Rheumatic fever recurrences: Controlled study of 3-week versus 4-week benzathine penicillin prevention programs

PEDIATRIC PHARMACOLOGY AND THERAPEUTICS

Rheumatic fever recurrences: Controlled study of 3-week versus 4-week benzathine penicillin prevention programs To c o m p a r e the merits of 3-week versus 4-week injections of benzathine penicillin G in preventing recurrence of rheumatic fever, 179 patients a g e d 4 to 19 years were assigned to one of the two programs. Age, weight, cardiac status, and streptococcal infections a m o n g the patients and their family members studied in each program were comparable. Eighty-two patients and their family members were monitored for streptococcal infections. Compliance in the two programs was comparable. Of the 63 patients who stayed in the 4-week program, RF recurred in six, as a result of prophylaxis failure in five and associated with partial compliance in one. Of the 90 patients in the 3-week program, RF recurred in one, associated with partial compliance; no failures occurred (P = 0.01). We r e c o m m e n d e d that for RF chemoprophylaxis in individuals at great risk, regardless of age, benzathine penicillin injections should be administered every 3 rather than every 4 weeks. (J PEDIATR1986;108:299-304)

Hung-Chi Lue, M.D., D.Sc., Mei-Hwan Wu, M.D., Kue-Hsiung Hsieh, M.D., Ghi-Jen Lin, M.D., Rhong-Phone Hsieh, B.S., a n d Jow-Farn Chiou, D.V.M., M.S. From the Departments of Pediatrics, Clinical Pathology, and Bacteriology, National Taiwan UniversityHospital,Taipei, Taiwan, Republic of China Benzathine penicillin G, administered intramuscularly once every 4 weeks, was shown by StOllerman and Rosoff 1 in 1952 to be effective for the prevention of group A streptococcal infections and recurrent attacks of rheumatic fever. Many subsequent studies confirmed these resutts. 2-v Injection of BPG, 1,200,000 U every 4 weeks, as recommended by the American Heart Association,8 has become the accepted form of continuous chemoprophylaxis in both adults and children with a documented history of RF. Recurrences of RF have continued, however, at a rate of 0.1 to 3.0 per 100 patient-years3'~'7"9.I~ in some highly endemic areas, the incidence of recurrence has been even Supported in part by funds provided by the Cardiac Children's Foundation, Republic of China. Submitted for publication April 30, 1985; accepted Aug. 8, 1985. Reprint requests: Hung-Chi Lue, M.D., Professor and Chairman, Department of Pediatrics, National Taiwan University Hospital, 1 Chang-Teh St., Taipei, Taiwan 100, R.O.C.

higher. 1~ For this reason, the World Health Organization recommends BPG injection every 4 weeks in children and every 3 weeks in adults? 2-14 Some patients may have inadequate serum penicillin levels during the fourth week after a single intramuscular

ASO BPG RF RHD

Antistreptolysin O Benzathine penicillin G Acute rheumatic fever Rheumatic heart disease

dosel'~5; thus prophylaxis failure, or "penicillin breakthrough," is possible, especially when the exposure to streptococci is heavy or the individual is for some reason at great risk. Reye et al., 16 Nordin, ~7 and Strasser et al. ~8 recently reported such cases among patients receiving regular monthly BPG injections, w e have conducted a 5-year prospective study in which patients with a history of

299

300

Lue et at.

The Journal ofPediatrics February1986

Table I. Age, cardiac status, and follow-up duration among patients in 3-week and 4-week programs Cardiac Clinic 3 Week (n = 68)

Patients who stayed Age (yr) Mean Range Sex (M/F) ratio Weight (kg) Mean +_SD Patients with RHD (%) Follow-up (yr) Mean Range

RFClinic

4-Week (n = 29)

3-Week (n = 37)

Total

4-Week (n = 45)

3-Week (n = 105)

4-Week (n = 74)

60

25

30

38

90

63

13.4 5-19 0.9

10.6 5-16 0.7

9.6 5-16 1.5

9.9 4-14 0.7

12.1" 5-19 1,1"

10.2 4-16 0.7

30.4 10.1 91.7

30.4 10.8 84.0

42.6 10.5 96.7

39.2 11.2 84,2

33,8* 11.4 93.3*

34.7 11.3 84.1

2.6 1-5

3.0 1-5

3.2 1-5

3.2 1-5

2.8* 1-5

3.1 t-5

*P >0.05 compared with 4-week group.

Table II. Compliance with prevention programs C a r d i a c Clinic 3-Week

Stay-in Complete Partial Dropout Total

RF Clinic

4-Week

3-Week

Total 4-Week

3-Week

4-week

n

%

n

%

n

%

n

%

n

%

n

%

50 10 8 68

73.5 14.7 11.8

24 1 4 29

82.8 3.4 13.8

25 5 7 37

67.6 13.5 18,9

30 8 7~ 45

66.7 17.8 15.5

75* 15" 15" 105

71.4 14.3 14.3

54 9 11 74

73.0 12.2 14.8

*P >0.05 compared with 4-week group. ~'One patient given sulfonamide.

R F or with rheumatic heart disease were assigned to 3-week or 4-week BPG programs. The study was designed to compare the efficacy of the two programs and their impact on patient compliance with long-term chemoprophylaxis. METHODS

Subject recruitment and assignment. Between June and October 1979, 61 patients with R F or R H D were being observed and were receiving BPG injections every 3 weeks or every 4 weeks at the Cardiac Clinic of the Department of Pediatrics, National Taiwan University Hospital. To monitor streptococcal infections among patients and family members, a new R F Clinic was set up and patients were informed of its availability. O f the 61 patients, 29 were transfered to the R F Clinic and 32 continued in a triweekly BPG program at the Cardiac Clinic. From October 1979 to February 1983, 132 new patients with a documented history of R F or R H D entered the Cardiac and R F clinics. Fourteen patients who either died (six) or dropped out of

the program (eight) within 2 months after a first visit were excluded. A total of 179 former and new patients were thus enrolled in the study, and were observed until February 1984 either at the R F Clinic (82 patients) or the Cardiac Clinic (97 patients). With the informed consent of their parents, those patients new to either clinic were randomly assigned to either a 3-week or 4-week program on the basis of odd or even hospital chart numbers. The new patients were instructed initially to return to the clinic either every 3 or every 4 weeks, on the basis of their chart numbers, to receive the BPG injection. Initially, follow-up examinations were conducted at each of these visits. Subsequently, when injections were permitted to be given at the clinic or elsewhere, using the same 3- or 4-week schedule, follow-up was conducted every 3 to 6 months or at any time a patient was sick. Eighty-two patients who entered the R F Clinic were monitored for streptococcal infections, as were close family members, including siblings and parents residing under the same roof.

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Rheumatic fever and benzathine penicillin prophylaxis

III. Streptococcal infections among patients in 3-week and 4-week prevention programs at R F Clinic

Table

3-week n = 30 n

Follow-up (pt-yr) Positive throat cultures* Rise in ASO titer Rise in Streptozyme titer lnfection/carriers'~ True Carriers Total

96 6/530 13/264 12/231

1,1 4.9 5.2

16 3 19

16.7:~ 3.1 19.8

n

3-Week n = 30 %

122 2/433 0.5 20/287 7.0 21/255 8.2 22 2 24

18.0 1.6 19.6

n

Family members (examined/total) Positive throat cultures* Rise in ASO titer Rise in Streptozyme titer In fection/carriers]" True Carriers Total

*Number positive/numberdone. "tNumber of infections or carriers per 100 pt-yr. :~P >0.05 compared with 4-week group.

Table

IV. Streptococcal infections among family members of patients at R F Clinic Table

4-Week n = 38 %

30 1

4-Week n = 37 %

n

110/150

%

114/171

15/375 43/292 45/294

4.0 14.7 15.3

20/490 40/336 41/327

4.1 11.9 12.5

48

43.6~:

51

44.7

6 54

5.5 49.1

13 64

11.4 56,1

*Number positive/numberdone. "tNumber of infections per 100 family members examined. :[:P >0,05 compared with 4-week group,

V. Total rheumatic fever recurrence and prophylaxis failure among patients in 3-week and 4-week programs Cardiac

Follow-up (pt-yr) Total RF recurrence Partial compliance Prophylaxis failure Prophylaxis failure (rate per 100 pt-yr)

Clinic

RFClinic

Total

3-Week (n = 6 0 )

4-Week (n = 2 5 )

3-Week (n = 3 0 )

4-Week (n = 2 8 )

3-Week (n = 9 0 )

4-Week (n = 6 3 )

157 1 1 0 0.0

74 1 1 0 0.0

95 0 0 0 0,0

121 5 0 5 4.1

252 1' 1 07 0.0

195 6 1 5 2,6

*P = 0.018 compared with 4-week group. #P = 0.01 compared with 4-week group. L a b o r a t o r y methods and diagnostic criteria. The disease, medication programs, and importance of long-term prophylaxis were explained by one of us (H.C.L.) to each patient and his or her parents. At each visit to the R F Clinic, throat cultures were taken from the patient and from accompanying family members. The swabs were immediately inoculated in pike broth with sheep blood. After 18 to 24 hours incubation, one loopful of inoculum was streaked onto a heart infusion agar plate with sheep blood. Plates were read 18 to 24 hours after incubation at 37 C. A colony of B-hemolytic streptococci was then used for subculture. A paper disk containing 0.2 U bacitracin was placed on the plate. Those isolates showing an inhibitory zone of >_ 12 mm were identified as group A streptococci? 9 Sera for antistreptolysin O and Streptozyme (Wampole Laboratories, Cranbury, N.J.) titers were obtained at the first, second, seventh, eighth, and subsequent follow-up visits or when decided on by the attending physician. The paired sera were measured for A S O and Streptozyme titers5 o,2~ When R F recurrence was suspected at either clinic,

chest radiographs, ECGs, throat cultures, serologic tests, and acute-phase reactants were obtained. The revised Jones criteria were used for the diagnosis of RF; 22 The streptococcal infections among patients and family members were identified as true or bona fide streptococcal infections when the A S O or Streptozyme titers showed two-tube or greater rises; carriers were identified when the culture was positive but the patient had no antibody response?9. 23 In the few cases of family members in whom paired sera were not available, a single A S O titer of >333 T U in children and >250 T U in adults was considered elevatedJ 9 A single Streptozyme titer of >200 U in children and >150 U in adults was considered elevated. BPG 1,200,000 U was given intramuscularly to all patients regardless of their age or weight. Patient compliance with the program was classified into three categories: those who missed fewer than one injection each year were classified as "stay-in, complete"; those who stayed for longer than 1 year but missed two or three injections a year as "stay-in, partial", and those who missed more than four injections a year as "dropout. TM

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Lue et al.

The Journal of Pediatrics February 1986

Table VI. Recurrence of rheumatic fever as a result of prophylaxis failure Prophylaxis failure

Previous RF attack Patient

Sex

Age (yr)

Date

Major manifestations

BPG given

RF relapse

Interval (days)

1

M

13

Aug. 1977

Carditis (AR)

May 20, 1980

June 16, 1980

27

2

F

10

Dec. 1978

Carditis (MR) Heart failure

June 3, July 1, 1980

July 6, 1980

28 5

3*

F

12

Dec. 1 9 7 9

Carditis (MR, AR) Heart failure

July 11, 1982

Aug. 5, 1982

24

4*

F

10

Dec. 1 9 7 9

Carditis (MR) Erythema marginatum

April 7, 1981

May 5, 1981

28

5

F

9

Aug. 1979

Chorea Carditis Erythema marginatum

Dec. 19, 1983

Jan. 17, 1984

29

AR, Aorticregurgitation;CRP, c-reactiveprotein;ESR, erythrocytesedimentationrate; MR, mitral regurgitation;MS, mitralstenosis. *Sisters. Statistical analysis. Characteristics of the patients and their family members in the two programs were compared for statistical significance using the Student t test and the chi-square test, with Yates continuity correction when required. RF recurrence rates were compared by Fisher exact test. RESULTS

Comparability of study groups. Between October 1979 and February 1984, a total of 90 children stayed in or partially completed the 3-week program: 60 in the Cardiac Clinic and 30 in the RF Clinic. Sixty-three children stayed in the 4-week program: 25 in the Cardiac Clinic and 38 in the RF Clinic (Table I). The patient variables age, sex, weight, cardiac status, and follow-up duration in each program at the Cardiac and RF clinics influencing recurrence rates were comparable (P >0.05). None of the patients had significant renal disease. Fifteen and 10 patients dropped out of the 3-week and 4-week programs, respectively (Table II). A single patient allergic to penicillin was given sulfonamide instead of BPG. Streptococcal infections among patients. Of the 530 and 433 throat cultures taken from the 3- and 4-week groups, six (1.1%) and two (0.5%) respectively, were positive for group A streptococci (Table III). The numbers of ASO and Streptozyme tests and the rises in titer in both groups of patients were also comparable. On the basis of these culture results and antibody responses, true group A streptococcal infections were found in 16 of 30 patients in the 3-week program and in 22 of 38 in the 4-week pro-

gram. The difference was not statistically significant (P >0.05). Comparability of patient families. Family studies at the RF Clinic showed that the numbers of family members and those examined from families of the two patient groups were comparable (Table IV). The numbers and results of throat cultures and of ASO and Streptozyme tests obtained in each group were also comparable. The true streptococcal infections detected among family members of the two groups were not statistically different (P >0.05). RF recurrence and manifestations. During the study period, acute RF attacks occurred in seven patients (Table V), one in the 3-week group and six in the 4-week group. Two recurrences, one each in the 3- and 4-week programs at the Cardiac Clinic, were associated with partial compliance. The relapses in five of the 63 patients in the 4-week program at the RF Clinic occurred because of prophylaxis failure. No such failures were observed, however, in the 90 patients who stayed in the 3-week program (P = 0.01). Dates of last BPG injections and of the onset of RF recurrences resulting from prophylaxis failure are listed in Table VI. The manifestations of both previous and recurrent attacks of RF were quite typical. Patients 3 and 4, who are sisters, had typical erythema marginatum with acutephase reactions. The heart in patient 3 became enlarged in the month after RF recurrence. The manifestations of recurrence in patient 4 mimicked those of his 1979 attack except that the cardiac murmur and heart size were unchanged. There were definite rises in the ASO and

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Rheumatic fever and benzathine penicillin prophylaxis

RF recurrence Major/minor manifestations

A$O titer

Streptozyme titer

Carditis Arthralgia Carditis Heart failure CRP (6+) ESR (60 mm/hr) Erythema marginatum Arthralgia, knee Carditis, mild Erythema marginatum ESR (21 mm/hr) History of RF Chorea Carditis (MS) Prolonged PR interval

1250

1800

2500

200

625

400

833

500

50

100

Streptozyme titers in all but patient 5, who had chorea, mild mitral stenosis, and PR interval prolongation. Throat cultures taken from the patients at the time of recurrence were all negative. DISCUSSION The data show that the incidence of true group A streptococcal infections among patients receiving BPG injections was significantly lower than that among their (nontreated) family members (P >0.05). Positive cultures for group A streptococci (either true infections or carriers) occurred in both 3-week and 4-week groups at a comparable rate. Four (18.2%) of the 22 documented group A streptococcal infections in the 4-week group led to R F recurrence despite continued monthly BPG injections. Observations would indicate that another group A streptococcal infection might have occurred, although it was not documented by culture or by serologic tests, in patient 5, who developed chorea and subclinical carditis leading to mitral stenosis. The intervals between the last BPG injection and the onset of R F recurrence from penicillin breakthrough varied from 5 to 29 days (Table VI). In patient 2, given two BPG injections 28 days apart, R F recurred 5 days later, with carditis with pericardial effusion and heart failure. It would appear that the penicillin was administered too late to prevent the RF. Our data suggest that regular triweekly BPG injections could not totally prevent streptococcal infections but prevented R F recurrence. The prophylaxis failures were limited to the 4-week group, indicating that the failure was

303

less likely caused by bacterial interference z4 or inactivation of penicillin,z5 Serum penicillin levels lower than the minimum inhibitory concentration of 0.01 to 0.03 #g/ml might be the cause. 15,26 Stollerman and Rosoff ~ and more recently Ginsburg et al. 26 have reported, respectively, that in 11% to one third of patients, BPG given monthly provided inadequate serum penicillin activity to prevent infections beginning at 21 days, or as early as 18 days, after the injection. In our study, in 23 (39%) of 59 children in the 3-week group the serum penicillin levels at 21 days after the injection were <0.02 #g/ml (unpublished observation). Our data indicate that BPG injection every 4 weeks, the accepted regimen for secondary prevention of RF, is effective but still allows significant risk of recurrence. For R F chemoprophylaxis in developing countries or in other regions where R F and RHD are prevalent because of endemic streptococcal infection, 27-29and in individuals who for some particular reason are at great risk, administration of BPG injections once every 3 rather than 4 weeks is recommended, regardless of patient age and weight. A 3-week program may adversely affect compliance rate, particularly in societies where the health care system remains limited, costly, or not readily accessible. The reasons for partial or noncompliance are diverse: the most important observed in Taipei were apparent recovery, cram sessions at school, and hospital inaccessibility.4 Our study showed that patient compliance in 3-week and 4-week programs was comparable, indicating that the hospital setting, the increase in the number of clinic visits, and the expense and effort required for the 3-week program compared with the 4-week program were not detrimental to compliance with long-term chemoprophylaxis. Daily oral administration of penicillin has been proved to be an effective and useful regimen in preventing R F recurrence, TM ~4but the long-term use of oral penicillin has not been popular in developing countries because of usually poor compliance rates.13' ~4.16Selection of a regimen for continuous prophylaxis against group A streptococcal infections in patients who have had R F should therefore be made, based on information regarding the epidemiology of group A streptococcal infections and the susceptibility of the host to R F attacks. We thank Miss Shu-Jen You for technical assistance; and Drs. Milton Markowitz, Edward L. Kaplan, Huoyao Wei, Chiung-Lin Chen, and Chien-Jen Chen, who served as consultants. REFERENCES

1. Stollerman GH, Rosoff JH. Prophylaxis against group A streptococcal infections in rheumatic fever patients. JAMA 1952;150:1571-1575.

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