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Rheumatic fever.

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The current status of rheumatic fever and rheumatic heart disease was reviewed for the World Health
Organization (S389), with a discussion of changing frequency of occurrence, morbidity and mortality trends,
socioeconomic correlates, and approaches to prevention
and control. Difficulties in obtaining accurate incidence
and prevalence data were noted; available figures indicate a decline of rheumatic fever, particularly in developed countries. Rheumatic fever remains a major
health problem in developing countries; socioeconomic
conditions were suggested as the primary factor, implying that rheumatic fever is indeed a “social” disease,
a disease of the poor. The frequency and severity of
rheumatic fever among children from tropical countries
were also attributed to generally poor socioeconomic
conditions which favor an increased number of streptococcal infections and lack of medical care.
Changing trends in rheumatic fever since 1960
were discussed, as were concepts of primary and secondary prevention of rheumatic fever by therapy and
prevention of streptococcal infections. The expense and
difficulty in preventing and controlling rheumatic fever
were stressed, and the existence of appropriately structured health services was presented as the single most
important requirement for adequate rheumatic fever
control programs. The importance of working to provide such health services for developing countries was
The changing picture of rheumatic fever was reviewed (M74); although the prevalence and severity of
rheumatic fever seem to be lessening, it was emphasized
that in many parts of the United States there continue
to be unacceptably high prevalence rates. Poor socioeconomic conditions were considered important in
the causation of rheumatic fever, and improved living
conditions with less crowding and adequate medical
therapy the most likely explanation for the general decrease in rheumatic fever.
The relative rarity of rheumatic fever and its
milder nature have caused diagnostic problems. Despite
many years of knowledge of the link between antecedent streptococcal infection and rheumatic fever, disappointingly little progress has been made. Six adults with
arthritis as the sole major manifestation of rheumatic fever had benign disease that responded well to salicylates
(M 136). All patients had demonstrated preceding group
A beta hemolytic streptococcal infection. The authors
discuss other possible causes of acute arthritis in adults
and postulate that the arthritis following yersinia, salmonella, or shigella responds less well to salicylates
than does the arthritis of rheumatic fever.
It was proposed that this condition be called
poststreptococcal arthritis rather than rheumatic fever,
since the patients had mild disease without the carditis
usually associated with rheumatic fever. In a companion editorial, the difficulties in applying the Jones criteria to adults with this type of poststreptococcal arthritis were emphasized (P91), and the opinion was given
that despite lack of cariditis in first attacks, this syndrome should be considered rheumatic fever and
treated with antibiotic prophylaxis for at least 5 years to
prevent recurrent streptococcal infections. [These patients are similar to those described by Barnert, Terry,
and Persellin, JAMA 232:925-928, 1975; see Twentythird Rheumatism Review. The most crucial question
would seem to be whether these individuals with arthritis after streptococcal infection are at risk to get later
carditis. The acute arthritis itself seems to be transient
and fairly benign. Ed.]
A number of reports described rheumatic fever
in various population groups. A study from Trinidad
compared 93 children with acute rheumatic fever with
195 children with acute glomerulonephritis during an
outbreak of scabies with secondary streptococcal infection (P150). The patients with rheumatic fever had a
low history of skin infections and a 50% occurrence of
recent sore throat; in contrast, the glomerulonephritis
patients had a high incidence of skin infections. No evidence was found that streptococcal skin infections alone
were an antecedent cause for rheumatic fever; no nephritogenic strains of streptococci were found in patients
with acute rheumatic fever. The severity of rheumatic
fever was not considered to be increased over that observed in temperate climates.
In a companion paper by the same authors
(P151), the families of 21 patients with rheumatic fever
were compared to those of 44 patients with acute glomerulonephritis. Sixty-one percent of family members
of nephritis patients had skin infections as compared to
only 22% of the rheumatic fever families. The size and
crowding of families were similar for both groups, as
was the recovery of streptococci from throat cultures
(19-25%). Streptococci isolated from rheumatic fever
members were 1 of 2 strains associated with rheumatic
fever in this study; in contrast, streptococci isolated
from nephritis family members tended to be nephrogenic strains. There was no difference in streptococcal
antibody titers between the 2 groups of families, nor in
the finding of abnormal urines, which would be consistent with subclinical glomerulonephritis (6%).
A study from India described the occurrence of
rheumatic fever there and in other developing countries
(P4); rheumatic fever remains a major problem in that
country, and effective and economically feasible methods of controlling rheumatic heart disease need to be
sought. A study from Thailand pointed out that rheumatic heart disease is the most common type of heart
disease in tropical countries, comprising 39% of all heart
disease cases admitted to hospitals in Bangkok (S405).
Of 100 cases included in this study, 93% had carditis
and 59% of these had severe carditis with congestive
heart failure. Subcutaneous nodules were found in 9%
of patients, but none had erythema marginatum.
Two papers described rheumatic fever in Japan
(K133,S183). The establishment of a registry for patients with rheumatic heart disease was described
briefly (K133); 562 patients were registered, half of
them adults over 50. A study of the epidemiology of
rheumatic fever and rheumatic heart disease in mainland Japan and the Ryukyu Islands suggested that the
incidence of rheumatic fever may be associated with
changes in T types of streptococci (S183).
Ninety-two cases of rheumatic fever were found
among inhabitants of southeastern Tehran during 1972
to 1974. The incidence among individuals between 5
and 19 years of age was 80/100,000. Fifty-three percent
of patients had carditis; carditis was more common in
females (71%) than males (29%). Four deaths occurred,
and there was a seasonal occurrence of cases favoring
the winter and spring months (G69).
A brief report presented data from Hawaii where
rheumatic fever remains the most common cause of arthritis in children (H127); the prevalence was highest in
children of Hawaiian ancestry as compared to the many
other racial groups in the islands. Thirty-eight percent
of the total group had carditis.
Rheumatic fever remains a problem in New Zealand, and no decline in incidence has been seen over the
past 20 years (F96). In the northern community of
Wairoa, the prevalence of rheumatic fever was established at 1.5%. Rheumatic fever was more common
among Maoris than other racial groups, but no clear socioeconomic factors could be identified.
A monograph from Finland presented a retrospective review of 253 patients with rheumatic fever
gathered from records in 2 Helsinki hospitals (L66); 116
of these patients were seen in followup. In this group of
patients carditis was generally mild. There were relatively few occurrences and only 7-1596 of patients had
evidence of rheumatic heart disease at followup. Studies
of HLA antigens suggested an association with HLABw35, and a lack of association with B5, particularly in
patients with recurrent attacks (see later discussion in
laboratory section).
[Exact reasons for the increased prevalence of
rheumatic fever among certain racial groups and in certain countries remain unexplained, although most observers seem to favor socioeconomic conditions. The
studies from New Zealand, however, contest this explanation, at least for that area. Ed.]
Several papers dealt with control and prevention
of rheumatic fever. The importance of continued efforts
for rheumatic fever prevention despite the decreased
prevalence of rheumatic fever in the United States was
stressed, and speculations were presented about possible
reasons for the decline in rheumatic fever other than
simply better control of streptococcal infections (M3 10).
An analysis of the cost effectiveness of management of pharyngitis in the prevention of rheumatic fever
suggested 3 possible strategies for management of patients with pharyngitis: l) culturing patients and treating only those with positive cultures; 2) no cultures,
treatment of all patients; 3) no cultures, no treatment of
any patients (T73). In populations where the yield of
streptococci is between 5 and 20%, throat cultures with
therapy of only those with positive cultures were advocated. For epidemic situations where the rate of positive
throat cultures in pharyngitis exceeds 20%, treatment of
all patients without doing cultures was recommended.
For situations where the streptococcal recovery rate
from pharyngitis patients is less than 5%, the authors
suggested no cultures and no treatment. Detailed discussions of various aspects of cost effectiveness were included. The statistical analyses were based on data from
the literature. It was not explained how the streptococcal recovery rate could be known in various nonepidemic populations.
Two accompanying editorials analyzed this paper and further reviewed the problem of detection and
treatment of streptococcal infections in the prevention
of rheumatic fever (B158,P28). [These papers are extremely interesting. It would seem that since the streptococcal carrier rate in school children is generally in the
range of 20%, the strategy of culturing patients and
treating those with positive cultures would be generally
continued, even if recommendations of this study were
adhered to. There would be little quarrel with treating
all individuals in an epidemic situation, although as
pointed out in the editorials, not all epidemics of
streptococcal pharyngitis have resulted in rheumatic fever. Ed.]
Three hundred and eleven patients with rheumatic fever from Nashville were studied between 1963
and 1969 (43); 53% adhered to regular penicillin prophylaxis, 36% received prophylaxis only sporadically,
and 11% not at all. No rheumatic fever recurrences occurred in patients treated by regular injection prophylaxis, but there were 6 recurrences among those taking
oral prophylaxis on a regular basis. No recurrences occurred among the 45 patients who took no prophylaxis
at all; however, the majority of these patients were not
recommended for prophylaxis by their physicians. Both
the prevalence of rheumatic heart disease and recurrent
attacks of rheumatic fever were greater in blacks than
Eight patients with Sydenham’s chorea were
treated with corticosteroids; all improved within 3 to 5
days (G219). [A retrospective, uncontrolled study. All 8
patients had chorea as a major manifestation of rheumatic fever; 4 of 8 had “some cardiac abnormality” but
there is no mention of other rheumatic manifestations.
Streptococcal infections
A medical progress article reviewed the broad aspects of group A streptococcal infections of the skin and
pharynx (P97). A prospective study of recurrent streptococcal infection among 124 rheumatic children and
adults receiving oral streptococcal prophylaxis showed
that 104 documented streptococcal infections occurred
between 1965 and 1972 without a single recurrence of
rheumatic fever. Most streptococcal infections were
subclinical, and many were of “pyoderma” serotypes
or demonstrated characteristics thought to be associated
with decreased immunogenicity (production of opacity
factor) (B159). It was postulated that the group A
streptococcal strains prevalent in this population may
have diminished rheumatogenic potential, but no
changes in prophylaxis policies for acute rheumatic fever were recommended.
In a 12-month study of 2,158 children with upper
respiratory symptoms, 21.4% were found to have positive streptococcal throat cultures (R159). [The authors
are not clear about whether all of these were group A
streptococci. Ed.] The authors point out the difficulty in
predicting streptococcal recovery on the basis of clinical
13 1
symptoms and advocate cultures with therapy based on
cultures in all patients.
A retrospective analysis of 39,116 throat cultures
taken between 1973 and 1975 showed that 16.5%of cultures had group A streptococci and 16.1% non-group
A streptococci. The recovery of group A streptococci
was highest in the winter and spring months, while the
recovery of non-group A showed no patterns (M350).
Therapy with corticosteroids was not found to influence
the carrier rates of streptococci in children with rheumatic fever (B219). Cephradine and amoxicillin were
proposed as effective alternatives to penicillin in the
treatment of streptococcal pharyngitis, based on a study
of 319 patients (C20).
A number of studies dealt with antibody responses to streptococci. Anti-hyaluronidase, anti-streptolysin 0, and streptozyme tests were compared in 125
patients with acute rheumatic fever from India (G16);
42.4% of patients had elevated anti-hyaluronidase titers,
6 1.6% elevated AS0 titers, and 93.6% elevated streptozyme tests. The combination of anti-hyaluronidase and
anti-streptolysin yielded a detection rate of 80%;6.4% of
patients had no positive streptococcal tests (G16). [The
authors are not clear as to whether these patients had
positive throat cultures or how the diagnosis of rheumatic fever was made in the absence of evidence of preceding streptococcal infection. Ed.] Elevated AS0 titers
were found in 84.5% of 39 rheumatic fever patients from
Japan, and either AS0 or anti-hyaluronidase was elevated in 100% of these patients (W42).
The streptozyme test was found to represent a
simple method for the detection of antibodies to streptococcal products in patients with rheumatic fever and
acute glomerulonephritis (K51); however, it was cautioned that more studies of this test in normal populations are required. No cases of rheumatic fever or
acute nephritis occurred in 280 patients with acute
streptococcal pharyngitis during an epidemic on an Israeli kibutz in 1972-1973, although 50-80% of patients
had vigorous immune responses to streptococcal products (Rl). The authors speculate that the streptococci
responsible for this outbreak were strains with low rheumatogenic potential.
Several studies dealt with experimental aspects
of streptococcal infection and their possible relation to
rheumatic fever. The adherence of streptococci to pharyngeal cells was studied in 9 patients with rheumatic
heart disease and 9 matched nonrheumatic controls
(S148). Pharyngeal cells of all 9 rheumatic heart disease
patients had an increased avidity for adherence of rheumatic fever-associated strains of streptococci, and it was
postulated that increased streptococcal adherence to
pharyngeal cells plays a role in the pathogenesis of
rheumatic fever. Bacterial adherence is a cell surface
phenomenon, but the exact cell surface components responsible remain to be identified. Immunologic studies
on 35 patients with rheumatic heart disease were compared to similar studies on 17 controls (S28). A study of
30 rheumatic disease patients for cutaneous hypersensitivity reactions suggested that cellular immunity as
expressed by positive skin tests to a variety of nonspecific antigens was lowered; among 24 patients studied for lymphocyte response to PHA, decreased responsiveness was found in 7 (S 182).
Heart antigens reacted with rabbit antisera to
human heart muscle were extracted and it was suggested that there is a cross reaction between human
myocardium and group A streptococci (K52). Rabbit
antisera to streptococci were shown to react not only
with myocardial fibers but also with conducting fibers
of the bundle of His (K40). [No one has yet clarified the
role, if any, of these various cross-reactive antibodies in
the pathogenesis of rheumatic fever. Ed.]
Guinea pig T lymphocytes sensitized to group A
streptococcal antigens were found to be cytotoxic for
fetal guinea heart (Y6), and a possible cell mediated
“autoimmune” mechanism was proposed for rheumatic
fever. Elevated levels of circulating immune complexes
as detected by both Clq and Raji cells assays were
found in patients from Trinidad with both rheumatic fever and poststreptococcal nephritis (V1 I). The incidence and molecular size of the immune complexes
appeared to be similar in both poststreptococcal states,
suggesting that factors such as the nature of antigen in
the complex were more important in pathogenesis than
the mere presence of complexes.
A retrospective record review of all patients undergoing cardiac valvular surgery at the National Heart,
Lung, and Blood Institute between 1954 and 1974 provided information about excised atrial appendages and
papillary muscles in 481 patients who had undergone
mitral valve surgery (V56). Twenty-one percent of patients had Aschoff bodies in left atrial appendages, and
only 2% in left ventricular papillary muscles. Nearly all
the patients with Aschoff bodies had mitral stenosis;
only 1 had pure mitral regurgitation. Only 58% of patients with Aschoff bodies had ever had an illness compatible with acute rheumatic fever. [Are Aschoff bodies
specific for rheumatic fever? Ed.]
Several studies dealt with HLA phenotypes in
patients with rheumatic fever. Two studies-one from
England including 94 rheumatic fever patients (J8 1)
and one of 49 Mexican-American adults with rheumatic
fever (M349Ffound no association, either positive or
negative, between HLA-A or -B antigens and rheumatic fever. Two studies describing Finnish patients
with rheumatic fever found an increased prevalence of
Bw35 in rheumatic fever patients and B18 in patients
with acute carditis (L66,67). Patients with recurrent
rheumatic fever were said to have a low prevalence of
HLA-B5, raising speculation that the reported connection between HLA-B5 and immune responsiveness
to streptococcal antigens indicates a relationship between lack of B5 and rheumatic fever. A study of families from Trinidad, inlcuding 30 families with 1 or more
cases of rheumatic fever, showed no significant association of HLA-A or -B antigens with any group, but a decreased prevalence of HLA-B5 in the mothers of the
rheumatic children as compared to those with nephritis
and the controls (R34). Again the relationship to a low
incidence of HLA-B5 and its known relationship to immune responsiveness to DNase A was speculated as perhaps reflecting linkage disequilibrium between B5 and
some immune response to a streptococcal antigen. [It
will be of great interest to see what D and DR typing reveals in these patients. Ed.]
Acute phase reactants
Several communications dealt with the sedimentation rate. Determination of sedimentation rates measured before and after defibrination of serum was proposed as a method of differentiating sedimentation rates
due to elevated fibrinogen levels from those due to excess of gamma globulin (H158). Plasma viscosity was
thought to be a more reliable measure of changes of
acute phase protein reactants than the sedimentation
rate and was proposed as a useful test for monitoring
clinical progress of various diseases (H242).
Recommendations for standard measurements of
erythrocyte sedimentation rates were presented by the
International Committee for Standardization in Hematology (I 15). The Guest method of measuring sedimentation rates utilizing disposable plastic tubes was found
to be comparable to the Westergren sedimentation rate
(N48). A general review described mechanisms and
measurements of the erythrocyte sedimentation rate
(R 156). Two hundred patients with sedimentation rates
greater than 100 were reviewed: infectious diseases were
found in 35%, noninfectious inflammatory diseases in
22%, and malignancies in 15% (W205).
Marked elevations in lymphocytes that bound Creactive protein (CRP) were found in 31 patients with
acute rheumatic fever, as compared to 30 control chil-
dren (W138), and it was suggested that CRP binding
lymphocytes represent a marker for immunologically
committed cells in acute rheumatic fever. Quantitation
of C-reactive protein by a rapid spot immunoprecipitate
assay was described (Wl). A new method for obtaining
C-reactive protein from acidic fluid was described
(V6 1). Rabbit studies suggested that C-reactive protein
was produced by hepatocytes after an inflammatory
stimulus that required a mediator to recruit cells for
CRP production (K185). A positive test for C-reactive
protein was found to be associated with streptococcal
antibody response in children with positive throat cultures for streptococci, and it was proposed that a positive CRP test may help to differentiate true streptococcal pharyngitis from the streptococcal carrier state
(K32). A procedure for isolating C-reactive protein utik i n g its binding to DEAE with and without calcium
was presented (566).
Research in rheumatoid arthritis (RA) has come
to focus increasingly on the cellular interactions responsible for the formation of immune complexes in relation
to a genetic predisposition coded at the D locus of the
immune response (Ir) gene. Hope was expressed that
this new focus might lead to a better definition of the
“real” rheumatoid arthritis and the identification of factors that might influence its development (S91). A largescale prospective survey from the United Kingdom
showed that oral contraceptives protect women against
the development of this disease (W158). In Rochester,
Minnesota, a fall in the rate of RA affecting women
since 1965 supported the idea that oral contraceptives
might protect against the development of RA (L146).
[Although the protective effect of contraceptives was not
great, these results draw attention to the role of hormonal factors in the pathogenesis of RA. Ed.]
Evidence that in some parts of the world RA
may be less common or milder was obtained in surveys
from South Africa and Iraq. The prevalence of definite
RA (0.68%) was lower in a black tribal population
(M214) and definite but mild RA affected 1% of an Arabian population (A50,5 1). [Could this lower prevalence
of RA in underdeveloped countries result from a lower
life expectancy of rheumatoid patients, a decreased frequency of HLA-DRw4, or a lack of urban environmental factors in the populations studied? Ed.]
Because there are few descriptions of rheumatoid
arthritis before 1800, the impression has been created
that this may be a disease of recent origin. However,
there is evidence in ancient India (S403) and paintings
of the Flemish school (1400-1700) showed a few examples of hand deformities resembling this type of arthritis (D77). Nevertheless, it has been suggested that,
like other bacterial and viral pandemics, RA may be a
disappearing disease (B273). [Although data are woefully lacking on this point, it is interesting that rheumatoid arthritis may be disappearing in at least 1 segment
of the population, i.e., women taking oral contraceptives. Ed.]
A pilot study from Scandinavia suggested a decreased prevalence of RA in schizophrenic patients
(046). The reason that these 2 disease entities may be
mutually exclusive was supported by the concept that
schizophrenia may be a prostaglandin deficiency disease
(H181). [The evidence that RA is uncommon in schizophrenia may suffer from some of the shortcomings associated with the case control method of analysis (B192).
The psychosocial impact of rheumatoid arthritis
was emphasized in a study where RA patients showed
more depression and psychological autoaggression than
osteoarthritic patients (P23). In another study using
controls a negative attitude toward self was related to
the severity of disease and the patients’ socioeconomic
status (E4). In a monumental monograph, conflicting
tensions between the need for autonomy and dependency were found in RA patients (K113). These conflicts
were associated with feelings of anxiety and insecurity
with a physiologic response pattern in keeping with a
stress reaction. Psychological testing of 46 patients with
RA, 22 men and 24 women ranging in age from 19 to 7 1
years, failed to provide support for the concept that
there is a rheumatoid arthritis personality, characterized
by repressed hostility and self-punishment (S3 13). The
findings were heterogeneous and it was stressed that
each patient must be viewed as an individual with personalized needs and desires.
The financial impact of this condition on both
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