The Carrier State of Group A Streptococci

Educational Objectives

After reading this article and answering the review questions, the reader will be able to:

1. Identify children who are carriers of Group A streptococcus (GAS)
2. Explain the epidemiology of GAS carriage
3. Manage GAS carriers in the office setting

Case

An 8-year-old girl presents to your office with a two-day history of sore throat and nasal discharge. She has had a low-grade fever of 100.8°F for one day. Today she developed a cough. She has no headache, abdominal pain or rash. No household contacts have had strep throat recently but the mother thinks there have been infected children in her school.

This child has been in to your office or the local urgent care four times in the past year for pharyngitis. On all occasions she has had either a positive rapid strep test (RST) or a positive throat culture for GAS. For these episodes she was treated with either penicillin or azithromycin.

On exam, her temperature is 99.1°F orally. She is talkative and not ill appearing. Her voice is hoarse. Her conjunctivae are mildly injected. She has bilateral clear middle ear effusions with no erythema or bulging of the tympanic membranes. Her nasal mucosa is injected and there is clear rhinorrhea present. Her throat is erythematous and the tonsils are mildly enlarged and cryptic. No pharyngeal exudate or petechiae are present. She has no significant cervical adenopathy. The remainder of her exam is unremarkable.

A rapid strep test (RST) is positive. The mother asks you why she keeps getting strep. Which antibiotic, if any, should you prescribe? Should you offer tonsillectomy as an option to prevent further recurrences of pharyngitis? Is she a carrier?

Group A Streptococci

Acute pharyngitis is the most common illness for which children seek acute medical care. In the United States upper respiratory infections, including pharyngitis, are responsible for 200 visits per 1000 population each year¹. Group A streptococcus (GAS) is the most frequent bacterial cause of pharyngitis in children and is responsible for 25-35 million cases of pharyngitis and 1-2 billion dollars in direct health care expenditures each year².

Acquisition of GAS results from person-to-person transmission. After acquisition, the patient will either develop clinical or subclinical infection. Most infections are cleared either spontaneously or after appropriate antibiotic administration. However, about 15% of children will incorporate GAS into their normal pharyngeal flora and become carriers³.

Definition of the Carrier State

Defining the carrier state has been a challenge for over 50 years⁴. In fact, it has been referred to as “an enigma” in the literature⁵. The historical definition has been detection of GAS in the pharynx without a rise is serum antibody to GAS antigens (such as anti-streptolysin A and anti-DNase B). In a clinical setting, it may be difficult to obtain the paired serological samples needed to support this definition⁶. In addition, the antibody response to GAS may be blunted by treatment and may not be reliable in detecting carriers⁷. It has been noted that most children who have experienced microbiological failure, defined as a positive throat culture after a course of appropriate antibiotics, are actually carriers.

Thus, a carrier may be identified when there is a positive throat culture after treatment with an otherwise effective antibiotic. Carriers may also be diagnosed when GAS is isolated from the pharynx in an asymptomatic patient. Although both of these definitions may over or under identify carriers, throat culture results are easier to obtain and interpret than serologic testing in the office setting.

The carrier state can confound the diagnosis of pharyngitis. When a child who has a viral URI develops sore throat and is brought in to clinic, the rapid strep test or throat culture will be positive and yet the etiology of the sore throat is viral. However, during an ill visit like this, the clinician has no means of making this determination and an antibiotic will be prescribed.

What We Know About the Carrier State

It is unclear as to why some children become carriers of GAS and some do not. In understanding the pathogenesis of the carrier state, both microbial and host theories have been offered. One possible mechanism for persistent colonization of the pharynx despite appropriate treatment involves the commensal flora. It is well-established that GAS are universally susceptible to penicillin but it is possible that non-GAS bacteria in the throat produce beta-lactamases that inactivate penicillin and thereby result in treatment failure. This theory is supported by studies that show a slightly higher GAS eradication rate when beta-lactamase stable antibiotics such as cephalosporins are prescribed.⁸ Other theories involve the production of various surface adhesion molecules and other virulence factors by carrier strains of GAS which enhance persistence. In addition, there may be genetic determinants in the host that allow for immunological tolerance of GAS in the pharynx.

Much about the natural history and epidemiology of the carrier state has been learned from a longitudinal study of school children in Pittsburgh in 1998.⁹ In this study, a cohort of elementary school children had throat cultures performed twice per month and also when they had respiratory illness. The study subjects were followed for a total of four years. About 30% of children were carriers at some point each year and, at any given time, 15% of children in the study were carriers. Over half of the children who were carriers in the first year of the study were carriers for all four years, though the mean duration of carriage for all carriers was about a year. In addition, carriage was noted to be intermittent in many children.

GAS are classified according to their emm type (named for the M protein on its surface). Interestingly, in this group of Pittsburgh school children who were carriers, over half who were carriers of one emm type switched to carrying a different emm type during the observation period. In addition, some children who were carriers of one emm type had clinical infection with a second emm type and then resumed carriage with the first emm type. This observation has important significance in management of carriers long term, as will be discussed below.

Notably,carriers are not at risk for the non-suppurative complications of GAS infection (rheumatic fever and glomerulonephritis), nor are they at risk for invasive disease. Furthermore, GAS carriers are not a significant source for transmission of infection to close contacts.⁴

Case Discussion

This patient's constellation of symptoms suggests a viral etiology. Cough, rhinorrhea and conjunctivitis are not typical symptoms of streptococcal infection. However, the RST was positive and cannot be ignored.

When assessing patients who have had recurrent episodes of GAS pharyngitis or those who have failed treatment, one must first determine whether the patient was adherent to the antibiotic regimen. Were all of the doses taken for the prescribed amount of time? Was an effective antibiotic prescribed? GAS are universally susceptible to penicillin but resistance to macrolides such as azithromycin is increasing. In some communities macrolide resistance rates over 40% have been reported.¹⁰ In the Madison, Wisconsin area, a small sampling of GAS isolates collected over the past five years from UW Health clinics showed a 30% rate of resistance to macrolides. Therefore, if a patient has received azithromycin for treatment of prior episodes of pharyngitis, treatment failure may be explained by macrolide resistance.

Assuming the child in this case was last treated with penicillin (or amoxicillin) then one approach is to treat her with another course of penicillin. Normally a "test of cure" is not recommended when treating GAS pharyngitis. However, when streptococcal carriage is suspected, a repeat throat culture should be obtained 2 to 4 days after the completion of treatment. If the throat culture is positive in an asymptomatic patient who has completed therapy with an appropriate antibiotic, the child can be assumed to be a carrier.

Performing routine cultures of the pharynx of household members of the index case of GAS is generally not recommended. However, when a child does present with recurrent streptococcal pharyngitis it may be useful to identify other family members who are infected and a potential source of transmission to the index patient.
Family pets, such as dogs, are not a source of transmission of GAS to children. In addition, the role of toothbrushes in causing reinfection has been overstated. Although GAS can be cultured from the surface of toothbrushes of patients who have had GAS pharyngitis, the importance of this in causing reinfection is frequently over emphasized. Simple rinsing of toothbrushes daily is usually sufficient to remove streptococci.¹¹

Eradication

In the majority of patients reassurance and watchful waiting are all that is sufficient in managing the carrier of GAS. Many children will spontaneously clear the organism with no intervention. If the patient is identified as a carrier in late spring or early summer, observation without treatment over the summer months is reasonable. Situations in which an attempt at eradicating the carrier state is appropriate include the following: 1) having a household contact with a history of acute rheumatic fever (ARF) or post-streptococcal glomerulonephritis (PSGN), 2) a community outbreak of ARF, PSGN or invasive GAS disease, 3) an outbreak of GAS pharyngitis in a closed community such as a long-term care facility, 4) multiple episodes of GAS pharyngitis occur within a family in a short period of time or 5) a child is identified as a carrier in the beginning or middle of the respiratory season. In addition, eradication may be considered when a child has had multiple episodes of GAS pharyngitis that are causing significant parental anxiety or loss of an undo amount of time from school or jobs.¹²

Several antimicrobial agents have been shown to be effective at eliminating GAS from the pharynx of carriers. In one study a combination of penicillin and rifampin was more effective than no treatment or treatment with penicillin alone¹³, as was amoxicillin/clavulanate.¹⁴ A randomized-controlled trial of clindamycin for 10 days showed a 92% eradication rate.¹⁵ However, clindamycin often shows cross-resistance with macrolides and this study was performed at a time when macrolide resistance was uncommon. Azithromycin should be avoided unless susceptibilities have been performed and do not demonstrate resistance.

Tonsillectomy is effective in reducing the number of episodes of pharyngitis of all causes when patients are selected using stringent clinical criteria. These include three episodes of pharyngitis in each of three successive years, five episodes in each of two successive years or seven episodes in a year.¹⁶ Evidence that tonsillectomy will eliminate GAS carriage is lacking.

In this patient, a period of watchful waiting would be prudent. If she has another episode of pharyngitis with a positive GAS test or if the parents are very anxious, then a culture should be performed 3 to 4 days after treatment has been completed. If this culture is positive then the patient is a carrier and a trial of an antibiotic could be offered as an attempt at eradication. A course of clindamycin for 10 days would be a first choice of therapy if the isolate of GAS is susceptible. Alternatives would include amoxicillin/clavulanate or penicillin with rifampin. It is important to note that, even if she is identified as a carrier, further episodes of symptomatic pharyngitis should be treated if either the rapid antigen or throat culture are positive for GAS. Though the etiology of the pharyngitis may be viral and the tests may be positive due to GAS carriage, it is possible for carriers to be infected with a different emm type of GAS.

There is no practical method of determining emm type in the acute care setting, and, because infection with a new serotype may impart a risk for rheumatic fever, the patient should be treated. This child would not meet the criteria for being severely affected to warrant tonsillectomy.

Carriage of GAS is common in the school age population. Most cases of carriage will resolve spontaneously or with a course of antibiotic. Further understanding of the mechanisms of colonization may lead to new preventive strategies in the future.

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References

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13. Tanz RR, Shulman ST, Barthel MJ, Willert C, Yogev R. Penicillin plus rifampin eradicates pharyngeal carriage of group A streptococci. J Pediatr. Jun 1985;106(6):876-880.
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16. Paradise JL, Bluestone CD, Bachman RZ, et al. Efficacy of tonsillectomy for recurrent throat infection in severely affected children. Results of parallel randomized and nonrandomized clinical trials. N Engl J Med. Mar 15 1984;310(11):674-683.

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