Current status of prophylaxis against rheumatic fever

o f t t ol~hvLtx~s A ~ a i n s l

Rheumatic

Fever

By A LvaN II, F~;axs'r~.:p~ PI'~EVENT|ON of rheumatic fc cl by d1~t • ~m~cro : " I~m[ ~* a g ~ t s re ~resents ew concept in both ¢,ardioh~#c a ~ d '~ubliel health technics. In cardiology, the redtietim~ of rheumatic attacks by an ti_~trepa.mocc~d tlmrapy is the orfly km~ ~ n medical measure which c-an eonsfstently preveHt a majm" [m'm of heart thscase, in public health, where large-scale attempts to centre! dL(..a.~;t, have ti'aditionaliy ~sed sanitations, isolation, immm~izatim~ or ~aecmatmn, tim attack against rheumatic fever is unique because it ~lses antimierobial agel~ts and beeause it dcn2s so in two differer~t ways: for finite|y long therapeutic courses h~ some patient~ and for mde~mte~x king prophylactic eom'ses in ethers. The measm,es used to prevent rheumatic fi2ver have d e v e t o ~ M a.~ a result of severa|, kmc s of ¢ a t a , (1) An infeeU'on with C r o u p A beta hemolytic streptococci is associated, probably as a trigger agent, with virtually every attack of rheumatic D','er3 (2) Since or, ly 3-5 per cent of these inDetions are followed by rhemnafie fever, -~ its occurrence implies a particular susceptibili~,, in the ho:~t. This susceptibility a l s o m a k e s the I~atient' liah/e to recurrent d-mumatic attacks x h~m streptococcal infcetifms ,recur, (3) "XVhen the infection is identified and a d e q u a t e l y ~eated, even suse ~ t i t ) l e pa~ents will usually avoid rheumatic fever, a,~ M a n y streptococcal iu* feetions are never identiged, however, because tufty about half o f these infections I~rad,ucx~ s~mptoms. "• "~-a ,~ T h e asymptomatic infectim~s will escape recognition m~d will not b e treated |~;eause the patmnt " : does not seek medieal attentlm~. In thN w a y rheumatic fever can d m M o p without any previous clinical wanamg, (4) F o r these reasons, the prevention of first attacks of rheumatic fever eammt b e e~tirelv, s.ueecssfuL" T h e rhemnatie attack rate can be r e d u c e d -~4 by Woviding effective treatment for those s~reptoeoeeal infections which can be ide~tified titanically or bacteriologically. To find the asymptomatie nfee|~ons wm~|d reqnire screening and examiaation teehnies whid~ are not et~rre~atly praetimd or established on a mass scale. ( o ) T h e prevention of recurrent attacks of heum,itm fever can be aeeom|~lished, with much greater sueeessd T h e o e e u ~ e n e e of a primary attack indicates the suseeI~tibilitv, of the subject, whose future ..streI~toe~meal inhre1<.~m~ l~Vh~g&m Ibm.co, t~ciugtm,-on-lhulson. N. T. ami the l~#p,~tamemt of MediNne, Nr.~e "£~n,k Unie,er~tfl College ~f Medicq~e', New York. N. 3"~ Some of the mafo~" data di.~~s'~ed here ~vete obtaim,d thr~tgh the treington ltou.~. Rheumatic Freer Prophylaxi.s Nea,a~tcl~ Clinic, *ehfch l~a,~ b~,~ .sell~/~m~ct/ ill ~tlrl t~tl gh.mt.~" # 0 ~ the" t;*ffled States Public lhraltl~ S~:~-t:ic~ A~erican Ih:art Asso~:iath~l, Neon York ltearl A~s'ociatio~. ~VeMdag,~le~ tl~.~a~ Aesoc~llt~t~, StsHt~:¢m Cm~t~t~ lteatt Chapter, Wyeth Imbora~o~cs and Parke~ Dat~is & Cornicing.

204

CUIIRI{NT

S'I'A'~:~S O F

l,,'lit)l~lr,d I ~ X I S

~ A l l A I N S T t~111~[: ", INI.~'.,'It(.-" FI~;VEtl "

0,~0;5

tions a r e e i t h e r p r e v e n t e d , b y alitimlerobhd, propl~ytaxis or inler~sivetv treated w h e n t h e y appear. Continuous~ ai~tistreptoeoeeat prophyl~.txis has t r e a t e d a consistent a n d d r a n l a t i e federation in the veem'ren(~x r a t e of r h e u m a t i c f e v e r , e-~= Many. of t h e existing t¢<:hnies a m ; p r o b l e m s ir~ tl)e antil~h~tie a l { p m a e h to r l m u m a t i e f e v e r preventio~ wilt L'~ altme¢ . . . . . t whm~ a~d if a N.,.I .{ .e l I"I e f~'a I I b e ¢ .v .loped t~ p r o t e c t a g a i n s t .~trei~t{moeei. a n d the//eompticatim~s. T h e m'eation ~af s u c h a v a e e h m. does n,}t a p p e a r likely in t h e f o r e s e e a b l e t:~|tn~e. "- Until snel~ t i m e the provocation of r l u m m a t i c fever" will rest upon fl~e eradication of streptococcal infections in all p a t i e n t s m~d the use of antistreptococeal prophylaxis in r h e u m a t i c patients. T h e s e concepts h a v e n o w b e c o m e s t a n d a r d m e d i c a l p r a t t l e . T h e b a c k g r m m d d a t a / o r t h e m h a v e b e e n thorougbIy e o n l l r m e d a n d the wtrious m e t h o d s reeommm~ded b y the A m e r i c a n I t e a r t Association ~ h a v e b e e n w i d e l y d i s s e m i n a t e d a n d so welt a c c e p t e d that there ~mw exisls n o question r e g a r d i n g desirability of r h e u m a t t e fever p r e v e n t i o n b y m~thnierobial agents. T h e q u e s t i o n s w h i c h rcrnai~ to b e a n s w e r e d deal w i t h the choice o f m e t h o d s for the identification a n d control of streptococcal infections a n d w i t h the selection, usage, effeeti~'cncss, c o m p l i c a t i o n s a n d long-term results of p r o p h y l a c t i c agents. Tt~e p r e s e n t r e v i e w will a n a l y z e s o m e of these q n e s t i o n s in the light of c u r r e n t d a t a a n d investigations. T h e g e n e r a l b a ~ ; g r o u o d m a t e r i a l anti o l d e r literature i n r h e n m a t i e fever h a v e l)een t h o r o u g h l y c~vered h~ several excellent recent p u b l i e a t i o n s , u'~a ][DGNTIFICA'rlON

OF ~TltEIYI'fK:O(;<:AL IN|~NC'FtONN

Clinical F e a t u r e s

i n order for a streptococcal infection to b e recognized, tile pafiel~t m u s t c o m e to m e d i c a l attention. T h i s t a n occur e i t h e r if ~t|m patient deveh)ps c l i ~ i c a | s)~nptoms or i f h e is p a r t of a p r o g r a m w M e h p e r i o n n s routi1~e p e r i o d i e e x a m i n a t i o n s of the throat. T h e d { n i e a l sympt~:ms whiM~ nmst sugg!est slreptocoeeal pha~Tngitls are sore throat, d y s p h a g i a , h e a d a d m a n d ~ v c r . ( I n children, abdorninM lxain aitd n a u s e a m a y be ~:onco|nitant.) T h e m{~st f r e q u e n t signs a r e t~.efy-red threat, e x u d a t e a n d cervia~l b , m p h a d m m p a t h y . ( Less comm o n sigas are t h e raMl of scarlet fever a n d c h i l d r e n ' s a c u t e otitis m e d i a a n d emote sillt~sitis.) T h e single s y m p t o m of sore throat is m o r e often d u e to nonstrcptoex~eeaI eaoscx such as viral {lln~sses, inh,ctious m o m m u e k , osis, Vineent's d i ~ a s e , a n d u n d i f f e r e n N a t e d u p p e r resI)iratoQ: disorders. A typic~d streptoc x ~ a l throat c a n g e n e r a l l y h e differentiated from tim latter eo,Jditions be:eel,st. t h e y often do not look beefy-red, b u t a throat e u | t u r e ~s necessary for certainty. F e v e r m a y b e the only p r e s e n t i n g s y m p t o m : h e m o l y t i c streptococci w e r e fretted in throat eultures of 50 p e r cent of a series ,~f d-~ildren w h o h a d fe~,er as t h e i r only m a n i f e s t a t i o n of illness2 * 'The relative value of certain signs is slm~x~ by. the f i n d i n g of positive throat euttures in 5(/ p e r cent of milita W p e r s m m d ~a w i t h e x u d a t i v e tonsillopharyngitis a n d in 30 p e r cent of c h i l d r e n ' " w i t h tonsillopharyngitis. Using p u r e l y clinical a c u m e n for t h e diaga~osis of streptococcal infeeti0ils in I200 eases of illness in children, Breeze a n d D i s n e y ~

~0(]

¢~I,VAN g. FGINSTI:IIN

were correct in 75 per cent of tl~ose Wire h~ter proved to have positive t h r o a t cultures. S i n e e so many streptococcal in~eetions are asympt:omatie and are detected only by-throat culture or antibc~ly tests, it is apparent that the most freprN~riate laboratory assistance. L a b o r a t o r y l;;eaturcs

The identification of streptocxmei rests upon their direct demonstration.* This can be done either by grouqng the o ~ a n i s m in culture ~9 or by reacting it with a H~meially prepared anti|mdy serum ~ ohlch combines with the streptococci on the glass slide to make a combination which is ~qsibly fluorescent. =t' ~ t e tluor¢~eent antilmdv, t:eehnies have the adv~mtage of simplicity and rapidity but have not yet become generally employed because of the expense of the eqt~ipment and Im~eause of the occasional false-positive results w h i d l enme from thmreseent reactions by, non-Group A ,slrel~ioeoeei. " T h e l>resel~:ee el a G r n n p A ~lrepto,:t~eca| inG.eti, m m a y also b e infcrced from s e q u e n t i a l a n t i l ~ d y testing, b u t this m e t h o d is ~ent.rMly too expensive for t~rdinar:.' actl/c i~fft~:tiolx.s tmtt its re.'~nlt~ maw not b e |x~sitive tln/il lotlg after tim i]ffet:Utm ts tlaM. |

(;UIIItI".NT S T A T U S Ot;" PI~OI'IIY1.AXIS A ( I A I N N T I t l t g l . ; ~ I A T I ( : I"I'Wt';II

--Oi

For greatest accuracy tile organisms should be grown in .ctdture" When beta hemolytic streptococci appear, they should preferably he tested with ant[sera to demonstrate that they b d o n g to the pathogenic Group A. "the growth on culture requires that the origina! throat s w a b he placx:-d directly (in or i n a n appropria{e medi{mL If it cannot IN~ streaked immediately on a bleed agar plate, the swab slmukt be kept frm~t drying by keeping it in at broth. Pik:e's enriched broth- ttas been used advar~ta, gcously for this p~lrpose because it ~revents the overgrowth of other organisms. When the swab is plated directly, the ordinm 3, sheep blood agar plates are quite satisf;mtory. They may also be used for streaking a Ioopfu| of the swab-in-i~roth, when preservation i~I broth is at tteeessary precursor to the n 1tmmtc " • . culture. |dentiflcation is often improved when a few deep eolonic~ are implar~ted t~) making stabs into t h e aga~. ' ~" • ~.Vhen a broth is used, some workers a~" prefer to make fresh pour p|a|es using melted agar. Streptococci whicI| are pathogenic in the throat create d e a r (or beta) hemolysis and must be differentiated from tho nonpathogens which produce no hemolysis or a partial green (alpha) form. Hemolytic staphylococci and gram-negative cocci may also proth|cc d e a r hemolysis o n blood agar plates but can !)e appropri~,tely identified. The methods for streptoeoceul culturing and identification have b,,ccn described in practical detail by XVam/amaker, t:" ;And msewnere.--,-

It sterns likely that direct eultm'e methods will continue to 1~ used for the |~reseeable futm,e. These technics may eventually be replaced by fhmrescent amtibody or other directly visible met!rods after their general practicability is established.

t:,))idcmiologic Fe~tlt~rcs ~,Vhun individuaI~ gather into groups x~hieh live, work or play together, respiratory pathogens are easi|y transmitted. "lira conmmnat features o| thes~e groups also simplify the identification and treatment of tim infections. Studies of military persom~e[ "~:~-''''-'~a:" have p r m i d c d major c~mtri|mtions to streptococ~c-al epidmniology and pafltology, m!d these studies trove clearly shown Omt ~ i d e m i e s of clinical strept(K-occaI inhmti~ns eaz~ he ~.xmtroIted by treating infected patients arid by giving pro#~ylaxis to those exposed. These studies have aNo shown that the treatment of dinic~d infections will r~luce tx~st strepmmweaI complications, tn civilian grou hiefly school ehiklren the presence of a high percentage ~d asymptomatic streptoc~c+.:aI carriers ha_,i created confusion. \Vhen sd~c,~l populatimis were ~a-;amined routinely during . . . . . . . one half the children were fotmd at various the school year, a:'-:~'~ approxnn.~tely times to harbor beta hemob'tie streptococci without clinical manifestations of infection. This occurred regardless of attempts to eontroI carriers l~r, penicillin treatment. C~mversely, the respiratory symptoms in these children were not associated with streptococci. [:or these reasons, there is some doubt that satisfactory primary prevention ~}f rheunmtic fever can be achieved, as has been reported, a'~':~ !.~" r,nntine cnturing of the throats of school ehihtren and t~+" treating all whose cultttres are ImMtive. This isstte i:+ still nnsettled.

Ancillary Features Stxe~toc~ceal irffections are less prevalent as patients grow older.': T h e infections a r e less pathogenic in children ~mder 4 years of ,.o~'-~"than in the older g r o ~ .

In l a t e adMeseence and bey~md, the rate with x~l ~cl r!mumatie fever fol{ows strept~a4~eeaI infections decreases with inereasiI~g age ,ff p a t i e n t ~ regardless of w h e t h e r or not they ~ire reeeiving pmphylaxis. ~.'~ .q~e infh~e~ee of economic and nutritional h~etors is uncertain. C o b m n bus reasoned that the poor nutrition of patie~ts i~ lower economic groups is responsible for thNr increased incidence of .s:~eptoeoeea! ufeet.mns'~ ' and of rheumatic fever, t i e assumed t{mt the ~ t a t i v e | y 10w eggyolk h~take of this group m~ght be the responsible factor m~d h~xs siudied ~Dr°Dhvlaxis~ ~ . . Of rheumatic fever using th~s n u ~ i t [ o n ~ supplement° T h e resMts are e t m e n t b iadecisive. Streptococcal infeetioos have also been rei)or|ed to be more f r e q u e n t in pat[ents wtmse tonsils are m h e t than i~ those wRh tonsillectomies/~ h-, smokers tha,t in nonsmokers, ~:~ and in the months of Janum T to June. TM Altho,~gh these a n d other an~:il|ar) features m a y be signi~emat, their role has not yet been suNeiently established to provide general a g r e e m e n t ~.m their importance or to w;~rrant spccqfi¢ attentio~ to them in therapeutic or prophyfaerie recommendations for t h e enera[ polmlatio~. T h e use of anthnierob'a| ageats for the treatment a n d prophylaxis of in%etions has become the major era'rent approaeh to streptococcal control. TI~Eak~[ENT OF STI~PTC)COCCAL INFECTIONS

It ~ clear that every sy~nt:)tomafic stre[)tococe;d infection should be treated in order t~ reduce its suppurative and nonsuplmrative c(~mp|icatiens. Altho~gh a s ) m p t o m a t m patients w~th p~sitive t h r o a t eult,,res m a y be ia a |mnnless carrier state, it is flu~po:~sibte to be certain that the organism ~~1I remain benign a n d wilt not lead to a ~ubehmeal inflammathm and its possible pathogenic cow,sequences. Therefore, it seems reasonable to treat all streptococcal inf e e t i o n s ~ s y m p t m n a t i c or ~symptomatie ..........whenever they ;use discovered. T h e treatment should be with a bactericidal agent given in a dosage adeq u a t e to eradieate the organism. Sulfonamlde p. r. e. .p. m a t m " n s do not perform . ~his therapeutic funetmn, although they m a y be highb~ effective w h e n used prophyLact~'a!ly to prevent i,ffeet~ons. T h e a~*ento of e~mic~ is peme,llm, . . . . . give~, in oue of the follown~g forms: single ir~ection (ff b e n z a t h h m penicil|in G; gg0,000 ~mits in children or 1,21)0,000 units ~n adolescenls a n d a d u l t , A

or

t~ec~{ons of procaine peuicit|h~ wlth a l m n i m m ~, monost~m~tc in oil; 800,0C~3 units h~ ch{ldren or 6 0 0 , ( ~ u ~" l,ts in adults, every third day for 3 doses. ,e

CUIltIEN'r

S ' r A T ' U S O I z P[l(.llf~f.f3"l-~XlS A ¢ ; A I N N T I l t l E U ~ A T I C

FI';',/I'~IIL

009

O,.ttV: 200,(I00 to ~50,000 units, three t i m e s daily~ Jot a [tdl 10 doy.s; even if the patient becomes afebrile a n d asymptomatie. Of tlmse, the ~Sngle benzathinc penicillin injection storms preferable because it is d m a p , effective, avoids the need h)r the patient's retm'.o to the physician or for the patient to r e m e m b e r to take the medicatiou. If oral penicillin is desired, there arc umnerous preparations available. Although they have m i n o r dift'erenees in reported, rates of absorption, none seenls outstanding M t e n used in the large, suggested doses. In these circumstances, the choice, of an oral preparation can be governed b), availability and price. W h e n definite or i)0s siblo sensitivity to penicillha precludes its u s e , one of the foI|owing alternatives m a y be used: Tetracycfline or its deriwmves, or erythron~'ein, given in therapeutic doses, ( usually at least 1 Gin. per d a y ) [or I0 d~tys-. T r e a t m e n t should begin as soon as the infection is diseovereo. ~ Eveo if the infection has been elinieally a p p a r e n t for as long as 9 days and elicits an antibody response, 4~; its rheumatic complications can often be prevented b y a d e q u a t e t h e r a p y begun at that time. In eases of I)ha~'ngitis or upper respiratory ailments which do n o t seem to be streptococcal a n d wlmrc the physician wants to withhold t h e r a p y for one day to obtain the results of throat culture, the time lag will m~t be harmful. I~iEV~';NTION OF STtlttPrOC~OCCAL [NFE¢TrIONS ANI) I:{ilEU~-.IA'rIc ]~ECbqII~ENCES

Sinco not all infections are clinically recognizable, m a n y will escape treatment. In order to prevent recurrences of r h e u m a t i c fever, the susceptible subjects cannot rely upon the identification of streptococcal infections a n d must a t t e m p t to prevent the infections. This is the rationale for the use 0[ antistreptococcal prophyluxis in these patients. Unless re[~laced by intervening courses of other antibiotics, the prophylaxis must be given continuously, or repetitively to avoid the possible e~ltrance of infections, T h e control of these infections by eontirmous prophylaxis or b y repeated intermittent treatment has been almost universally accepted.; Itowcver, one recent report ~7 has re~ecte¢l this a p p r o a c h a n d claims success in preventing rheumatic fever t~" avoiding prol)hyl,~ds and b y treating streptococcal infections as tlley appear. "/'tie validi%- of this latter m e t h o d cannot be d e t e r m i n e d from its available data for the rec~sons cited in the editorial *s which accompanied the report and because the s t u d y ttid not comply witt, m a n y of the scientific prerequisites cited below.

Scientific Aspects o] Prophyh~xis Stmlies It has been ditBcult to compare the effectiveness of tl~e various agents anti regimens used for the prevention of rheunaatie fever because t h e y have rarely been subjected to rigorollsly controlled investigations. T h e problems

010

ALVAN lI. |"EINSTEIN

inheren t in st~di Studies are rmt generally a~roeiatedtt For scicnt~e and statistical .vMidity, studie~s of th~ long-term prevention of rheumatic recurfences must do the lfollow!ng: ( I ) "l~le pa~ents must all l~ave h a d px'e-eious tmeqtdvoeal attacks o£ thenmarie feve:r., (Despite t h e almost universal usage o f the modified Jones criteria *~ many studies :*,s~ employ their owxl local diagnostic variagons ~.) (2) :Tlie number of patients must be large e~mugh for statistical analyMs. The groups t o be compared should b-a studied simultaneot,sly, not seqtmntialty. m , d they nmst be comparable in regard to certain crucial clinical parameters whiela c a n effect, patients" Susceptibility to streptococcal infections mid rheumatic recurrences. Among these parameters are ag% n u m b e r of previo,as rheumatic a~aeks, presenc-e of rheumatic heart disease, and the JntervaI since the previous attack of rheumaNe revery ,~.~°,~* Tim allocation of patients and the ~hoice of W0phylac6e agents for each group must be done by statistically v ~ d methods of randomizatmn: ().tal~y stndies have tmforh|nately used e0n~ot groups of one year to compare against treated groups of anofl,er year. .The allocation of patients into different groups-has ofte~ not been done randomly and the paHent-group distribu~on for age and other pertinent elanteal paxar.ncters has f r e q u e n ~ b~en i ~ o r e d . ) (3 } The patients miist be e.~:a~ned frequently; preferaMy at least monthly, and vig~orous attempts must be made to ensmre their attendance at the clinic or the acquisition of their data if they fail to attend. (These pursuits require arrangements for home -~sits ~ , nurses and pyh~ieim~.~;;~ many studies have not been able to do so.) (4) Any antibiotic therapy, other than the plarmed regimen, should, pxeferat>Iy be avoided, beeam~e it would affect the streptococcal flo~'a and alter the results of I~r°phy..daxls alone. This is ~mportant because a major purpose of prophyl~-uxis is the prevention el s~belinical infections, l~v. inadvertently eradicating subclinical infections, additional anHbioties preclude an adequate evaIuation of the action of the p~oi~h)laetic agent in preventing rheumatic fever. For the same reason, in a study of prophylaxis, it is Janpo~ant to avoffI treating streptococcal infections* which have heeome clinically or bacteriologically evident, since their treatment wo~ttd no longer make the course of these overt three!ions c~mpantble with the course of the untreated ones which are recognized only by retrospective titration of antibodies. TMs seientiaqe requirement h~s not always been obse~wed. In mat'ay" s t u d i ~ streptococcal infections were Ireated whei',cwer the)- were identified beem~se the invesNgators were reluctant to withl~old treatment. In other sh~dies, the patients were examined so infrecluently that no del3nite evidence c~:mld be obtained regarding the presence or treatment of possible chmeal " *,- or subclinical infections. In all s t o d i ~ there is an uncon~ollable and vaNabIe element of additional antibioties administered by hunily phyMeians, dentists, or hospital emergency rooms for acute situations which could not be managed by personnel of the .

* I n a progran~ ~'a~hcv tha~, ,~ ~ud.~, Of t>rt~p,hyla~i~, thi:~ i~ Tin: l~exti¢~ont, a n d tr¢,~atment s h c m | d t)(, g i v e n to at~y ittfertt(ms wl-~i¢:|) art,' di,c¢~vcrt~l.

C U I I I ! f E N T S'l\&'l'US O F I ~ I l O P I I Y L A X I S .-kl-IAI:NST B I t E U F . I A T I G F E V E R

o 1.[

study. (In investigations of prophylaxis w!~ere streptococcal infections were deliberately treated, tl~e data are no longer usefuI for determining how well proph)daxis has prevented recurrences of rhemnatie fever altli0ugh the results may still be valid for measuring 'the oc'ctl~e!ace (ff strei)tococcal infeet.i0ns. ) (5) The detection o f strct)toeoct.~d infections requires frequent testing of antibodies as well as ttn~oat cultures. The antibo@ tests should be done as sequential measurements (to determine incremental ehan gres in titer rather J thml absolum leveN) n o d should include me~-~nrement of antihyaturonidase and antistrepiokinase in order to avoid missing the NJ per cent of infections w'hid~ fail to elevate the antistreptc~lysin O (ASO) titer. :;~ Tee|mie:s f o r measm-ing an additional antibody, antidexo~2,'~qbo~luclease B, b a r e recently been described r'u and e l)i ~ear q~ite useful, but the method has not yet reached application in mass studies. ( M a n y programs have used ~no antil)o(ty measurements, most programs have measured only ASO titers, and only rarely t:ave all three antibodies been measured. As a result, the incidence of stlliclinical streptococ~.a] infections in most studies is falsely low.) ( 6 ) IJ~ patients recev~m~ , " ," c, o~'al propl~,;laxis, an attempt must be ma(te to evaluate the f i d e ~ , with which it is maintained, since many patients forget, misplace~ or otherwise fail to take the drugs. The ettects of failure to take the medication should be separated, whenever posslb c, [rom the fMltires ¢~f the medication itself. (This is a dJt~c~clt prohtem, ned althougit it has been attacked in digercnt w~tys,~ no ent~re.l) satisfactory methods for making these dtsgnetions have yet been evolved.) q"1 t e lrvington Hot~se Prophylaxis Study (table 1 } N one of the most sati:~factory of existing investigations because it was de!ibemtely planned to adhere to the prineiplcvs noted above. I roph~lax~s studies from the IIouse eft the Good Samaritan (table 1) have also been importm~t but, for internal c~}mparisons, they are somewhat limited by the ab~ ,nec of a n t i b a d , measurements ott~er than ASO titers and by the pol'icy of treating iutereurrent streptococcal infections. There are no other large-seah:, statistically controlled invesliga~ions tff methods for preventing rhemnatie fever reeurrenc~,s in civilian populations, and relativeS" few of the smaller studies have managed to comply ~Mth the pNneiples noted above.

Choice o/Prophylaxis Agent When the results of prophylaxis sit, dies are analyzed, it is important to sep~wate fl~e effects of the medication itself from tlmse of the regimen in which it is employed. Thus, eral prophylaxis prepmratkm~ may not be taken fettlefully and for t ~s reason, the regimen which t|se5 them may have poor results in large scale studkes, When rhem~m~e fever ree~rs in s u d t a regm e.n, it is legiNmately at~ibutable to tl.te regimen, although the. medication may not be F~ *** responsible l~er se, The Good Ntlnaritalx prophylaxis data' ~....... emmet be used Ior assessing fl~e prevention of r h e u m a t i c rccurre~ccs" because extra antibiotics were used for the treatment of ilatercurrent streptococcal inh~cti~ms. The Irvington House data ~,".r'~ show that monthly benzathine penicillin injeeticms prt?-

21 ~

ALV~tN ti- FEiNSTEII"~

Table 1..;-l~vsults h, Two Large.Scate Comparati,~e Studies of Yroplayhtxls l~um~r '~f • :PRODtlYLAC~TIC ~,GENT

Ye~'~ of Obaer~'ati~n

~ u m h ~ : r ~ n d q ' y p c s of 8 ~ r c p ~ e v c ~ d I n Ic'¢tlol~ . a ~ 4 A g l ~ ¢ k ~a~[c l ~ r l ~ g i e ~ t Y(.'~t¢ Car~er Stn~

lliVII'IG~'C~ N H O t J S E Sulfrali~zti,e, I G i n . by

2~

Sll~nle~ll lnI~tious

Number of I~heur;aatt,,

al~Q A t t a , : k l i a i C

Clin|eat Infections

Tot~fl

I"erPatler~l, ~,ar

S T { J I > ¥ ; ~,¢-~ 4.y(-ar d a ~ a 56

28

10~

~0

-I4fi

200,000 u n | t a by m o u t h ~ n e e dMly

411

B e n z : ~ t h i n e t ) e n i e i l ] i n G, 41~5 I401JSE OF GOOD ~O(L~O u ~ t t ~ b~" mt~a~h

SAMARglAN 5 I4

STUDY; ~,~ 4.year dat~ ~ if6

2

I26 1A;%

~ e n J e i l B n V, 2C#~,000 u O t ~ b r mn~,t~

*6

5

1

ll

0

1...6 ,~

2.55{~

27.5 a:{,

0

2.5%

Z.5%

8.8%

0

4O

t l e ~ l ~ t h l n e P e n i e i l J i n G~ ~0 ~ u~eularly every, 4 ~vt,vks

S,S%

vent rheumatic reeuxrenees better than fl~e oral preparatjm~s, even when the latter are takc~n faitIffully. The repository penicillin injections, however, may not always b¢ desirable because of the m~2rked pain and ~scomfort which tl~e), prnvoke in about ]0 per cent of patients :',~" and because of their sensitizalion poteatiaIities, Sm~Mtivffy rcac~ons ;u'c- rareb¢ observed in t | le- childreaaadolescent a g e group, but mzE¢ later become prominent and a slgmficant deten-ent to usage of the d_o.~gin older }2atAents/'7 Of tim two ora| prcparatio~s. snlfadia~ne, L0 Gin. per day, has been at least as good as penic~ilh~, 200,000 units per day, ia preventing rheumatic recurrences. ',:~:~ Tiffs surprising observation is wei|-docum~mted and eoiltradiets the many unsupported claims for the sttperiori D" of oral penieilHn as a propl~;taetie agent, To rule out t3~e posMbiti W that tile G;ral penieillhl £aiitlres arc. a de, age phenomenon, file Irvington House study is ncnv comparing stdfadiazine against a double dosage (~0,gu30 units twice dadly) of ond penieillim in the prevenUon of streptococcal infections, oral sulfadiazine and oral peaicillia (=20,0,000 ,_u~ts daily) ha',~ been approximately equally elfcctive *~,~'a The streptococcal infection a t t u ~ rate i,~ the Good Samaritan stn ;~" of orM penicillin, 400,000 units daily, is ahnost identical to that observed in the lrvington House studies of t=ueniciltin, omits daily. This suggests that doubting tl,c penicillin dosage may not make it superior to stdfadiazine for preventing streptococcal infeclions. The effect of increased dosage on preventing dmumatic recurrences remains to be seen. Although oral penicillin

c[3~l~l,:N'l" S ' I ' A q l T S O F P[1Ol~! ! Y L A X T S A ( : A I N S T B I tl~12~,I~k'l'l(3 17Evi~i~

Z 10

can be bactericidal, it may not be so i n doses of 200,000-.500,t)0() units p e r day. Its opt!maI effects may require much higher lherapeUtic doses which are not used in the ordinary prophylactic regimen. An alternative possfl)ility to that of t~Cking oral penicillin i n continuems daily prophylactic doses is that of taking an eradicating course of oral penicilli n once montMy. 'Iqais regimen has not been tested witl~ statistical rigor, lint its results":: have beert quite favorable and its ralionale is reasonable, The latent interval between a streptococcal pharyngitis and the onset of rheumatic f e v e r is generally assumed to t~e less than 35 days. Pharyngitisl of course, m a y b e the first clinical manifestation of an infection whicla w;as present for unkno~n lengths of time before it became symptomatic, Tiros the latent period bet~veen. floe. streptococcal entrance in the throat and the development ot" tqm~tm:Ltie fever may aeta~alIy be nmch lounger tlmn the tlSUa] ioterval as measured from the onset of clil~ical pharyngitis. If the in[ectkm does take more tlmn 30 days, the repetitive monthly eradication of streptococci might regularly remove ~iny Kesratmg infection and could thereh~re pr{:vent rheumatic recurrei~ces more eft'cctively than the use of a prophylactic oral agent which does not reach therapeutic levels. In this regard, i t is imporhmt to recall that the monthly injections of benz;tthh~e penicillin are large enot=gh Io eradicate streploeocei as well as to pro~qde a persistent blood level thercafh:;r. T h e an tM~eumatic effectb,,eness of these injections Ires usnaIIv }~een attributed to their persistent blood level, but it may conceivably be d=;e to the effects of the higher, streptocoecidM levels which exist for the fi~7;t few days after :ldmir|istration. For these reasons, the utilit3.~ of repetitive monthly ~he.rapeutfc courses of oral penicillin as a prophyhtcti~: r¢\gimen will need fnrthcr investigation. Alternative agents are available for prophylaxis: Erytbromycin has been employed .~s.a° with contradictory results, m~d ehlortetracyqline has also been used. a¢' The rathmale for these preparations is that they, avoid the penicillin sensitivity prt~:~lem and are presmnably more effeeth-e than the baeteriostatic sulfonamides, The reluctance to use sulf:mmnktes in pIaee of penicillin aP" parently comes from the fear el sensitivity reactions to sulfonamides and the realization that st|lfonamides rio not eradicate streptococci. This reltmtance is inconsistent with the data which sh6w the demoastrated effectiveness of sulfadiazine as a prophylacth', agent and the low or negligibl e incidence of reactions to it (eornpared t~ older sulfa preparations, where reaetioris were more frequent). Since tetracycline and erythromyein are considerably more e-q)ensive than sttlfadiazine and since they have not had t~alid comparison.~ against it, their utility remains uncertain. One of the major di~eultic.~ in oral prophylatxis regimens is that patients must remember to take the medicine daily. An oral preparation which need not be taken daily would therefore represent a significant advance in the field. Sulfamethoxyp)a'idazine, a long acting sulfonamtde preparation, seems to offer this advantage. Several reports au'~" indicate that it can be taken once weekly (in a single dose of 3 Gin.) and provide effective oral prophylaxis. Its long range effectiveness and the incidence of sensitization are now under study.

~[A

ALVA,'4 tL F g l N S T E I N

Comp{icatiotx~ j~f Long-Term Pr~bg!axis" TLe incidenee~of reactions to m'Y of the current oral ~ro hvlactic agents has been so small that they need n~t affect the choice of medieatiom With repository tYenicHIin in~cetfons, the local reactions described pre~qously etch.,,r h ~ q u e a t I y enough to cause diseontimmtion of this agent in abot~t 10 per cent of the patients who begin R. Although trt,e sensitivity reaetkms have been . ~are i~ chiktren, they are more freq{~ent in adults }or whom the therapeutic -J~ecd Sho~|ld be Carefully emluated wlien this agent ~s chosen for long-term prophylaxis. The long-acting sulfonamidds are newly introduced and a~tuiring tI~ei~ share, of reports of sensltfzation. None of |hese reactions ~ -* seems to }lave at P~, eared in the yolm g er age group, and t t ~elr c general inOdenee in older pa. ffems has not yet been deteanfl~ed The enle~4enec o f resistant organisms or tim adverse Mteration of normal throat flora }ias been feared as a compJieation of |nag.term prophylaxis, but these effects have lint taeen M)sei-ved to any signi~eant extent;

Choice of Patients for Propl~ylaxis The Grst decision ¢0 be made is that the patient has definitely had rhenmatic fever. The diagnosis appeared e~roneot,s in I2 p e r eerJt of a series of l?atients referred m tr~dngton H o ~ . , and the incidence of these errors may be even higher.in some o f the state-wide pr(~grams e~ which do n o t attempt to confirm t h e dmgno::is i~ each patien!. It is imperative that tim olqgi~ml diaglmsis of rheumatic fever he correct hefore assigning the patie, R to a tong peri(~d, and p()ssibly a lifethne, of conHnuous prophylaxis which may othera'ise Be ueedless and poten~ialiy lmrmfnL If has t~en s~ggested ~ that (lc~onstration of a recent streptoeoeez~ infection }m made a prere
D,,ra{ ion of

ltyNxL~

~ e recurrence rate of rheumatic fever is t~ighest in the first three years after an a ~ a ~ , remains rclah~ ely h i ~ t for the next two ve~s, and dimh~ishes thereafter wit}~ t h e passage of timeJ ~'u It is fl~erefore ~ecessary to n~aintain prophylaxN for at least fl~ree years, and preferably for W e years, aftra, the arrack. Tile length of time thai proplaylaxis should'be conti£~ed fl~ereaf!er has not been determined and the e ~ e n t recommendations a r e that it l~e maintained mdeRmtelv . The aee~u-n|_|tatmn of additional data in ehe next %w vea~ may modify this recommendation. For the present time, it seems reasonable to ~ n t i n u e prophylax~s for at least 6re years i~ all patients, to maintain {t througtmut t h e elementau; a~d ld~h school years in all pa~ents, a~d to rest, me it (if it has been stopped) when the patient becomes particularly susc~pNMe or exposed to streptococcal infections, as ~n p r e g n a n ~ or in rnilita~. ser'vlee. R ~ e n t studie.s of rheumatic recurrences ~ have suggested tlnat cardiac dam, age in the r e p e a t ~ attacks o ~ u r s ~mly in patients who had Valvular revolve"

CUtl]~KN'r

srATUS

OF

VI~r~PH~'LAX~S :~.t : A t N N r tlI-I|'X~.XIATR;

l:gVfgl

~. l-.~

m e a t w~th t h d r initial attack and that those w h o w e r e spar~xl i n t|~c fit-st t;pisode r e m a i n free of v a l v u l a r invoIvt:ment despite s u b s e q u e n t attad-:.s. Cm,firmatlon of these results m a y e n a b l e prophyiaxis to b e d i s c o n t i n u e d at an earlier time in pa{ieuts w h o h a v e not h a d valvular.in;¢o!vcment. T h e d e c r e a s i n g suseeptil~lity to recurrent attacks b e y o n d a d o l e s c e n c e *~at .and tlie essentially b e n i g n n a t u r e of t h e first attacks w h i c h occur in a d t d t l m o d ':r suggests that the use of p r o p h y h x i s in adults n e e d not be m a i n t a i n e d as long as in the y o u n g e r age group. A .frequent p r o b I e m occurs w i t h the a d u l t whose fnaetive r h e u m a t i c h e a r t d i s e a s e is discovered d e n e r o or exists as a residue of. at remote, k n o w n attacdh:, l t e e u r r e n c e s in a d u l t s w i t h h e a r t disease are potentialb: far more dangerous t h a n in those w h o h a v e o~fiv a r h e m n a t i e l~ist~r)' "withm~t residual heart disease or in those w h o h a v e h a d a r e c e n t prim-try attack w i t l w u t ~a-,1vulitis~ T h e choice lies betaveen the" use of continuous propltytaxi.'/or a vigorous attempt to k l e n t i ~ , and treat streptococcal infections as they ov,r:ur; current data do not indicate whid~ a p p r o a d t is p r e f e r a b l e .

• In fl~c g e n e r a l p o p u l a t i o n , r h e u m a t i c fever can b e p r e v e n t e d b y the prompt. i d e n t i f i c a t i o n atld a d e q u a t e treah~lent of Gt'oup A streptococcal p h a r y n g i t i s . T h e increased use of a c c u r a t e throat cultures in n i l f o r m s of r(:spirato~' illness wilt e n a b l e s y m p t o m a t i c streptococcal infections to be recogn!zed w h e n tl~m, are present a n d ,.rill a v d d tmneeessm3" antibiotic tt~eral-0", w h e n they are absent. Since a b o u t h a l f of streptococcal infections are as v p m t o m a t i c . - t h e y Will escape detection b e c a u s e the p a t i e n t &~es not seek m e d i c a l atte3~tiou, lrt the best of circumstances, therefore, it w o u k l b e i m p o s s i b l e to r e d u c e the rate ~f first attacks of r h e u m a t i c f e v e r b y m o r e than 50 per c e , l. O n c e ~'.n attack has o~.,eurred a n d the indi~qdual-patient's s u s c e p t i b i l i t y is noted, tl~e preventior~ of recurrel~ces b e c o m e s p a r t i c u l a r l y important. This involves the a d e q u a t e t r e a t m e n t of streptococcal infections w h e n e v e r they are brand, b u t also dem,'tnds p r o p h y l a c t i c measl~res to cope w i t h tt~e h a z a r d s of mlr~zc~gnized infections. T h e prophylaxis can b e a c c o m p l i s h e d b y g i v i n g d a i l y doses of oral antimlcf-obial agents, m o n t h l y injcetions of a r e p o s i t m y penicillin preparation, or monttflv courses of an oral a n t i b i o t i c at t h e r a p e u t i c dosage. A t the p r e s e n t time, the m.~st effective m e t h o d of p r o p h y l a x i s i s a m o n t h l y infection of 1 2 million units d b e n z a t h i n e penicillin, bec-ause the m a h , t e n a n e e o f prophylaxis is assured a n d b e c a u s e the m e d i c a t i o n b o l h eradicates strept~4cocd arid p r o d u c e s a persistent penieiltin b l o n d level tl~ereafter. T h e g e n e r a l appl[c ab i l i t y of the injections is r e d u c e d b-,; their potential for sensitization, partieu]arl-vi in adults, a n d the t 0 p e r etmt i n c i d e n c e of severeIy u n c o m f o r t a b l e local reactions to them. O~ t h e da~lv oral p r o p h y l a c t i c m e t h o d s , sulfadiazir~e, I Gin., a p p e a r s to w e v e n t rt{emnatie recurrences at least as well ,-Ks 200,000 units of penicillin. It is now b e i n g c o m p a r e d against a larger dose o f oral penicillin. C r e a t e r a w a r e n e s s of ehe eoml~arative proph~flactic effectiveness of sulfadiarAne a n d the a b s e n c e of a n y s i g n i f i c a n t reactions to it, m a y b e [dh.r, ved b y its i w creased use as an oral p r o p h y l a c t i c a~ent, either in p r e f e r e n c e to ,.)ral p e n i c i l l i n or as an a l t e r n a t i v e to it. T h e role of l ~ m g - a c t i n g oral s . I f a m e t h o x y p y r i d a z i n e

~.](i

A L V A N . !L V~IN." " ".q'l'l~IN""

h a s n o t y e t b e e n e s t a b l i s h { ~ ] . I f its o n e - d o s e , - l ~ e r - w e e k c o n n)t.n~c vs m a t e h e d b): i t s p ~ 0 p h y l a e t i e e f f e c t i v e n e s s , it m~9: b e c o m e a h i g h l y ttsef'u[ o r a l a g e n t . A / t h o u g h t h e c o n t i n u a t i o n o f p r o p h ) ' ] a × i s is n o w r e c o m m e , ~ d c d h~r a n i n d e f i n i t e p e ~ o d o f t i m e . m o r e f i n i t e d u r a t i o n s c a n b e r a t i o n a l l y e s t a b l i s h e d in m a n y ' s i t u a t i o n s . - T h e m a j o r f a c t o r s w h i c } t infl,_~ence tl~is c h o i c e w i l t be t h e a g e o f t h e p a t i e t t t , d i n b c a t s t a t u s , a r i d t h e -rcmoterv~.ss from t h e p r c v i o t ~ s r h e u matic attack. Bcffore c o n t i n u o ~ ) s h ~ d e f i n i t c W o p b y I a x i s is u n d c r t a k e n i n a n y p a t t e r , l, a c o n c e d e d a t t e n a p t s h o t i ] d b e m a d e t o v e r i f y t h e diagnoa~is o f r h e u m a t i c f e v e r o r t h e c:'~istence of r h e u m a t i c h e a r t d i s e a s e . ItEFEI~ENCES i.el-dh~g methods for evM.a~ing the 1- ?.leCarty. M,; Naivete of rhemm~tk" mah~te,alle~ of oral ~rophy|~xis. fever. Circ~dation 14:1 I3~~1143, Dec. Nvw En~iand J.M,~L 2 ~ 0 J t956, Al~ril 2, I95'3. 2, ~l/'nltlo]kIlltip, C. 11.. J r , , ~ 2 i n I ~ ; l l l t a k v r , 7. At)wrJeatn H{-*;~tt Assot:httiol); CoMmittt'P L. XV. aml Dem)y. F. XV.: "~lc cpon Provt..tiort of t{houmatlv Fever idemiology $,tltl preveBti~m of rhPu* tl;l~lI[¢ fPver. BI]ll.N.Y.Aead.Med. 2,% and l~:tvlvriat Entloo~tr¢Iitfn. Pr...votl3 2 1 ~ 3 4 , M a ) ; 1.(}52, O(nt o~ rheulnotic, fever ;rod baet~-ri:d {-ndocarditis l|lrot,~h contr,[ of slzt,p. 3, %%~m~am~ker, L. %V., I~mnmvlk;m~p, C. t o ~ e e a I i))t'ecli(m~. Circ~)hdion 2 t; 1t., Jr., I ) e ~ y . tv. ~,V., })rink. %V, B,. }Io~]SvL It. B.. IIalm. E. O. a)]d Di~8. K~tt~nt~r, A. C;.: Prv-ventio~ ~}f rh~,mm~tic gl{', J. tL: Prophylaxis of ae~t{e rhe]/m;~fic few:r by t~{:atmera of precedi~,~ fcvvr ;rod* rht.mlmtic heart dist-~,se. streDt~ct~,:cal i¢ffcctkms wid~ va.rhm~ Ihtstgr~t¢|.Mvd. t4:-|2~.)-~132. Nov.. ;m~n.n{s of {h~pot p,.mk'tIli:]. Am.J. !~153, Med, 10:67,3--695. Jmxe, 1951, 9. ?~hwtim~w. E. A. ~md !Lunmelkm~p. C. -I. Massell. 1}, F.. St.rgis, {"L P., Ktvfl}h}vh, 1[,. Jr.: ProlilLviaxis ,mr rheu;l~atie fcvc,r+ C i r e n h l i o n 14:1144-1152. I)ec., J. 1),, S~rt,vper, ]C B., ItaIL T, N. 1956. m~d Nor{:rn~s, tL: Preventi{m of rh{..matic fovvr tIy prompt IIV~lh:i||~II lltvrapy ()f luq))o|ylic x|r(,,'Dh}(:oc(i respirto~ Ihc prevc=lti,]~ of rhvlmut¢ic l e v e l atory h]fccti{m~. Progre,~s r{'port. J.A. A*~*.J.Med. 17:757-767. l)vc.. 1954. I [ . . . . : *~]}** pFt'vlqiI~OIl Of rItvliti};t~iP hrv(.r. ,~LA, 148:1-16,%--1478. AltO. I8, tflSl. 5. ")Voo{I, tI. 1;,, StolIcrt.:m, C,. II., i:vin~[Pt|.C]II]I,NI,).AIII. 4 I : ] 3 ~ I 4 8 . Jan.. .~tcin, A. R,, tlirshfel{!. 1.. R~t~.If, ,l. 1957, I t . %~ra.la. A.. l laas. IL C. ~md El)1~. XV{)(Id. {I. tC: P r , : v c r ~ t l o . . f rl|~-.zr~a~dc stein. J. A.: A controlled study of ft'V{'r. Am.J.CardioL t:gS&-4{L3. Apr. 1958. lhr)-{> ))~t'th~n|s ()f i)r,]l)hYlaxts aguh)~t I3. Miller, J. M = Prop)Lvlaxis td rb{,tmmtic ~Irel}l~c~)cca] inft~,ti{m in a pol)lliatio)~ of r|~et)nlatk, cllih|r(*t}. I. Slr**l)loGyver a,)d ~hetunati¢ hi,art di,;ca~e. (,)coal Infectio)ts an'd revttrr~.nct's - f Nc'w Et~gla.{) J.Nhn]. :2(t0:~20-13f}, ~)t'~|t~ rivet)marie [Pv,,r in t|))" (irst two yvars t)f tile .'it}iriS". NeV¢ Enghmd J. 1,1. - - , Stanc'er, S, I.... and ~ta,~,~el|, B. F.: A ,Med. 237:3~.)4-3~18, Au~, 2~¢, I957, eonttollt,d stmly t,[ | ~ t r hl'mo|yt~e ~t, Fvitr, h:in. A, tL, \V<~.l, !1, F., l
CURRENT STATUS OF I'ItOPHYL~XXIS AG.AtNST I~I~tEUJxtA~LC FEV]5"R case. A t n J . P t t b . H e a l t h . 36:675--(~t2: July, 1945. 16. Breesc, B. B: a n d I)isnt:y, F. A.: T h e accur.~c:,' of diagnosis of beta hemolytic streptococcal infections ou er~ink,al .gTounds. J.Pcdiat. 44:I'I'[0-(Y73, brae, 195't. 17. Greegor, D. H.: U p p e r respinttory infection.% antimierohial agents and a c u t e rheunltttio fever. Ohio State Mcd,J. 53:1421-1,123, Dec., lfJ57. I 8 - B y w a t e r s , E. G. a n d T h o m a s , G. T.: Prevention Of thcumath2 fever rt?ellrfences. Brit.hh,d.J. 2:350.-4352, Aug, 9, 1958. 1.9. V~qmnamaker, L..~,V.: A m e t l m d for e u t t n r i n g beta h e m o l y t i c streptococci from the throat. N e w York, American H e a r t Assn(q;,.tlon P a m p h l e t . 1956. 20. M o o d y , hL D., Ellis, E. C. a n d Ypdykc, E. L.: Staining bacterial sraear~ with fluorescent a n t i b o d y . IV. Grmtplng stxept(:coeci with fluorescent nnti* body, J.Baet. 7,~:.553--560, May, 1958. fiI. Pike, Fi, NI.: A n emichtne*tt hrolt~ 1%r isolating hemolyti,: streptococci from throat swabs, i'roc.Soe_t':xper.Bio].& M,ad. o 7 : I 8 ) - - 1 8 , , Nov., 194'1. 2:2- Nlackenzie, G . . M . : T h e streptococci, [rt (Iia~nostie prt-~,cednr¢,s arnl rea~cnls. N e w York, A m e r i c a n t'ut)lic l-teahlt Association, 1950. 23. l lolli,~ger, N. F. and Rimt~-, L.: I n p e r st,it o f the ~trel)toeoc'cu'~, N e w e r ( e t h nics for their recovery and identi[it,atiolt, alltl rllnical impli('alions. i'ediat. 24:1] 12-1117. Dec., 1959. 24. Cedmrn, A. F, an¢l Yotmg. D. C,: T h e cpidemkflt~gly O[ hemolytic strl,ptl~t,occtts ( l , r i n g XVt~rld W a r l[ it, t h e IJ,S. Ballimt~re. XVilli:m~s & \Vilkins Co,, t-q49. 25. liouser, 1I. B. :rod Kekhardt, (;. G.: licit.at devuh)pmettts in the prcvt.ntion o[ rhomTmtic fc~er. Aan.lnt..kh.d. 37: , IP,,~2. 1035--10-t3, tN ox., 2(I, ~Vatmamake~, L. kV,, I)vm~y, F. V~'., Perry, -~$r l)., ltammelk:tmp. (L It,. Jr,, Eckt~ardt. G. C.. Houser, It. Band Hahn, E. O.: The ette~..t of penlcillln prophylaxis on streptococcal disease rates and the cartier state. New England J.Med. 249:1-7, July 2, 1853.

217

-°,7, MorrL% A , .|, Chamovitz, IL, Cat;mz,'lro~ F. J. ~md B a m m e l k a m p , C. It., Jr.: l ' r e v u . t i o n of r h e u m a t k : h:ver b y hrealment of prc'viot~s streptoco¢ci~.~ infectiom, Ell'ect o f sulfa(liakine. J'AM.A. 16():IL4-.I.1G, j a n , 14, 19S6. 28. C a t a n z ~ m . F*. J., R a m m e l k a m p , C. 1t,, Jr, a n d Chmnovitz, t{.: l~revc~tlon o f rhemtl;~Lie *fever by t r e a t m e n t of slreptococca| infections. 1I. t:acR~rs responsible [or faihm~.,g. N e w l~nghind J.Mvd. 259:53-57, Jt[1): t0, 1958. 29. I-hdght, T. l-t.: Er'ythromycirm th'zralW oil n~. piratory infections. 1. Controlled s t u d y on th,-." von~par;tti,Je, efficacy Of er)'throtnycht a n d penicillin i n scarlet Fever, J.I_~dx.& Clin..XIed, 4,,: " l o- 30, J~m., 1954. 30, Bt, rnstvin, S. t1., Feldm:,n, I't. A., I]larlmr. O. F.. KiiltRensmith. '~V. lSl. :mtl Cantor, J. A.: Observations in air {o;ce recruits of streptoc~acal discasc.~ a n d thoir control w i d l orally admii~i~tered penicillin. J.Lab.& Clim Xled. ,14:1~13, July, 19,54. 3 I . Seal, J. t2.: Oral ptmicillin pmphyl:txis o f strcptoc~'>,_-c;d infections. A~ILJ.Ptlb. IIealth 45:6@2-672, .May. 1955, 32. I)avis, J. and Schmidt, ~V. C.: Bet~zat h i n e pe~ffcillin (;, It:-; effectiveness in the prevcntitm o f streptucoccal infections in ;~ |wavily expostxl i~t)tdation. N e w E n g l a n d J+M+.:¢]. 256:,%39-342, Feb, 21..1957. 33. Pike, R. M . . n d F'ashena, G. L: Vreq u e n e y of henmlytic .~t~eptococci ill the throats of ,well L-hildren in Dailas. Anl,J.Pt~b.lh'alth 36:600--62~, June, 19~t6. 31. C,~rnh'hL l)., \V~.r~tvr, G., XVt-aver, H., Bellows, El. T. aud |{uhlmrd. J. P.: S t , e p t o c o c r a l infectiott in a school tmlml:ttion: p r e l i m i a a r y report. Ann. tat+Meal+ 49:I305--1319. Dec+, 1958. 35. ~,Verner. iS:., Cornfehl, t),. lind)bard, J+ l ). and Hakc, (1,: A .~httly of strcptoC~'clll illfeetion in it .,,chool implah'tlion: t,aln~ratoO" lttet|~t~ttnlgy. Ann. [nt.Nhxl..19:I321t-I331, Dee., 1958. 36. l h m n , '~V. tl. a n d Bennett, 1I, N-: Community control of r h e u m a t i c fever. J.A,M,A, 157:986, Mar, 19. tf~55. 37. Phibbs, B., Bc-cker, O., I ~ w e , G. R., Holmes, R,, Fowler, R,, Scott, O. K., Roberts, K., Watson, "~V,, and Malott,

~18

:~LVAN 1t. I:EINS'I'I~IN

H.: T h e Casper p r o j e c t ~ a n ,,nforcc~l study~ New E~lgtand J.Med. 2~2: mass-a~it~re streptoet)eeie eonlrol 3 2 1 - e ~ , Feb. 18, !960o program. J.A.M.A2 26#:111NtlI9, 4 & Edi~orlah |hteven~ioll Of rec~rrene~: o{ Mar. 8, 1.%58. rheumatic v a , d i t i s . Nt~" E n g h m d J. 3:8. }Lai*~, S\ M,: llhtm~f, tie fevc~ preyer,Med. 2 ~ 2 : 3 ~ 5 - 3 ~ , bk:b, 18, 19(~0. lion. ties.ells of a two-year s c h ~ I 49, A m e d ~ a n H~
CUI~RI£NT Sq'A'YUS OF PI1OI~HYLAXIS AtIA[NST RI,IEUMATIC F~WI'~)I

tococca] hffecti0ns to rhemnatic fever patients, Use of new repository ~nicil{in p~paration, j,A.M,A, 150:. 1571-t Dee. E0, 105fi. 57. Iim, L anti E~eans, ~, M.: Untr~waxd reactions to ~umzathine l~eaiei}lin G i~l a study of rhemnat£e fever prop]ty{axb; ie adults. New En~and J.Med. 259:581 Sept. 18, 1 9 ~ . 58. F, iedman, J,, Iiar~is, T, N., McLear,, D. C, and Tall, M. G.: A t)ial of erythrmnyetn i)) ,heumatie fever prophyta×is. New York, Antibiotics Anm,a! I957-1958, pp, 203-21t. 59. Stal~lman, ?-,L T, and l)e))ny, F, "W.: Tim prophylaxis of streptocnccal i,~fecti(ms i)l patie))ts with rhcumatic fever. A comparison between s,,Ifadiazine amt erythromyci,). J.Dis. O~ild..98:6~71, J~dy, 1959, ~.*0. k[e~'ily) L, V,~ JG a~d Sprttllt, l). H,: Aitreomycin in the pmpiLv|ax£:, ~ff flmtm~ttic fever.. New EnglamI J. Med. Sept. 3, 1!153. ill. l~cpper, M. H., Simon, A. I. and Marien}'eld, C. J o Use of stdfamethoxypyridazi~m in the prevention Of streptococca! hffeetinns in rheumatic patients. AnnN,Y.Aead.Se. 60:485,

2]9

492, Oct, 12, I~.7. 62~ Johnson, E, E,, Mathews, M, L m~d S~@erman, G, I | : The use of weekly

oTal dos,~ of st~Ifamctlmx~yddaziae fi~r rhe,m)aOc fever prevem~n, l,~ l)~{ial. 54:4~.473, Apr. 1 0 ~ . )33. Kohn, K. IL, M A. and MacLcan, H.: Prophy}axis o[ recu~cuees~ o~ flun,matic |ever Wifl~ peni~|{II #yen orally, J,A,M,A, 15I:347---35I, Jan, 31, 1953. 6,1. Feinsteh~, A, K, Timmta. A. ;'.nd Di Massa, 14.: Errors ill the diagimMs of ac,utv rhelm)attc fevvr, New York Stale J, Med, (Complete re/ere)Ice not availahte at press time). 65. Z,,kc{, W. j.: Prevention ¢ff .~ce0ndary attacks tff rbe,imatic h,'ver, Ptd)lie Hea|th Reports 72;,$9~-901, Oct., 1957. 6& F~mk.'iu, A. IL a~d Spagnuo{o. M.: Mh))etk~ feattm.'s of rheumatic fever" rove)trench.. New Eugland J.Med. (Complete refercuc~: not availabD at prc~s time)+ 67. l:r~|berg, C. K+: Editorkd: Rhe~matic fever in O)e adu|t: criteria ~md implieatitm~. Circt,iathm 1,9:161-I~1, Feb., I959.