Defining and dealing with carriers of group A streptococci

By Michael E. Pichichero, MD, and Janet R. Casey, MD

Who, exactly, is a carrier of group A streptococci? How high is the carriage rate? And once you've identified a carrier, is treatment warranted? What kind? Read on for answers to these vexing questions.

Carriers of group A streptococci (GAS) present a clinical challenge in both diagnosis and treatment. Identifying carriers can be confusing and deciding whether and how to treat them a dilemma. Although carriers are generally considered to be innocuous, the risk of transmission of GAS is always an issue. This review addresses questions surrounding diagnosis, incidence, and contagiousness of GAS carriers and offers treatment recommendations.

What is the definition of a GAS carrier?

When group A streptococci colonize the nasopharynx or oropharynx and can be cultured, but the patient has no other evidence of acute infection, the patient is said to be a carrier. Throat cultures and rapid antigen detection tests for GAS generally are performed for patients who have a sore throat, so it may be unclear whether the symptoms and signs are caused by a virus when the patient happens to be a GAS carrier. (Most of the rapid tests in use today are as effective as culture in identifying the presence of GAS. Until the 1980s, a low number of organisms—fewer than 10 cfu—on throat culture was considered to suggest a carrier, but this premise has since been clearly refuted.) More certain diagnosis of a carrier requires serologic evidence demonstrating an absence of rising GAS–specific antibody levels over time while the patient is not receiving antibiotic therapy.¹

Because of its cost and difficulty in interpretation, antibody titer measurement is mostly a research undertaking, and the tests are rarely helpful to the clinician. The results can be difficult to interpret because GAS carriers can have elevated antistreptolysin O (ASO) and anti-deoxyribonuclease B (ADB) antibody levels if, as usually happens, the carrier state is preceded by a symptomatic bona fide or subclinical GAS pharyngitis.²

A more practical definition of a carrier might be a patient who does not have symptoms of GAS sore throat after adequate antibiotic therapy but does have a positive throat culture for GAS. Siegel and colleagues found that about 10% of children treated with benzathine penicillin V were GAS carriers when evaluated 35 days after infection.³ In a recent study, we found 81 (11%) of 718 children to be carriers 10 to 21 days after penicillin V therapy compared with 22 (4%) of 508 children treated with an oral cephalosporin and 10 (7%) of 140 children treated with a macrolide antibiotic (P <.001).⁴

Even with this definition of GAS carriage, the clinician must be careful to determine whether symptoms are really absent or just mild and to define "adequate therapy." We recently published results calling attention to the possibility of milder and fewer GAS symptoms and signs with same-serotype pharyngitis infections in close temporal association.⁵ The trial design was randomized, double-blind, and prospective, with cross-over treatment of GAS pharyngitis comparing penicillin V and cephalexin. Any patient who had a positive culture for GAS within one to three weeks of completing 10 days of therapy was crossed over to the opposite treatment. GAS serology was obtained before and after initial and crossover treatments, and all GAS strains were serotyped to identify same-serotype and new GAS infections.

Some treatment failures occurred, of course, and if the study protocol had not mandated follow-up appointments, very few patients would have returned voluntarily because symptoms were few and mild. When asked a general question about their health, nearly all patients responded that they felt fine. On direct questioning, however, they did report some mild symptoms of GAS pharyngitis, and on examination they had some signs of GAS pharyngitis—albeit few and mild.

Yet GAS serologic analysis showed that the patients were experiencing a second, new rise in the level of GAS antibodies, indicating bona fide new, second infection with the same GAS strains (same serotype). Were it not for our study protocol, these patients might have been classified as carriers and their bona fide GAS relapses easily missed.

"Adequate therapy" is a second issue. A physician may prescribe an adequate treatment but never be sure if the patient was fully compliant (as many are not). Furthermore, penicillin, the recommended treatment for GAS infections, may not be "adequate therapy" for some patients. Last year, a seminal paper by Kaplan and Johnson reported a 42% failure rate for GAS pharyngitis after penicillin therapy—both oral and injectable benzathine penicillin.⁶

What is the incidence of GAS carriers?

Estimates of the number of GAS carriers vary with the population studied and the methods used. The most important rate estimate for the clinician and for interpreting research trials of antibiotics would be from a clinical practice.

Two studies have been completed at the Elmwood Pediatric Group (EPG) in Rochester, N.Y.^4,7 The first, done during the 1950s and 1960s, analyzed well-child visits and visits for upper respiratory tract infection (URI) during which cultures for GAS were taken to determine the frequency of carriers. Among 1,400 well children, 3.4% had a positive culture, and, among 78 children with URI, 11.5% had a positive culture.⁷ In a second study almost 30 years later, the incidence of GAS carriers was 2.5% among 277 well children, 4.4% among 296 children with URI, including sore throat of a presumedly viral nature, and 6.9% among 87 children with URI, including sore throat and culture-proven viral cause.⁴

The observations at EPG are similar to those of Ginsberg and colleagues at a Dallas, Texas, private pediatric practice, in which 3.3% of 1,362 children who were brought to the office for well-child care were carriers.⁸ They also mirror the findings of a Danish study from a general medical practice, in which 10.9% of 2,626 patients under 15 years of age were carriers.⁹

Some authorities point to school surveys—most taken in the 1940s and 1950s—to define the incidence of carriers among normal children. The carrier rates in those surveys were 5% to 20%.^10-15

Several factors might account for the difference in the estimate of the incidence of carriers in physician practices and schools:

• The frequency and number of cultures taken from children in the study populations vary. Physicians in office practice are interested primarily in the rate of carriage at the time when a patient with a sore throat comes in for care. Epidemiologic surveys in schools, on the other hand, usually call for repeated cultures from a child to estimate the pattern of GAS carriage.

• The bacteriologic methods used vary. The studies that proved antibiotic treatment prevented acute rheumatic fever used the same simple methodology that most office and clinical reference laboratories do today—blood agar plates and aerobic incubation for 48 hours. Some school surveys have relied on highly sensitive bacteriologic methods, including selective media, pour plates, and anaerobic or carbon dioxide incubation. Such procedures increase the percentage of positive cultures, but the clinical relevance of this finding is unknown.

• Socioeconomic status and access to and use of medical care in the populations studied vary. These variables influence carrier rate estimates because treatment of patients with GAS pharyngitis results in a lower carrier rate. Patients with GAS pharyngitis feel well within five days of onset of illness with or without antibiotic treatment, so children who do not seek medical care for a sore throat and return to school untreated more often become carriers. In contrast, children studied in primary care practices are readily seeking care for sore throat. If a diagnosis of GAS pharyngitis is established, adequate antibiotic therapy would be the rule. This inevitably leads to a lower carrier rate in pediatric practice.

Are GAS carriers contagious?

A study of families in Cleveland found that, if the index family member acquiring GAS had clinical illness, other members of the family acquired the microorganism about 25% of the time. If the index family member was a carrier, on the other hand, other members of the family acquired the microorganism only 9% of the time.¹⁶ The interval between introduction of the index case of GAS into a family and development of infection or asymptomatic carriage in other members averaged about 15 days. (Although in the Cleveland family study the average time from index to second case was 15 days, other studies have shown a much shorter time between child and mother.)

The ages and relationships of the members of a family into which a GAS infection had been introduced influenced the likelihood of other family members becoming secondary carriers. Children younger than 2 years who had been exposed to a carrier became infected 6% of the time; children 5 years of age or older developed infection 11% of the time. Mothers became infected 8% of the time; fathers, 5% of the time.¹⁶ Krause and Rammelkamp documented that a GAS strain isolated from a carrier could cause active throat infection.¹⁷

Because patients usually harbor more GAS microorganisms during acute active infection than in the recovery stage, when they may become a carrier, carriers may be more contagious earlier in the carrier state than later. A study of 519 children untreated for GAS tonsillopharyngitis found that 50% had GAS in the throat nine days after clinical presentation, 44% had GAS 21 days later, 33% had GAS 35 days later, and 20% had GAS 60 days later. Two-thirds of the GAS isolates found at follow-up were the same strain found at initial presentation and one-third were new types. The children were not described as symptomatic during follow-up.³ Krause and colleagues showed that GAS can persist in the upper respiratory tract of adults for months after infection, although, as in children, the quantity of GAS organisms decreases over time.¹⁷

Some of the best studies on the carrier state were done before the advent of antibiotics and examined GAS outbreaks in rheumatic fever hospitals such as Good Samaritan in Boston¹⁸ and Irvington House on the Hudson.¹⁹ These well-documented studies provide evidence no longer available regarding the possible importance of the carrier in transmitting GAS infection. They show that:

• outbreaks of GAS infection can be caused by carriers

• carriers are most contagious when the carried strain is recently acquired

• the percentage of contacts infected varies from 38% to 57%

• the incidence of clinical illness in persons infected by a carrier (a measure of virulence) varies from 4% to 89%.¹⁹

The threat posed to a contact by a carrier therefore appears to be determined largely by three factors:

• the number of microorganisms found in the nasopharynx, which is highest early in the course of carriage

• the timing of exposure to the carrier, again with greater risk earlier in the course of carriage

• the nature of the strain carried.

Is it GAS carriage or a GAS infection?

Certain clinical and epidemiologic factors should be considered in deciding whether to perform a throat culture in a patient with acute pharyngitis (Table 1).²⁰ GAS pharyngitis is primarily a disease of winter and early spring that affects children 3 to 18 years old. Relatively few throat cultures should be performed in children younger than 3 years or older than 18 years or during the summer, except in specific circumstances such as epidemics or school outbreaks.

TABLE 1
To culture or not to culture?

Clinical findings, such as sudden onset of sore throat, headache, fever, nausea, vomiting, abdominal pain, erythema of the throat and tonsils, tonsillar exudate, cervical lymphadenitis, and a scarlatiniform rash suggest that GAS is the cause of an episode of acute pharyngitis. Findings such as conjunctivitis, rhinorrhea, cough, diarrhea, and a viral exanthem suggest that the cause is a virus. Throat cultures should not be performed on patients with acute pharyngitis whose clinical findings suggest a viral cause because a positive throat culture more likely indicates streptococcal carriage than bona fide GAS pharyngitis.

A child with repeated episodes of acute pharyngitis accompanied by a positive throat culture for GAS often presents a difficult problem for the practicing physician. The fundamental question that must be asked and answered is whether the patient is having repeated episodes of acute GAS pharyngitis or is a streptococcal carrier experiencing repeated episodes of concurrent viral pharyngitis (Table 1). Such a patient is likely to be a GAS carrier if:

• the clinical findings suggest a viral cause

• the epidemiologic findings (age, season) suggest a viral cause

• clinical response to antibiotic therapy is minimal

• throat cultures are positive between episodes of pharyngitis and

• no serologic response to GAS extracellular antigens (ASO, ADB) occurs. Serotyping of GAS cannot be easily obtained; if performed, however, it would demonstrate that all isolates are the same serotype.

A patient with repeated episodes of acute pharyngitis and a positive throat culture for GAS is likely to be experiencing repeated occurrences of acute group A ß-hemolytic streptococcal (GABHS) pharyngitis if:

• clinical findings suggest that GABHS is the cause

• the epidemiologic findings (age, season) suggest that GAS is the cause

• clinical response to antibiotic therapy is marked

• throat cultures are negative between episodes of pharyngitis and

• a serologic response to GABHS extracellular antigens occurs.

Should GAS carriers be treated?

Although most streptococcal carriers require no medical intervention, specific situations occur in which identification and eradication of the streptococcal carrier is desirable. They include the following:

• when there is a family history of rheumatic fever

• when "ping-pong" spread of GAS has been occurring within a family

• when a family has an inordinate amount of anxiety about GAS

• when outbreaks of GAS pharyngitis occur in closed or semiclosed communities

• when an outbreak of acute rheumatic fever occurs

• when tonsillectomy is being considered only because of chronic carriage of GAS

• when, based on observations that recently established carriers may more often be contagious than long-standing carriers, one might consider a single course of antibiotic therapy to rid the patient of the microorganism and secure a longer interval of low infectivity to others.

In treating a GAS carrier, a regimen of oral or injected penicillin V alone is usually ineffective.^21,22 Clindamycin (Cleocin)²³ for 10 days or a combination regimen consisting of a ß-lactam antibiotic (benzathine penicillin V, amoxicillin) or a cephalosporin for 10 days with a concomitant course of rifampin for four of the days²⁴ are recommended (Table 2). Ten days of cefprozil (Cefzil), the only cephalosporin for which data have been published so far, also may be effective.²⁵

TABLE 2
Three options for treating GAS carriers

The superior efficacy of these antibiotic regimens for treating carriers probably results from higher concentrations of drug in noninflamed tissues, activity against GAS microorganisms that are not actively dividing, or effective penetration of drug into epithelial cells where GAS at times reside.²⁶ If the GAS carrier state arises from intracellular localization of the organism, antibiotics such as macrolides (erythromycin, clarithromycin, and azithromycin), clindamycin, and rifampin would have an advantage over ß-lactam antibiotics because the latter concentrate in the extracellular space.

Not to worry (a lot)

Although it is probably true that any carrier may transmit GAS under the right conditions, most carriers are innocuous and, in the absence of recent illness, most can be left untreated without harm to themselves or others. If the practitioner has reason to believe that the patient is a recently established carrier (just having finished a course of antibiotic for acute GAS infection, asymptomatic or with an apparent viral URI, and culture-positive for GAS), giving one additional course of an appropriate antibiotic (not penicillin V alone) might be reasonable in an attempt to eradicate the pathogen and buy time to reduce contagiousness.

REFERENCES

1. Kaplan EL, Top FH Jr, Dudding BA, et al: Diagnosis of streptococcal pharyngitis: Differentiation of active infection from the carrier state in the symptomatic child. J Infect Dis 1971;123:490

2. Tanz RR, Shulman ST, Barthel MJ, et al: Penicillin plus rifampin eradicates pharyngeal carriage of group A streptococci. J Pediatr 1985;106:876

3. Siegel AC, Johnson EE, Stollerman GH: Controlled studies of streptococcal pharyngitis in a pediatric population. N Engl J Med 1961;265(12):559

4. Pichichero ME, Marsocci SM, Murphy ML, et al: Incidence of streptococcal carriers in private pediatric practice. Arch Pediatr Adolesc Med 1999;153:624

5. Lee LH, Ayoub E, Pichichero ME: Fewer symptoms occur in same-serotype recurrent streptococcal tonsillopharyngitis. Arch Otolaryngol Head Neck Surg 2000;126:1359

6. Kaplan EL, Johnson DR: Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of Group A streptococci from children with acute pharyngitis. Pediatrics 2001;108(5):1180

7. Breese BB, Disney FA, Talpey W: The incidence of beta-hemolytic streptococcal illness in a private pediatric practice. Pediatrics 1966;38(2):277

8. Ginsberg CM, McCracken GH, Crow SD, et al: Seroepidemiology of the group A streptococcal carriage state in a private pediatric practice. Am J Dis Child 1985;139:614

9. Hoffman S: The throat carrier rate of group A and other beta-hemolytic streptococci among patients in general practice. Acta Pathol Microbial Immunol Scand 1985;93:347(Sect B).

10. Pike M, Fashena GJ: Frequency of hemolytic streptococci in the throats of well children in Dallas. Am J Public Health 1946;36:611

11. Saslaw MS, Streitfeld MM: Group A beta-hemolytic streptococci and rheumatic fever in Miami, Florida. Bacteriologic observations, from October 1954 through May 1955. Dis Chest 1959;35:175

12. Cornfeld D, Werner G, Weaver R, et al: Streptococcal infection in a school population. Ann Intern Med 1958;49:1305

13. Cornfeld D, Hubbard JP: A four-year study of the occurrence of beta-hemolytic streptococci in 64 school children. N Engl J Med 1961;264:211

14. Quinn RW, Federspiel FC: The occurrence of hemolytic streptococci in school children in Nashville, Tennessee, 1961–1967. Am J Epidemiol 1973;97:22

15. Quinn RW: Hemolytic streptococci in Nashville school children. South Med J 1980;73(3):288

16. James WE, Badger GF, Dingle JH: A study of illnesses in a group of Cleveland families. XIX. The epidemiology of the acquisition of group A streptococcal and of associated illness. N Engl J Med 1960;262:687

17. Krause RM, Rammelkamp CH: Studies of the carrier state following infection with group A streptococci. II. Infectivity of streptococci isolated during acute pharyngitis and during the carrier state. J Clin Invest 1962;41(3):575

18. Wheeler SM, Jones TD: Studies on the aerial transmission of hemolytic streptococci in a rheumatic fever hospital. Publication of the American Association for the Advancement of Science No.1941;17:237

19. Kuttner AG, Krumwiede E: Observations on the effect of streptococcal upper respiratory infections on rheumatic children: A three-year study. J Clin Invest 1941;20:273

20. Bisno AL, Gerber MA, Gwaltney JM, et al: Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infect Dis 1997;25:574

21. Gastanaduy AS, Kaplan EL, Huwe BB, et al: Failure of penicillin to eradicate group A streptococci during an outbreak of pharyngitis. Lancet 1980;2:498

22. Kaplan EL, Gastanaduy AS, Huwe BB: The role of the carrier in the treatment failures after antibiotic therapy for group A streptococci in the upper respiratory tract. J Lab Clin Med 1981;98:326

23. Tanz RR, Poncher JR, Corydon KE, et al: Clindamycin treatment of chronic pharyngeal carriage of group A streptococci. J Pediatr 1991;119:123

24. Tanz RR, Shulman ST, Barthel MJ, et al: Penicillin plus rifampin eradicates pharyngeal carriage of group A streptococci. J Pediatr 1985;106:876

25. Standaert BB, Finney K, Taylor MT, et al: Comparison between cefprozil and penicillin to eradicate pharyngeal colonization of group A beta-hemolytic streptococci. Pediatr Infect Dis J 1998;17:39

26. Molinari G, Talay SR, Valentin-Weigand P, et al:. The fibronectin-binding protein of Streptococcus pyrogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells. Infect Immun 1997; 65:1357

DR. PICHICHERO is a partner in the Elmwood Pediatric Group, Rochester, N.Y., and professor of microbiology and immunology, pediatrics, and medicine, University of Rochester Medical Center.

DR. CASEY is a partner in the Elmwood Pediatric Group, Rochester, N.Y.

FAQs about GAS carriers

What is the definition of a GAS carrier?

Current definitions are a clinical conundrum. GAS serology is impractical, expensive, and difficult to interpret. The determination of "asymptomatic" carrier needs to be carefully assessed in light of evidence suggesting same serotype infections cause fewer and milder symptoms. The definition of "adequate therapy" needs to be re-examined in light of recent documented 40% failure rates following penicillin treatment.

What is the incidence of GAS carriage?

In a private practice, about 2% to 4%. In a school classroom survey, about 15% to 20%.

Are GAS carriers contagious?

Yes—but about three-fold less so than patients with active acute infection. Contagiousness decreases with longer duration of carriage and fewer organisms in the throat.

What clinical and epidemiologic findings help differentiate a patient with a GAS infection from one with a non–GAS infection?

In brief, if the patient appears to have a viral URI, don't even take a throat culture. If the patient does not respond to antibiotics within 48 hours, most likely the sore throat was not caused by GAS.

Should GAS carriers be treated?

Yes, in certain circumstances, but not with penicillin alone. Use clindamycin; penicillin, amoxicillin, or a cephalosporin in combination with rifampin; or cefprozil.

 

Michael Pichichero, Janet Casey. Defining and dealing with carriers of group A streptococci. Contemporary Pediatrics 2003;1:46.