CLINICAL OBSERVATIONS ON THE EVENTSPRECEDING THE APPEARANCE OFRHEUMATIC FEVER

Edward F. Bland, T. Duckett Jones

J Clin Invest. 1935;14(5):633-648. https://doi.org/10.1172/JCI100712.

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CLINICAL OBSERVATIONSONTHE EVENTSPRECEDINGTHEAPPEARANCEOF RHEUMATICFEVER1, 2

BY EDWARDF. BLANDAND T. DUCKETTJONES(From the Hoiuse of the Good Samaritan, Boston)

(Received for publication May 27, 1935)

The frequent association between tonsillitis andupper respiratory tract infection and subsequentrheumatic fever has been observed and commentedupon by many students of the disease. It is gen-erally agreed that this relationship between thepreceding infection and subsequent rheumaticfever is too consistent to be merely a chance oc-currence. This important phase of the naturalcourse of rheumatic fever has been commentedupon by Coburn (1, 2), Schlesinger (3), Collis(4), Sheldon (5), Gibson, Thomson, and Stewart(6), Boas and Schwartz (7), Hiller and Graef(8), and others. In general, we agree with theseinvestigators both as regards the association be-tween infection of the upper respiratory tract andrheumatic fever, as well as to apparent epidemicsof rheumatic fever, following prevalent respira-tory infection in groups of closely associated in-dividuals. The percentage of instances of rheu-matic fever preceded by recent upper respiratoryinfection may be as high as 75 per cent. Notonly does this relationship hold for the initialappearance of the disease, but also for subsequentrecurrences or recrudescenses. It is of furtherinterest that in most instances there exists, aspointed out by Schlesinger (3), a well defined la-tent period varying from a few days up to fourweeks between the febrile respiratory tract infec-tion and the occurrence. of the clinical signs andsymptoms of rheumatic fever. Less frequentlythe disease appears to be ushered in or occurs con-currently with the respiratory infection.

Because of the obscure nature of the etiologicalfactors involved, attention has been directed, andwe believe rightly, to this so-called respiratoryphase of the disease and the subsequent latent pe-riod. Its analogy to the sequence of events oc-curring in serum sickness and other frankly al-

1 Presented at the meeting of the American Society forClinical Investigation, Atlantic City, April 30, 1934.

2 The expenses of this study have been defrayed by agrant from The Commonwealth Fund.

lergic conditions has been commented upon byZinsser (9), Swift (10), and others. Exhaustivestudy has been centered upon the cultural charac-teristics of the respiratory flora during these pre-ceding infections in an attempt to establish a spe-cific causative agent. In so far as we are awareno proof has yet been presented that any organismfound in the upper respiratory tract is the causeof rheumatic fever.

It is the purpose of this paper to present cer-tain clinical observations on rheumatic fever whichare of interest and may be of importance in fu-ture considerations of possible -factors in thecausation of the disease. During the past thirteenyears at the House of the Good Samaritan therehas been an opportunity to observe the clinicalcourse of a large number of children and adoles-cents (over 1,200) during various phases of rheu-matic fever in a hospital where they receive bedcare until all clinical and laboratory evidence ofinfection has subsided. The average period ofobservation in the hospital is four months, but notinfrequently is as long as several years. Duringthis period of prolonged observation, the evidenceof persistent low-grade and sub-clinical infectionhas been largely that of a slight fever (rectal),subcutaneous nodules, erythema multiforme, amoderate leukocytosis, increased sedimentationrate of the red blood cells, or prolongation of theauriculoventricular conduction time. It is in thismildly active group that we have observed re-peatedly the importance of respiratory infectionin precipitating relapses or recrudescences of theclinical manifestations of the acute disease. Fig-ure 1 shows the bedside chart of a boy, aged thir-teen, convalescing from recent rheumatic fever inwhom the clinical and laboratory evidence of ac-tive disease had subsided. Following the febrilerespiratory infection shown on the chart and aftera latent period of two weeks, the boy developedfulminant rheumatic fever with pericarditis andcongestive failure. He died at the end of one

633

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week, and rheumatic fever was confirmed byautopsy.

Recurrent rheumatic fever has been observed attimes following infections other than tonsillitis orpharyngitis. Scarlet fever apparently is frequentas a precipitating factor and further data on thisinteresting relationship will be published subse-quently. These episodes are closely related tostreptococcus infection. Instances of other pre-cipitating infections, frequently associated withor subsequent to ordinary respiratory infectionnoted in our series are: "pneumonia" 4, otitismedia 5, measles 3, and erysipelas 1. One mightadd here single episodes, seemingly independentof respiratory infection, which we have observedto precede recurrent rheumatic fever; namely,pyelitis, herpes zoster, and a febrile reaction tothe Schick test.

Wehave been impressed by the occurrence, nowand then, of an equally striking though less fre-quent association between other (non-infectious)and apparently non-specific episodes and subse-quent recurrent rheumatic fever. These episodesexhibit a suggestively similar relationship to theoccurrence of subsequent rheumatic fever as haspreviously been noted between respiratory infec-tion and the acute phase of the disease. Subse-quent observations herewith recorded appear tothrow additional light upon this interesting butimperfectly understood phenomenon.

Transient and unexplained temperature

When recrudescences followed respiratory in-fection, a mild fever of two or three degrees at thetime of the infection has been the rule. In con-trast, however, we have seen on several occasionsa transient fever of two or three degrees for a fewhours, unassociated with evident infection or othermanifest cause and apparently precipitating afterthe usual " latent period " a recrudesence of typ-ical rheumatic fever. Figure 2 shows the courseof the disease in a child, four years of age, whoappeared to be convalescing satisfactorily fromrheumatic fever which began twelve months pre-viously. On February 26, as indicated in thechart, there occurred a transient and entirely un-explained elevation of the temperature and pulsefor a few hours, followed in two weeks by ful-minant rheumatic fever associated with pericar-

litis, congestive failure and death eleven days afterthe onset. The response of the temperature tosalicylates without clinical improvement in thepatient is of interest. Postmortem examinationconfirmed the clinical impression of severe andfulminant rheumatic fever. In the light of pre-vious observations on the apparent relationshipof respiratory infection to acute rheumatic feverthe association here seems equally striking, but inthis instance recrudescence followed a tempera-ture reaction alone. The relationship appearseven more convincing when we consider that thebedside chart for the preceding six months hadshown a consistently normal temperature andsteady pulse rate.

Accidents and operations

In our experience this same sequence of eventshas been precipitated apparently by accidents in-volving fractured bones or sprained joints. Sur-gical operations have also appeared to reactivate,occasionally, a latent rheumatic infection. It isnot an infrequent experience in general hospitalsto observe the recurrence of the signs and symp-toms of rheumatic fever following tonsillectomy.Indeed, on rare occasions, the initial attack ofrheumatic fever is observed following this proce-dure. Wehave rarely encountered such a seriesof events (in 7 instances), since it has been ourpolicy to delay tonsillectomy until all clinical andlaboratory evidence of active rheumatic fever hasdisappeared. This precaution is probably respon-sible for the small number of recurrences that wehave observed after tonsillectomy. The explana-tions for the reappearance of rheumatic fever fol-lowing tonsillectomy have been many and incon-clusive. Appendectomy has seemingly been re-lated in 10 instances to a subsequent attack ofrheumatic fever. Frequently the appendix, at thetime of removal, has appeared to be normal. Itmay be that some of these cases, at least, exemplifyan onset of rheumatic fever with abdominal symp-toms rather than a true initiation or reactivationof the rheumatic process by the surgical procedure.Of this we have no proof.

The clinical course of the disease as illustratedin Figure 3 is of unusual interest in this connec-tion. A girl of thirteen years had had four pre-

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vious attacks of rheumatic fever, the last havingsubsided at the age of twelve, one year before therecorded events transpired. In the interim shehad been well. She entered the Orthopedic Serv-ice of the Massachusetts General Hospital forsurgical correction of an old ankle injury. OnMarch 28 (Figure 3), under ethylene anesthesia,an arthrodesis of the ankle was performed. Im-mediately following the operation a persistent andincreasing fever appeared for which there was noobvious explanation. On the ninth day, becauseof the continued and unexplained fever, the woundwas explored under gas and oxygen anesthesia andfound to be entirely clean. Cultures were ster-ile. The second operation appeared to aggravatethe temperature and leukocytosis, the true nature

of which was not suspected until a to and fro peri-cardial friction rub was discovered together withsigns of early congestive heart failure. Subse-quently, the electrocardiogram showed a delayedauriculoventricular conduction time. The pa-tient's condition, after a rather stormy course,slowly improved on salicylates and digitalis, andshe was discharged from the hospital a monthlater clinically well but still with a leukocytosis of13,800. There were no joint pains at any time.The evidence seems clear that, in this instance,the general disturbance resulting from the anes-thesia and surgical operation in a rheumatic child,who was clinically well, was responsible for thereactivation of a latent rheumatic process. Webelieve this to be more than a coincidence, in

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EDWARDF. BLAND AND T. DUCKETTJONES

view of the entire absence of infection either inthe respiratory tract or elsewhere.

There remains to be recorded a crucial observa-tion on a girl aged twenty years who entered themedical wards (E. M. 319,881) of the Massachu-setts General Hospital with severe chorea andminimal rheumatic heart disease. For the pre-ceding six months she had been in relatively poorhealth, with vague and repeated joint pains andoccasional nosebleeds, prior to the onset of choreatwo months before entry. Because of the in-creasing severity of the chorea, in spite of rest inbed and sedatives, she was given protein shocktherapy. After the third daily injection of 0.1cc. of stock typhoid-paratyphoid vaccine intra-venously, she exhibited an unusual and alarmingrise in temperature to 108.90 F. (rectal), whichsubsided promptly after ice packs had been ap-plied. No further immediate complications ap-peared, and the severity of the chorea was con-siderably reduced. Two weeks after the lastprotein shock the patient developed a low-gradefever of from two to three degrees, complained ofmultiple joint pains, and an aortic diastolic mur-mur, not previously noted, was heard. The elec-trocardiogram, taken for the first time, showed adelay in auriculoventricular conduction with aP-R interval of 0.30 second. The joint pains andfever responded promptly to salicylates, and thepatient left the hospital against advice. Twelvemonths later she reported at our request for afollow-up examination. She was in good healthand had had no further recurrences of rheumaticfever. There was evidence on physical examina-tion of slight cardiac enlargement with minimaldisease of mitral and aortic valves. It occurredto us, in retrospect, that perhaps in this instanceby reactivation a low-grade rheumatic fever hadbeen brought to a clinical level as a result of thetherapeutic injections of typhoid-paratyphoid vac-cine.

Reactions after typhoid-paratyphoid vaccine

Numerous observers have reported favorablyupon the use of intravenous typhoid-paratyphoidvaccine (as an agent for non-specific proteinshock) in the treatment of a large number andvariety of diseases. This procedure is widelyused, especially in treating diseases of unknown

etiology. It seemed logical and justifiable to usethis (typhoid-paratyphoid) vaccine intravenouslyin patients with rheumatic fever in a dosage com-parable to that of usual therapeutic procedures.The value of this therapeutic measure has notbeen completely studied in rheumatic fever. Inaddition, it was thought possible that one mightsecure information concerning the role of non-specific fever in patients with rheumatic fever, aswell as the significance of the febrile episodesoften observed before recurrences. The proce-dure determined upon was to give a single intra-venous dose of stock typhoid-paratyphoid vaccine(0.1 cc. of vaccine containing 250,000,000 or-ganisms). This quantity tsually results in a mod-erate temperature reaction and a chill. Themethod of repeated doses of typhoid-paratyphoidvaccine, as used by Sutton and her co-workers inthe treatment of chorea (11) and as has been em-ployed in rheumatic fever (12), has not been fol-lowed.

The patients chosen for this procedure werecarefully selected. They were chiefly adolescentindividuals who had shown no tendency to pro-gressive cardiac disease in spite of frequent at-tacks of rheumatic fever. Most of the cases hadhad a number of attacks during a long period ofobservation. In addition, all were in excellentgeneral physical condition but exhibited evidence,chiefly from laboratory examination, of low-gradechronic rheumatic fever. Save for recent jointpain, occasional epistaxis and an occasional tran-sient erythema marginata in three cases, the evi-dence of continued rheumatic fever was basedentirely on abnormal laboratory findings. A few,as will be pointed out later, had shown in the pasta clear relationship between respiratory infectionand a subsequent attack of rheumatic fever. Wedesire to record in some detail the results of thesefew observations.

Case IR. M., H.G.S. 5614, female, age 16, gave a history of

frequent attacks of rheumatic fever since the age of sixyears, usually following a cold but on two occasionsafter pneumonia. On entrance to the hospital, in No-vember, 1932, she had laboratory evidence of low-graderheumatic infection with moderate enlargement of theheart and the murmurs of mitral stenosis and regurgita-tion and slight aortic regurgitation.

Observation L. In May, 1933, Figure 4, she developed

638

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a sore throat and fever for two days. After a latent pe-riod of three weeks a recrudescence of clinically activerheumatic fever appeared, associated with fever, jointand precordial pain and erythema multiforme. Hemolyticstreptococci were present in throat cultures throughoutboth the respiratory and the rheumatic fever phases ofthis observation.

Observation II. After this episode had subsided shewas given, in July, 1933, an intravenous injection of 0.1cc. of stock typhoid-paratyphoid vaccine, which resultedin a mild and transient temperature reaction as indicatedin Figure 5. Af ter a latent period of three weeks atypical recrudescence of clinically active rheumatic f ever

appeared with f ever, multiple polyarthritis and erythemamultif orme. The response to salicylates was striking.

Observation III. In January, 1934, a temperature of1030 F. (rectal) was induced artificially f or three hoursby means of exposure in a hyperthermia box. Thistreatment was not f ollowed by any evidence, during sub-sequent observation, of a clinical recurrence of rheumaticf ever. Hemolytic streptococci were absent throughoutthis observation.

Observation IV. In February, 1934, and seven weeksafter the third observation, the patient received for thesecond time a single injection of 0.1 cc. of vaccine whichprecipitated a slight chill and the usual febrile reaction

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(Figure 6). In contrast to the previous postvaccinal re-

action, an immediate reactivation of the latent rheumaticinfection became manifest with the appearance of fever,multiple arthritis, erythema multiforme, and an eleva-tion of the corrected sedimentation index (method ofRourke and Ernstene (13)) from a previously normallevel of 0.28 mm. per minute to 1.10 mm. per minute, to-gether with an increase in auriculoventricular conductiontime from 0.16 second to 0.19 second. 'The symptomssubsided spontaneously without salicylate therapy. He-molytic streptococci were absent throughout this observa-tion. Of considerable interest is the fact that our clinicalimpression suggests that in spite of the apparently in-

duced recrudescence of rheumatic fever this patient'slow-grade infection of several years standing was defi-nitely improved following the last episode, so that inMay, 1934, all laboratory and clinical evidence of infec-tion had disappeared and she was discharged from thehospital. Her cardiac status remained essentially as atentry.

Case II

I. P., H.G.S. 5703, female, age 17, gave a history ofrheumatic fever at the age of twelve years, with prob-able low-grade activity during subsequent winters as

indicated by frequent joint pains, poor health and nose-

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bleeds. In October, 1932, following a tonsillectomy, shehad mild rheumatic fever with symptoms for threeweeks. In February, 1933, she had a sore throat andthe "grippe." Three weeks later she entered the hos-pital because of general poor condition and was found tohave evidence of active rheumatic infection with fever,precordial pain, occasional nosebleeds, and a well markedelevation of the corrected sedimentation index of 1.40mm. per minute. The heart was moderately enlarged,with the murmurs of mitral regurgitation and stenosisand aortic regurgitation. She improved with rest in bed,and after one week the temperature returned to normal.

Observation I. In April, 1933, she was given a singleintravenous injection of 0.1 cc. typhoid-paratyphoid vac-cine, which was followed by a transient elevation oftemperature and a slight chill (Figure 7). During thesubsequent three weeks there occurred frequent slightnosebleeds (present before), vague ankle pains, occasionalprecordial and abdominal pain. At the end of the thirdweek there appeared a frank flare-up with fever and anacutely swollen, red and tender wrist, which became sopainful that salicylates were required. Prompt reliefresulted, but a vague discomfort in the wrist and fingerspersisted for several days. Throat cultures were notdone at this time. The patient was discharged from thehospital in November, 1933, without further occurrenceof acute rheumatic fever. The heart remained as atentry.

Case IIIE. F., H.G.S. 5876, female, age 16, gave a history of

the onset of rheumatic fever and rheumatic heart diseaseat the age of six years. At the age of thirteen she had arecurrence of rheumatic fever. In January, 1933, at theage of 16, there was a third attack one week after a sorethroat, and she entered the hospital for prolonged bedcare. She appeared to be in good general condition, andthe only evidence of low-grade infection was an occa-sional nosebleed and almost daily erythema multiforme.The auriculoventricular conduction time by electrocardio-gram remained at 0.20-0.21 second.

Observation I. In April, 1933, a temperature and as-sociated chill was induced by the intravenous administra-tion of 0.1 cc. of typhoid-paratyphoid vaccine as before.A slight rise in temperature to l0 to 100.50 F. (rectal)persisted for five days, but there was no definite evidenceof a subsequent flare-up of the rheumatic process. He-molytic streptococci were present in throat cultures takenon the day of the protein shock, absent on the fifth day,and again present on the ninth day after the injection.The white blood count and the auriculoventricular con-duction time remained unchanged.

Observation II. In January, 1934, an artificial feverof 102.50 F. (rectal) induced by means of a hyperthermiabox was not followed by any clinical manifestations ofrheumatic fever. Throat cultures showed no hemolyticstreptococci before the procedure. Hemolytic strepto-cocci were present in the throat on the first day after thetreatment, and absent on subsequent days.

Observation III. In February, 1934, a single proteinshock was induced in the usual manner by the intra-venous injection of 0.1 cc. of vaccine (Figure 8). Thiswas followed by a low-grade fever for five days asso-ciated with a nosebleed and the reappearance of erythemamultiforme on the seventh day, but of most interest, per-haps, was the electrocardiographic evidence of slightlydelayed but progressively increasing block in auriculo-ventricular conduction from a P-R interval of 0.18 sec-ond up to 0.25 second on the tenth day. From a normallevel of 0.25 mm. per minute the corrected sedimentationindex rose to 1.60 mm. per minute. Hemolytic strepto-cocci were present in the throat cultures before the pro-tein shock, but absent afterwards. We have consideredthis a definite recrudescence of rheumatic fever followingprotein shock.

Case IV

A. C., H.G.S. 5351, male, age 10, gave a history offour previous attacks of rheumatic fever and one ofchorea during the preceding five years, in spite of whichhe had developed only minimal rheumatic heart disease,with the murmurs of slight mitral disease together withslight cardiac enlargement. In March, 1933, he againdeveloped rheumatic fever, precipitated by a cold, withpolyarthritis, nosebleeds, loss of weight and mild chorei-form movements. On April 13, 1933, he entered thehospital for his second admission, where his subsidingjoint pains as well as his fever responded promptly tosalicylates.

Observation I. As shown in Figure 9, protein shockwas induced by the intravenous injection of 0.1 cc. oftyphoid-paratyphoid vaccine, which gave rise to a severechill and a rather unusual temperature reaction to 105° F.(rectal). Within an hour from the onset of the chilltwo joints of the left hand, which had been involved onadmission, became acutely tender, definitely red, hot andswollen. On the second day another finger and the wristjoint showed similar involvement. Because of the per-sistent and brisk temperature reaction, together with theconsiderable joint discomfort, salicylates were startedwith a prompt and striking subsidence of both fever andarthritis, even with minimal doses. Slight joint painsand an occasional slight fever persisted during the sub-sequent two weeks. It is of interest that the mild chorei-form movements became quiescent after the febrile re-

action. The corrected sedimentation index on April 28was 1.40 mm. per minute. A study of the pharyngealflora was not made during this episode. There were nofurther recrudescences, and by June, 1933, all clinical andlaboratory evidence of infection had subsided. The heartremained as at entry. It is to be noted that clinical evi-dence of rheumatic fever was present in this patient atthe time of the protein shock, and was manifested by re-

cently swollen and painful joints which had been relievedby salicylates, by mildly active chorea and by a leuko-cytosis of 16,000.

643

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FURTHEROBSERVATIONS

In addition to, and concurrently with, the aboverecorded observations, five other patients of simi-lar ages with either low-grade subclinical rheu-matic fever or recently quiescent infection re-

ceived a single protein shock by means of an in-travenous injection of 0.1 cc. of typhoid-para-typhoid vaccine. The general reaction with chilland fever was similar in all respects, but subse-quent clinical and laboratory study failed to revealfrank evidence of a reactivation of the rheumaticprocess. In two instances there was a short pe-

riod in which doubtful signs and symptoms sug-

gestive of rheumatic fever occurred. In one ofthe above instances a comparable fever producedby means of the hyperthermia box was not fol-lowed by any evidence of a recrudescence.

In summary, it may be stated that ten patientshave received twelve injections of typhoid-para-typhoid vaccine. The usual chill and temperaturewere noted. In six instances clinical symptoms ofactive rheumatic fever appeared either imme-diately following the injection or after an inter-val of two to three weeks. In two instances therewas a questionable reaction of this type. In theremaining four instances no clinical or laboratoryevidence of a reactivation of rheumatic fever was

demonstrable. No untoward effects of seriousimport were noted. Following the reactions totyphoid-paratyphoid vaccine there seemed to be a

more rapid progress to quiescent rheumatic feverthan was previously noted.

DISCUSSION

Respiratory infection and its relation to rheu-matic fever has for years received much attention.The recurrence of rheumatic fever followingrespiratory infection, often after an interval ofa few days to two or three weeks, is generallyknown to students of the disease. It is also wellrecognized that recurrences are observed in theabsence of evident previous infection or of otherdisturbing factors. In our series there has beena preceding respiratory infection in 75 per centof observed recurrences; whereas, in the remain-ing 25 per cent there were no obvious precipi-tating causes. On the other hand it may be wellto point out that attacks of definite tonsillitis or

pharyngitis are not consistently followed by re-

currences of rheumatic fever. That other events,such as tonsillectomy, may at times be associatedwith subsequent rheumatic fever has also beennoted in the past. Attention is called to a vari-ety of episodes which appear to have been relatedto recurrent rheumatic fever. If one omits scar-let fever and other infections usually associatedwith infection of the upper respiratory tract,there still remain other events which appear to beof importance. Under these circumstances, a re-liable history must be obtained soon after theevent has transpired, as is often necessary even inthe case of respiratory infections, since transientminor illness or injury may be quickly forgottenby the patient. Although it is obvious that therelative number of such events is small in solarge a group of cases, no statistical study hasbeen presented for two reasons: first, a historyfrom this point of view is reliable only if one iscognizant of the possibility of such a relation-ship; and second, as noted above, it is necessaryto obtain the history while events are fresh in thepatient's mind. The majority of our patientshave had rheumatic fever for a considerable pe-riod of time prior to admission to the hospital,and only recently has this sequence of events beensearched for. Second, in a hospital such as ourstraumatic accidents are not observed, nor are ill-nesses other than rheumatic fever common. Areliable statistical study, although difficult to ob-tain, we believe would be valuable. Since we havebeen aware of the possible importance of eventsother than streptococcal infections prior to recur-rences of rheumatic fever, the frequency withwhich they have been encountered has increasedsurprisingly.

It is not rare to find instances in which an ab-dominal operation is a precursor of clinical rheu-matic fever. This would seem to hold, regardlessof the need for the surgical procedure or thediagnosis for which it is undertaken.

It seems evident to us that it is not rare forevents other than respiratory infection to precedethe appearance of clinical rheumatic fever, andthat they must be considered in some manner aprecipitating factor, possibly non-specific.

The clinical observation of the reappearance ofthe symptoms of rheumatic fever following a

single treatment with non-specific protein therapy

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seems of considerable importance to us. Rheu-matic fever was not produced in normal humanbeings, but the asymptomatic phase of the diseasewas brought to a clinical level in known rheumaticindividuals by non-specific means. The frequencyand definiteness of these few observations con-vince us that we are dealing with more than achance relationship. The studies have not beenpursued further for the obvious reason that wedid not wish to cause clinical disturbances in ourpatients. It is generally accepted that subjectswith rheumatic fever, especially those with recenthistories of rheumatic fever, are very susceptibleto recurrences. It is evident that these may beprecipitated frequently by purely non-specificmeans. These observed recurrences were, on thewhole, of shorter duration and were milder thanthose occurring naturally. No evident alterationof the cardiac state, other than the temporaryprolongation of the auriculoventricular conductiontime, was noted. The symptoms noted during therecurrences of clinically active rheumatic fever,following the reaction to a single injection of non-specific protein, reproduced in a striking fashionthe rheumatic manifestations which had beenpreviously observed in the individual patient dur-ing a naturally occurring recrudescence.

As noted previously, the initiating factor mostcommonly encountered in patients with rheumaticfever is respiratory infection. In view of the datapresented, bacterial activity during respiratory in-fection may prove to be of secondary importance.The crowded, unhygienic living conditions of thenmajority of patients with rheumatic fever maywell account for the frequency of respiratory in-fections. In addition, the study of any group ofpatients with rheumatic fever will show a largenumber of such respiratory infections even undersatisfactory living conditions.

In view of the observations herein recorded, itis suggested that the r6le of infections or of epi-sodes seemingly related to recurrent rheumatic fe-ver may not be as specific as has been previouslythought. Respiratory infection, often accompa-nied by hemolytic streptococci, is frequently theprecipitating agent of rheumatic fever, but otherevents likewise may be important. The appear-ance of the clinical symptoms and signs of thedisease are not, therefore, entirely dependent

upon recognizable respiratory infection. This ap-parently non-specific relationship may be of im-portance in future etiological considerations.

CONCLUSIONS

1. There appears to be no significant clinicaldifference between the recurrences or recru-descences of rheumatic fever following (1)respiratory infection, (2) other forms of infec-tion, (3) accidents or operative procedures, and(4) a single intravenous injection of typhoid-paratyphoid vaccine sufficient to cause a slightfebrile reaction and chill.

2. The probable significance of these observa-tions has been discussed. It is evident that vari-ous events precede and apparently influence theappearance of the signs and symptoms of recur-rent rheumatic fever.

3. It seems desirable, in view of the observa-tions presented, to consider the role of such eventsas non-specific until more definite information isavailable concerning the etiological agent.

Wewish to gratefully acknowledge our indebt-edness to Doctors James H. Means and M. N.Smith-Petersen of the Massachusetts GeneralHospital for allowing us to cite cases from theirrespective services. The typhoid-paratyphoidvaccine used throughout these observations wasobtained from the Antitoxin Laboratory of theMassachusetts Department of Public Health.

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