pathogenesis of tuberculosis by charles nice

8/13/2019 Pathogenesis of Tuberculosis by Charles Nice

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V ol X V II T H E P A T H O G E N E S IS O F T U B E R C U L O S I S 55 1

siv e d isea se , m ore o r le ss lim ited to an organ sy stem , and Is usua llyused In conn ec tion w ith lung d isease .

Po rta ls o f E n tr y-3In cou n tr ies w he re pasteu riza tion of m ilk Is ex tensive ly p rac -

ticed the po rta l o f en try is v ia th e resp ira to ry trac t in w ell o ve r90 p er cen t o f the cases. O ccasion ally the re is in fec tion v ia theo ra l cav ity w ith a p rim ary focu s in the ton sil o r in th e g as tro -in te stina l trac t. T he sk in has b een m en tioned as a porta l o f en tryin r itua l c ircum cis ion and ra rely at o the r sites o f traum a. T rans-m issio n th ro ugh the p lacen ta is ra re, b u t is rep o rted . O ne po rta lo f en try , fo r exam p le th e ton sil, m ay no t p rec lude a la te r p o rtalo f en try in an o the r tissu e su ch as th e lun g .

M odes o f S pread 2T ub ercu lou s in fec tion m ay be p ro paga ted by con tig uou s sp read ,

v ia ly m ph atic s o r b loo d stream , b y ly m ph -hem a to genou s sp read(e .g ., th o rac ic duc t to le ft sub c lav ian ve in ) , th roug h the b ron ch ialtree (b roncho gen ic sp read ) , o r b y in tracana licu la r sp read (e .g .,b ronch i to trachea to la rynx to gastro in te stina l trac t) .

Bas ic Pa ttern o f T ub ercu lous In fec tionT he ind iv idu al is u naw are o f th e en tran ce o f tube rcle b acilli

In to the bod y fo r som e tim e: T he prim ary focu s of In fec tion inthe lungs m ay b e located in any lo be , usua lly subp leu ra lly . A fteran in cu ba tion pe rio d o f th ree to eig h t w eeks (ave rage fou r to s ixw eeks) , th e tu be rcu lin reac tio n can be elic ited an d th e p rim aryfocu s o r p rim ary co m plex m ay o r m ay no t be v isib le upo n x -rayexam ina tion . L ev ine4 fou nd 16 ch ild ren w ho had le sion s dem on -strab le b y roen tg en ogram befo re the deve lopm en t o f tube rcu linreac tion . H ow eve r , In m o st ca se s th e reve rse m ay be true . U sua llythe ro en tgen sig ns, w hen pre sen t, m ay b e d em ons tra ted w ith in1 0 to 1 6 w eeks a fte r in fec tio n occurs . Indeed , the tub ercu lin reac-tion m ay be the o n ly in d icatio n o f in fec tion , o r th e p eriod ofin itia l in vasion m ay b e acco m pan ied b y sym p tom s and sig ns. T heseinc lu de feve r, m a la ise , ano rex ia , w e igh t lo ss , cou gh , w h eez ing ,inc rea sed e ry th rocy te sed im en ta tion ra te , n eu trop h ilic leuk ocy to sisfo llow ed b y m on ocy tosis o r lym p hocy to sis , p h lyc tenu la r co n j un c-tiv itis and e ry them a n odo sum . T he la st-m en tioned is qu ite com m onin th e S cand inav ian coun trie s , b u t is u ncom m on In the U n itedS ta te s . T he subseq uen t cou rse o f even ts m ay b e m o dif ied by fac-to rs o f ind Iv idua l res is tan ce , ag e, sex , race , soc lo -eco nom ic fac to rs ,etc.2 T he p e riod o f In itia l Invasio n is especia lly dang erou s In theages of b irth to th ree years and from 15 to 35 years , w h ich W all-g ren d es igna te s a s the firs t an d second dang er pe rio ds.1 I t Is lik e-

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55 2 C H A R L E S M . N I C E JR . M a y 1 9 5 0w ise dang erou s in th e N egro and in som e soc ia l g rou ps, and seem sto be in flu en ced b y geograph ic va riatio ns (e .g ., le ss dang erou sin M inneso ta than in the S cand inav ian cou n tr ies) .D urin g th e stage o f In itial inv as ion th ere is usua lly a firs th em a togeno us sp read . B y th is Is m ean t tha t in m os t ca se s tub erc leb acilli a re d iss em ina ted th roug hou t the b ody b y the b lo od stream ,p ro bab ly be fo re6 th e tu be rcu lin reac tion is in ev idence . S ubseq uen tle sio ns ten d to be lo ca lized by th e K o ch p heno m enon w hen a lle rg yd eve lops. H o w eve r , g en era lized h em a togeno us m ilia ry tub ercu losiso r m en ing itis m ay resu lt a t th is tim e , o r the foc i m ay tend to healo n ly to reac tiva te at a late r da te.

A fte r fo u r to six m on ths (b u t som e tim es lo nge r) the in itia lcom p lex ten ds to stab iliz e , an d to hea l b y fib ro sis , ca lcif icatio nand /o r re so lu tion .7 T h e pa tien t m ay thu s h ave co m ple ted thetriad d ep icted In figu re 1 , an d ye t fu lly 75 pe r cen t m ay no t showev idence of d is ea se o n the roen tgeno gram . O n th e o the r hand ,the p rim ary le sio n m ay p ro ceed d irec tly o r a f ter a v ariab le la ten tp eriod to a m ore adv anced d isease p ro cess,8 o r even to a w as tingp h th lsis ,9 w ith ex tensive Inv o lvem en t o f the con tiguo us pu lm on arytissue (figu re 2 ) . A lso , a non -caseatin g or se ro us pn eu m on ia m aydeve lop in th e su rrou nd in g a rea , and b ro nch ia l com pres sion o rinv asio n m ay lead to obstruc tive em p hysem a, {1 76} in clu d ing fo rm a-tion o f cyst- like b lebs o r bu llae , an d a te lecta sis . T h ese la tte r con -d ition s w ere p rev io usly d es igna ted as ep itube rcu losis to design atetha t th e en tire roen tg en ograph ic p ic tu re d id no t co nsis t o f ca seouso r tu be rcu lo us in f lam m ato ry tis sue , an d cou ld re so lv e in a fewm o nths, leav in g at tim es o n ly a sm a ll fib ro us o r calc if ic n odu leas ev id en ce o f d isea se . T h is a telec tas is m ay resu lt in b ro nch iec tas isIn a h ig h pe rcen tage of cases , ho w eve r , if it do esn t reso lve w ith in9 to 1 2 m o nths .1 1

S ince the p rim ary le sion is usua lly loca ted subp leu ra lly , on ly

F i rs fHe ma lo g e n o u sD is s e m in a t io n

In v o lv e me n tF o c u s - 0 eq ionaym p h N o d e s

F IG U R E 1 : Basic Pat te rn o f I nf e ct io n .



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V o l X V I I T H E P A T H O G E N E S IS O F T U B E R C U L O S I S 55 3

F IG U R E 2: W h at H ap pens to th e Prim ary F ocus?

m in im al ex tension is req u ired to reach the p leu ra l su rface , andp neum o thorax or p leu ral effu sion m ay resu lt.

I f th e p rim ary le sio n appea rs to be co n tro lled , an end ogen ousex ace rb a tion or exo geno us re in fec tion m ay lead to b ro nchog en icd issem in atio n of d isea se. T h is qu ite co m m o nly resu lts in the sub -c lav icu la r m in im al in filtra te , sin g le o r m ultip le tu be rcu lom a ta(roun d fo ci) o r m ilia ry endo bronch ia l m e tas tases. A p ico -caud adex ten sion m ay then prod uce m o dera te ly advan ced o r even fa rad vanced le sio ns. A t an y tim e du rin g th is p rog re ssion the bacillim ay en te r th e b lood stream fo r a second a ry hem a togeno us d is -sem in atio n , o r a sm a ll focus o f d is ea se in so m e o th e r o rgan m ayreactiv ate , p rog re ss and inv ad e the b lo od stream .

S upe rin fec tion , occu rr ing in th e p re sence o f u nhea led le sio ns,m ay be a fac to r , bu t th is s till aw a its de fin ite p roo f. It is inc lud edon ly fo r co m ple teness.

T h u s , ph th is is o r w asting of the lun g tissue m ay resu lt f ro mth e progre ssion o f the p rim ary le sion , endo genou s exacerba tion ,ex ogenous re in fec tio n , o r from any one of the th ree p lus th epossib le sup erin fectio n , if th e b alan ce o f bac illa ry v iru len ce an dhos t res is tan ce is d istu rbed . T h is p ro g re ss iv e d isea se m ay o ccurin o rgans or sys tem s o ther than the lu ngs . A t any s tage o f d iseasein an y o rgan a le sion m ay progre ss to p ro duce loca l p h th ls is o rto in vade th e b loo d stream .

W hat H app en s to In vo lved R eg iona l N odes? figure 3W e hav e alread y d iscussed the va riou s con sequences o f the

p rim ary focus . T he nod al le sion s m ay likew ise hea l o r p roceed to



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Invo lvedR e g io n a lN o d e s

55 4 C H A R L E S M . N IC E , JR . M a y 1 9 5 0

F I G U R E 3 : W ha t H ap pens to Inv o lved R eg iona l N o des?

casea tion . T h e caseou s no de m ay p erfo ra te a b ro nchu s,2 lead ingto p ositive sp u tum , and the bacilli m ay tak e the in tracana licu la rrou te to th e la ryn x and gastro - in tes tin al trac t. B ronch ia l com -p ressio n or in vasion leads to m an ifes tatio ns o f ob stru ctiv e em -ph ysem a or a telec tas is . D ischa rge o f a la rge caseou s m ass m ayresu lt in a com p lete b lockag e o f the r im a g lo ttis w ith su ddend ea th . T he caseou s nod e m ay p erfo ra te th e tho rac ic du ct and thebac illi a re th en co ndu cted to the sub clav ian ve in to in itiate ahem a tog enou s d iss em ina tion . R up tu re o f caseo us m ate r ial in to thep ericard lu m m ay cause tu be rcu lo us p e rica rd itis . C alc if ied h ila rno des m ay produ ce broncho stenos is ,3 lead ing to fu tu re d iff icu ltiessuch as recu rren t p neum o nia s an d ate lecta sis , w h ich m ay in tu rnlead to b ro nch iec tasis .

W ha t H appens to th e P rogress ive P rim ary L esion ?In fig u re 4 th e p ro gre ss ive p rim ary les ion and its sub sequen t

p ossib ilities a re sh ow n . B rie f ly , it m ay hea l, sp read th roug h thesu rro und ing tissu e, inv o lve th e b ron ch ial tree , o r invade the b loods t r eam .

W ha t H app ens to th e F irst H em a togeno us S pread ? figu re 5A tran sien t b ac illu r ia m ay be th e o n ly d em on strab le ev idence

o f the firs t h em ato genou s sp read . T h is m ay occur in the absen ceof any o the r u rina ry fin d ing s, and som e even be lieve tha t thetub erc le b ac illi go th ro ugh the in tac t g lom eru lu s. T h is is d ifficu ltto p rove . H em a tog en ous m illary tub e rcu los is o r m en in g itis m ay



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F IG U R E 4: C onsequences of F irs t H em atog en ous D issem ina tion .

Tubercu loma Paraverfebro f bra in abscess

I ITubercu lous P leu ra lmening ihs L fus Ion

V o l X V I I T H E P A T H O G E N E S IS O F T U B E R C U L O S I S 55 5

,

o ccur . M ore o ften the d is sem ina ted fo ci rem a in q u ie scen t, bu tm ay reactiv a te a fte r a pe riod of a few m onth s o r yea rs , g iv Ingrise to p rog re ssive o rgan d isease and a t tim es to a secon da ry he -m a tog en ou s sp read . T hu s, a ch est roen tgeno gram m ay rev ea l anactiv e le sio n , an app a ren tly healed le sion , o r no th ing a t a ll, w h ilea p rog re ssiv e tu be rcu lo us le sion is p resen t in the ske le tal systemo r k id ney .

B one tub e rcu los is freq uen tly sta rts in th e m e taph ysis , le ss fre -

Progress iveP r ima ry

Les ion

F IG U R E 5 : W hat H app ens to P rogres sive P r im ary L es ion s?



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55 6 C H A R L E S M N I C E J R M a y 1 9 5 0qu en tly in the ep iphy sis . T h e les ions m ay p en etra te the jo in ts ,s low ly d es tro y ing th e cartilag e .4 P on ce ts rheum atism is an a lle r-g ic type of jo in t sw e lling w h ich m ay d isappea r in tw o to th reew eek s, an d does no t Ind ica te th e p re sence of tub erc le bac illi in thejo in t sp ace . R a rely , cy st-lik e le sion s ap pea r in the d iap hyses o fthe lo ng bon es and the pha lang es (sp ina v en tosa ), s im u la tingle s ions seen in sa rco ld an d co cc ido idom ycosis . T ube rcu losis o f th esp in e is the m o st frequen t type o f bon e tub ercu losis ; th is m aylead to th e fo rm a tion of pa rave rteb ra l abscess , and th us be re -spo nsib le fo r the d ev elo pm en t o f m en ing itis o r p leu ral e ffusio n .

In the b rain so lita ry o r m ultip le tub ercu lom ata m ay fo rm . L a rgea reas o f inv o lvem en t in the m id -b rain m ay lead to ven tricu la rb lock , and cortica l le sio ns m ay rup tu re in to th e su ba rachno idsp ace2 to p rod uce m en ing itis . M en ing itis m ay be bacilla ry (w ithd em ons trab le b ac illi) o r se rous (w itho u t dem o nstrab le bacilli) .

In the live r, sp leen and k id neys sing le o r m ultip le foc i m ay eith erh ea l and ca lc ify o r fo rm p ro gres sive lesio ns. R ena l tu be rcu lo sis5sp reads Inw ard from the cortex to th e ren al p elv is and thenceby in tracana licu la r sp read d ow n w ard . T ubercu lous sa lp ing ltis m aysp read to Invo lve the o va rie s o r u te ru s. L es ions o f th e uv eal trac tan d cho ro id o f th e eye m ay be no ted in som e cases. Inv o lvem en to f the ad rena ls m ay prod uce A dd ison s d isea se, and the rare p an-c rea tic tube rcu losis m ay lead to sign s o f pan creatic in su ffic iencyand sk in p igm en tatio n .

P at ho genesis o f P h th is iogen ic In filtra te sF rom the preced in g d iscussio n and in figu re 6 it is seen tha t a

w asting ph th isis m ay occu r in an y org an in w h ich any tu be rcu lo usle sion m ay prog re ss b y sp read ing th ro ugh th e con tig uou s tissue .T h us, th is po ssib ility m us t b e kep t in m in d from the tim e of th eappea rance o f th e p rim ary focus un til th e death o f the p a tien t.T h is w ou ld seem to Ind ica te tha t the th erapy of the pa tien t sho u ldd ep en d u pon the pa tho log ica l p rocess p re sen t, and no t b e lim itedby th e design atio n of a lesio n as p rim ary o r o the r fo rm of tub er-cu losis .

Th e S econ dary H em ato geno us Sprea dT he seco nda ry h em ato genou s sp read is a te rm used in th is pape r

to ind ica te an y hem a to genou s d issem in atio n o f d isea se th at occu rsa fte r the f irs t hem a to genou s sp read . I t m ay occu r in pa tien ts w hohave a p ro gress ive p rim ary le sion in the lun g as w e ll a s in thosew ho h av e les ions tha t have sp read to o the r pa rts o f the lu ngs .It m ay b e In itia ted in an area o f in fec tion th at has been prev ious lyestab lished by th e firs t h em ato geno us d issem in atio n . A t po st-m ortem o ne m ay find a hem a tog en ou s m lllary tube rcu losis o r



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V ol xv i i T H E P A T H O G E N E S IS O F T U B E R C U L O S IS 55 7

tub ercu lou s m en in g itis an d a fte r th o ro ugh search find on ly asm all caseo us p rocess in bon e, k idney , p ro sta te, e tc ., th a t hasp rod uced the o ve rw he lm in g in fectio n by in vad ing the b loo d stream .A ny un healed lesion in any organ m ay progre ss and inv ad e theb lo od stream .

E ffec t o f N on-Spec ific D isease sIn ch ild ren in ciden ta l d isease su ch as non -tu bercu lous pneu -

m on ia , upper resp irato ry in fec tions , e tc ., m ay resu lt in v isib lep ro g re ss io n of d is ea se . In ad u lts , on th e o th er hand , the spu tu mm ay tem po ra rily tu rn p ositive , bu t dem o nstrab le p rog re ssio n orex tens ion of d isea se is le ss lik ely to o ccu r. N ec ro tizin g pneu m on iais m ost po ten t in ac tiva tin g tubercu lo us les io ns.6 Sa tisfac to ryco llapse u sua lly p reven ts sp read .

T he presen ce of inc iden ta l in fec tio ns m ay a lso lead to th e fa lseco nc lusio n tha t tub ercu lou s d isease has p rog re ssed . C e rtain ly inread ing ch est roen tgeno gram s, the po ssib ility o f v ira l an d non -tu bercu lous bacte ria l pn eu m onias, L oeffle rs eo sinop h ilic in filtra-t ion , lip iod al reac tions af te r b ron ch ogram s an d p leu ra l e ffusio nssuch as o ccu r in d issem ina ted lu pus ery them atos is m u st be kep tin m ind .

Th e N ega tive T u bercu linF a ilu re to reac t to tu be rcu lin m ay s ig n ify th at the ind iv idua l

has neve r susta ined tu be rcu lo us infection or is in the p rea lle rg icincub atio n p eriod . A sm a ll p ercen tag e o f pa tien ts hea l the ir in fec -

P ro g re ss ive p rim a ry I In vo lve d re g io n a l n o d e sE nd o 9 e n o u s e x a ce r- Lbaf ion

E x o g e no u s re in fe c tio n B ron ch ia l inv as io n- i-I l 1

C o n tiq u o u s sp re a dfh ro u g h issu e

JrPhthis is

T u b e rcu lo u sP n e u m o n i a

F IG U R E 6: Pa th ogenesis o f P h th isis .



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V ol X V II T H E P A T H O G E N E S IS O F T U B E R C U L O S IS 559

C e llu la r trans fe r o f tube rcu lin sensitiv ity ha s a lso been reported .7A ltho ugh a llergy and im m un ity appea r to b e du e to sepa rate fac -to rs2 they usu ally co -ex ist to so m e deg ree . S om e say tha t alle rgyis dang erous , w h ile o the rs c laim tha t th e p ro tectiv e im m un itytha t co -ex is ts w ith th e a lle rg y m o re th an offse ts th is dange r .M any stud ies d iscussin g th is p ro b lem have b een in ad eq ua te lycon tro lled , bu t it is hop ed tha t In a few yea rs m o re scien tif icconc lusio ns m ay be draw n . R ega rd le ss o f the resu lts , o th er triedand p ro ved m e tho ds o f co n tro l m us t no t b e n eg lected . F u rth erd is cu ssion of th is p rob lem is beyon d th e scope of th is p ap e r.

Discus s i onT he stu dy of tube rcu losis ha s m an y In tere sting face ts . T he d iag -

n osis a lone is o ften d iff icu lt to e stab lish , an d G arlan d8 lis ts 89con d ition s tha t h av e caused co nfu sion in chest roen tg en ogram sa lon e. B eyon d th is each case p oses an ind iv idu al p ro b lem of m an-agem en t, and pub lic h ea lth con tro l aspects fo rm groun ds fo rend less d is cu ssion . M any ph ysic ians f ind them se lves lost in thecon trov e rsia l op in ions ex pre ssed in th e litera tu re. H o w eve r , I tseem s log ica l tha t the adop tion of u n ifo rm term in o log y and thereco gn itio n of a un ified co ncep tion o f the deve lop m en t o f tub er-cu lo us le sio ns as dep icted in figu re 7 m ay fo rm a b asis o f th oug h tto aid one in th e stud y o f tub ercu los is in its va rious aspec ts.

S U M M A R Y A N D C O N C L U S I O N ST he b asic pa tte rn o f tu be rcu lo us in fectio n has been d iscus sed .

V arious theo rie s o f the m echan ism s invo lved have been purpo se lyo m itted in m an y instances, and ind eed , m any a re unso lved . It ishop ed tha t fu r the r re search an d c lin ica l o bse rv atio ns w ill se rveto c la rify fu rth er the ev o lu tio n of th is d isease. A lthou gh w e m ayn o t be ab le to sta te do gm a tically th at a g iven les ion is a p rog re ssiv ep rim ary le sion or is th e resu lt o f en dog en ous ex ace rb atio n orexo geno us rein fec tion , a u n ified co ncep t o f the pa thog en es is o ftu be rcu lo sis w ill a id in the in te rp reta tion and m anagem en t o feach in d iv id ua l case.

R E S U M E N Y C O N C L U S IO N E SL as fo rm as b {2 25} sicas de la in fecciO n tube rcu losa se d iscu ten .

V arias teo ria s de los m ecan ism os qu e se pon en en juego se h anom itid o in tenc lona lm en te y desde lu eg o m ucho s m ecan ism o s noes t {2 26} n ac la rado s. S e espe ra q ue es tud io s u lter io res y la ob servac lO nclln ica serv ir { 225 }n pa ra ac la ra r la evo lu ciO n de la en ferm edad .

A un que estam os incapac itad os pa ra asen ta r do gm a ticam en tesi un a les iO n es p rim aria p rog res iva o es resu ltad o de una in fec-c O n ex O g en a, u na un ificaciO n de l co ncep to pa tog en ico d e la tu be r-



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56 0 C H A R L E S M N IC E JR M a y 1 950cu lo sis ay uda ra pa ra In te rp re taciO n y e l tratam ien to de cada casoind iv idual .

T h e au tho r w ishes to exp re ss g ra titud e to D r. A llan H u rst an d sta ff o fth e N a tion al Jew ish H osp ita l, D env er , C o lo rad o , fo r th e op portun ity o fstu dy in g case m a te ria l, and to D r. Jay Arthur M y ers o f the U n ive rsity o fM inn eso ta fo r he lp fu l g u idance in the p repa ratio n o f th is p ap er .

R E F E R E N C E S1 M ille r, J. A . and W alig ren , A .: P u lm o na ry T ube rcu losis in A du lts and

C hild ren , N e lson Loose -L ea f M ed icin e , T h om as N elson and So ns, N ewY o r k .2 R ich , A . R .: T h e P a thog en esis o f T u be rcu lo sis , Cha rles C . T hom as ,S pring fie ld , Illino Is , 19 44 .3 C affey , J. : P ed iatr ic X -ray D iagn osis , Y ear B ook P ub lishers , 1 9 4 5 ,C hicago , Illino is .4 L evIne , M . I.: S equence of R oen tgen E v idence o f T u be rcu lo sis andC utaneo us S en sitiv ity to T ube rcu lin , Am . J . D is . C h ild ., 58 :799 , 19 39 .5 L inco ln , D . M .: H em atog en ous T ube rcu losis in C h ild ren , A m . J . D is .Chi ld. , 50 :84 , 193 5 .6 O rnste ln , G eorge G .: H em ato geno us D issem ina tion o f T ube rcle B a-cilli in P rim ary an d R e in fectio n F orm s of T ub ercu losis , Sea V iewH osp . Q uart., 6 :343 , 1 94 1 .7 S w eany , H . C .: S tud ie s on th e N a tu re o f P rim ary T ub ercu lou s In fec-tion, Am . Rev . Tu berc ., 2 7 :55 9 , 193 3 .8 A uerb ach , 0 .: T he P rogre ssive P rim ary C o m plex , A m . R ev . T ub erc .,37 :3 46 , 193 8 .9 C hris tlan sen , N .: O n the D iffe ren t F orm s of P h th is iogeno us In fil-tra te s and th e D eve lopm en t o f P h th isis , A cta R ad ., V ol. 30 , F asc. 1 -2 ,17 -3 5 , 19 48 .

10 Ju llen -M arie , G . S . e t M a they , R .: L E m phy sem e B ulleux P seudo -cav ita ire au cou rs de la P rim o-In fec tion T ube rcu leuse de L E n fan t,Rev . de la Tu b ., T om e 1 2 , N o . 5 -6 , 331 , 19 48 .11 Jones, E d na M ., R a ffer ty , T . N . an d W illis , H . S .: P rim ary T u be rcu -losis , C o m plica ted b y B ronch ia l T ube rcu losis w ith A telec ta sis (E p i-tubercu losis) , A m . Rev. T u berc., 46 :392 , 1 942 .12 G o rg en y l-G o ttch e, 0 . an d K asay , D .: Im po rtance o f B ro nch ia l R up -tu re in T ub ercu los is o f E nd o tho rac ic L ym p h N od es, Am . J . D is C h ild .,74 :1 66 , 1 947 .13 H ead , J . and M oen , C . W .: L a te N o n-T u be rcu lo us C om p licatio ns o fC alc if ied H ilu s L y m ph N od es, Am . Rev . T u berc ., 60 :1 , 1 949 .14 M ann , K . J .: L u n g L esions in S k ele ta l T ub e rcu lo sis , Lance t , 2 :744 ,1946 .15 U stv ed t, H . J . and W erge lan d , H .: In vestiga tion s on the P a thog en es iso f R ena l T u be rcu lo sis , A c ta Tbs ., V ol. X X III , F asc . I , 3 6 -6 2 , 19 49 .16 B a u m , 0 . S . and B a um , L . M .: T he E ffec t o f N o n-T ub ercu lou s P u l-m on ary In flam m ation o n P u lm ona ry T ube rcu losis , A m . R ev . T ubere .,59 :6 8 , 194 9 .17 E d ito ria l: C ellu lar T ransfer o f T u be rcu lin S ensitiv ity , J .A .M.A . , 141 :130 1 , 194 9 .18 G arland , L . H .: C ond itions to b e D iffe ren tiated in th e R oen tg enD iagn osis o f P u lm ona ry T u be rcu lo sis , A nn . m t. M ed ., 29 :878 , 19 48 .

pathogenesis of tuberculosis by charles nice

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