The macroli$e a%e!ts er'throm'ci!0 clarithrom'ci!0 a!$ aCithrom'ci! are &referre$ for the treatme!t of &ertussis i! &erso!s a%e$ U1 mo!th* For i!fa!ts a%e$ V1 mo!th0 aCithrom'ci! is &referre$? er'throm'ci! a!$ clarithrom'ci! are !ot recomme!$e$* For treatme!t of &erso!s a%e$ U- mo!ths0 a! alter!ati e a%e!t to macroli$es is trimetho&rim/sulfametho@aCole "T>P,S>J# The choice of a!timicro1ial for treatme!t or &ro&h'la@is shoul$ ta=e i!to accou!t effecti e!ess0 safet' "i!clu$i!% the &ote!tial for a$ erse e e!ts a!$ $ru% i!teractio!s#0 tolera1ilit'0 ease of a$here!ce to the re%ime! &rescri1e$0 a!$ cost* ACithrom'ci! a!$ clarithrom'ci! are as effecti e as er'throm'ci! for treatme!t of &ertussis i! &erso!s a%e$ U6 mo!ths0 are 1etter tolerate$0 a!$ are associate$ 8ith fe8er a!$ mil$er si$e effects tha! er'throm'ci!* Er'throm'ci! a!$ clarithrom'ci!0 1ut !ot aCithrom'ci!0 are i!hi1itors

-.

RESURGENCE OF BORDETELLA PERTUSSIS

of the c'tochrome P+7) e!C'me s'stem "CHP4A su1class# a!$ ca! i!teract 8ith other $ru%s that are meta1oliCe$ 1' this s'stem* ACithrom'ci! a!$ clarithrom'ci! are more resista!t to %astric aci$0 achie e hi%her tissue co!ce!tratio!s0 a!$ ha e a lo!%er half/life tha! er'throm'ci!0 allo8i!% less freFue!t a$mi!istratio! "1,- $oses &er $a'# a!$ shorter treatme!t re%ime!s "7,. $a's#* Er'throm'ci! is a aila1le as %e!eric &re&aratio!s a!$ is co!si$era1l' less e@&e!si e tha! aCithrom'ci! a!$ Clarithrom'ci!*

Poste@&osure &ro&h'la@is/
A macroli$e ca! 1e a$mi!istere$ as &ro&h'la@is for close co!tacts of a &erso! 8ith &ertussis if the &erso! has !o co!trai!$icatio! to its use* The $ecisio! to a$mi!ister &oste@&osure chemo&ro&h'la@is is ma$e after co!si$eri!% the i!fectious!ess of the &atie!t a!$ the i!te!sit' of the e@&osure0 the &ote!tial co!seFue!ces of se ere &ertussis i! the co!tact0 a!$ &ossi1ilities for seco!$ar' e@&osure of &erso!s at hi%h ris= from the co!tact "e*%*0 i!fa!ts a%e$ V1- mo!ths#* For &oste@&osure &ro&h'la@is0 the 1e!efits of a$mi!isteri!% a! a!timicro1ial a%e!t to re$uce the ris= for &ertussis a!$ its com&licatio!s shoul$ 1e 8ei%he$ a%ai!st the &ote!tial a$ erse effects of the $ru%* A$mi!istratio! of &oste@&osure &ro&h'la@is to as'm&tomatic househol$ co!tacts 8ithi! -1 $a's of o!set of cou%h i! the i!$e@ &atie!t ca! &re e!t s'm&tomatic i!fectio!* Cou%hi!% "s'm&tomatic# househol$ mem1ers of a &ertussis &atie!t shoul$ 1e treate$ as if the' ha e &ertussis* Because se ere a!$ sometimes fatal &ertussis/relate$ com&licatio!s occur i! i!fa!ts a%e$ V1- mo!ths0 es&eciall' amo!% i!fa!ts a%e$ V+ mo!ths0 &oste@&osure &ro&h'la@is shoul$ 1e a$mi!istere$ i! e@&osure setti!%s that i!clu$e i!fa!ts a%e$ V1- mo!ths or 8ome! i! the thir$ trimester of &re%!a!c'* The recomme!$e$ a!timicro1ial a%e!ts a!$ $osi!% re%ime!s for &oste@&osure &ro&h'la@is are the same as those for treatme!t of &ertussis

A close co!tact of a &atie!t 8ith &ertussis is a &erso! 8ho ha$ face/to/face e@&osure 8ithi! 4 feet of a s'm&tomatic &atie!t* Res&irator' $ro&lets "&articles U7 3m i! siCe# are %e!erate$ $uri!% cou%hi!%0 s!eeCi!%0 or tal=i!% a!$ $uri!% the &erforma!ce of certai! &roce$ures such as 1ro!chosco&' or suctio!i!%? these &articles ca! 1e &ro&elle$ throu%h the air for $ista!ces of a&&ro@imatel' 4 feet*

-<

RESURGENCE OF BORDETELLA PERTUSSIS

CLOSE CONTACT PROP3HLAGIS/


Close co!tacts also ca! i!clu$e &erso!s 8ho 3a e $irect co!tact 8ith res&irator'0 oral0 or !asal secretio!s from a s'm&tomatic &atie!t*

EG* cou%h0 s!eeCe0 shari!% foo$ a!$ eati!% ute!sils0 mouth/to/mouth resuscitatio!0 or &erformi!% ame$ical e@ami!atio! of the mouth0 !ose0 a!$ throat# Share$ the same co!fi!e$ s&ace i! close &ro@imit' 8ith a s'm&tomatic &atie!t for U1 hour*

T Some close co!tacts are at hi%h ris= for acFuiri!% se ere $isease follo8i!% e@&osure to &ertussis* These co!tacts i!clu$e i!fa!ts a%e$ V1 'ear0 &erso!s 8ith some immu!o$eficie!c' co!$itio!s0 or other u!$erl'i!% me$ical co!$itio!s such as chro!ic lu!% $isease0 res&irator' i!sufficie!c'0 or c'stic fi1rosis Poste@&osure &ro&h'la@is 8ith a! a&&ro&riate a!timicro1ial a%e!t ca! 1e a$mi!istere$ to close co!tacts of &atie!ts a!$ to &erso!s 8ho are at hi%h ris= for ha i!% se ere or com&licate$ &ertussis*

ANTIBIOTICS TREAT>ENT/ AJIT3RO>HCIN/


ACithrom'ci! is a semi/s'!thetic macroli$e a!ti1iotic that &re e!ts 1acteria from %ro8i!% 1' i!terferi!% 8ith their a1ilit' to ma=e &rotei!s* It acts 1' 1i!$i!% to the 7)S ri1osomal su1u!it of susce&ti1le microor%a!isms a!$0 thus0 i!terferi!% 8ith micro1ial &rotei! s'!thesis* Nucleic aci$ s'!thesis is !ot affecte$* Due to the $iffere!ces i! the 8a' &rotei!s are ma$e i! 1acteria a!$ huma!s0 the macroli$e a!ti1iotics $o !ot i!terfere 8ith huma!sD a1ilit' to ma=e &rotei!s 3U>AN P3AR>ACOQINETICS/ After oral a$mi!istratio!0 this &ro$uct 8ill Fuic=l' 1e a1sor1e$ ha i!% a 1ioa aila1ilit' of 4.(* I! the case to oral a$mi!istratio! of 7))m% i! a si!%le $ose0 the time to reach &ea= co!ce!tratio! is -*7 to -*6 hrs a!$ the &ea= co!ce!tratio! alue of the $ru% i! the 1loo$0 Cma@0 is )*+ to )*+7m%KL* This &ro$uct ma' 1e 8i$el' $istri1ute$ throu%hout the huma! 1o$'* The co!ce!tratio! i! arious tissues ma' reach 1)B1)) times of the co!ce!tratio! i! the 1loo$ at the same time* A$ erse Reactio!s of ACithrom'ci! is %e!erall' 8ell tolerate$* I! cli!ical trials0 most of the re&orte$ si$e effects 8ere mil$ to mo$erate i! se erit' a!$ 8ere re ersi1le u&o! $isco!ti!uatio! of the $ru%*

-9

RESURGENCE OF BORDETELLA PERTUSSIS

The most commo! si$e effects are $iarrhea or loose stools0 !ausea0 a1$omi!al &ai!0 a!$ omiti!%0 each of 8hich ma' occur i! fe8er tha! o!e i! t8e!t' &erso!s 8ho recei e aCithrom'ci!* Rarer si$e effects i!clu$e a1!ormal li er tests0 aller%ic reactio!s0 a!$ !er ous!ess* Pote!tiall' serious si$e effects of a!%ioe$ema a!$ cholestatic :au!$ice 8ere re&orte$ rarel'* >ost of the si$e effects lea$i!% to $isco!ti!uatio! 8ere relate$ to the %astroi!testi!al tract0 e*%*0 !ausea0 omiti!%0 $iarrhea0 or a1$omi!al &ai!* Dru% I!teractio!s U!li=e er'throm'ci! a!$ clarithrom'ci!0 aCithrom'ci! is %e!erall' co!si$ere$ free of i!teractio!s 8ith most other me$ici!es* It is recomme!$e$ that aCithrom'ci! !ot 1e ta=e! at the same time as alumi!um/ or ma%!esium/ 1ase$ a!taci$s0 such as >'la!ta or >aalo@ 1ecause a!taci$s 8ill 1i!$ the aCithrom'ci! a!$ &re e!t it from 1ei!% a1sor1e$ from the i!testi!e

CLARIT3RO>HCIN AND ERHT3RO>HCIN/


Act as same mecha!ism as aCithrom'ci!0 1ut Dose shoul$ 1e a$:uste$ for &atie!ts 8ith im&aire$ re!al Fu!ctio! a!$ Ca! 1e a$mi!istere$ 8ithout re%ar$ to meals*FreFue!t si$e effects are Gastroi!testi!al $istur1a!ces "a1$omi!al $iscomfort or &ai!0 $iarrhea0 "!ausea a!$ ;omiti!%# * 3e&atoto@icit' 3'&erse!siti it' reactio! rash0 &ruritis0 a!$ $'s&!ea# Pseu$omem1ra!ous colitis Throm1oc'to&e!ia are rare*

TRI>ET3OPRI>/SULFA>ET3AGOLE/ Sulfametho@aCole a!$ trimetho&rim* Both $ru%s re$uce the a1ilit' of some 1acteria to utiliCe folic aci$

4)

RESURGENCE OF BORDETELLA PERTUSSIS

for %ro8i!%* Sulfametho@aCole is a! a!ti/1acterial sulfo!ami$e0 a OsulfaO $ru%* It $isru&ts the &ro$uctio! of $ih'$rofolic aci$ 8hile trimetho&rim $isru&ts the &ro$uctio! of tetrah'$rofolic aci$* Dih'$rofolic aci$ a!$ tetrah'$rofolic aci$ are forms of folic aci$ that 1acteria a!$ huma! cells use for &ro$uci!% &rotei!s* Trimetho&rim i!hi1its &ro$uctio! of tetrah'$rofolic aci$ 1' i!hi1iti!% the e!C'me res&o!si1le for ma=i!% tetrah'$rofolic aci$ from $ih'$rofolic aci$* B' com1i!i!% 1oth $ru%s0 t8o im&orta!t ste&s reFuire$ i! the &ro$uctio! of 1acterial &rotei!s are i!terru&te$0 a!$ the com1i!atio! is more effecti e tha! either $ru% alo!e* Si$e effects of Sulfametho@aColeKtrimetho&rim are $iCCi!ess0 hea$ache0 lethar%'0 $iarrhea0 a!ore@ia0 !ausea0 omiti!%0 a!$ rash* Sulfametho@aColeKtrimetho&rim shoul$ 1e sto&&e$ at the first a&&eara!ce of a s=i! rash 1efore the rash 1ecomes se ere* Serious rashes i!clu$e Ste e!s/5oh!so! s'!$rome "achi!% :oi!ts a!$ muscles? re$!ess0 1listeri!%0 a!$ &eeli!% of the s=i!#? to@ic e&i$ermal !ecrol'sis "$ifficult' i! s8allo8i!%? &eeli!%0 re$!ess0 loose!i!%0 a!$ 1listeri!% of the s=i!#* Sulfametho@aColeKtrimetho&rim thera&' also ca! cause e@te!si e su!1ur!0 follo8i!% e@&osure to su!li%ht* Patie!ts recei i!% Sulfametho@aColeKtrimetho&rim shoul$ a oi$ e@cessi e e@&osure to su! li%ht "&hotose!siti it' to $ru%s# a!$ shoul$ 8ear su!scree!* Sulfametho@aColeKtrimetho&rim ma' form cr'stals i! the uri!e 8hich ma' $ama%e the =i$!e' a!$ cause 1lee$i!% i!to uri!e* It is im&orta!t to $ri!= a$$itio!al liFui$s $uri!% thera&' to &re e!t these si$e effects*

PERTUSSIS ;ACCINE/ The &ertussis acci!e is a aila1le as)


DTaP "Di&htheria To@oi$/Teta!us To@oi$/acellular Pertussis acci!e# DTaP i! com1i!atio! 8ith 3aemo&hilus i!flue!Cae t'&e 1 "3i1# acci!e DTaP i! com1i!atio! 8ith he&atitis B a!$ i!acti ate$ &olio acci!es DTaP i! com1i!atio! 8ith 3i10 he&atitis B a!$ i!acti ate$ &olio acci!es T$a& "Teta!us To@oi$ re$uce$/Di&htheria/acellular Pertussis acci!e#

41

RESURGENCE OF BORDETELLA PERTUSSIS

;ACCINE RECO>>ENDATIONS "CDC#/ 2ho shoul$ recei e the acci!eW


>ost i!fa!ts a!$ chil$re! 'ou!%er tha! se e! 'ears of a%e shoul$ recei e DTaP 1e%i!!i!% at t8o mo!ths of a%e* Chil$re! ./1) 'ears of a%e 8ho are i!com&letel' immu!iCe$ a%ai!st &ertussis shoul$ recei e T$a&* 11/1< 'ear ol$s shoul$ recei e a si!%le $ose of T$a& i!stea$ of a T$ 1ooster if the' ha e com&lete$ the recomme!$e$ chil$hoo$ DTPKDTaP immu!iCatio! series a!$ ha e !ot recei e$ T$a&* The &referre$ a%e for T$a& acci!atio! is 11/1- 'ears* A$ults 19/6+ 'ears of a%e shoul$ also recei e a si!%le $ose of T$a& to re&lace a si!%le $ose of T$ for 1ooster immu!iCatio! if their most rece!t teta!us to@oi$/co!tai!i!% acci!e 8as 1) or more 'ears earlier* T$a& ma' 1e %i e! at a! i!ter al shorter tha! 1) 'ears si!ce the last teta!us to@oi$/co!tai!i!% acci!e i! or$er to &rotect a%ai!st &ertussis0 es&eciall' forE 2ome! V67 'ears of a%e 8ho mi%ht 1ecome &re%!a!t* 2ome! 8ho ha e !ot &re iousl' recei e$ T$a& "i!clu$i!% those 8ho are 1reatfee$i!%# shoul$ recei e T$a& as soo! after 1irth as is feasi1le* >a!' e@&erts also recomme!$ that T$a& 1e co!si$ere$ for &re%!a!t tee!a%ers* A$ults 8ho ha e or a!tici&ate ha i!% close co!tact 8ith a! i!fa!t a%e$ V1- mo!ths shoul$ recei e a si!%le $ose of T$a& a!$ tri ale!t i!acti ate$ i!flue!Ca acci!e* I$eall' the acci!es shoul$ 1e %i e! at least - 8ee=s 1efore co!tact* 3ealth/care &erso!!el 8ho ha e $irect &atie!t co!tact shoul$ recei e a si!%le $ose

2ho shoul$ !ot recei e the acci!eW


Those 8ith a histor' of a serious aller%ic reactio! "such as a!a&h'la@is# to a!' of the

4-

RESURGENCE OF BORDETELLA PERTUSSIS

acci!e com&o!e!ts* Those 8ith a histor' of e!ce&halo&ath' "e*%* coma or &rolo!%e$ seiCures# !ot attri1uta1le to a! i$e!tifia1le cause 8ithi! . $a's of a$mi!istratio! of a acci!e 8ith &ertussis com&o!e!ts* Peo&le 8ith the follo8i!% co!$itio!s shoul$ $iscuss 8ith their health care &rofessio!al 8hether the' shoul$ recei e DTaP acci!eE >o$erate or serious reactio! after recei i!% DTP or DTaP i! the &ast SeiCure or ha e a &are!t or si1li!% 8ho has ha$ a seiCure Brai! &ro1lem that is u!sta1le or %etti!% 8orse Peo&le 8ho are mo$eratel' or se erel' ill shoul$ co!sult 8ith their &h'sicia! 1efore recei i!% a!' acci!e*

;ACCINATION SC3EDULE/
A DTaP acci!e is %i e! to most chil$re! at t8o0 four0 a!$ si@ mo!ths of a%e* A fourth $ose of DTaP is %i e! 1et8ee! 17 a!$ 1< mo!ths "1./-) mo!ths for Da&tacel#0 a!$ a fifth $ose is %i e! at a%e four to si@ 'ears* Pe$iari@ T>* ca! o!l' 1e %i e! for the first three $oses a chil$ recei es* If the fourth $ose 8as %i e! after a%e four 'ears0 the! !o fifth $ose is !ee$e$* Recei i!% com1i!atio! acci!es from $iffere!t ma!ufacturers0 8hich ma' i!clu$e $iffere!t com&o!e!t acci!es0 ca! ma=e the $ose sche$ule more com&le@* 3o8e er0 si!ce %i i!% com1i!atio! acci!es mea!s fe8er shots o erall for a chil$0 healthcare &ro i$ers 8ill usuall' choose to a$mi!ister them* 3ealthcare &rofessio!als shoul$ attem&t to select acci!es for their &atie!ts0 es&eciall' chil$re! 8ho ha e 1ee! see! 1' others0 1ase$ o! 8hat the' ha e alrea$' 1ee! %i e!* Chil$re! 'ou!%er tha! a%e se e! 8ho shoul$ !ot recei e the &ertussis acci!e shoul$ recei e the DT "$i&htheria/teta!us# acci!e* Bet8ee! the a%es of se e! a!$ !i!e0 T$a&T8hich co!tai!s the same amou!t of teta!us acci!e as DTaP or DT0 1ut co!tai!s much less $i&htheria to@oi$T is %i e! to &rotect a%ai!st
44

RESURGENCE OF BORDETELLA PERTUSSIS

teta!us0 $i&htheria a!$ &ertussis* At a%e 11/1- 'ears0 a 1ooster shot of teta!us/$i&htheria/acellular &ertussis "T$a&# is !ee$e$* It shoul$ 1e %i e! !o later tha! 16 'ears of a%e* E er' 1) 'ears a!$ thereafter0 a 1ooster of T$ is !ee$e$ to mai!tai! &rotectio! a%ai!st $i&htheria a!$ teta!us* O!e 1ooster $ose of T$a& is recomme!$e$ for a$ults to re&lace a T$ 1ooster* E er' 1) 'ears thereafter0 a 1ooster of T$ is !ee$e$ to mai!tai! &rotectio! a%ai!st $i&htheria a!$ teta!us*

AD;ERSE REACTIONS/
>il$ Pro1lems "Commo!# X X X Fe er "u& to a1out 1 chil$ i! +# Re$!ess or s8elli!% 8here the shot 8as %i e! "u& to a1out 1 chil$ i! +# Sore!ess or te!$er!ess 8here the shot 8as %i e! "u& to a1out 1 chil$ i! +# These &ro1lems occur more ofte! after the +th a!$ 7th $oses of the DTaP series tha! after earlier $oses* Sometimes the +th or 7th $ose of DTaP acci!e is follo8e$ 1' s8elli!% of the e!tire arm or le% i! 8hich the shot 8as %i e!0 for 1 to . $a's "u& to a1out 1 chil$ i! 4)#* Other mil$ &ro1lems i!clu$eE X X X X Fussi!ess "u& to a1out 1 chil$ i! 4# Tire$!ess or &oor a&&etite "u& to a1out 1 chil$ i! 1)# ;omiti!% "u& to a1out 1 chil$ i! 7)# These &ro1lems %e!erall' occur 1 to 4 $a's after the shot*

>o$erate Pro1lems "U!commo!#


X SeiCure ":er=i!% or stari!%# "a1out 1 chil$ out of 1+0)))#
4+

RESURGENCE OF BORDETELLA PERTUSSIS

X X

No!/sto& cr'i!%0 for 4 hours or more "u& to a1out 1 chil$ out of 10)))# 3i%h fe er0 1)7 $e%rees Fahre!heit or hi%her "a1out 1 chil$ out of 160)))#

Se ere Pro1lems ";er' Rare#


Serious aller%ic reactio! "less tha! 1 out of a millio! $oses# Se eral other se ere &ro1lems ha e 1ee! re&orte$ after DTaP acci!e* These i!clu$eE Lo!%/term seiCures0 coma0 or lo8ere$ co!scious!ess Perma!e!t 1rai! $ama%e* These are so rare it is har$ to tell if the' are cause$ 1' the acci!e* Co!trolli!% fe er is es&eciall' im&orta!t for chil$re! 8ho ha e ha$ seiCures0 for a!' reaso!* It is also im&orta!t if a!other famil' mem1er has ha$ seiCures* Hou ca! re$uce fe er a!$ &ai! 1' %i i!% 'our chil$ a! as&iri!/free &ai! relie er 8he! the shot is %i e!0 a!$ for the !e@t -+ hours*

CRO2CROFT FOR>ULA/
Cro8croft et al $e elo&e$ a metho$ to estimate the %lo1al 1ur$e! of &ertussis to hel& set &riorities for acci!atio! &ro%rams* Accor$i!% to these authors0 the &ro&ortio! of susce&ti1le chil$re! 8ith i!fectio!s i! cou!tries 8ith %oo$ acci!atio! co era%e "P .)(# 8as estimate$ at 1)( 1' 1 'ear0 6)( 1' 7 'ears0 a!$ 1))( 1' 17 'ear*

47

RESURGENCE OF BORDETELLA PERTUSSIS

RECO>>ENDED M23ON CASE DEFINATION OF PERTUSSIS/ 1* Cli!ical case $efi!itio!


A case $ia%!ose$ as &ertussis 1' a &h'sicia! % A &erso! 8ith a cou%h lasti!% at least t8o 8ee=s 8ith at least o!e of the follo8i!% s'm&tomsE Paro@'sms "i*e* fits# of cou%hi!% I!s&irator' 8hoo&i!% Post/tussi e omiti!% "i*e* omiti!% imme$iatel' after cou%hi!%# 8ithout other a&&are!t cause

-* Criteria for la1orator' co!firmatio!/


Isolatio! of Bordetella pertussis % Detectio! of %e!omic seFue!ces 1' mea!s of the &ol'merase chai! reactio! "PCR# % Positi e &aire$ serolo%'

4* Sus&ect Case/
A cli!ical s'!$rome or ill!ess co!siste!t or com&ati1le 8ith &ertussis a!$ 8ithout other a&&are!t cause such asE X A!' acute cou%h ill!ess 8ith &aro@'smal cou%h or i!s&irator' 8hoo& X A!' acute cou%h ill!ess i! a &erso! 8ho is a close co!tact to a &atie!t 8ith a co!firme$ or &ro1a1le case* X A!' cou%h associate$ 8ith a&!ea i! a! i!fa!t X A!' acute cou%h ill!ess lasti!% P. $a's 8he! there is a re&orte$ out1rea= of &ertussis i! the commu!it'* X A!' acute cou%h ill!ess 8ith &ositi e PCR results for B* &ertussis that $oes !ot meet the cli!ical case $efi!itio!*
46

RESURGENCE OF BORDETELLA PERTUSSIS

;ACCINES OF B&'(%)%** +%'),!!-! WA CAUSE OF RESURGENCE /


Is &ol'mor&hism i! &ertacti! a!$ &ertussis to@i! $ri e! 1' host immu!it'0 or is it the result of ra!$om fi@atio! $ue to %e!etic $riftW The latter &ossi1ilit' is hi%hl' u!li=el' si!ce esse!tiall' all DNA mutatio!s 8e $etecte$ i! the &ertacti! a!$ &ertussis to@i! %e!es 8ere !o!co!ser ati e* I! co!trast0 ra!$om %e!etic $rift is characteriCe$ 1' a hi%h $e%ree of co!ser ati e mutatio!s i! &rotei! co$i!% re%io!s* Further0 the &ol'mor&hic re%io!s i!teract $irectl' 8ith the immu!e s'stem* The &ol'mor&hic re%io! of &ertacti! i!$uces a &rotecti e immu!e res&o!se* O!e of the &ol'mor&hic resi$ues i! Pt@S1 has 1ee! im&licate$ i! 1i!$i!% to the T/cell rece&tor* Fi!all'0 the fact that the same tem&oral tre!$s i! allele freFue!cies are o1ser e$ i! %eo%ra&hicall' $isti!ct re%io!s such as Fi!la!$0 the U!ite$ States0 a!$ The Netherla!$s ar%ues a%ai!st ra!$om %e!etic $rift* It is &ossi1le that the &ol'mor&hic loci 8e ha e i$e!tifie$ are li!=e$ to other0 as 'et u!=!o8!0 &ol'mor&hic loci that i!crease fit!ess of strai!s i! acci!ate$ &o&ulatio!s "hitchhi=i!%#* Strai!s carr'i!% !o! acci!e/t'&e &ertacti! or &ertussis to@i! aria!ts 8ere !ot fou!$ i! the &re acci!atio! era* Althou%h the !um1er of strai!s a!al'Ce$ from this &erio$ 8as limite$0 these $ata su%%est that the !o! acci!e/t'&e aria!ts are !ot a1le to $is&lace the acci!e/t'&e strai!s i! u! acci!ate$ &o&ulatio!s "i*e*0 the' ha e a lo8er fit!ess le el0 or re&ro$ucti e rate0 i! u! acci!ate$ commu!ities#* Alter!ati el'0 the !o! acci!e/t'&e strai!s ma' ha e e ol e$ relati el' rece!tl'* Co!siste!t 8ith the first h'&othesis0 8e ha e o1ser e$ that !o! acci!e/t'&e strai!s are less fit i! !ai e mice tha! acci!e/t'&e strai!s** Thus acci!atio! has acte$ to shift the com&etiti e 1ala!ce 1et8ee! strai!s* A! im&orta!t Fuestio! to a$$ress is 8hether a$a&tatio! of the B. pertussis &o&ulatio! has affecte$ acci!e efficac'0 i*e*0 co!tri1ute$ to the reemer%e!ce of B. pertussis* A!imal e@&erime!ts ha e i!$icate$ that ariatio! i! &ertacti! affects acci!e efficac'* Further0 8e fou!$ acci!e t'&e &ertacti! aria!ts less freFue!tl' amo!% acci!ate$ &erso!s tha! amo!% u! acci!ate$ &erso!s0 8hich 8oul$ 1e e@&ecte$ if the acci!e &rotects $iffere!tiall' a%ai!st strai!s 8ith $isti!ct &ertacti! t'&es* 3o8e er0 the e@te!t to 8hich &ol'mor&hism affects acci!e efficac' is &ro1a1l' $e&e!$e!t o! the acci!e use$* It is co!cei a1le that the i!crease i! fit!ess associate$ 8ith !o! acci!e t'&es of &ertacti! a!$ &ertussis to@i! i! acci!ate$ &o&ulatio!s is su1sta!tial e!ou%h to $ri e e@&a!sio! of strai!s carr'i!% these &rotei! aria!ts 1ut that the effect is too small to result i! a
4.

RESURGENCE OF BORDETELLA PERTUSSIS

measura1le $ro& i! acci!e efficac'* Further stu$ies are reFuire$ to assess the effect of the o1ser e$ a$a&tatio!s o! the efficac' of &ertussis acci!es* I! this &erio$0 8he! 8hole/cell acci!es are 1ei!% re&lace$ 1' acellular im&orta!ce* acci!es i! ma!' cou!tries0 co!ti!ue$ strai! sur eilla!ce is of &aramou!t

;NTR C3ANGES AND >ODIFICATION OF BACTERIAL GENO>E/


The com1i!e$ >AST/>L;A &rofiles 8ere use$ to &erform clusteri!% a!al'ses of the Dutch B. pertussisstrai!s isolate$ 1efore the i!tro$uctio! of the &ertussis acci!e i! 1974 a!$ isolates o1tai!e$ 1efore a!$ after the &ertussis e&i$emics i! the 199)s0 a &erio$ i! 8hich !either acci!e formulatio! !or acci!e co era%e ha e cha!%e$* The a!al'sis sho8e$ that the &rofiles from strai!s &re$ati!% the acci!atio! era 8ere more $i erse tha! those isolate$ i! the 199)s a!$ o!l' $ista!tl' relate$ to the rece!t strai!s* Furthermore0 there 8as a stro!% $ecrease i! $i ersit' i! the %e!ot'&es of the B. pertussis strai!s $uri!% a!$ after the e&i$emics i! the 199)s0 su%%esti!% that these e&i$emics 8ere cause$ 1' a limite$ !um1er of strai!s "clo!al e@&a!sio!#* The $iffere!t $'!amics of >L;A a!$ >AST $i ersit' tre!$s ma' 1e $ue to the fact that ;NTRs e ol e more ra&i$l' tha! Co!siste!t 8ith this assum&tio!0 si!%le/locus irule!ce %e!es* aria!ts of the most rece!t &re$omi!a!t com1i!e$

">L;A/>AST# %e!ot'&e 8ere almost com&letel' $ue to cha!%es i! the ;NTR loci* Thus0 ;NTR a!al'ses ma' 1e es&eciall' suita1le to $etect short/term cha!%es i! &atho%e! &o&ulatio!s* >L;A mar=ers ma' !ot re eal causal relatio!shi&s 1ut ca! 1e hel&ful to si%!al clo!al e@&a!sio!s a!$ thus isualiCe the s&rea$ of a su1%rou& of the B. pertussis &o&ulatio! 8ith i!crease$ fit!ess0 e*%*0 1ecause B. pertussis is a1le to esca&e host immu!it'* Pre ious stu$ies sho8e$ that a!ti1o$ies a%ai!st Pr!10 &rese!t i! the curre!t acci!e0 are less efficie!t i! &rotecti!% a%ai!st &ertussis i! a!imals challe!%e$ 8ith the other Pr! aria!ts* ;ariatio! of the prn %e!e is cause$ 1' ariatio! i! the !um1er a!$ com&ositio! of the re&eats i! this irule!ce %e!e* 3e!ce0 this is a! e@am&le of a ;NTR 8ithi! a irule!ce %e!e i! 8hich ariatio! results i! a!ti%e!ic cha!%e a!$ &ossi1le acci!e esca&e* As irtuall' all Bordetella ;NTRs are locate$ i! o&e! rea$i!% frames e!co$i!% &ossi1l' surface/e@&ose$ &rotei!s0 this su%%ests that ariatio! i! the ;NTRs ma' 1e relate$ to a!ti%e!ic ariatio!* I! 1iolo%'0 mi!imum s&a!!i!% trees ca! easil' 1e a&&lie$ to multistate $ata such as >L;A0 >AST0 or >LST &rofiles* I! the trees0 the &re$omi!a!t t'&es ca! 1e co!si$ere$ the most li=el' a!cestors0 8ith

4<

RESURGENCE OF BORDETELLA PERTUSSIS

their $esce!$a!ts ra$iati!% as aria!ts of the a!cestral t'&e* The mi!imum s&a!!i!% trees 8ere easier to i!ter&ret tha! lar%e $e!$ro%rams*

>INI>U> SPANNING TREE OF BORDETELLA PERTUSSIS

ADAPTATION AND 2ANING I>>UNITH/


The resur%e!ce of &ertussis i! the face of i!te!se acci!atio! is u!e@&ecte$ 1ecause B. pertussis is e@tremel' homo%e!eous0 ho8e er0 the Pt@ &romoter sho8e$ a relati el' hi%h $e%ree of &ol'mor&hism0 su%%esti!% that fi!e tu!i!% of Pt@ &ro$uctio! has a$a&ti e alue* Glo1all'0 pt#+1 a!$ pt#+3 8ere the most &re ale!t pt#+ alleles*The re&laceme!t of pt#+1 strai!s 1' pt#+3 strai!s i! rece!t times is a %lo1al &he!ome!o! 1ecause it has 1ee! o1ser e$ i! 11 cou!tries re&rese!ti!% + co!ti!e!ts? Asia0 Euro&e0 a!$ North a!$ South America* The %lo1al re%ulator of irule!ce %e!e e@&ressio! i! B. pertussis.h'&othesiCe that the pt#+3 allele co!fers i!crease$ 1i!$i!% of B %A com&are$ to pt#+1, resulti!% i! i!crease$ to@i! &ro$uctio!* 2he! com&are$ 8ith pt#+1 strai!s0 pt#+3 strai!s &ro$uce$ 1*6- times more Pt@* First0 the hi%h $e%ree of &ol'mor&hism i! the pt#+ &romoter i!$icates &ositi e selectio!* Seco!$0 the i!crease$ Pt@ &ro$uctio! o1ser e$ 1' pt#+3 strai!s &ro i$es a ratio!ale for its emer%e!ce*
49

RESURGENCE OF BORDETELLA PERTUSSIS

It has 1ee! 8ell esta1lishe$ that Pt@ &la's a ce!tral role i! immu!e su&&ressio!* A! im&orta!t issue is 8hether acci!atio! has selecte$ for the pt#+3 strai!s* Se eral li!es of e i$e!ce su&&ort this co!te!tio!* First0 pt#+3 strai!s 8ere !ot fou!$ i! the &re acci!atio! era* Se eral stu$ies ha e &ro i$e$ e i$e!ce that i!crease$ host immu!it' ma' select for hi%her irule!ce* The crucial e e!t0 8hich shifte$ the com&etiti e 1ala!ce 1et8ee! pt#+1 a!$ pt#+3 strai!s0 8as the remo al 1' acci!atio! of immu!olo%icall' !ai e i!fa!ts as the ma:or source for tra!smissio!0 selecti!% for strai!s0 8hich are more efficie!tl' tra!smitte$ 1' &rime$ hosts* I! most cou!tries i!fa!ts recei e their first acci!atio! at the a%e of - or 4 mo!ths0 esse!tiall' elimi!ati!% tra!smissio! 1' immu!olo%icall' !ai e hosts* I! &rime$ hosts0 i!crease$ Pt@ &ro$uctio! ma' $ela' a! effecti e immu!e res&o!se e!ha!ci!% tra!smissio!0 a!$ he!ce0 &atho%e! fit!ess* I!crease$ Pt@ &ro$uctio! ma' also 1e 1e!eficial for the &atho%e! 1ecause the host reFuires hi%her le els of a!ti1o$ies a%ai!st Pt@ for to@i! !eutraliCatio!* The a!ti%e!ic $i er%e!ce o1ser e$ 1et8ee! acci!e strai!s a!$ circulati!% strai!s ma' act s'!er%isticall'* 2ith the pt#+3 &ol'mor&hism 1' e!ha!ci!% tra!smissio! 1' hosts &rime$ 1' acci!atio!* Pertussis amo!% rece!tl' acci!ate$ chil$re! is rare0 i!$icati!% that &atho%e! a$a&tatio! $oes !ot &la' a role u!less immu!it' has 8a!e$*

INCREASED DIAGNOSIS AND REPORTING/


I! $e elo&e$ cou!tries it is li=el' that im&ro e$ $ia%!ostic tech!iFues a!$ re&orti!% ma' 1e a ma:or co!tri1utio! to i!crease$ !otificatio! rates for &ertussis* A rece!t stu$' i! Toro!to0 Ca!a$a0 re&orts that a mar=e$ i!crease i! &ertussis i!ci$e!ce i! -))6 8as associate$ 8ith a mar=e$l' i!crease$ olume of tests &erforme$0 &rimaril' PCR/1ase$ assa's* I!crease$ &ress re&orts a!$ scie!tific literature o! the Yresur%e!ce of &ertussisR0 as 8ell as re&orts of &ertussis acci!e trials a!$ su1seFue!t lice!sure of lo8

+)

RESURGENCE OF BORDETELLA PERTUSSIS

$ose acellular &ertussis acci!es for use i! a$ults0 ma' ha e also le$ to a! i!crease i! cli!icia! a8are!ess a!$ re&orti!%* 3o8e er0 i! ma!' $e elo&i!% a!$ some $e elo&e$ cou!tries0 i$e!tificatio! of &ertussis is still limite$ 1' &atie!t a!$ &h'sicia! a8are!ess a!$ the limite$ se!siti it' of $ia%!ostic tests* I! i!fa!ts0 i!crease$ rates of &ertussis ma' 1e relate$ to 1oth cha!%es i! acci!atio! strate%ies a!$ i!fectio! sources as 8ell as the a aila1ilit' of PCR as a $ia%!ostic tool*

+1