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The virtual disappearance of rheumatic fever in theUnited States: lessons in the rise and fall of diseaseT. Duckett Jones Memorial Lecture

LEON GORDIS, M.D., DR.P.H.

I AM DEEPLY HONORED to have been invited togive the 1984 T. Duckett Jones Memorial Lecture.This year marks 40 years since Dr. Jones first pub-lished his paper entitled "The Diagnosis of RheumaticFever."' Jones had the foresight to recognize the im-portance of standardized diagnostic criteria from threepoints of view. He wrote: "(1) Otherwise, [withoutstandardized criteria] the incidence of rheumatic fevermay be interpreted as varying greatly whether the dataare collected by surveys, the development of a rheu-matic fever register, making the disease reportable, orthe study of hospital records. (2) The interpretation ofstudy programs of prevention and care is obviouslydependent on such diagnostic criteria." Jones' thirdpoint dealt with the importance of standardized diag-nostic criteria if valid information regarding ultimateprognosis were to be obtained and provided to patientsand their families. It is noteworthy that the primarybenefits he described were not so much the improvedclinical management of individual patients with rheu-matic fever, but rather facilitation of the collection ofmeaningful incidence data and evaluation of the effec-tiveness of prevention programs. In this article I wouldlike to discuss the dramatically changing incidence ofrheumatic fever and its relation to our preventive ef-forts. The studies I will present were possible onlybecause of the broad acceptance and utilization of thediagnostic criteria promulgated by Dr. Jones 40 yearsago.

Throughout history people have been intrigued bythe apparent appearance and disappearance of humandisease, believed by many to be actions of the gods indirect response to humain behavior. Over the yearsthere have been attempts to develop a scientific ration-

From the Department of Epidemiology, Johns Hopkins School ofHygiene and Public Health, Baltimore.

Supported in part by NHLBI grant T32HL07024.Address for correspondence: Leon Gordis, M.D., Dr. P.H., Depart-

ment of Epidemiology, Johns Hopkins School of Hygiene and PublicHealth, 615 N. Wolfe St., Baltimore, MD 21205.

This Perspective summarizes Dr. Gordis' presentation as the T.Duckett Jones Memorial Lecturer at the Annual Meeting of the Ameri-can Heart Association, Miami Beach, November 1984.

Vol. 72, No. 6, December 1985

ale for explaining these phenomena. I would like toreview the picture of rheumatic fever as it has emergedin studies we have carried out in Baltimore over aperiod of more than two decades. I shall then try toplace the changes that have occurred in the context ofother diseases that have either increased or decreasedin incidence or mortality in the United States duringthe 20th century.

The Baltimore studies. The earliest of these studieswere carried out in collaboration with Dr. MiltonMarkowitz. In the ensuing years he has continued to bea stimulus and constructive critic and is, in essence, aspiritual collaborator in all these investigations. Ourfirst study in Baltimore examined the incidence pat-terns of acute rheumatic fever from 1960 to 1964.2 Thefindings were marked by dramatic racial differences.Rates of both initial and recurrent attacks were morethan twice as frequent in blacks as in whites. Thesefindings were consistent with the observation that thedisease tended to cluster in the predominantly blackareas of the inner city of Baltimore. Relatively few ofthe cases occurred in suburban areas.

In a second study we found that from 1960-64 to1968-70, the rates in blacks in Baltimore dropped dra-matically while the rates in whites remained relativelyunchanged. To explain this change we asked the ques-tion: Could the decline in incidence in black childrenbe due to the inner city comprehensive care programsfor children and youth that had been established in themid-1960s? A study was therefore carried out to com-pare the incidence of rheumatic fever in census tractseligible for comprehensive care compared to censustracts not eligible for comprehensive care.' As seen infigure 1, in the census tracts that were eligible forcomprehensive care, incidence of rheumatic feverdropped 60% from 1960-64 to 1968-70. In contrast,there was virtually no change in noneligible censustracts.

Because many social and economic changes hadtaken place during this time, it would be difficult toascribe the decline in rheumatic fever specifically to

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>. BLACKS

'.;WHITES

1968 -70COMPREHENSIVE

CARENfET CHANGE - 60.4 %

ALL NON-ELIGIBLE ALL OFTRACTS BALTIMORE

+2.0% -35.4%

FIGURE 3. Average annual incidence of first attacks of rheumaticfever ages 5 to 19, by race. Baltimore, 1960-81.

FIGURE 1. Comprehensive care and changes in rheumatic fever inci-dence, 1960-64 to 1968-70 (Baltimore, black population, ages 5 to 14years).

comprehensive care solely on the basis of these find-ings. A further analysis was therefore carried out withthe following rationale: If the comprehensive care pro-grams were indeed responsible for the observed de-cline in rheumatic fever by providing quality ambula-tory care to children, they could have had such animpact only in children who had clinically overt phar-yngitis. If so, we would expect the decline observed inrheumatic fever to have been limited to those cases thathad been preceded by clinical pharyngitis and to seerelatively little change in the incidence of cases preced-ed by subclinical pharyngitis, since such childrenwould have had no reason to seek medical care andconsequently the comprehensive care programs wouldnot be expected to have any impact in this group. Asseen in figure 2, when analyzed in this fashion theentire decline in rheumatic fever was found in casesthat had been preceded by clinically overt acute phar-

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yngitis. Thus the data up to 1970 were highly consis-tent with the hypothesis that in Baltimore, the declinein rheumatic fever, which was limited to blacks, wasprimarily a result of the comprehensive care programsin the inner city.More recently, we carried out a third study in Balti-

more utilizing the same methods as the two previousinvestigations. As seen in figure 3, from 1968-70 to1977-81, incidence rates of rheumatic fever droppeddramatically in both whites and blacks to extremelylow rates. Perhaps the most dramatic view of thesechanges is seen in figure 4, which shows spot maps forrheumatic fever cases for the first and last 5 year pe-riods of this study, 1960-64 on the left and 1977-81 onthe right. Only five cases were seen in Baltimore from1977 to 1981, and all were clinically mild.

National data for the United States. These findings areconsistent with data reported from other communities,such as those of Land and Bisno from Memphis, Ten-nessee.4 Available evidence suggests that this is alsothe pattern in other cities in the United States in mostpopulations. National data for hospital discharges witha diagnosis of rheumatic fever from the National Hos-pital Discharge Survey conducted by the National Cen-ter for Health Statistics, and kindly provided by Dr.Edward Bacon of the Center, confirm this decline (ta-ble 1). The decline is also seen when the rates are

1960 -64 1977*81 7FIGURE 4. Spot maps for rheumatic fever cases in Baltimore 1960-64and 1977-81.

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1960-64 1977-81

FIGURE 2. Changes in the annual incidence of first attacks of rheumat-ic fever in relation to preceding clinical respiratory infection.

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TABLE 1Annual rates (per 100,000) of discharges of patients with rheumaticfever from short-stay non-federal hospitals in the United States,1965-83

Discharge DischargeYear rate Year rate

1965 14.0 1973 5.11966 13.3 1974 4.81967 10.2 1975 4.11968 8.4 1976 3.31969 NAA 1977 3.51970 7.8 1978 3.01971 8.1 1979-80 2. OB1972 5.6 1981-83 1.0B

Source: National Hospital Discharge Survey, NCHS.AData not available.BAverage annual rate per time period.

examined by age and race (table 2). Thus we have amarked decline in rheumatic fever, indeed a virtualdisappearance of the disease in both blacks and whitesin Baltimore, and this appears consistent with mostavailable data from elsewhere in the United States.

"New" and "disappearing" diseases. What can accountfor the extraordinary phenomenon we are observing inacute rheumatic fever in the United States? To addressthis issue I would like to discuss briefly other diseasesthat have either appeared or at least increased in inci-dence or disappeared or declined in incidence in thecourse of the 20th century. Among the "new" diseases,or those that have at least increased markedly in inci-dence during the last few decades, are: lung cancer,clear cell carcinoma of the vagina, phocomelia, toxicshock syndrome, legionnaires disease, Kawasaki dis-ease, Reye syndrome, Lyme arthritis, and AIDS. Eachhas attracted considerable interest, including perhapsmost notably the rapid increase in AIDS.What can account for the relatively rapid appearance

TABLE 2Annual rates of hospital discharges of patients with rheumaticfever by age and race, United States, 1965-67, 1972-76, and1979-83A

Rates per 100,000

1965-67 1972-76 1979-83

Age0-19 yr 19.2 7.0 2.8

20 yr and older 8.0 3.2 0.8Race

White 11.8 4.4 1.4Nonwhite 17.3 5.6 1.4B

AShort-stay non-federal hospitals (source: National Hospital Dis-charge Survey, NCHS).

BBased on a small sample of records.

Vol. 72, No. 6, December 1985

of a disease? Certainly better diagnosis and recognitionor differences in artifacts of coding can also play arole. Increased physician awareness of infectiousagents and changes in the prevalence of the agents or inthe biological characteristics of the agents that relate tovirulence may also be critical. For diseases havingother causes, new agents introduced into the environ-ment or new exposures to them may account for theincrease. Finally, removal of certain protective mecha-nisms may play a role. For example, it has been sug-gested that Hodgkin's disease has a higher incidence inupper socioeconomic individuals because such indi-viduals are protected from certain early childhood in-fections such as Epstein-Barr virus, a model similar tothat seen in polio.5Below are listed some diseases that seem to have

disappeared or at least declined in incidence during the20th century:As a result of planned eradication campaigns:

Infectious diseasesSmallpoxPolio

Nutritional ricketsAs a result of changes in medical practice:

Retrolental fibroplasiaNot completely understood:

Stomach cancerUterine cancerPeptic ulcerCeliac diseaseStrokeMyocardial infarctionEndocardial fibroelastosis

Some of these diseases seem to have declined primar-ily as a result of planned and well-organized eradica-tion campaigns. These include infectious diseases suchas smallpox and poliomyelitis and diseases such asnutritional rickets, which have declined in incidence asa result of specific dietary supplementation. Second,we have diseases that have almost disappeared as aresult of changes in medical practice. Perhaps the mostdramatic example is retrolental fibroplasia.

Other diseases have disappeared without any specif-ic eradication campaign. For example, stomach cancerhas declined markedly in the United States, as hasuterine cancer, with no explanation immediately athand to account for these changes. Other diseases suchas peptic ulcer and celiac disease have also declinedand the causes for the declines remain unknown. Iso-lated endocardial fibroelastosis, without aortic dis-ease, appears to be much less frequent than in previousyears. Finally, and perhaps most noteworthy are the

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declines in mortality from stroke and coronary heartdisease.What can account for dramatic decreases in inci-

dence and mortality of disease? Changing diagnosticapproaches and changes in coding can play a role andproduce artifactual changes. For diseases caused byinfectious agents, it is at least theoretically possiblethat the virulence of the agent may diminish or theprevalence of human exposure to the agent may de-cline. If caused by exposures to other etiologic agentsin the environment, such may change over time as

existing hazards are recognized and controlled. Final-ly, changes in lifestyle or changes in the quality andaccessibility of medical care may play a role in de-clines observed in the incidence of disease.

Possible explanations for the virtual disappearance of

rheumatic fever. With this background, how can we

explain the changes observed in the incidence of rheu-matic fever? Reasonably valid population-based inci-dence data for rheumatic fever did not become avail-able until the 20th century. Hence, although rheumaticfever has been present for centuries and according to

some, may have been present in antiquity, it is difficultto state whether at some point in time there was a

sudden appearance of the disease or a sudden rise in theincidence of the disease. What is clear, however, isthat the 20th century has witnessed a sharp decline in

rheumatic fever, at least in the United States and inother economically developed countries.

Could the decline in rheumatic fever be due tochanges in the streptococcus itself? Let us examine thepossibilities. The first would be that the incidence ofstreptococcal infections has declined. Although some

experts believe that there has, in fact, been a decline inthe incidence of streptococcal infections, it is difficultto document such a change. In fact, Hall and Breesehave reported from Rochester, New York, that thenumber of throat cultures positive for group A strepto-cocci did not decline during a time period when a

decline in rheumatic fever was observed (unpublishedobservations). Unfortunately, there is no ongoing sys-

tematic data collection system in the United States thatcould provide the information needed to address thisissue.

If the incidence of streptococcal infections has infact declined, the decline could be part of a cyclicalpattern of increases and decreases in incidence ofstreptococcal infections and that we may just be on thedown side of the curve at this point in time. If indeedthere is such a cyclic phenomenon, we might anticipateanother rise in streptococcal incidence in the future andwith it a possible rise in rheumatic fever incidence.

Could there have been a change in the prevalence ofrheumatogenic types in our communities or in the inci-dence of infections produced by rheumatogenic types?Although there is strong evidence that there are nephri-togenic types, the case for rheumatogenic types is notclear. Support for this contention comes from severaltypes of evidence: (1) The temporal and geographicvariations observed in rheumatic fever incidence areconsistent with the existence of rheumatogenic andnonrheumatogenic types. (2) Early data from Kuttnerand Krumweidef suggested differences in rheumaticfever attack rates depending on the serologic type ofstreptococcus in the outbreak. (3) Data from Potter etal.7 suggest that in Trinidad the serologic types ofstreptococci causing rheumatic fever differ from thosecausing nephritis even in the same families. (4) Sea-sonal differences reported in occurrence of rheumaticfever and of glomerulonephritis are also consistentwith different rheumatogenic potential of different ser-otypes.8 (5) Rheumatic fever and nephritis rarely occursimultaneously.

Could there have been a change in the virulence ofthe streptococcus over time? This is certainly a possi-bility, although as McCarty has suggested, given thefact that no single serologic type has been demonstrat-ed to be rheumatogenic, any changes in virulencewould have had to occur in several serologic types ofstreptococci simultaneously.9 Nevertheless, we do seesome evidence consistent with changes in the virulenceof the streptococcus. Scarlet fever has become a muchmilder disease over the last few decades and its inci-dence has perhaps declined. Data from Baltimore sug-gest that the incidence of poststreptococcal acute glo-merulonephritis may also have declined, although notas markedly as that of rheumatic fever (figure 5). Fur-ther evidence consistent with a possible change in viru-lence of the organism is the changing pattern of antibi-otic sensitivity of the streptococcus. High rates ofresistance of streptococci to tetracycline, and to a less-er extent to erythromycin and lincomycin, have beenreported. '0

There is some ambiguity associated with the term"virulence." Virulence may refer to the capacity of thestreptococcus to adhere to human epithelium, to itsability to evoke an antibody response, to its ability toproduce clincial pharyngitis or other infection, or to itsrheumatogenic or nephritogenic potential. Streptococ-cal virulence has been associated with the M protein ofthe cell surface, which has antiphagocytic propertiesand may also enhance the adherence of the streptococ-cus to epithelial cells by forming a complex with lipo-teichoic acid.11 To date, there is no evidence that the

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FIGURE 5. Incidenresidents, ages 0-19

percentage of stitypeable has decter suggest that tthat are M-typ(years. Data are

ability of strept

If a change inindeed taken plabeen suggestedpeople in the p

levels at any tintransmission, whanced virulencexpect a decreasthat were M-typthe streptococciwith specific antUnfortunately,lence rates of a

Another poss

rheumatic fevermay operate tog'rheumatic feverhost resistance 2

It is well recogi

there is an incre,nary infectionsHemophilus inflseria Meningitiicus pneumonia(viral infections'to be particularl,cocci, streptoci

adherence had tmentally and IAntecedent viraseveral organisntococci.'6 Viral

inhibit normal antibacterial defenses, and all measuresof macrophage function seem to be affected. 13 Thus thepossibility that viruses may act as a cofactor in promot-ing the establishment of streptococcal infections or insome other fashion is not unreasonable. Althoughstudies in the past of possible associations of viral andstreptococcal infections were not rewarding, the mar-kedly improved technology for viral studies availableonly in recent years has not yet been adequately ap-

plied to exploring this possibility.

1974 1976 1 78

It is also possible that some other environmentalagent could be serving as a cofactor. Fainstein and

ice of hospitalized glomerulonephritis, Baltimore Musherl7 found that smokers had increased adherence

years, 1972-81years,1972-81. of pneumococci compared with nonsmokers. Al-

reptococcal strains isolated that are M- though they did not observe such differences for strep-reased and, in fact, data from Roches- tococci, their findings exemplify the possibility thathe percentage of streptococcal isolates environmental factors may, in principle, affect bacte-eable may have increased in recent rial adherence and that such a mechanism could beneeded on changes in the adherence operating with the streptococcus, although the possibleococcal strains isolated over time. agent or agents that may be involved is not known.the virulence of the streptococcus has To what extent can we attribute the decline in rheu-ce, what could have produced it? It has matic fever to medical care and primary preventionthat the relatively high proportion of efforts? It seems an inescapable conclusion that at leastiopulation who have serum penicillin part of the observed decline in rheumatic fever must bene may serve to interrupt the chain of due to the prompt and appropriate antistreptococcalrhich is often also associated with en- treatment given by physicians throughout the country.:e. If this were the case, one would However, although the data in Baltimore for 1968-70se in the percentage of isolated strains suggest such an explanation, it is difficult to reconcile,eable. It is also possible that nowadays the more recent decline in rheumatic fever that has,is more frequently encounters people occurred in both blacks and whites in Baltimore, withtibodies that prevent this transmission. changes in medical care and in the way health servicespopulation-based data on the preva- are delivered. In assessing any decline in disease inci-nti-M antibodies are not available. dence, however, there are potential hazards in assum-

sibility for explaining the decline in ing that the changes observed are in fact due to medicalis the disappearance of a cofactor that advances and to the care provided. Rene Dubos wrote,ether with the streptococcus to produce "When the tide is receding from the beach, it is easy to

Viruses have been known to affect have the illusion that one can empty the ocean byand responses to bacterial infections.'2 removing water with a pail."'8 Some years ago, Dr.nized that during influenza epidemics Edward Kass pointed out that major scientific ad-ased risk for both systemic and pulmo- vances that have enhanced our medical care for dis-caused by many organisms, including eases such as tuberculosis have not been clearly relatedluenzae, Staphylococcus aureus, Neis- to the major declines in incidence and mortality of suchdis, Escherichia coli, and Streptococ- diseases'9 (figure 6). When we examine a similar pre-C. 3 Newborns with upper respiratory sentation of the data for rheumatic fever as shown in

were reported long ago by Eichenwald figure 7, we see that the decline in rheumatic fevery susceptible to infections by staphylo- mortality clearly began before antistreptococcal agentsocci, and H. influenzae."4 Bacterial became available.been found to be enhanced by experi- Could the decline in rheumatic fever be due to some

naturally acquired viral infections.'5 change or changes in the host? Given the relativelyil infection potentiates the growth of short period of time during which the incidence of thens in the lung, including group B strep- disease has declined, the changes cannot be accountedinfections have also been shown to for by genetic alterations in human populations. It is

I

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1860 1870 1880 1890 1900 1910 1920 1930 1940 1950

Mean annual deoth rote from diptheria in childrenunder 15 years of age, Englond and Woles. Koss 1971.

1860 1870 1880 1890 1900 1910 1920 1930 1940 1950

Mean annuol death rate from scorlet fever in childrenunder 15 years of age, England and Woles. Kass 1971.

1860 1870 1880 1890 1900 1910 1920 1930 1940 1950

Meon annual deoth rote from whooping cough inchildren under 15 yeors of age, Englond ond Wales.Koss 1971.

Mean annual deoth rate from respirotory tuberculosis,Englond and Wales. Koss 1971

FIGURE 6. Decline in death rates of diphtheria, whooping cough, Scarlet fever, and respiratory tuberculosis in England andWales. (Reprinted, with permission, from Kass. 19)

conceivable, however, that improved life-style factorssuch as nutrition may have affected the host and madehim more resistant to streptococcal infections.

It is important to note that host factors have longbeen recognized as playing a role in the risk of rheu-matic fever. The higher risk of rheumatic fever inchildren has generally been attributed to their greaterexposure to streptococcal infections. However, it hasbeen reported that streptococci adhere more vigorouslyto cells from young compared with middle-aged sub-jects. 17 This suggests the possibility that endocrine fac-tors, for example, may affect infectivity and rheumato-genicity. Examples from other diseases support thenotion that such host factors above and beyond any

genetically determined susceptibility may play a role.For example, it is well recognized that pregnancy

places a woman at increased risk of acquiring poliomy-elitis. Particularly in the prevaccine era, it was alsorecognized that tonsillectomy increased the risk forbulbar poliomyelitis.

It is interesting to reflect on the reasons we have so

much difficulty today in explaining the marked declinein the incidence of rheumatic fever. One aspect of thisproblem specifically merits discussion because it mayhave implications for our approaches to the etiologiesof other diseases in the future. After Lancefield pub-

1160

lished her landmark work on the streptococcus, inves-tigators interested in rheumatic fever quite appropri-ately focused their attention on confirming therelationship between the streptococcus and rheumaticfever and on elucidating the pathogenetic pathwaysinvolved. As the streptococcus was pursued, the possi-

ble etiologic role of factors other than the streptococ-cus in rheumatic fever received relatively little atten-tion. That such factors genetic, environmental, or a

combination thereof are in fact probably playing

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FIGURE 7. Crude death rates from rheumatic fever, United States,1910-1977.

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such a role is suggested by the data from the studiesthat yielded estimated rheumatic fever attack rates of3% in the military and of 0.3% in civilian populationsof children. Thus 97 of every 100 recruits who ac-quired a streptococcal infection did not develop rheu-matic fever and 997 of every 1000 children who ac-quired streptococcal infections did not developrheumatic fever. Why not? What factors could accountfor the small percentage of individuals with streptococ-cal sore throats who subsequently developed rheumat-ic fever, even in days when rheumatic fever was morecommon in the United States?

In this context, it is worthwhile to look at the ap-proaches taken by epidemiologists to study the etiol-ogy of chronic diseases today, particularly when it isdesired to explore the possible role of a number ofetiologic agents. The approach often used initially isthe case-control study (figure 8). In this design, pa-tients with the disease ("cases") are compared withcontrol subjects without the disease and the propor-tions of cases and controls with specific characteristicsor exposures are compared. In the case of rheumaticfever, in which the streptococcus had been clearly im-plicated, case-control studies addressing genetic andenvironmental factors other than the streptococcuswould have been very valuable. Thus a study of viralfactors in rheumatic fever in association with strepto-coccal infections could be carried out by comparingcases of rheumatic fever with appropriately selectedcontrols and determining what proportion of cases andof controls had specific prior viral infections of inter-est. Because the case-control design permits the inves-tigation of a number of possible etiologic factors at thesame time, it would be possible to develop a predictivemodel of which patients with streptococcal infectionsare at high risk for rheumatic fever. Until now, predic-tion of development of rheumatic fever has primarilybeen addressed by focusing on the characteristics ofthe streptococcus. Although this is a reasonable ap-proach, it should not exclude consideration of host andother environmental characteristics. In his 1982 T.Duckett Jones Lecture, Dr. Elia Ayoub addressed hostgenetic factors in the genesis of rheumatic fever.20 I

EXPOSED ED EXPOSED

DISEASE NO|DISEASE 1 | DISEASE

"CASES" "CONTROLS"

FIGURE 8. Schematic design of a case-control study.

would suggest that other host and environmental char-acteristics should also be considered.The relative lack of rigorously designed and con-

ducted case-control studies in the search for a fullunderstanding of the etiology of rheumatic fever isunderstandable, since much of Lancefield's work waspublished at a time when the case-control design hadnot yet received full recognition and acceptability andwas ony sporadically used. Not until the 1950s, whenthe case-control study design played a major role inestablishing the relationship between cigarette smok-ing and lung cancer, was the case-control study fullylegitimized. By this time the streptococcus was viewedas the full solution to the etiology of rheumatic fever,and as a result, a diligent search for other variables thatmight be involved was never carried out. Thus rheu-matic fever began its dramatic decline in the UnitedStates before adequate attempts had been made to in-vestigate the role of other etiologic agents above andbeyond the streptococcus. Consequently, in the ab-sence of a full understanding of the etiology of rheu-matic fever today, we are unable to definitively explainits decline.Rheumatic fever in the third world. Although the risk of

rheumatic fever has been sharply declining in the Unit-ed States, the picture is far different in developingcountries. Worldwide, rheumatic heart disease re-mains the most common form of acquired heart diseasein children and young adults and an important cause ofall heart disease seen in adults. The status of rheumaticfever and rheumatic heart disease in developing coun-tries has been succinctly summarized by Markowitz2l:(1) Rheumatic fever is the most frequent cause of heartdisease in the 5 to 30 year age group. (2) Acute rheu-matic fever and rheumatic heart disease are two of themost common causes of death in young people. (3)Rheumatic heart disease causes 25% to 40% of allcardiovascular disease. Estimated prevalence of rheu-matic heart disease in India schoolchildren is six to 11per 1000.22 Thirty-three to fifty percent of all hospitaladmissions for heart disease are for rheumatic heartdisease.Even in the United States, however, there are areas

and population groups that have not clearly shared inthe decline in incidence of rheumatic fever. For exam-ple, in the Navajo from 1962 to 1977, the annual attackrate was 12.4 per 100,000 for all ages, with the highestrate of 23.4 per 100,000 in the 10 to 14 year age

23group. Rates of 96.5 per 100,000 have been reportedin Samoans living in Hawaii, with 50% of the patientshaving carditis.24 Recently, the Colorado Departmentof Health reported 14 confirmed cases of rheumatic

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fever in the first 6 months of 1984 compared with onlytwo to three cases reported annually in recent years.25Two points emerge: First, any hypothesis developed toexplain the decline observed in rheumatic fever in mostof the United States must also explain its persistence incertain American population subgroups and in the de-veloping world. Second, this persistence both in theUnited States and abroad should preclude any compla-cency on our part in regard to rheumatic fever.

Conclusion. In conclusion, although the group Astreptococcus is the critical etiologic agent of rheumat-ic fever, the disease may well be multifactorial inorigin. While improved medical care and the use ofpenicillin and other antibiotics have contributed sig-nificantly to the decline of rheumatic fever in the Unit-ed States, the decline antedated the availability of anti-biotics, and in addition the changes in rheumatic feverin the United States cannot be fully accounted for sole-ly by medical care and antibiotic use. The difficulty isthat we lack adequate information regarding other pos-sible cofactors. Studies of such factors are not feasiblein the United States today in view of the very lowincidence of the disease, but such etiologic investiga-tions could be initiated and conducted in developingcountries.From the clinical standpoint, the low risk of rheu-

matic fever today suggests that perhaps we shouldreassess present policies regarding our hunt for thestreptococcus and our determination to eradicate it.However, any relaxation of our currently recommend-ed approaches to streptococcal infections should beundertaken with great caution, since we do not under-stand the reasons for the decline and consequently can-not fully anticipate the possible results of any relax-ation in policy. In any case, such a relaxation would behighly inappropriate for developing countries in whichthe risks of rheumatic fever and rheumatic heart dis-ease remain so high.

Finally, there is an urgent need for additional re-search both on the biology of the streptococcus and thepathogenetic mechanisms involved in the developmentof rheumatic fever as well as on other factors that mayinteract with the streptococcus and influence the risk ofdisease. Such research may not only be valuable inimproving the health of populations that are at highrisk for rheumatic fever in developing countries, butmay also shed light on the pathogenesis of other non-suppurative sequelae of infectious diseases.

References1. Jones TD: The diagnosis of rheumatic fever. JAMA 126: 481, 19442. Gordis L, Lilienfeld A, Rodriguez R: Studies in the epidemiology

and preventability of rheumatic fever. I. Demographic factors andthe incidence of acute attacks. J Chron Dis 21: 645, 1969

3. Gordis L: Effectiveness of comprehensive-care programs in pre-venting rheumatic fever. N Engl J Med 289: 331, 1973

4. Land MA, Bisno AL: Acute rheumatic fever: a vanishing disease insuburbia. JAMA 249: 895, 1983

5. Gutensohn N, Cole P: Epidemiology of Hodgkin's disease in theyoung. Int J Cancer 19: 595, 1977

6. Kuttner AG, Krumwiede E: Observations on the effect of strepto-coccal upper respiratory infections on rheumatic children: a three-year study. J Clin Invest 20: 273, 1941

7. Potter EV, Svartman M, Poon-King T, Earle DP: The families ofpatients with acute rheumatic fever or glomerulonephritis in Trini-dad. Am J Epidemiol 106: 130, 1977

8. Bisno AL, Pearce IA, Wall HP, Moody MD, Stollerman GH:Contrasting epidemiology of acute rheumatic fever and acute glo-merulonephritis: nature of the antecedent streptococcal infection. NEngl J Med 283: 561, 1970

9. McCarty M: The streptococcus and human disease. Am J Med 65:717, 1978

10. Maruyama S, Yoshioka H, Fujita K, Takimoto M, Satake Y: Sensi-tivity of group A streptococci to antibiotics: prevalence of resis-tance to erythromycin in Japan. Am J Dis Child 133: 1143, 1979

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