The fall and rise of rheumatic fever in the United States: a commentary

International Elsevier

Journal of Cardiology,

21 (1988) 3-10

IJC 00745

Review

The fall and rise of rheumatic fever in the United States: a commentary Edward

’ and

L. Kaplan

Milton

Markowitz

2

’ Department~JPediatrics,

University of Minnesota School of Medrine. Minneapolis, Minnesota. of Pediatrics, Umuerslty of Connecticut Medical School, Farmington, Connecticut,

’ Department

(Received

18 March

1988; accepted

21 March

Kaplan EL, Markowitz M. The fall and rise of rheumatic a commentary. Int J Cardiol 1988;21:3-10.

U.S.A., U.S.A.

1988)

fever in the United

States:

After a documented decline in the incidence of acute rheumatic fever in the United States during the past three decades, an apparent resurgence has occurred in the mid-1980s. Although standards of living have continued to improve with concomitant decrease

in crowding

and easier accessibility

to medical

care, the precise

reasons

for

the decline remain unexplained. Furthermore, the decline has occurred even though there is no epidemiologic evidence to suggest any reduction in the incidence of group A streptococcal Just

as the

considerable

pharyngitis. decline

interest

remains

unexplained,

so also

are the facts that the preceding

does

the

pharyngitis

“resurgence”.

Of

has been mild in the

majority of cases, the incidence of documented carditis has been high (over 90% in one series), and the rheumatic fever has been concentrated in middle class families with ready access to medical care. Even more intriguing has been the appearance of very mucoid strains of group A streptococci at the same time. While this simultaneous appearance suggests “rheumatogenicity”, this has not been substantiated; no “rheumatogenic factor” has yet been isolated from these strains. This outbreak, although small in comparison with the number of cases occurring in many of the developing countries of the world, has important implications for those countries. Unless and until the pathogenesis methods of control will not be optimal.

Key words:

Rheumatic

fever; Streptococcal

Correspondence to: Edward L. Kaplan. School. 420 Delaware St. S.E.. Minneapolis,

0167-5273/88/$03.50

of rheumatic

infection;

M.D.. Box 296 UMHC. MN 55455, U.S.A.

0 1988 Elsevier Science Publishers

fever

Group

A streptococcus

University

B.V. (Biomedical

is fully understood,

of Minnesota

Division)

Medical

Introduction The incidence of rheumatic fever in the United States fell so dramatically by 1980 that many young physicians had never seen a patient with this disease [l]. However, beginning in 1985, reports were published describing several outbreaks of rheumatic fever in this country [225]. In addition, the authors are aware of smaller and unreported rheumatic

increases

in

cases

of

rheumatic

fever has been encountered

fever

in

the

United

States

where

rarely in recent years.

During the period of declining incidence of rheumatic fever, the clinical severity of the acute attack and the frequency of cardiac sequelae declined as well [6]. However, during these recent outbreaks, an unusually large percentage of patients had carditis, and congestive heart failure was not unknown [2]. Thus, not only has there been an apparent resurgence of rheumatic fever, but also the reappearance the more classical, severe form of this disease familiar to many older clinicians. In this commentary matic fever declined the significance

we present

our impressions

in this country,

of this unexpected

Decline

of why the incidence

why there now appears

of

of rheu-

to be a resurgence.

and

occurrence.

of Rheumatic

Fever in Western

Countries

Rheumatic fever was the scourge of children during the middle of the last century, reaching an annual incidence of 250 per 100,000 population in Denmark, a country where rheumatic fever has been a reportable disease for over 100 years [7]. The incidence began to decline slowly after the turn of the century, but children’s hospitals in London still had wards filled with rheumatic Recognition of the importance of this disease in the

fever patients in 1920 [8]. United States led to the

establishment between 1925 and 1935 of a number of hospitals for the convalescent care of rheumatic patients. One of the authors (M.M.) had a fellowship in 1946 in a loo-bed rheumatic fever hospital at which there was often a waiting list for admission. The decline in the incidence of rheumatic fever became more pronounced Western European countries after World War 11, falling to an annual incidence 12 per 100,000

in Denmark

by 1962.

rheumatic

during

this period.

fever still remained

problem

1951-1961, Children’s

there were 258 rheumatic fever admissions to the Johns Hopkins Hospital [9]. A population based study in Baltimore between 1960-1964. an annual

incidence

States

However,

significant

revealed

in the United

in of

of 26 per 100.000

[lo]. Acceleration of the decline in the United 1980 an annual incidence of 0.5 per 100,000

For example,

in the 5- to 19-year-old

a

between

age group

States began in the late 1960s and by was recorded in Baltimore, a 50-fold

decline from the incidence only 20 years earlier [l]. Similar figures were reported from other parts of the country [11,12]. This decline in the incidence of rheumatic fever in the United States, Western Europe and Japan was in contrast to the developing countries of the world [13]. What changes may have occurred in the environment, in the host or in the group A beta-hemolytic streptococcus to account for the virtual disappearance of rheumatic fever?

The Environment and the Delivery of Health Care The slow but steady declining incidence of rheumatic fever in the industrialized countries during the pre-antibiotic period has been attributed to improved housing, smaller families and therefore less crowding. Following the introduction and availability of antibiotics, the decline in incidence increased, occurring, as noted previously, during the last 20 years. factors temporally associated with the precipitous decline

with the sharpest fall There were two major in incidence: improved

accessibility of health care and medical intervention with antibiotics preventing both initial and recurrent attacks of rheumatic fever [14,15]. The ability

to prevent

the initial attack

of rheumatic

capable

fever by adequately

of

treating

the preceding episode of streptococcal pharyngitis with penicillin was demonstrated in 1950 [16]. Nevertheless, a considerable amount of time passed before many clinicians

routinely

upper respiratory

began to obtain tract infections

throat cultures

and to treat proven streptococcal

with the necessary

lo-day

oral course

of antibio-

tics or an injection of long-acting repository penicillin. However, prior to 1965, this form of medical intervention was not readily available to many of the children in the United federal proved

States

who were at greatest

risk for developing

rheumatic

fever.

The

government Medicaid program enacted into law in 1965 resulted in imaccess to health care for children of many socially and disadvantaged

families, that segment of the population introduction of Medicaid, the average

which was more severely affected. number of annual health-related

medically indigent children in the United from more affluent families [17].

States has almost

reached

Since the visits by

that of children

The Human Host It is difficult to identify specific host factors responsible for the decline in the incidence of rheumatic fever, other than those related to environmental changes. Poor nutrition infections. predisposing posed

[18].

is often

Although dietary Possible

associated

with poverty

there is no convincing influence changes

for developing in the human

and may increase

scientific

evidence

rheumatic host related

susceptibility

to indicate

fever,

this has been

to the effects

to

a specific pro-

of poverty

alone, however, cannot account for the marked fall in the attack rate of rheumatic fever during the past two decades. There are still significant numbers of children living in poverty in the United States, and yet from the mid-1960’s until the recent outbreaks, there was no overwhelming epidemiologic evidence to indicate an extraordinary high incidence of rheumatic fever. One hypothesis to explain the host factors

related

to

the

pathogenesis

of

rheumatic fever postulates a genetic susceptibility to rheumatic fever. For example, a high prevalence of a specific B-cell alloantigen in patients who have had rheumatic fever has been reported [19-211, but the significance of this observation requires additional explanation. Despite this intriguing observation, it is unlikely that a genetic change in the population could have occurred in the relatively brief period during which the incidence of rheumatic fever declined so dramatically, nor would

b

this alone explain the mid-1980s resurgence in the United States. The specific genetic influence on rheumatic fever susceptibility remains unknown at the present time.

The Etiologic

Agent

Perhaps a more important factor to consider is the possibility that a change has occurred in the virulence or the “rheumatogenicity” of the group A streptococcus. Is it possible that the incidence of infections virulence diminished, or that so-called became

less prevalent?

that occurred

beginning

caused by this organism declined. that its “rheumatogenic” strains of streptococci

Could any of these explain

the decline

in the United

Clinicians continue to see many children with tonsillitis or pharyngitis. (or more) of whom have a positive throat culture for group A streptococci. in the incidence to account

States

in the 196Os?

of streptococcal

for the decline

upper respiratory

in rheumatic

tract infections

fever in the United

States

15 to 30% A decline

does not appear in recent

years

FQ.1. The virulence of group A streptococci has been defined in a number of different ways. In addition to bacteriologic factors, another way to define virulence has been based upon the clinical spectrum of streptococcal pharyngitis. Many clinicians agree that group A streptococcal infections, including scarlet fever, have been milder in recent years than in the past. However, it is not clear that there is a correlation between clinical severity of a streptococcal infection developing rheumatic fever. Indeed, evidence that suggested history acteristic

by the fact

of a preceding of the current

that

at least

one-third

and the risk of subsequently there is little correlation is

of rheumatic

fever patients

give no

symptomatic

pharyngitis

[23]. In fact. one interesting

char-

resurgence

of rheumatic

fever has been the relatively

small

percentage of patients reported with symptomatic pharyngitis [2]. The classical and more precise way of evaluating the virulence is by the presence of M-protein,

an important

constituent

of the cell wall in group

There appears to be a close relationship between virulence decline in the prevalence of group A streptococci which

A streptococci.

and M typability. But a contains M-protein has

been difficult to substantiate. A study of the percentage of M-typable strains of group A streptococci during the past two decades in Rochester, New York showed no significant change (C.B. Hall, unpublished observations) and the experience in Minnesota has been similar. Thus, at least by this indirect measure, there is no suggestion that the “virulence” of group A streptococci has diminished. Many believe that all serotypes of group A beta-hemolytic streptococci can trigger the as yet undefined process that leads to rheumatic fever. However, epidemiologic data have suggested that some serotypes of group A streptococci are more frequently isolated from the upper respiratory tract of patients with rheumatic fever. These (e.g. M-l, M-3, M-5, M-18, M-24) have been proposed to be “rheumatogenic” types. It is difficult to ascertain whether a decline in the frequency of these so-called “rheumatogenic” serotypes of group A streptococci may be associated with a decline in the incidence of rheumatic fever. But in fact, the question of

7

whether rheumatogenic serotypes exist at all remains unsettled; no “rheumatogenic factor” has ever been isolated from group A streptococci. The authors are aware of only one extended prospective longitudinal study of M serotypes in a community during the period of declining incidence of rheumatic fever (C.B. Hall, unpublished observations). While this study found that one possible “ rheumatogenic” serotype, M type 5, virtually disappeared from the community during the past two decades, it is not certain whether this finding was coincidental or bore a relationship to the declining incidence of rheumatic fever in that community during the same period. The Mid 1980s Resurgence

of Rheumatic

Fever in the United

States

In 1985, an intriguing change in the incidence of rheumatic fever took place in several different geographic areas within the United States. Children with acute rheumatic fever were seen in increased numbers in communities in Utah, Ohio, and Pennsylvania [2-51. The largest outbreak occurred in the Salt Lake City area; this initial report of the resurgence was from the Primary Children’s Hospital in Salt Lake City [2]. Furthermore, clinicians at children’s hospitals in other cities in Colorado and Texas also noted a distinct change in the number of cases from the previous decade [24]. Rheumatic fever in increased numbers has been reported at a military base [25]. Although the absolute numbers of cases in these latter states were not large, relatively speaking, the increase was remarkable to the clinicians there. Equally impressive has been the fact that this rheumatic fever has not been mild. For example, at the Primary Children’s Hospital in Salt Lake City, over 90% of the patients were found to have evidence of carditis, either clinically and/or with the assistance of echocardiography [2]. Many of the cases of carditis were severe. There have been occasional reports of the necessity for acute surgical intervention and mitral valve replacement in the United States. The typical clinical manifestations in two of the outbreaks are presented in Table 1. More disturbing, as previously mentioned, was the fact that the majority of these patients experienced minimal or very mild signs and symptoms of pharyngitis. Thus, despite the fact that the majority of the cases came from middle-class families with

TABLE

1

Manifestations

of acute rheumatic

fever in two recent outbreaks

in the United

States.

No. (%) of patients utah Carditis Congenital heart failure Polyarthritis Chorea Erythema marginatum Nodules * Ref. [2]; ** Ref. [4].

64 13 34 23

74 *

(91) (19) (46) (31)

2 (3) 1 (0.7)

Ohio40

**

20 (50) 5 (12) 26 (65) 7 (18) 5 (12) 1 (0.25)

8 ready access to medical care, medical attention often was not sought because of the mildness of the preceding group A streptococcal upper respiratory tract infection. That this resurgence has not been centered in socially and economically disadvantaged populations is a striking change from previous years. The reason, or reasons, for the mid 1980’s resurgence remains mentioned

previously,

these patients decrease decades,

just as it is unlikely

to respond

that a change

to group A streptococcal

unexplained.

in the genetic

infections

capability

was responsible

As of

for the

in rheumatic fever in the United States occurring in the two previous it is equally unlikely that genetic changes are the sole explanation for the

sudden mid 1980s increase logic data are incomplete, streptococcal

sore throats

What is of considerable cal reappearance of very mucoid

in rheumatic fever. Furthermore, although the epidemiothere is little to suggest an increase in the number of in the United interest

States.

is the fact that concommitant

with this multifo-

of acute rheumatic fever in the United States has been the recovery strains of group A streptococci from patients with pharyngitis.

These mucoid strains were initially recognized at the Primary Children’s Hospital in Salt Lake City, but since that time mucoid strains of group A streptococci have been recovered from patients with pharyngitis (and from other patients with severe infections) from coast to coast. Most of these mucoid strains have been serotyped to be M type 18, but mucoid strains of M type 3 and M type 1 also have been recovered serotypes

(E.L. Kaplan, D.R. Johnson, unpublished observations). All of these of group A streptococci have been associated in the past with rheumatic

fever, although it should be noted that mucoid strains of these serotypes of group A streptococci associated with pharyngitis have not been reported with any frequency in the United States in the decade or two prior to 1985. Although these mucoid strains, especially the M-18 serotype, have been widely recovered in the United States since 1985, rheumatic fever has not occurred in all communities where they have been isolated. Some communities have had a marked increase in the number of mucoid streptococcal strains isolated, but no identified increase

in rheumatic

fever.

In other

communities,

concommitant

with

the ap-

pearance of mucoid strains, cases of rheumatic fever have appeared. This fact plus the observation that a variety of M types (particularly M-18, M-6, M-3 and M-l) have been isolated from either cases of rheumatic fever or simultaneously from siblings of cases of rheumatic fever, lends considerable support to the possibility that “rheumatogenicity” of group A streptococci is not simply serotype-related. but may be only associated with certain strains of a given serotype [24]. For example, is it not

possible that a phage or plasmid in a given strain may contribute to its factor has never been isolated, this “rheumatogenicity”? Since a “rheumatogenic” represents only a hypothesis at the present time, but certainly one worth pursuing. It

is also noteworthy that the M-type 18 mucoid strains have recently been isolated in at least two countries in Western Europe (G. Colman, A. Spillaerr, unpublished observations). One wonders if outbreaks of rheumatic fever will next occur in the economically developed countries of Western Europe. The current resurgence of acute rheumatic fever in the United States provides an unusual opportunity to study this unique cardiovascular disease which has puzzled

9

clinicians, epidemiologists, and basic scientists for almost unusual mucoid (and virulent) strains of group A streptococci using modern the association to rheumatic

five decades. These now can be studied

molecular biologic techniques. The recent observations postulating of a marker B cell alloantigen on lymphocytes of patients susceptible fever can be thoroughly

investigated

with carefully

matched

control

groups. Furthermore, with the documented clinical observations, attempts to associate specific strains of group A streptococci and/or specific serotypes of these bacteria with clinical manifestation of arthritis, carditis and chorea can be carried out to attempt to explain the varied clinical manifestations in the human The lessons from this resurgence are important. It is clearer than

host. ever that

antibiotics alone, while effective in primary and secondary prophylaxis for prevention of rheumatic fever, are not the optimal solution to this problem either in the United States or worldwide. The fact that the mid-1980s resurgence of rheumatic fever in the United States has occurred in middle class families with ready access to medical care documents this. Furthermore, and of great significance, is the fact that this outbreak of rheumatic fever in the United States has been associated with mild pharyngitis. This has important implications for the developing countries of the world, countries where rheumatic fever and rheumatic heart disease remain a major, if not the major, cause of cardiovascular disease. While improvements in standards of living and medical rheumatic

care ultimately

can influence

the decrease

fever, the disease will not be controlled

The obvious

conclusion

reached

in the incidence

of

by these means alone.

is that until one understands

the pathogenesis

of

this unique nonsuppurative sequel to group A streptococcal upper respiratory tract infections, methods for prevention of acute rheumatic fever will remain less than optimal. It is therefore necessary that renewed interest be given to basic, applied. and epidemiological research in order to explain the mystery of rheumatic fever and rheumatic

heart disease,

including

its fall and rise.

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