resurgence of bordetella pertussis

8/13/2019 Resurgence of Bordetella Pertussis

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RESURGENCE OF BORDETELLA PERTUSSIS

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IN AMERICA-

Data 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$/-)110 a susta!tial rise i! &ertussis cases has ee! re&orte$ 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$emic o! A&ril 40 -)1-* B' 5u!e 160 the re&orte$ !umer 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 !umer of cases re&orte$ i! a!' 'ear

si!ce 19+-*

IN EUROPE/

The sureilla!ce &ro:ect EU;AC/NET has recor$e$ a 117( i!crease i! i!ci$e!ce rates i!chil$re! a%e$ oer 1+ 'ears et8ee! 199< a!$ -))-*

IN AUSTRALIA/

There 8ere 4+0+9) &ertussis !otificatio!s receie$ ' the Natio!al Notifiale Diseases

Sureilla!ce S'stem "NNDS# i! -)1)0 the hi%hest recor$e$ si!ce 1991*Rece!tl'0 there has ee! a

rise i! !otificatio! rates i! the -)/79 'ear ol$ a%e %rou&0 a!$ i! those oer the a%e of 6)0

i!creasi!% ' 7.( a!$ 1.( res&ectiel' i! -)1)*

IN NET3ERLAND/

I! the Netherla!$s0 $es&ite co!siste!tl' hi%h acci!atio! coera%e for $eca$es0 i!crease$

!umers of &ertussis !otificatio!s hae ee! osere$ si!ce 1996 8ith e&i$emic &ea=s eer' -,4

'ears*The Netherla!$s recor$e$ more tha! 60))) cases i! -))90 u& from 4) cases i! 19


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INCIDENCE OF PERTUSSIS IN ADULT/

PERTUSSIS EPIDE>IC AND GENO>E >ODIFICATION/

INTRODUCTION/

Bordetella pertussis8as first isolate$ i! &ure culture i! 19)6 ' Bor$et a!$ Ge!%ou* To$a'0 B

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pertussis elo!%s to the %e!us Bordetellai! the famil' Alcali%e!aceae0 8hich co!tai!s seeral

s&ecies of closel' relate$ acteria 8ith similar mor&holo%'* 2hile !i!e s&ecies of Bordetella

hae ee! i$e!tifie$ to $ate0 o!l' three a$$itio!al memers0 B. bronchiseptica0B. parapertussis0

a!$B. holmesii0 hae ee! associate$ 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 seere i!fectio!s hae ee! !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 reseroir* B. holmesii0 the most rece!t of theBordetella s&ecies associate$ 8ith

huma! res&irator' tract i!fectio!0 has ee! fou!$ i! the loo$ of 'ou!% a$ults a!$ occasio!all'

i! the s&utum

Bordetella pertussisis a small "a&&ro@imatel' )*< m ' )*+ m#0 ro$/sha&e$0 coccoi$0 or ooi$

%ram !e%atie acterium that is e!ca&sulate$ a!$ $oes !ot &ro$uce s&ores* It is a strict aeroe* It

is arra!%e$ si!%l' or i! small %rou&s a!$ is motile*

ELECTRON >ICROSCOPE OF BORDETELLA PERTUSSIS/

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VIRULENCE FACTORS OF BORDETELLA PERTUSSIS-

The bvglocus/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$i!atel' re%ulate$ ' the &ro$ucts of the bvglocus*It

occu&ies 7 = o! the total %e!ome a!$ co$es for B%A0 B%S a!$ a!other &rotei! $o8!stream0

B%R* Stu$ies o! this locus hae reeale$ that its tra!scri&tio! is co!trolle$ ' a 47) & DNA

fra%me!t hai!% four &romoters* Three of them0 P10 P-a!$ P4are i!ole$ i! the tra!scri&tio! of

the bvg locus 8hile the fourth0 P+0is i!ole$ i! the s'!thesis of a! a!tise!se RNA* A!other

&romoter PF3A0 locate$ !ear the bvglocus is res&o!sile for the tra!scri&tio! of a irule!t a$hesio!

factor "F3A0 $iscusse$ later#* U!$er !o!/i!$uci!% co!$itio!s0 the &romoter P-is actie a!$

mai!tai!s a lo8 leel of the re%ulator' &rotei! B%A 8hich is !ot e!ou%h to actiate the irule!ce

%e!es* U!$er i!$uci!% co!$itio!s0 B%A is actiate$ ' &hos&hor'latio!0 follo8i!% 8hich it

actiates the &romoters P10 P-0 P40 P+0 PF3A0 a!$ other &romoters of the ;irule!ce Actiate$ Ge!es

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"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

theBvg+&he!ot'&e* The a!tise!se RNA co$e$ from P+&ositiel' re%ulates P10 P- a!$ P4 '

h'ri$ii!% to their 7 u!tra!slate$ re%io!s* 3'ri$iatio! i!hiits the formatio! of seco!$ar'

structure i! the mRNAs0 there' faori!% their i!teractio! 8ith the riosome* This causes a 7)/fol$

i!crease i! the rate of tra!slatio!*

Fi%ure/ 4

The % locus 8ith % ASR %e!es a!$ the &romoters P10 P-0 P4a!$ P+*

The B%/&hase is $efi!e$ ' the ase!ce of vag/e!co$e$ factors a!$ occurs 8he! the bvglocus is

$elete$ or 8he! B%AS actiit' is su&&resse$ ' 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!oles the e@&ressio! of a seco!$

class of bvgre%ulate$ %e!es $uri!% the mo$ulate$ &hase0 the ;irule!ce Re&resse$ Ge!es

"vrg#* Namel' vrg6, vrg 18, vrg 24, vrg 53a!$ vrg 73* The first four of the fie vrg%e!es me!tio!e$

are re%ulate$ ' bvgactiate$ re&ressor molecule "B%R# throu%h a co!sere$ re&ressor i!$i!%

site* 2hile the bvg/re&resse$ %e!es ofB. bronchisepticaa&&ear to e i!ole$ i! surial outsi$e

the host0 their fu!ctio! i!B. pertussis is relatiel' u!=!o8!* 3o8eer it has ee! sho8! that B%R

me$iate$ re%ulatio! of %e!e e@&ressio! co!triutes to res&irator' i!fectio! i! mice*

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

Bordetella pertussisem&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 $omai! a!$ seeral c'to&lasmic $omai!s0 the li!=er0 tra!smitter0 receier a!$ the

C/termi!us* The B%S &eri&lasmic $omai! se!ses e@ter!al stimuli "&erha&s ia $imeriatio!# a!$

tri%%ers a series of &hos&hor'latio! ste&s starti!% 8ith auto&hos&hor'latio! i! the tra!smitter

$omai! at a co!sere$ histi$i!e resi$ue* This is follo8e$ ' the tra!sfer of the &hos&hate %rou& to a

co!sere$ as&artic aci$ i! the receier $omai! 8hich tra!sfers it to a histi$i!e at the C/termi!al

$omai!*

Fi%ure +

Pro&ose$ mo$el of the re%ulator' !et8or= of the % locus* "a# No!/i!$uci!% co!$itio!s 'iel$ a lo8

amou!t of B%A0 8hich is i!actie* "# U!$er i!$uci!% co!$itio!s0 B%A is co!erte$ to a! actie

form "$e&icte$ as &hos&hor'late$# a!$ tra!sactiates P10 P-0 P40 P+0 PF3Aa!$ all other &romoters of

the % re%ulo!* "c# The actie form of B%A is am&lifie$ ' this &ositie tra!scri&tio!al fee$ac=

at the % locus* "$# Cha!%i!% to !o!/i!$uci!% co!$itio!s 8here B%A is &rese!t i! lar%e amou!ts

ut i! a! i!actie form.

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B%A0 the res&o!se re%ulator0 is a -4/=Da c'to&lasmic &rotei! com&risi!% a N/termi!al receier

a!$ a C/termi!al out&ut $omai!0 8hich co!tai!s a heli@/tur!/heli@ "3T3# DNA i!$i!% motif*

B%A is actiate$ ' the tra!sfer of the &hos&hate %rou& from the C/termi!al of B%S to a

co!sere$ as&artic aci$ i! the B%A N/termi!al receier $omai!* U&o! &hos&hor'latio!0 B%A

&ositiel' re%ulates the bvg!a!$ other irule!ce factor &romoters ' i!$i!% to the tar%et

seue!ce TTTCCTA* It has also ee! sho8! that B%A is ale to $imerie i! solutio! as a &ossile

mea!s to ri!% aout its DNA i!$i!% &ro&ert'*

Fi%ure/7

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


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Seeral li!es of ei$e!ce su%%est that the mecha!ism of re%ulatio! ' the bvglocus is $iffere!t for

$iffere!t irule!ce loci* Althou%h B%A ca! $irectl' actiate tra!scri&tio! from

the"haa!$ bvg&romoters0 the bvg locus is !ot sufficie!t for the actiatio! of

thept# a!$ c$a&romoters "$etaile$ later#* This ca! e i!ter&rete$ i! terms of the lo8er i!$i!%

affi!it' or hi%her leels of actiate$ B%A reuire$ to stimulate tra!scri&tio! at thept#com&are$ to

the"ha&romoter* Rece!t 8or= has also im&licate$ the reuireme!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

selectie actiatio! of some &romoters* Gie! the arie$ as&ects of B%A me$iate$ tra!scri&tio!al

actiatio!0 the bvgre%ulo! has &roe$ to e a! e@celle!t s'stem for the stu$' of $iffere!tial a!$

timel' re%ulatio! of tar%et &romoters to o&timie 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 i!$s to %alactose resi$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 ailit' of

the or%a!ism to colo!ie0 a!$ a!tio$ies a%ai!st F3A &roi$e &rotectio! a%ai!st i!fectio!*

3o8eer0 it is u!li=el' that F3A is the o!l' a$hesi! i!ole$ i! colo!iatio!* The structural %e!e

for F3A has ee! clo!e$ a!$ e@&resse$ i!%. coli0 raisi!% the &ossiilit' of its &ro$uctio! for use i!

a com&o!e!t acci!e*

FI>BRIAE/

B.pertussis fimriae are sumicrosco&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 suu!it a!$ are eliee$ to cause &ersiste!c' of

i!fectio!* The mi!or suu!it0 !ame$ FimD i!$s to the i!te%ri! ;la/70 locate$ o! mo!oc'tes* The

ma:or suu!it i!$s to sulfate$ su%ars li=e he&ara! sulfate0 cho!$roiti! sulfate a!$ $e@tra! sulfate

8hich are uiuitous i! the res&irator' tract* Stu$ies hae sho8! that oth the $e%ree a!$

arra!%eme!t of sulfate %rou&s $etermi!es the affi!it' of the i!$i!% of fimriae* It is i!teresti!% to

!ote that these i!$i!% actiities are also fou!$ i! firo!ecti!0 a host &rotei! fou!$ i! the

e@tracellular matri@0 a!$ that the ma:or suu!it share co!si$erale homolo%' 8ith firo!ecti!

8ithi! re%io!s im&licate$ 8ith he&ari! i!$i!%* Thus B. pertussis fimriae mimics !atural host

li%a!$/rece&tor i!teractio!s to further its i!fectio! &rocess* Sulfate$ su%ars o! res&irator' tract cells

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are also reco%!ie$ ' F3A0 he!ce &rese!ce of fimriae coul$ &ossil' e to $iffere!tiate et8ee!

$iffere!t host cells a!$ tissues e@hiiti!% ma!' $iffere!t co!fi%uratio!s of he&ara! sulfate* Bi!$i!%

of fimriae to mo!oc'tes results i! actiatio! 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!fimrial outer memra!e &rotei!0 u!$er the co!trol of the bvglocus0 is

&artl' res&o!sile for the a$hesio! of the acteria to the host cells* It also fu!ctio!s as a &rotectie

a!ti%e! i! a!imal mo$els*

The mature &rotei! has t8o Ar%i!i!e/Gl'ci!e/As&artic aci$ "RGD# seue!ces0 at --7/--. a!$ 667/

66.* These seue!ces are also &rese!t o! other mammalia! a$hesio! &rotei!s li=e firo!ecti!0

itro!ecti! a!$ firi!o%e! a!$ i!$ 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!'me0 EF#* This

to@i! acts locall' to re$uce &ha%oc'tic actiit' a!$ &roal' hel&s the or%a!ism i!itiate i!fectio!*

This to@i! is a +7 =Da &rotei! that ma' e cell/associate$ or release$ i!to the e!iro!me!t* >uta!ts

of B. pertussis i! the a$e!'late c'clase %e!e hae re$uce$ irule!ce i! mouse mo$els* The

or%a!isms ca! still colo!ie ut 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!'matic $omai! "i*e*0 a$e!'late c'clase actiit'# a!$ a i!$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!

ecause it 8ill l'se re$ loo$ cells* I! fact0 it is res&o!sile for hemol'tic o!es arou!$ colo!ies of

Bordetella pertussis %ro8i!% o! loo$ a%ar* Proal' it i!serts i!to the er'throc'te memra!e

8hich causes hemol'sis* A! i!teresti!% feature of the a$e!'late c'clase to@i! is that it is actie o!l'

i! the &rese!ce of a eu=ar'otic re%ulator' molecule calle$ calmo$uli!0 8hich u&/re%ulates the

actiit' of the eu=ar'otic a$e!'late c'clase* The a$e!'late c'clase to@i! is o!l' actie i! the

eu=ar'otic cell si!ce !o similar re%ulator' molecule e@ists i! &rocar'otes* Thus0 the molecule seems

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to hae eole$ s&ecificall' to &arasitie 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 TOIN/

It &ro$uces a hi%hl' lethal to@i! 8hich causes i!flammatio! a!$ local !ecrosis a$:ace!t to sites

8hereB. pertussisis locate$* The lethal to@i! is a 1)- =Da &rotei! com&ose$ of four suu!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$ sucuta!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 CHTOTOIN/

It &ro$uces a susta!ce calle$ the tracheal c'toto@i! 8hich is to@ic for ciliate$ res&irator'

e&ithelium a!$ 8hich 8ill sto& the ciliate$ cells from eati!%* This susta!ce is !ot a classic

acterial 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 acteria are actiel' %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 feer*

PERTUSSIS TOIN/

A &rotei! that me$iates oth the colo!iatio! a!$ to@emic sta%es of the $isease* PT@ is a t8o

com&o!e!t0 AB acterial e@oto@i!* The A suu!it "S1# is a! ADP rios'l tra!sferase* The B

com&o!e!t0 com&ose$ of fie &ol'&e&ti$e suu!its "S- throu%h S7#0 i!$s to s&ecific caroh'$rates

o! cell surfaces* The role of PT@ i! i!asio! has alrea$' ee! $iscusse$* PT@ is tra!s&orte$ from

the site of %ro8th of the Bor$etella to arious susce&tile cells a!$ tissues of the host* Follo8i!%

i!$i!% of the B com&o!e!t to host cells0 the A suu!it is i!serte$ throu%h the memra!e a!$

release$ i!to the c'to&lasm i! a mecha!ism of $irect e!tr'* The A suu!it %ai!s e!'matic actiit'

a!$ tra!sfers the ADP rios'l moiet' of NAD to the memra!e/ou!$ re%ulator' &rotei! Gi that

!ormall' i!hiits the eu=ar'otic a$e!'late c'clase* The Gi &rotei! is i!actiate$ a!$ ca!!ot &erform

its !ormal fu!ctio! to i!hiit a$e!'late c'clase* The co!ersio! of ATP to c'clic A>P ca!!ot e

sto&&e$ a!$ i!tracellular leels 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 actiities such as chemota@is0

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e!%ulfme!t0 the o@i$atie urst0 a!$ acteri$ci$al =illi!%* S'stemic effects of the to@i! i!clu$e

l'm&hoc'tosis a!$ alteratio! of hormo!al actiities that are re%ulate$ ' cA>P0 such as i!crease$

i!suli! &ro$uctio! "resulti!% i! h'&o%l'cemia# a!$ i!crease$ se!sitiit' to histami!e "resulti!% i!

i!crease$ ca&illar' &ermeailit'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 leae the l'm&hatics sho8 a! i!ailit' to retur!* This

alters oth A>I a!$ C>I res&o!ses a!$ ma' e@&lai! the hi%h free!c' of seco!$ar' i!fectio!s that

accom&a!' &ertussis "the most freue!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 rios'latio!0 it has ee! sho8!

that mere i!$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 actiatio!0 a!$ &ro$uctio! of i!suli! effects* The &ertussis to@i! %e!e has ee!

clo!e$ a!$ seue!ce$ a!$ the suu!its e@&resse$ i! %. coli* The to@i! ca! e i!actiate$ a!$

co!erte$ to to@oi$ for use i! com&o!e!t acci!es* Com&ariso! et8ee! cholera to@i! a!$ &ertussis

to@i! "&t@# i! their ailit' to i!terfere 8ith the re%ulatio! of the eucar'otic a$e!'late c'clase

com&le@*

Normal re%ulatio! of a$e!'late c'clase actiit' i! mammalia! cells is actiate$ !ormall' ' a

stimulator' re%ulator' &rotei! "Gs# a!$ %ua!osi!e tri&hos&hate "GTP#? ho8eer the actiatio! is

!ormall' rief ecause a! i!hiitor' re%ulator' &rotei! "Gi# h'$rol'es the GTP* A$e!'late c'clase

actiate$ ' cholera to@i!* The cholera to@i! A1 fra%me!t catal'es the attachme!t of ADP/Riose

"ADPR to the re%ulator' &rotei! Gs0 formi!% Gs/ADPR from 8hich GTP ca!!ot e h'$rol'e$*

Si!ce GTP h'$rol'sis is the ee!t that i!actiates a$e!'late c'clase "AC#0 the e!'me remai!s

co!ti!uall' actiate$*

A$e!'late c'clase actiate$ ' &ertussis to@i! "The &ertussis A suu!it tra!sfers the ADP rios'l

moiet' of NAD to the memra!e/ou!$ re%ulator' &rotei! Gi that !ormall' i!hiits the eu=ar'otic

a$e!'late c'clase* The Gi &rotei! is i!actiate$ a!$ ca!!ot &erform its !ormal fu!ctio! to i!hiit

a$e!'late c'clase* The co!ersio! of ATP to c'clic A>P ca!!ot e sto&&e$*

LIPOPOLYSACCHARIDE-

As a Gram/!e%atie acteriumBordetella pertussis&ossesses li&o&ol'sacchari$e "e!$oto@i!# i! its

outer memra!e0 ut 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!atie form of Li&i$ A is $esi%!ate$ Li&i$ * The

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u!fractio!ate$ material elicits the usual effects of LPS "i*e*0 i!$uctio! of IL/10 actiatio! of

com&leme!t0 feer0 h'&ote!sio!0 etc*#0 ut the $istriutio! of those actiities is $iffere!t i! the t8o

forms of LPS* For e@am&le0 Li&i$ 0 ut !ot Li&i$ A0 is &'ro%e!ic0 a!$ its O/si$e chai! is a er'

&o8erful immu!e a$:ua!t* Furthermore0 Bor$etella LPS is more &ote!t i! the limulus assa' tha!

LPS from other Gram/!e%atie acteria0 so it is !ot reliale to a&&l' =!o8le$%e of the iolo%ical

actiit' of LPS i! the%nterobacteriaceaeto the LPS ofBordetella* The role of this u!usual LPS i!

the &atho%e!esis of 8hoo&i!% cou%h has !ot ee! 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!iatio!

a!$ ra&i$ multi&licatio! of the acteria o! the mucous memra!es of the res&irator' tract*

Bacteremia $oes !ot occur* Electro! microsco&ic stu$ies hae $emo!strate$ that &hase I strai!s of

B pertussisa$here o!l' to the tuft of ciliate$ cells i! the mucosa of the huma! res&irator' tract? !o

attachme!t to !o!ciliate$ cells 8as osere$* Co!i!ci!% e@&erime!tal $ata i!$icate that the

a$here!ce of B pertussisto huma! cilia is affecte$ ' a s'!er%istic actio! of &ertussis to@i! a!$

filame!tous hema%%luti!i!0 each acti!% as a iale!t ri$%e et8ee! the acterium a!$ the ciliar'

rece&tor*

COLONIJATION/

Stu$ies ofB. pertussisa!$ its a$hesi!s hae focuse$ o! culture$ mammalia! cells that lac= most of

the features of ciliate$ e&ithelial cells* 3o8eer0 some %e!eralities hae ee! $ra8!* The t8o most

im&orta!t colo!iatio! 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 i!$s to %alactose resi$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 ailit' of

the or%a!ism to colo!ie0 a!$ a!tio$ies a%ai!st F3A &roi$e &rotectio! a%ai!st i!fectio!*

3o8eer0 it is u!li=el' that F3A is the o!l' a$hesi! i!ole$ i! colo!iatio!* The structural %e!e

for F3A has ee! clo!e$ a!$ e@&resse$ i!%. coli0 raisi!% the &ossiilit' of its &ro$uctio! for use i!

a com&o!e!t acci!e*

14


14/41


O!e of the to@i!s ofB. pertussis0 the &ertussis to@i! "PT@#0 is also i!ole$ i! a$here!ce to the

tracheal e&ithelium* Pertussis to@i! is a 1)7 =Da &rotei! com&ose$ of si@ suu!its S10 S-0 S40 S+0

a!$ S7* The to@i! is oth secrete$ i!to the e@tracellular flui$ a!$ cell ou!$* Some com&o!e!ts of

the cell/ou!$ to@i! "S- a!$ S4# fu!ctio! as a$hesi!s0 a!$ a&&ear to i!$ the acteria to host cells*

S- a!$ S4 utilie $iffere!t rece&tors o! host cells* S- i!$s s&ecificall' to a %l'coli&i$ calle$

lactos'lcerami$e0 8hich is fou!$ &rimaril' o! the ciliate$ e&ithelial cells* S4 i!$s to a

%l'co&rotei! fou!$ mai!l' o! &ha%oc'tic cells*

PAT3OGENESIS OF INFECTION/

Si!ce the S4 suu!it of &ertussis to@i! is ale to i!$ 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 C4#0 it has ee!

s&eculate$ that the acterium mi%ht i!$ &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& ' this

a!ormal route ma' aoi$ stimulati!% the o@i$atie urst that !ormall' accom&a!ies &ha%oc'tic

u&ta=e of acterial cells 8hich are o&so!ie$ ' a!tio$ies or com&leme!t C4* O!ce i!si$e of

cells the acteria mi%ht utilie other to@i!s "i*e* a$e!'late c'clase to@i!# to com&romise the

acterici$al actiities of &ha%oc'tes* I! a!' case0 there is some ei$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* IfB.

pertussisis a! i!tracellular &arasite it 8oul$ e@&lai! 8h' immu!it' to &ertussis correlates etter

8ith the &rese!ce of s&ecific c'toto@ic T cells tha! it $oes 8ith the &rese!ce of a!tio$ies to

acterial &ro$ucts*

The to@i!s a!$ a$hesi!s are im&orta!t oth 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!$ fimriae are a$hesi!s that are com&o!e!ts of

some of the acellular acci!es0 ut all curre!tl' aailale acci!es i!clu$e &ertussis to@i! "PT#* I!

a$$itio! to ei!% a! a$hesi!0 F3A has ee! sho8! to co!tai! a! RGD "ar%i!i!e/%l'ci!e/

as&ara%i!e,co!tai!i!% seue!ce# site0 i!teract 8ith the i!te%ri! CD11KCD1< "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 memer of the famil' of a$e!osi!e $i&hos&hate,rios'lati!% to@i!s that i!clu$es cholera

to@i! a!$ $i&htheria to@i!0 a!$ it has as its i!tracellular tar%et seeral %ua!osi!e tri&hos&hate,

1+


15/41


i!$i!% &rotei!s such as Gi* PT@ is a t8o com&o!e!t0 AB acterial e@oto@i!* a!$ release$ i!to the

c'to&lasm i! a mecha!ism of $irect e!tr'* The A suu!it %ai!s e!'matic actiit' a!$ tra!sfers the

ADP rios'l moiet' of NAD* The co!ersio! of ATP to c'clic A>P ca!!ot e sto&&e$ a!$

i!tracellular leels 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 actiities such as chemota@is0 e!%ulfme!t0 the o@i$atie urst0 a!$ acteri$ci$al =illi!%*

S'stemic effects of the to@i! i!clu$e l'm&hoc'tosis a!$ alteratio! of hormo!al actiities that are

re%ulate$ ' cA>P0 such as i!crease$ i!suli! &ro$uctio! "resulti!% i! h'&o%l'cemia# a!$ i!crease$

se!sitiit' to histami!e "resulti!% i! i!crease$ ca&illar' &ermeailit'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 leae the

l'm&hatics sho8 a! i!ailit' to retur!* This alters oth A>I a!$ C>I res&o!ses a!$ ma' e@&lai!

the hi%h free!c' of seco!$ar' i!fectio!s that accom&a!' &ertussis "the most freue!t seco!$ar'

i!fectio!s $uri!% 8hoo&i!% cou%h are &!eumomia a!$ otitis me$ia#*

LIPOPOLHSACC3ARIDE/

As a Gram/!e%atie acteriumBordetella pertussis&ossesses li&o&ol'sacchari$e "e!$oto@i!# i! its

outer memra!e0 ut 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!atie form of Li&i$ A is $esi%!ate$ Li&i$ * The

u!fractio!ate$ material elicits the usual effects of LPS "i*e*0 i!$uctio! of IL/10 actiatio! of

com&leme!t0 feer0 h'&ote!sio!0 etc*#

17


16/41


P3ASE ;ARIATION AND P3ENOTHPIC >ODULATION/

Li=e ma!' other acterial &atho%e!s0 the e@&ressio! of the irule!ce factors i!Bordetella

pertussisis co!trolle$ ' %ro8th co!$itio!s* T8o im&orta!t &he!ome!a i! the re%ulatio! of the

irule!ce %e!es arephase variationa!$phenot$pic modulation*

Phase ariatio! i!$icates a reersilealteratio! i! the %e!ot'&e cause$ ' frameshift mutatio!s i!

8hich the irule!t acteria simulta!eousl' lose the ailit' to s'!thesie to@i!s a!$ other factors

associate$ 8ith &atho%e!icit'*Er'throm'ci! tolera!ce has ee! sho8! a &hase mar=er cause$ '

e@te!sie alteratio!s i! the surface &ro&erties et8ee! the irule!t a!$ the airule!t strai!s0 8hich

co!fer susce&tiilit' to this a!tiiotic* The !atural emer%e!ce of &hase aria!ts i! the later sta%es of

i!fectio! im&lies that &hase cha!%e coul$ e a $efe!se mecha!ism to esca&e immu!e $etectio!0

li=e !almonellafla%ellar &hase ariatio! 8here the cha!%e of a!ti%e!ic t'&e hel&s the acteria to

ea$e the immu!e s'stem.

The other &he!ome!o! terme$ &he!ot'&ic mo$ulatio! 8as first osere$ ' 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!sile for oth the &he!ome!a 8as

i$e!tifie$* This 8as terme$ the bvg"Bordetellavirule!cege!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*

16


17/41


CLINICAL FEATURE/

CATARRA3AL STAGE

Im&orta!tl'0 the s'm&toms that i!itiate the catarrhal &hase "rhi!orrhea0 i!crease$ lacrimatio!0co!:u!ctial i!:ectio!0 a!$ sometimes lo8/%ra$e feer# are !o!s&ecific a!$ !ot o!es that su%%est

&ertussis0 e@ce&t i! the setti!% of a! o!%oi!% hos&ital or commu!it' outrea=* 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$uctie cou%h*

PAROHS>AL STAGE

This stri=i!% cou%h co!sists of a series of u!co!trollale e@&iratio!s0 follo8e$ ' %as&i!%

i!halatio!0 8hich $e&e!$i!% o! the air8a' a!atom'0 is res&o!sile for the M8hoo&i!% sou!$*

2hoo& is more freue!t i! chil$re! tha! a$ults* It is !ot u!commo! for each e&iso$e of cou%hi!% to

e 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 $eelo&me!t of feer or 8orse!i!% &ulmo!ar' fu!ctio! $uri!% this time shoul$

su%%est the &ossiilit' of seco!$ar' &!eumo!ia

CON;ALESCENT P3ASE/

Re$uctio! i! the freue!c' a!$ seerit' of cou%hi!% attac=s mar=s the tra!sitio! to the

co!alesce!t &hase0 8hich ca! last seeral mo!ths* It is $uri!% this time that a$ults &rese!t to the

health care s'stem 8ith Mchro!ic cou%h a!$ ma' e ealuate$ for co!$itio!s such as asthma0

tuerculosis0 other chro!ic lu!% $iseases0 mali%!a!cies0 a!$ %astroeso&ha%eal reflu@* After the

cou%hi!% s&ells hae e!$e$0 &atie!ts ma' hae 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 hae a! ill!ess of at least 4 8ee=s $uratio!0 a!$ -.( are

still cou%hi!% after 9) $a's*

1.


18/41


Length Clinical Featue!

Sta%e 1

Catarrhal

Usuall' ./1) $a's? ra!%e of

+/-1

Characterie$ '

Cor'a

Lo8/%ra$e feer

>il$0 occasio!al cou%h "8hich %ra$uall'

ecomes more seere#

Sta%e -

Paro@'sma

l

Usuall' lasts 1/6 8ee=s0 ut

ma' &ersist for u& to 1)

8ee=s

Characterie$ '

Paro@'sms of !umerous0 ra&i$ cou%hs

$ue to $ifficult' e@&elli!% thic= mucus from

the tracheoro!chial tree*

Lo!% as&irator' effort accom&a!ie$ ' a

hi%h/&itche$ 8hoo& at the e!$ of the&aro@'sms

C'a!osis

;omiti!% a!$ e@haustio!

Paro@'smal attac=s

Occur freue!tl' at !i%ht0 8ith a!

aera%e of 17 attac=s &er -+ hours*

I!crease i! freue!c' $uri!% the first 1/-

8ee=s0 remai! at the same freue!c' for -/4

8ee=s0 a!$ the! %ra$uall' $ecrease*

Sta%e 4

Co!alesc

e!t

Usuall' ./1) $a's? ra!%e of

+/-1

Characterie$ '

Gra$ual recoer'

Less &ersiste!t0 &aro@'smal cou%hs that

$isa&&ear i! -/4 8ee=s

Paro@'sms ofte! recur 8ith suseue!t

res&irator' i!fectio!s for ma!' mo!ths after the

o!set of &ertussis*

1


19/41


Classificatio! of cou%hi!% e&iso$es i!oli!% &ertussis ase$ o! cultures0 serolo%'0

famil' e@&osure0 a!$ cli!ical s'm&toms/

Classificatio! a!$ criteria

Pertussis

1*B. pertussisisolate$ from the !aso&har'!@

-* At least o!e of the follo8i!% criteria fulfille$

a* Si%!ifica!t i!crease i! PT I%G

* Si%!ifica!t i!crease i! F3A I%G 8ithout other criteria for &ara&ertussis

c* Both PT I%G a!$ F3A I%G 60))) i! the same co!alesce!t serum

$* Famil' memer 8ith &ertussis erifie$ ' 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 suo&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

ealuale ecause of earl' er'throm'ci! treatme!t

BORDETELLA PERTUSSIS IN ADULTS-

Duri!% the last t8o $eca$es0 a !umer of stu$ies hae i!$icate$ that B. pertussis i!fectio!s i!

a$olesce!ts a!$ a$ults are commo!* There has also ee! a! i!crease i! the !umer re&orte$ 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 haeB. pertussisi!fectio!s hae ha$ a &reiousB. pertussisi!fectio!0 hae ee! acci!ate$0

or oth* Preious i!fectio! or &reious immu!iatio! te!$s to mo$if' ill!ess i! a$ults*

Neertheless0 a$olesce!ts a!$ a$ults ca! hae s'm&tomatic i!fectio!0 mil$ $isease0 or classic

&ertussis* The results of seeral stu$ies su%%est that a$ults 8ho 8ere &rime$ ' &reious i!fectio!

"as o&&ose$ to &rimi!% ' immu!iatio!# are more li=el' to hae t'&ical &ertussis*

I! a U*S* stu$' of -. a$olesce!ts a!$ a$ults0 the follo8i!% cli!ical fi!$i!%s 8ere !ote$ "i# the

me$ia! $uratio! of cou%h 8as +- $a's0 8ith a ra!%e from -. to 66 $a's? "ii# all su:ects ha$

&aro@'smal cou%h? "iii# -6( of the su:ects ha$ 8hoo&i!%? "i# 76( ha$ &ost/tussie omiti!%? a!$

"# 1))( ha$ &ost/tussie %a%%i!%* Ei%ht' &erce!t or more of a$olesce!ts a!$ a$ults 8ith &ertussis

19


20/41


hae &aro@'smal cou%h0 ut the freue!c' of 8hoo& a!$ &ost/tussie omiti!% i! this &o&ulatio! is

uite ariale* I! a$$itio!0 $uri!% the &aro@'smal sta%e0 a$ults e@&erie!ce s'm&toms !ot $escrie$

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 $ia%!ose &ertussis i! 41 u!iersit' stu$e!ts 8hosho8e$ laorator' ei$e!ce of Bordetella i!fectio!* I!stea$0 their $ia%!oses i!clu$e$ u&&er

res&irator' tract i!fectio! "49(#0 ro!chitis "+PLICATIONS OFB&'(%)%** %')!!-!/

The most freue!t com&licatio! osere$ 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!$ acterial 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&ectie 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 seiures a!$ e!ce&halo&ath' hae ee! re&orte$ i! -7(0 4( a!$ 1( of cases0

res&ectiel'* Car$iac arrh'thmias a!$ e&iso$es of i!tractale h'&o%l'cemia hae also ee!

re&orte$* After chil$hoo$0 the ris= of com&licatio!s i!creases 8ith a%e* P!eumo!ia has ee!

osere$ 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 ac= &ai!0 ri fracture a!$ her!ia hae ee! also $escrie$* Seere

-)


21/41


&aro@'sm0 &ost/tussie c'a!osis0 8hoo&i!%0 &osttussie omiti!%0 a&!ea0 &!eumo!ia a!$ seiures

are the most freue!t reaso!s &atie!ts are a$mitte$ to hos&ital0 re%ar$less of a%e* I!fa!ts0 es&eciall'

those 8ho hae !ot ee! acci!ate$ or hae ee! i!com&letel' acci!ate$0 are the most li=el' to

reuire hos&ital care*

Birth efore 4. 8ee=s %estatio! a!$ lo8 irth 8ei%ht hae ee! 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

hae a case/fatalit' rate of )*6(* 3i%h leels of leu=oc'tosis a!$ l'm&hoc'tosis ma' &re$ict a fatal

outcome i! chil$re! a$mitte$ to hos&ital*

FREUENCH OF SH>PTO>S IN ADULT PERTUSSIS/

-1


22/41


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

CULTURE/Culture is co!si$ere$ to e the %ol$ sta!$ar$0 ho8eer0 its se!sitiit' $ecreases stee&l' if the

s&ecime! is ta=e! more tha! - 8ee=s after o!set of cou%h a!$ is re$uce$ ' &rior immu!it' from

$isease or immu!isatio!* Three 8ee=s after comme!ceme!t of cou%h0 se!sitiit' of culture is o!l'

1,4(0 ee! lo8er i! a$ults a!$ a$olesce!ts 8ho are more li=el' to &rese!t late* 3o8eer0 culture

allo8s t'&i!% a!$ a!tiiotic se!sitiit' to e $etermi!e$* Results ca! e aailale i! .- h0 es&eciall'

i! hi%h titre i!fectio!0 ut - 8ee=s are reuire$ efore culture ma' e $efi!itiel' re&orte$ as

!e%atie* The se!sitiit' of culture is re$uce$ ' the t'&e of s&ecime! collecte$ "8ith a

!aso&har'!%eal s8a etter tha! &er!asal#0 the metho$ of collectio! "&referal' i! 'ou!%er chil$re!

a !aso&har'!%eal as&irate# a!$ the use of cotto! or ra'o! s8as0 8hich are i!hiitor'

--


23/41


DNA POLH>ERASE C3AIN REACTION-

Pol'merase chai! reactio! "PCR# metho$s e!ha!ce the &roailit' of i$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$ forthe $etectio! of B* &ertussis 8ith the former $etecti!% am&lifie$ tar%et %e!e &ro$ucts isualie$ '

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!* Noel real/

time PCR assa's tar%eti!% the Bor$etella &ertussis i!sertio! seue!ce IS+


24/41


Tale 1 T'&ical course of &ertussis eolutio! of s'm&toms0 relatie se!sitiit' of $ia%!ostic

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

;ariale

Catarrhal &hase"1,- 8=# Paro@'smal &hase"4,6 8=# Co!alesce!t &hase" 6 8=#

S"#$t%#

Cou%h

Paro@'smal cou%h ,K ,K

2hoo&i!% cou%h , ,K

;omiti!% , ,K

C'a!osis , ,

A&!ea , ,

Te!t !en!iti&it"

Culture ,K ,

PCR ,

Serolo%' ,K

E''ect %' anti(i%tic thea$"

S'm&toms alleiate$ ,K ,

SEROLOGICAL >ET3ODS/

I!fectio! of or$etella &ertusis is follo8e$ ' i!crease i! the co!ce!tratio!s i! serum of I%A0 I%G0

a!$ I%> a!tio$ies to s&ecific a!ti%e!s as 8ell as to &re&aratio!s of the 8hole or%a!ism* Prior to

the $eelo&me!t of ELISA tech!iues0 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!tio$' titer* The a!tio$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!al'

%oo$ s&ecificit' ut lac=e$ se!sitiit'* The mai!sta' of the serolo%ic $ia%!osis of &ertussis $uri!%

the last 17 'ears has ee! ELISA0 usi!% s&ecific B. pertussis&rotei!s as a!ti%e!s* Sta!$ar$ie$

tech!iues hae ee! $eelo&e$0 a!$ a!tio$ies are ua!titate$ ' the refere!ce li!e com&uter

&ro%ramme a!$ refere!ce sera from the Ce!ter for Biolo%ics Ealuatio! a!$ Research0 U*S* Foo$

a!$ Dru% A$mi!istratio!* The &recisio! of the test is such that i!tra/assa' coefficie!ts of ariatio!hae ee! re$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!iatio! of chil$re! i!$uces mai!l' I%> a!$ I%G

a!tio$ies* Serolo%ic $ia%!osis of &ertussis ma' e sus&ecte$ ' 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!tio$' titer to PT0 F3A0

-+


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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!tio$' res&o!ses to F3A a!$ PRN also occur follo8i!% other Bordetella

i!fectio!s0 so that isolate$ i!creases i! titers of a!tio$' a%ai!st these a!ti%e!s are !ot s&ecific for

B. pertussisi!fectio!* I! a$$itio!0 hi%h titers of a!tio$' to F3A ma' e the result of cross/reacti!%

e&ito&es of !o!e!ca&sulate$ /.in"luen0ae0 .pneumoniae0 .pneumoniae0 a!$ &erha&s other

acteria* Some culture/&ositie &atie!ts0 &articularl' chil$re! 'ou!%er tha! 4 mo!ths0 fail to

$eelo& measurale a!tio$ies*

The &rimar' &rolem i! the serolo%ic $ia%!osis ofB. pertussisi!fectio! ' ELISA is the $ela' i!

otai!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 hae alrea$' &ea=e$ a!$ further titer

i!creases et8ee! the acute/&hase a!$ co!alesce!t/&hase sera ma' !ot e osere$* 3o8eer0 for

those !ot rece!tl' immu!ie$0 this &rolem ca! e circume!te$ ' usi!% si!%le/serum ELISA*

S&ecificall'0 &atie!ts 8ith ill!ess 8ill hae ELISA titers that are si%!ifica!tl' hi%her tha! G>T*

The %reatest se!sitiit' a!$ s&ecificit' for the serolo%ical $ia%!osis of B. pertussis i!fectio! is

achiee$ ' ELISA a!$ measureme!t of I%G a!$ I%A a!tio$ies to PT* A si%!ifica!t rise i! titer

"%reater tha! or eual to t8ofol$# et8ee! acute/&hase a!$ co!alesce!t/&hase sera !ee$s to e

$emo!strate$* I! a$olesce!ts a!$ a$ults0 si!%le hi%h alues of I%G or I%A a!tio$ies to PT also

i!$icate i!fectio!* Althou%h I%A a!tio$' to PT is more i!$icatie of a rece!t a!tio$' res&o!se0 it

is less co!siste!t tha! a PT I%G res&o!se*

Si!%le serum s&ecime!s Si!%le/sam&le serolo%' tests for a!ti&ertussis to@i! I%G must e

collecte$ at least t8o 8ee=s after s'm&tom o!set* A hi%h a!tio$' titer more tha! t8o 'ears

follo8i!% acci!atio! su&&orts the $ia%!osis of &ertussis*

A solitar' a!tio$' 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!sitiit' 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


26/41


Si%!ifica!t i!crease i! ELISA $ia%!ostics

1* Co!troll serum i!terassa' ariatio! Acute to co!alasce!t &hase i!crease i! AB

V1)( 7)( V17( 1))(

-* >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


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>ANAGE>ENT OF BORDETELLA PERTUSSIS/

>ai!tai!i!% hi%h acci!atio! coera%e rates amo!% &reschool chil$re!0 a$olesce!ts0 a!$ a$ults a!$

mi!imii!% e@&osures of i!fa!ts a!$ &erso!s at hi%h ris= for &ertussis is the most effectie 8a' to&ree!t &ertussis* A!tiiotic treatme!t of &ertussis a!$ :u$icious use of a!timicroial 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

$uratio! a!$ seerit' of s'm&toms a!$ lesse! the &erio$ of commu!icailit'* A&&ro@imatel'


28/41


of the c'tochrome P+7) e!'me s'stem "CHP4A suclass# a!$ ca! i!teract 8ith other $ru%s that are

metaolie$ ' this s'stem* Aithrom'ci! a!$ clarithrom'ci! are more resista!t to %astric aci$0

achiee hi%her tissue co!ce!tratio!s0 a!$ hae a lo!%er half/life tha! er'throm'ci!0 allo8i!% less

freue!t a$mi!istratio! "1,- $oses &er $a'# a!$ shorter treatme!t re%ime!s "7,. $a's#* Er'throm'ci!

is aailale as %e!eric &re&aratio!s a!$ is co!si$eral' less e@&e!sie tha! aithrom'ci! a!$

Clarithrom'ci!*

Poste@&osure &ro&h'la@is/

A macroli$e ca! e a$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!seue!ces of seere &ertussis i! the co!tact0 a!$ &ossiilities 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 e!efits

of a$mi!isteri!% a! a!timicroial a%e!t to re$uce the ris= for &ertussis a!$ its com&licatio!s shoul$ e

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! &ree!t

s'm&tomatic i!fectio!* Cou%hi!% "s'm&tomatic# househol$ memers of a &ertussis &atie!t shoul$ e

treate$ as if the' hae &ertussis* Because seere 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@isshoul$ e 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!timicroial 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' $ro&lets "&articles 7 m i! sie# are %e!erate$ $uri!% cou%hi!%0

s!eei!%0 or tal=i!% a!$ $uri!% the &erforma!ce of certai! &roce$ures such as ro!chosco&' or

suctio!i!%? these &articles ca! e &ro&elle$ throu%h the air for $ista!ces of a&&ro@imatel' 4 feet*

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CLOSE CONTACT PROP3HLAIS/

Close co!tacts also ca! i!clu$e &erso!s 8ho

3ae $irect co!tact 8ith res&irator'0 oral0 or !asal secretio!s from a s'm&tomatic &atie!t*

E* cou%h0 s!eee0 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 1 hour*

Some close co!tacts are at hi%h ris= for acuiri!% seere $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 firosis

Poste@&osure &ro&h'la@is 8ith a! a&&ro&riate a!timicroial a%e!t ca! e a$mi!istere$ to close

co!tacts of &atie!ts a!$ to &erso!s 8ho are at hi%h ris= for hai!% seere or com&licate$

&ertussis*

ANTIBIOTICS TREAT>ENT/

AJIT3RO>HCIN/

Aithrom'ci! is a semi/s'!thetic macroli$e a!tiiotic that &ree!ts acteria from %ro8i!% '

i!terferi!% 8ith their ailit' to ma=e &rotei!s* It acts ' i!$i!% to the 7)S riosomal suu!it of

susce&tile microor%a!isms a!$0 thus0 i!terferi!% 8ith microial &rotei! s'!thesis* Nucleic aci$

s'!thesis is !ot affecte$* Due to the $iffere!ces i! the 8a' &rotei!s are ma$e i! acteria a!$ huma!s0

the macroli$e a!tiiotics $o !ot i!terfere 8ith huma!s ailit' to ma=e &rotei!s

3U>AN P3AR>ACOQINETICS/

After oral a$mi!istratio!0 this &ro$uct 8ill uic=l' e asore$ hai!% a ioaailailit' 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 loo$0 Cma@0 is )*+ to )*+7m%KL* This &ro$uct

ma' e 8i$el' $istriute$ throu%hout the huma! o$'* The co!ce!tratio! i! arious tissues ma' reach

1)1)) times of the co!ce!tratio! i! the loo$ at the same time*

A$erse Reactio!s of Aithrom'ci! is %e!erall' 8ell tolerate$* I! cli!ical trials0 most of the re&orte$

si$e effects 8ere mil$ to mo$erate i! seerit' a!$ 8ere reersile u&o! $isco!ti!uatio! of the $ru%*

-9


30/41


The most commo! si$e effects are $iarrhea or loose stools0 !ausea0 a$omi!al &ai!0 a!$

omiti!%0 each of 8hich ma' occur i! fe8er tha! o!e i! t8e!t' &erso!s 8ho receie aithrom'ci!*

Rarer si$e effects i!clu$e a!ormal lier tests0 aller%ic reactio!s0 a!$ !erous!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

a$omi!al &ai!*

Dru% I!teractio!s U!li=e er'throm'ci! a!$ clarithrom'ci!0 aithrom'ci! is %e!erall' co!si$ere$ free

of i!teractio!s 8ith most other me$ici!es* It is recomme!$e$ that aithrom'ci! !ot e ta=e! at the

same time as alumi!um/ or ma%!esium/ ase$ a!taci$s0 such as >'la!ta or >aalo@ ecause a!taci$s

8ill i!$ the aithrom'ci! a!$ &ree!t it from ei!% asore$ from the i!testi!e

CLARIT3RO>HCIN AND ERHT3RO>HCIN/

Act as same mecha!ism as aithrom'ci!0 ut Dose shoul$ e a$:uste$ for &atie!ts 8ith im&aire$ re!al

Fu!ctio! a!$ Ca! e a$mi!istere$ 8ithout re%ar$ to meals*Freue!t si$e effects are Gastroi!testi!al

$istura!ces "a$omi!al $iscomfort or &ai!0 $iarrhea0 "!ausea a!$ ;omiti!%# * 3e&atoto@icit'

3'&erse!sitiit' reactio! rash0 &ruritis0 a!$ $'s&!ea# Pseu$omemra!ous colitis Thromoc'to&e!ia

are rare*

TRI>ET3OPRI>/SULFA>ET3AOLE/

Sulfametho@aole a!$ trimetho&rim* Both $ru%s re$uce the ailit' of some acteria to utilie folic aci$

4)


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for %ro8i!%* Sulfametho@aole is a! a!ti/acterial sulfo!ami$e0 a sulfa $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 acteria a!$ huma! cells use for

&ro$uci!% &rotei!s* Trimetho&rim i!hiits &ro$uctio! of tetrah'$rofolic aci$ ' i!hiiti!% the e!'me

res&o!sile for ma=i!% tetrah'$rofolic aci$ from $ih'$rofolic aci$* B' comi!i!% oth $ru%s0 t8o

im&orta!t ste&s reuire$ i! the &ro$uctio! of acterial &rotei!s are i!terru&te$0 a!$ the comi!atio! is

more effectie tha! either $ru% alo!e*

Si$e effects of Sulfametho@aoleKtrimetho&rim are $ii!ess0 hea$ache0 lethar%'0 $iarrhea0 a!ore@ia0

!ausea0 omiti!%0 a!$ rash* Sulfametho@aoleKtrimetho&rim shoul$ e sto&&e$ at the first a&&eara!ce

of a s=i! rash efore the rash ecomes seere* Serious rashes i!clu$e Stee!s/5oh!so! s'!$rome

"achi!% :oi!ts a!$ muscles? re$!ess0 listeri!%0 a!$ &eeli!% of the s=i!#? to@ic e&i$ermal !ecrol'sis

"$ifficult' i! s8allo8i!%? &eeli!%0 re$!ess0 loose!i!%0 a!$ listeri!% of the s=i!#*

Sulfametho@aoleKtrimetho&rim thera&' also ca! cause e@te!sie su!ur!0 follo8i!% e@&osure to

su!li%ht* Patie!ts receii!% Sulfametho@aoleKtrimetho&rim shoul$ aoi$ e@cessie e@&osure to su!

li%ht "&hotose!sitiit' to $ru%s# a!$ shoul$ 8ear su!scree!*

Sulfametho@aoleKtrimetho&rim ma' form cr'stals i! the uri!e 8hich ma' $ama%e the =i$!e' a!$

cause lee$i!% i!to uri!e* It is im&orta!t to $ri!= a$$itio!al liui$s $uri!% thera&' to &ree!t these

si$e effects*

PERTUSSIS ;ACCINE/

The &ertussis acci!e is aailale as)

DTaP "Di&htheria To@oi$/Teta!us To@oi$/acellular Pertussis acci!e#

DTaP i! comi!atio! 8ith 3aemo&hilus i!flue!ae t'&e "3i# acci!e

DTaP i! comi!atio! 8ith he&atitis B a!$ i!actiate$ &olio acci!es

DTaP i! comi!atio! 8ith 3i0 he&atitis B a!$ i!actiate$ &olio acci!es

T$a& "Teta!us To@oi$ re$uce$/Di&htheria/acellular Pertussis acci!e#

41


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;ACCINE RECO>>ENDATIONS "CDC#/

2ho shoul$ receie the acci!eW

>ost i!fa!ts a!$ chil$re! 'ou!%er tha! see! 'ears of a%e shoul$ receie DTaP e%i!!i!% at

t8o mo!ths of a%e*

Chil$re! ./1) 'ears of a%e 8ho are i!com&letel' immu!ie$ a%ai!st &ertussis shoul$ receie

T$a&*

11/1< 'ear ol$s shoul$ receie a si!%le $ose of T$a& i!stea$ of a T$ ooster if the' hae

com&lete$ the recomme!$e$ chil$hoo$ DTPKDTaP immu!iatio! series a!$ hae !ot receie$

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 receie a si!%le $ose of T$a& to re&lace a si!%le $ose of T$ for ooster immu!iatio! if

their most rece!t teta!us to@oi$/co!tai!i!% acci!e 8as 1) or more 'ears earlier* T$a& ma' e

%ie! at a! i!teral 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' for

2ome! V67 'ears of a%e 8ho mi%ht ecome &re%!a!t*

2ome! 8ho hae !ot &reiousl' receie$ T$a& "i!clu$i!% those 8ho are reatfee$i!%#

shoul$ receie T$a& as soo! after irth as is feasile* >a!' e@&erts also recomme!$

that T$a& e co!si$ere$ for &re%!a!t tee!a%ers*

A$ults 8ho hae or a!tici&ate hai!% close co!tact 8ith a! i!fa!t a%e$ V1- mo!ths

shoul$ receie a si!%le $ose of T$a& a!$ triale!t i!actiate$ i!flue!a acci!e* I$eall'

the acci!es shoul$ e %ie! at least - 8ee=s efore co!tact*

3ealth/care &erso!!el 8ho hae $irect &atie!t co!tact shoul$ receie a si!%le $ose

2ho shoul$ !ot receie 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-


33/41


acci!e com&o!e!ts*

Those 8ith a histor' of e!ce&halo&ath' "e*%* coma or &rolo!%e$ seiures# !ot attriutale to a!

i$e!tifiale 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$ receie DTaP acci!e

>o$erate or serious reactio! after receii!% DTP or DTaP i! the &ast

Seiure or hae a &are!t or sili!% 8ho has ha$ a seiure

Brai! &rolem that is u!stale or %etti!% 8orse

Peo&le 8ho are mo$eratel' or seerel' ill shoul$ co!sult 8ith their &h'sicia! efore receii!%a!' acci!e*

;ACCINATION SC3EDULE/

A DTaP acci!e is %ie! to most chil$re! at t8o0 four0 a!$ si@ mo!ths of a%e* A fourth $ose of

DTaP is %ie! et8ee! 17 a!$ 1< mo!ths "1./-) mo!ths for Da&tacel#0 a!$ a fifth $ose is

%ie! at a%e four to si@ 'ears* Pe$iari@

T>

*ca! o!l' e %ie! for the first three $oses a chil$receies* If the fourth $ose 8as %ie! after a%e four 'ears0 the! !o fifth $ose is !ee$e$*

Receii!% comi!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@* 3o8eer0 si!ce %ii!%

comi!atio! acci!es mea!s fe8er shots oerall for a chil$0 healthcare &roi$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$re! 8ho hae ee! see! ' others0 ase$ o! 8hat the' hae alrea$'

ee! %ie!*

Chil$re! 'ou!%er tha! a%e see! 8ho shoul$ !ot receie the &ertussis acci!e shoul$ receie

the DT "$i&htheria/teta!us# acci!e*

Bet8ee! the a%es of see! a!$ !i!e0 T$a&8hich co!tai!s the same amou!t of teta!us

acci!e as DTaP or DT0 ut co!tai!s much less $i&htheria to@oi$ is %ie! to &rotect a%ai!st

44
http://www.immunizationinfo.org/vaccines/pertussis-whooping-cough#footnote1_wcsi4ajhttp://www.immunizationinfo.org/vaccines/pertussis-whooping-cough#footnote1_wcsi4aj


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teta!us0 $i&htheria a!$ &ertussis*

At a%e 11/1- 'ears0 a ooster shot of teta!us/$i&htheria/acellular &ertussis "T$a is !ee$e$* It

shoul$ e %ie! !o later tha! 16 'ears of a%e* Eer' 1) 'ears a!$ thereafter0 a ooster of T$ is

!ee$e$ to mai!tai! &rotectio! a%ai!st $i&htheria a!$ teta!us*

O!e ooster $ose of T$a& is recomme!$e$ for a$ults to re&lace a T$ ooster* Eer' 1) 'ears

thereafter0 a ooster of T$ is !ee$e$ to mai!tai! &rotectio! a%ai!st $i&htheria a!$ teta!us*

AD;ERSE REACTIONS/

>il$ Prolems "Commo!#

X Feer "u& to aout 1 chil$ i! +#

X Re$!ess or s8elli!% 8here the shot 8as %ie! "u& to aout 1 chil$ i! +#

X Sore!ess or te!$er!ess 8here the shot 8as %ie! "u& to aout 1 chil$ i! +#

These &rolems occur more ofte! after the +th a!$ 7th $oses of the DTaP series tha!

after earlier $oses*

Sometimes the +th or 7th $ose of DTaP acci!e is follo8e$ ' s8elli!% of the e!tire

arm or le% i! 8hich the shot 8as %ie!0 for 1 to . $a's "u& to aout 1 chil$ i! 4)#*

Other mil$ &rolems i!clu$e

X Fussi!ess "u& to aout 1 chil$ i! 4#

X Tire$!ess or &oor a&&etite "u& to aout 1 chil$ i! 1)#

X ;omiti!% "u& to aout 1 chil$ i! 7)#

X These &rolems %e!erall' occur 1 to 4 $a's after the shot*

>o$erate Prolems "U!commo!#

X Seiure ":er=i!% or stari!%# "aout 1 chil$ out of 1+0)))#

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X No!/sto& cr'i!%0 for 4 hours or more "u& to aout 1 chil$ out of 10)))#

X 3i%h feer0 1)7 $e%rees Fahre!heit or hi%her "aout 1 chil$ out of 160)))#

Seere Prolems ";er' Rare#

Serious aller%ic reactio! "less tha! 1 out of a millio! $oses# Seeral other seere &rolems hae

ee! re&orte$ after DTaP acci!e* These i!clu$e

Lo!%/term seiures0 coma0 or lo8ere$ co!scious!ess

Perma!e!t rai! $ama%e*

These are so rare it is har$ to tell if the' are cause$ ' the acci!e*

Co!trolli!% feer is es&eciall' im&orta!t for chil$re! 8ho hae ha$ seiures0 for a!' reaso!* It is alsoim&orta!t if a!other famil' memer has ha$ seiures*

Hou ca! re$uce feer a!$ &ai! ' %ii!% 'our chil$ a! as&iri!/free &ai! relieer 8he! the shot is %ie!0

a!$ for the !e@t -+ hours*

CRO2CROFT FOR>ULA/

Cro8croft et al $eelo&e$ a metho$ to estimate the %loal ur$e! of &ertussis to hel& set &riorities for

acci!atio! &ro%rams* Accor$i!% to these authors0 the &ro&ortio! of susce&tile chil$re! 8ith

i!fectio!s i! cou!tries 8ith %oo$ acci!atio! coera%e " .)(# 8as estimate$ at 1)( ' 1 'ear0 6)(

' 7 'ears0 a!$ 1))( ' 17 'ear*

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RECO>>ENDED M23O CASE DEFINATION OF PERTUSSIS/

1* Cli!ical case $efi!itio!

A case $ia%!ose$ as &ertussis ' 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&toms

Paro@'sms "i*e* fits# of cou%hi!%

I!s&irator' 8hoo&i!%

Post/tussie omiti!% "i*e* omiti!% imme$iatel' after cou%hi!%# 8ithout other a&&are!t cause

-* Criteria for laorator' co!firmatio!/

Isolatio! ofBordetella pertussis%

Detectio! of %e!omic seue!ces ' mea!s of the &ol'merase chai! reactio! "PCR# %

Positie &aire$ serolo%'

4* Sus&ect Case/

A cli!ical s'!$rome or ill!ess co!siste!t or com&atile 8ith &ertussis a!$ 8ithout other a&&are!t cause

such as

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 &roale case*X A!' cou%h associate$ 8ith a&!ea i! a! i!fa!t

X A!' acute cou%h ill!ess lasti!% . $a's 8he! there is a re&orte$ outrea= of

&ertussis i! the commu!it'*

X A!' acute cou%h ill!ess 8ith &ositie PCR results for B* &ertussis that $oes !ot

meet the cli!ical case $efi!itio!*

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;ACCINES OFB&'(%)%** %')!!-!WA CAUSE OF RESURGENCE/Is &ol'mor&hism i! &ertacti! a!$ &ertussis to@i! $rie! ' host immu!it'0 or is it the result of ra!$om

fi@atio! $ue to %e!etic $riftW The latter &ossiilit' 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!seratie* I! co!trast0

ra!$om %e!etic $rift is characterie$ ' a hi%h $e%ree of co!seratie mutatio!s i! &rotei! co$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!$uces a &rotectie immu!e res&o!se* O!e of the &ol'mor&hic resi$ues i! Pt@S1

has ee! im&licate$ i! i!$i!% to the T/cell rece&tor* Fi!all'0 the fact that the same tem&oral tre!$s i!

allele freue!cies are osere$ 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 &ossile that the &ol'mor&hic loci 8e

hae 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 &reacci!atio! era*

Althou%h the !umer of strai!s a!al'e$ from this &erio$ 8as limite$0 these $ata su%%est that the

!o!acci!e/t'&e aria!ts are !ot ale to $is&lace the acci!e/t'&e strai!s i! u!acci!ate$ &o&ulatio!s

"i*e*0 the' hae a lo8er fit!ess leel0 or re&ro$uctie rate0 i! u!acci!ate$ commu!ities#* Alter!atiel'0

the !o!acci!e/t'&e strai!s ma' hae eole$

relatiel' rece!tl'* Co!siste!t 8ith the first h'&othesis0 8e hae osere$ that !o!acci!e/t'&e strai!s

are less fit i! !aie mice tha! acci!e/t'&e strai!s** Thus acci!atio! has acte$ to shift the com&etitie

ala!ce et8ee! strai!s* A! im&orta!t uestio! to a$$ress is 8hether a$a&tatio! of the B. pertussis

&o&ulatio! has affecte$ acci!e efficac'0 i*e*0 co!triute$ to the reemer%e!ce of B. pertussis* A!imal

e@&erime!ts hae i!$icate$ that ariatio! i! &ertacti! affects acci!e efficac'* Further0 8e fou!$

acci!e t'&e &ertacti! aria!ts less freue!tl' amo!% acci!ate$ &erso!s tha! amo!% u!acci!ate$

&erso!s0 8hich 8oul$ e e@&ecte$ if the acci!e &rotects $iffere!tiall' a%ai!st strai!s 8ith $isti!ct

&ertacti! t'&es* 3o8eer0 the e@te!t to 8hich &ol'mor&hism affects acci!e efficac' is &roal'

$e&e!$e!t o! the acci!e use$* It is co!ceiale that the i!crease i! fit!ess associate$ 8ith !o!acci!e

t'&es of &ertacti! a!$ &ertussis to@i! i! acci!ate$ &o&ulatio!s is susta!tial e!ou%h to $rie

e@&a!sio! of strai!s carr'i!% these &rotei! aria!ts ut that the effect is too small to result i! a

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measurale $ro& i! acci!e efficac'* Further stu$ies are reuire$ to assess the effect of the osere$

a$a&tatio!s o! the efficac' of &ertussis acci!es* I! this &erio$0 8he! 8hole/cell acci!es are ei!%

re&lace$ ' acellular acci!es i! ma!' cou!tries0 co!ti!ue$ strai! sureilla!ce is of &aramou!t

im&orta!ce*

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

The comi!e$ >AST/>L;A &rofiles 8ere use$ to &erform clusteri!% a!al'ses of the Dutch B.

pertussisstrai!s isolate$ efore the i!tro$uctio! of the &ertussis acci!e i! 1974 a!$ isolates otai!e$

efore a!$ after the &ertussis e&i$emics i! the 199)s0 a &erio$ i! 8hich !either acci!e formulatio!

!or acci!e coera%e hae cha!%e$* The a!al'sis sho8e$ that the &rofiles from strai!s &re$ati!% the

acci!atio! era 8ere more $ierse tha! those isolate$ i! the 199)s a!$ o!l' $ista!tl' relate$ to the

rece!t strai!s* Furthermore0 there 8as a stro!% $ecrease i! $iersit' i! the %e!ot'&es of the B.

pertussisstrai!s $uri!% a!$ after the e&i$emics i! the 199)s0 su%%esti!% that these e&i$emics 8ere

cause$ ' a limite$ !umer of strai!s "clo!al e@&a!sio!#* The $iffere!t $'!amics of >L;A a!$ >AST

$iersit' tre!$s ma' e $ue to the fact that ;NTRs eole more ra&i$l' tha! irule!ce %e!es*

Co!siste!t 8ith this assum&tio!0 si!%le/locus aria!ts of the most rece!t &re$omi!a!t comi!e$

">L;A/>AST# %e!ot'&e 8ere almost com&letel' $ue to cha!%es i! the ;NTR loci* Thus0 ;NTR

a!al'ses ma' e es&eciall' suitale to $etect short/term cha!%es i! &atho%e! &o&ulatio!s*

>L;A mar=ers ma' !ot reeal causal relatio!shi&s ut ca! e hel&ful to si%!al clo!al e@&a!sio!s a!$

thus isualie the s&rea$ of a su%rou& of the B. pertussis&o&ulatio! 8ith i!crease$ fit!ess0 e*%*0

ecauseB. pertussisis ale to esca&e host immu!it'* Preious stu$ies sho8e$ that a!tio$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 theprn%e!e is cause$ ' ariatio! i! the !umer

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!$ &ossile acci!e esca&e* As irtuall'

allBordetella;NTRs are locate$ i! o&e! rea$i!% frames e!co$i!% &ossil' surface/e@&ose$ &rotei!s0

this su%%ests that ariatio! i! the ;NTRs ma' e relate$ to a!ti%e!ic ariatio!*

I! iolo%'0 mi!imum s&a!!i!% trees ca! easil' e a&&lie$ to multistate $ata such as >L;A0 >AST0 or

>LST &rofiles* I! the trees0 the &re$omi!a!t t'&es ca! e co!si$ere$ the most li=el' a!cestors0 8ith

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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$ ecause B. pertussis is

e@tremel' homo%e!eous0 ho8eer0 the Pt@ &romoter sho8e$ a relatiel' hi%h $e%ree of &ol'mor&hism0

su%%esti!% that fi!e tu!i!% of Pt@ &ro$uctio! has a$a&tie alue* Gloall'0pt#1 a!$pt#3 8ere the

most &reale!t pt# alleles*The re&laceme!t of pt#1 strai!s ' pt#3 strai!s i! rece!t times is a

%loal &he!ome!o! ecause it has ee! osere$ i! 11 cou!tries re&rese!ti!% + co!ti!e!ts? Asia0

Euro&e0 a!$ North a!$ South America* The %loal re%ulator of irule!ce %e!e e@&ressio! i! B.

pertussis.h'&othesie that the pt#3 allele co!fers i!crease$ i!$i!% of B%A com&are$ 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 &ositie

selectio!* Seco!$0 the i!crease$ Pt@ &ro$uctio! osere$ ' pt#3 strai!s &roi$es a ratio!ale for its

emer%e!ce*

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$ose acellular &ertussis acci!es for use i! a$ults0 ma' hae also le$ to a! i!crease i! cli!icia!

a8are!ess a!$ re&orti!%* 3o8eer0 i! ma!' $eelo&i!% a!$ some $eelo&e$ cou!tries0 i$e!tificatio!

of &ertussis is still limite$ ' &atie!t a!$ &h'sicia! a8are!ess a!$ the limite$ se!sitiit' of $ia%!ostic

tests* I! i!fa!ts0 i!crease$ rates of &ertussis ma' e relate$ to oth cha!%es i! acci!atio! strate%ies

a!$ i!fectio! sources as 8ell as the aailailit' of PCR as a $ia%!ostic tool*

resurgence of bordetella pertussis

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