Group
A Streptococcal
Infections
Rheumatic
as Related
to
Fever
Seiichi KAWAKITA, M.D., * Tsune TAKEUCHI, M.D., ** Yoshio UEMURA, M.D., ** Toyohiko ONISHI, M.D., ** Koichi SAITO, M.D., *** Hideo NAGAMI, M.D., *** Taketoshi WATANABE,M.D., *** and Tetsujiro WATANABE,M.D. *** SUMMARY Beta-hemolytic streptococci were recovered frequently, particularly from the throats of children, and the same type of group A strains was isolated from both throats and tonsils. A significant antibody response to streptolysin O was observed in 44.8 to 43.5% of children whom group A streptococci were recovered. It is considered that these children had the definite evidence of acute streptococcal infections, and administration of josamycin, penicillin G, and benzyl penicillin V benzathine decreases the frequency of recovery of beta-hemolytic streptococci and prevents rheumatic fever. Additional Indexing Words: Acute rheumatic fever Rheumatic heart disease streptococci ASO titer Prophylaxis
T
has
been
disease upper
were tonsillitis
incidence throats
tract.
frequently
infections.
and The
tonsillar
for an eradication patients
with
Several
became present
rheumatic
throats
dangerous
A
reported
from
and
with
that children
of transmission
designed
in patients
and
to provide
throats
rheumatic
streptococcal
of school
sources
were
streptococci
of streptococci,
fever
group
investigators from
reports
tissues
rheumatic
acute
antecedent
isolated
of recovering and
that
following
respiratory
cocci tive
established
occur
Group A
heart
infections group
in
A strepto-
without
exuda-
of streptococcal informations
in school
chronic
tonsillitis,
streptococcal
antibody
children effect
on the and
both
of therapy
response
of the
fever.
From *the Third Department of Internal Medicine, Kyoto University Hospital, **Control Study Group for Streptococcal Disease, Otsu, and ***Control Study Group for Streptococcal Disease, Matsue. Reprint request: Seiichi Kawakita, M.D., The First Department of Internal Medicine, School of Medicine, Siga University of Medical Science, Seta, Otsu, 520-21. Received for publication November 27, 1975. 592
Vol.17 No.5
GROUP A STREPTOCOCCAL INFECTIONS
593
MATERIALS ANDMETHODS 1) Throat cultures were collected on swabs from elementary school children during the 3 seasons between October 1970 and October 1972in Otsu City, Shiga Prefecture. 2) Tonsillectomy was performedin the patients with chronic tonsillitisduring the period from March 1972to August 1973at the Matsue City Hospital, Shimane Prefecture. At tonsillectomy throat cultures were taken at least 10days before and immediately prior to surgery. Excised tonsils were cultured for detection of beta-hemolyticstreptococci. 3) Isolated beta-hemolytic streptococciwere grouped and all strains of group A were typed according to the method of agglutination. 4) Blood samples were employed in the determination of antibodies to streptococcal extracellular products. Anti-streptolysin O titers were measured by the method of Rantz and Randall. Anti-hyaluronidase was assayed by turbidimetric method of Harris and Harris. Anti-streptokinasewas determined by the agglutination method, and anti-streptozymedeterminations were made by the slide agglutination method. 5) Antibioticswere administeredfor at least 10days by mouth. Josamycin, penicillin G and benzyl penicillin V benzathine were given. 6) Follow-up examination of antibodies to streptococcal products of sera of patients with rheumatic fever and rheumatic heart disease recently admitted to the Kyoto University Hospital was done after the treatment. RESULTS 1) The prevalence rates of beta-hemolytic streptococci in school children: Beta-hemolytic streptococci were isolated from 532 of the 2,154 children (24.6%) and 250 (11.6%) out of these harbored group A strains in October 1970. The recovery rates of beta-hemolytic streptococci were 691 of the 2,655 (26.0%) in October 1971, and 550 of the 2,616 (21.0%) in October 1972. Four hundred and twenty-two (15.8%) and 320 (12.2%) of beta-hemolytic streptococci isolated belonged to group A strains. The majority of group A strains was identified with their types, and the most common were types 12, 4, 3, and 1 as shown in Table I. ASO titer determinations were carried out on elementary school children in 1971 and 1972. It is generally accepted that the upper limits of normal titer for ASO in school age children is 333 units. By this definition, 44.8% and 43.5% of children who harbored group A streptococci showed elevated titers and the average titers of children with group A streptococci in their throats were significantly higher than those with negative cultures as shown in Table II.
594
Jap. Heart J. S eptember, 1976
KAWAKITA, ET AL.
Table I. Recovery of Beta-Hemolytic Streptococci from Throats and Strains of Group A Streptococci (Typable School Children of Otsu City)
Table
II.
Frequency Positive
and
Magnitude
Cultures
of ASO
for Group
Titer
in Children
with
A Streptococci
2) Recovery of streptococci in tonsils, swabs or both: Tonsillectomy was performed in 62 cases. Beta-hemolytic streptococci were isolated from throats of 27 patients at more than 10days before operation, and antibiotics were administered in these cases. In 25 out of 27 cases, beta-hemolytic streptococci were eradicated from throats by therapy. Only in 2 cases, therapy failed to eradicate them. However, 6 strains were recovered from tonsillar tissues as shown in Table III. In other 20 cases treated with antibiotics, beta-hemolytic streptococci were negative in throat cultures preoperatively. However, 1 strain was isolated from tonsillar tissue as shown in Table IV. In untreated 15 cases, 2 yielded group A strains in throat swabs and 3 in tonsillar tissues as shown in Table V. Ten of 62 cultures
Vol.17 No.5
Table III.
GROUP A STREPTOCOCCAL INFECTIONS
595
Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (with Treatment)
yielded beta-hemolytic streptococci in tonsils. Five strains were recovered from tonsils of subjects whose preoperative cultures had been negative, and same serotype of group A strain was isolated from both swabs and tonsillar tissues in 4 patients. 3) Follow-up study of streptococcal antibody response of rheumatic fever: One patient with acute rheumatic fever (12 years of age) and 2 patients with rheumatic heart disease with recurrent attack of rheumatic fever, mitral insufficiency (22years of age) and aortic insufficiency (42years of age) were studied. Streptococcal antibodies (ASO, ASK, AH, and anti-streptozyme) showed high titers in all cases at admission. Antibody levels fell to normal with considerable regularity after antiinflammatory and antistreptococcal treatments as shown in Fig.1.
596
Table IV.
KAWAKITA, ET AL.
J ap. Heart J. September, 1976
Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (with Treatment)
Table V. Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (without Treatment)
DISCUSSION Age appears to play a definite role in streptococcal disease. Kaplan reported that in a total of 624 children (mean age, 6.8years) with pharyngitis, beta-hemolytic streptococci were isolated from 2,56 (41%) and 218 (31%) of
Vol.17 No.5
GROUP A STREPTOCOCCAL INFECTIONS
Fig.1.
Streptococcal
597
antibody response in acute rheumatic fever (E.K., 12y)
these were group A strains.1) According to Siegel study, of 2,545 children with nasopharyngitis 1,213 (47.7%) harbored beta-liemolytic streptococci in their throats, and 86% of these strains were group A streptococci.2) Saslaw observed that in healthy school children 6 to 9 age, 25 to 40% of those studied by monthly throat swabbing had group A organism in their throats.3) In our studies 23.8% of children harbored beta-hemolytic streptococci and group A strains were detected in rate of 13.4%. The average ASO titers of children who harbored group A streptococci were higher than those with other groups of streptococci or negative cultures. The recovery of group A streptococci from throat cultures and high titers of ASO suggest that these findings reflect "i nfection" rather than "carrier state". No rheumatic attack was found in present study. Of 47 children who received antibiotics prior to tonsillectomy, 7 (14.8%) harbored beta-hemolytic streptococci in tonsillar tissues. Moreover, isolation of the same serotype of streptococci was observed in both throat swabs and tonsillar tissues. Saslaw suggested that because of the histological structure of tonsils, organism might remain within deep crypts, secure from contact with, and hence action of, antibiotics from their research works.4) In general, the frequency with which rheumatic fever follows streptococcal disease appears to be related to the intensity of the antigenic stimulus produced in the rheumatic
host by the infecting strains.5)
Stollerman
report-
598
KAWAKITA, ET AL.
Jap. Heart J. September, 1976
ed that a high initial titer of antistreptococcal antibodies was found in the sera of 95% of patients who could be studied within the first 2 months of onset of the rheumatic attack and the rate of fall of the antibodies studied may serve as a guide to the efficacy of antistreptococcal prophylactic measures.6) In one patient with rheumatic fever antibodies fall to normal level after one year of freedom from streptococcal infections. In rheumatic patients who do not maintain effective antimicrobial treatment large tonsils appear to increase the susceptibility to streptococcal infections according to the investigations of Feinstein.7) Moreover, the presence of rheumatic heart disease is apt to complicate recurrent rheumatic fever following streptococcal infections, as indicated in our 2 cases. Therefore, it is very important to make accurate diagnosis of streptococcal infections and also rational decisions about the necessity for antibiotic therapy for rheuamtic heart disease.
REFERENCES 1.
2.
3. 4. 5. 6.
7.
Kaplan EL, Top FH, Dudding BA, Wannamaker LW: Diagnosis of streptococcal pharyngitis. Differentiation of active infection from the carrier state in the symptomatic child. J Inf Dis 123: 490, 1971 Siegel AC, Johnson EE, Stollerman GH: Controlled studies of streptococcal pharyngitis in a pediatric population I. Factors related to the attack rate of rheumatic fever. New Eng J Med 265: 559, 1961 Saslaw MS, Streitfeld MM: Group A beta-hemolytic streptococci in relation to rheumatic fever. Study of school children in Miami, Florida, A.M.A. Am J Dis Child 92: 550, 1956 Saslaw MS, Joblon JM, Jenks SA, Branch CC: Beta-hemolytic streptococci in tonsillar tissue. The efficacy of penicillin. Am J Dis Child 103: 19, 1962 Stollerman GH: Factors determining the attack rate of rheumatic fever. JAMA 177: 323, 1961 Stollerman GH, Lewis AJ, Schultz I, Taranta A: Relationship of immune response to group A streptococci to the course of acute, chronic and recurrent rheumatic fever. Am J Med 20: 163, 1956 Feinstein AR, Levitt MBA: The role of tonsils in predisposing to streptococcal infections and recurrences of rheumatic fever. New Eng J Med 282: 285, 1970
A Streptococcal
Infections
Rheumatic
as Related
to
Fever
Seiichi KAWAKITA, M.D., * Tsune TAKEUCHI, M.D., ** Yoshio UEMURA, M.D., ** Toyohiko ONISHI, M.D., ** Koichi SAITO, M.D., *** Hideo NAGAMI, M.D., *** Taketoshi WATANABE,M.D., *** and Tetsujiro WATANABE,M.D. *** SUMMARY Beta-hemolytic streptococci were recovered frequently, particularly from the throats of children, and the same type of group A strains was isolated from both throats and tonsils. A significant antibody response to streptolysin O was observed in 44.8 to 43.5% of children whom group A streptococci were recovered. It is considered that these children had the definite evidence of acute streptococcal infections, and administration of josamycin, penicillin G, and benzyl penicillin V benzathine decreases the frequency of recovery of beta-hemolytic streptococci and prevents rheumatic fever. Additional Indexing Words: Acute rheumatic fever Rheumatic heart disease streptococci ASO titer Prophylaxis
T
has
been
disease upper
were tonsillitis
incidence throats
tract.
frequently
infections.
and The
tonsillar
for an eradication patients
with
Several
became present
rheumatic
throats
dangerous
A
reported
from
and
with
that children
of transmission
designed
in patients
and
to provide
throats
rheumatic
streptococcal
of school
sources
were
streptococci
of streptococci,
fever
group
investigators from
reports
tissues
rheumatic
acute
antecedent
isolated
of recovering and
that
following
respiratory
cocci tive
established
occur
Group A
heart
infections group
in
A strepto-
without
exuda-
of streptococcal informations
in school
chronic
tonsillitis,
streptococcal
antibody
children effect
on the and
both
of therapy
response
of the
fever.
From *the Third Department of Internal Medicine, Kyoto University Hospital, **Control Study Group for Streptococcal Disease, Otsu, and ***Control Study Group for Streptococcal Disease, Matsue. Reprint request: Seiichi Kawakita, M.D., The First Department of Internal Medicine, School of Medicine, Siga University of Medical Science, Seta, Otsu, 520-21. Received for publication November 27, 1975. 592
Vol.17 No.5
GROUP A STREPTOCOCCAL INFECTIONS
593
MATERIALS ANDMETHODS 1) Throat cultures were collected on swabs from elementary school children during the 3 seasons between October 1970 and October 1972in Otsu City, Shiga Prefecture. 2) Tonsillectomy was performedin the patients with chronic tonsillitisduring the period from March 1972to August 1973at the Matsue City Hospital, Shimane Prefecture. At tonsillectomy throat cultures were taken at least 10days before and immediately prior to surgery. Excised tonsils were cultured for detection of beta-hemolyticstreptococci. 3) Isolated beta-hemolytic streptococciwere grouped and all strains of group A were typed according to the method of agglutination. 4) Blood samples were employed in the determination of antibodies to streptococcal extracellular products. Anti-streptolysin O titers were measured by the method of Rantz and Randall. Anti-hyaluronidase was assayed by turbidimetric method of Harris and Harris. Anti-streptokinasewas determined by the agglutination method, and anti-streptozymedeterminations were made by the slide agglutination method. 5) Antibioticswere administeredfor at least 10days by mouth. Josamycin, penicillin G and benzyl penicillin V benzathine were given. 6) Follow-up examination of antibodies to streptococcal products of sera of patients with rheumatic fever and rheumatic heart disease recently admitted to the Kyoto University Hospital was done after the treatment. RESULTS 1) The prevalence rates of beta-hemolytic streptococci in school children: Beta-hemolytic streptococci were isolated from 532 of the 2,154 children (24.6%) and 250 (11.6%) out of these harbored group A strains in October 1970. The recovery rates of beta-hemolytic streptococci were 691 of the 2,655 (26.0%) in October 1971, and 550 of the 2,616 (21.0%) in October 1972. Four hundred and twenty-two (15.8%) and 320 (12.2%) of beta-hemolytic streptococci isolated belonged to group A strains. The majority of group A strains was identified with their types, and the most common were types 12, 4, 3, and 1 as shown in Table I. ASO titer determinations were carried out on elementary school children in 1971 and 1972. It is generally accepted that the upper limits of normal titer for ASO in school age children is 333 units. By this definition, 44.8% and 43.5% of children who harbored group A streptococci showed elevated titers and the average titers of children with group A streptococci in their throats were significantly higher than those with negative cultures as shown in Table II.
594
Jap. Heart J. S eptember, 1976
KAWAKITA, ET AL.
Table I. Recovery of Beta-Hemolytic Streptococci from Throats and Strains of Group A Streptococci (Typable School Children of Otsu City)
Table
II.
Frequency Positive
and
Magnitude
Cultures
of ASO
for Group
Titer
in Children
with
A Streptococci
2) Recovery of streptococci in tonsils, swabs or both: Tonsillectomy was performed in 62 cases. Beta-hemolytic streptococci were isolated from throats of 27 patients at more than 10days before operation, and antibiotics were administered in these cases. In 25 out of 27 cases, beta-hemolytic streptococci were eradicated from throats by therapy. Only in 2 cases, therapy failed to eradicate them. However, 6 strains were recovered from tonsillar tissues as shown in Table III. In other 20 cases treated with antibiotics, beta-hemolytic streptococci were negative in throat cultures preoperatively. However, 1 strain was isolated from tonsillar tissue as shown in Table IV. In untreated 15 cases, 2 yielded group A strains in throat swabs and 3 in tonsillar tissues as shown in Table V. Ten of 62 cultures
Vol.17 No.5
Table III.
GROUP A STREPTOCOCCAL INFECTIONS
595
Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (with Treatment)
yielded beta-hemolytic streptococci in tonsils. Five strains were recovered from tonsils of subjects whose preoperative cultures had been negative, and same serotype of group A strain was isolated from both swabs and tonsillar tissues in 4 patients. 3) Follow-up study of streptococcal antibody response of rheumatic fever: One patient with acute rheumatic fever (12 years of age) and 2 patients with rheumatic heart disease with recurrent attack of rheumatic fever, mitral insufficiency (22years of age) and aortic insufficiency (42years of age) were studied. Streptococcal antibodies (ASO, ASK, AH, and anti-streptozyme) showed high titers in all cases at admission. Antibody levels fell to normal with considerable regularity after antiinflammatory and antistreptococcal treatments as shown in Fig.1.
596
Table IV.
KAWAKITA, ET AL.
J ap. Heart J. September, 1976
Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (with Treatment)
Table V. Beta-Hemolytic Streptococci Recovered from Throats of Patients Subjected to Tonsillectomy Efficacy of Therapy (without Treatment)
DISCUSSION Age appears to play a definite role in streptococcal disease. Kaplan reported that in a total of 624 children (mean age, 6.8years) with pharyngitis, beta-hemolytic streptococci were isolated from 2,56 (41%) and 218 (31%) of
Vol.17 No.5
GROUP A STREPTOCOCCAL INFECTIONS
Fig.1.
Streptococcal
597
antibody response in acute rheumatic fever (E.K., 12y)
these were group A strains.1) According to Siegel study, of 2,545 children with nasopharyngitis 1,213 (47.7%) harbored beta-liemolytic streptococci in their throats, and 86% of these strains were group A streptococci.2) Saslaw observed that in healthy school children 6 to 9 age, 25 to 40% of those studied by monthly throat swabbing had group A organism in their throats.3) In our studies 23.8% of children harbored beta-hemolytic streptococci and group A strains were detected in rate of 13.4%. The average ASO titers of children who harbored group A streptococci were higher than those with other groups of streptococci or negative cultures. The recovery of group A streptococci from throat cultures and high titers of ASO suggest that these findings reflect "i nfection" rather than "carrier state". No rheumatic attack was found in present study. Of 47 children who received antibiotics prior to tonsillectomy, 7 (14.8%) harbored beta-hemolytic streptococci in tonsillar tissues. Moreover, isolation of the same serotype of streptococci was observed in both throat swabs and tonsillar tissues. Saslaw suggested that because of the histological structure of tonsils, organism might remain within deep crypts, secure from contact with, and hence action of, antibiotics from their research works.4) In general, the frequency with which rheumatic fever follows streptococcal disease appears to be related to the intensity of the antigenic stimulus produced in the rheumatic
host by the infecting strains.5)
Stollerman
report-
598
KAWAKITA, ET AL.
Jap. Heart J. September, 1976
ed that a high initial titer of antistreptococcal antibodies was found in the sera of 95% of patients who could be studied within the first 2 months of onset of the rheumatic attack and the rate of fall of the antibodies studied may serve as a guide to the efficacy of antistreptococcal prophylactic measures.6) In one patient with rheumatic fever antibodies fall to normal level after one year of freedom from streptococcal infections. In rheumatic patients who do not maintain effective antimicrobial treatment large tonsils appear to increase the susceptibility to streptococcal infections according to the investigations of Feinstein.7) Moreover, the presence of rheumatic heart disease is apt to complicate recurrent rheumatic fever following streptococcal infections, as indicated in our 2 cases. Therefore, it is very important to make accurate diagnosis of streptococcal infections and also rational decisions about the necessity for antibiotic therapy for rheuamtic heart disease.
REFERENCES 1.
2.
3. 4. 5. 6.
7.
Kaplan EL, Top FH, Dudding BA, Wannamaker LW: Diagnosis of streptococcal pharyngitis. Differentiation of active infection from the carrier state in the symptomatic child. J Inf Dis 123: 490, 1971 Siegel AC, Johnson EE, Stollerman GH: Controlled studies of streptococcal pharyngitis in a pediatric population I. Factors related to the attack rate of rheumatic fever. New Eng J Med 265: 559, 1961 Saslaw MS, Streitfeld MM: Group A beta-hemolytic streptococci in relation to rheumatic fever. Study of school children in Miami, Florida, A.M.A. Am J Dis Child 92: 550, 1956 Saslaw MS, Joblon JM, Jenks SA, Branch CC: Beta-hemolytic streptococci in tonsillar tissue. The efficacy of penicillin. Am J Dis Child 103: 19, 1962 Stollerman GH: Factors determining the attack rate of rheumatic fever. JAMA 177: 323, 1961 Stollerman GH, Lewis AJ, Schultz I, Taranta A: Relationship of immune response to group A streptococci to the course of acute, chronic and recurrent rheumatic fever. Am J Med 20: 163, 1956 Feinstein AR, Levitt MBA: The role of tonsils in predisposing to streptococcal infections and recurrences of rheumatic fever. New Eng J Med 282: 285, 1970
