The Group A Streptococcal Carrier State Reviewed: Still an Enigma

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1 Invited Review The Group A Streptococcal Carrier State Reviewed: Still an Enigma Gregory P. DeMuri and Ellen R. Wald University of Wisconsin School of Medicine and Public Health, Madison Corresponding Author: Gregory P. DeMuri, MD, Department of Pediatrics, 600 Highland Ave, H6/570 Madison, WI demuri@pediatrics.wisc.edu. Received August 15, 2013; accepted March 19, 2014; electronically published April 30, Despite the common nature of group A streptococcal (GAS) infections, the carrier state of this organism is not well understood. In this article, we review the historical and recent research on the definition, epidemiology, and pathogenesis of the GAS carrier state. In addition, we outline trials of antimicrobial agents in the eradication of the carrier state and discuss indications for providing treatment to patients in the clinical setting. Key words. carrier state; group A Streptococcus; pharyngitis; Streptococcus pyogenes. Pharyngitis is one of the most common reasons for which children and young adults seek medical care, and the group A streptococcus (GAS) is the most frequent cause of bacterial pharyngitis in these age groups [1]. Group A streptococcus is also responsible for invasive disease and nonsuppurative sequelae such as acute rheumatic fever and glomerulonephritis. Despite the common nature of GAS infections, the carrier state is not well understood and has been referred to as an enigma by some experts [2]. Identification and management of GAS carriers often causes frustration for the clinician, the patient, parents, and researchers. The GAS carrier was first described in the pre-antibiotic era during outbreaks of GAS disease. It was observed that many individuals during an outbreak harbored GAS in their pharynx but did not have any clinical symptoms [3]. These individuals did not suffer from the nonsuppurative complications of GAS infection and tended to carry GAS in the throat for a prolonged period. Children who are carriers of GAS must be distinguished from those with asymptomatic or subclinical infection. Although this latter group of children does not have overt clinical symptoms of GAS pharyngitis, they transiently acquire a pharyngeal infection and may be at risk for nonsuppurative sequelae (Figure 1)[2]. In fact, 66% to as many as 75% of individuals who are diagnosed with acute rheumatic fever do not recall a pharyngeal infection in the preceding 3 months [4, 5]. The Definition of the Carrier State Despite over 70 years of observation and research, an exact definition of the GAS carrier remains elusive. Historically, carriers were defined as patients who were asymptomatic but had a positive throat culture. However, this definition excludes children with symptomatic pharyngitis from a viral infection who have a positive throat culture for GAS. Another definition found in the literature is an individual who has a positive throat culture for GAS but does not develop an antibody to the extracellular antigens (antistreptolysin-o [ASO], anti-deoxyribonuclease B, antihyaluronidase) or M proteins elaborated by the organism. However, a study by Gerber et al [6] casts doubt as to the validity of this definition. In their study, children who presented with symptoms of pharyngitis were divided into 3 groups: those with negative throat cultures, those with positive throat cultures and negative serology, and those with positive throat cultures and positive serology. As expected, it was observed that children with negative throat cultures did not respond to antibiotics. However, both children with and without serologic responses reacted similarly to antibiotic therapy, suggesting that some children without a serological response were in fact actively infected. In another study, over 50% of children who presented with signs and symptoms of pharyngitis and a positive pharyngeal culture for GAS did not develop a detectable antibody response to the extracellular proteins elaborated by GAS [7]. These studies suggest that early treatment aborts the development of antibody to the extracellular antigens in many children. In addition, using serology to distinguish carriers from acutely infected children with GAS also presents practical challenges because Journal of the Pediatric Infectious Diseases Society, Vol. 3, No. 4, pp , DOI: /jpids/piu030 The Author Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please journals.permissions@oup.com.

2 The Group A Streptococcal Carrier State Reviewed 337 Figure 1. Outcome of GAS infection (derived from Kaplan [2]). *Subclinical infection may result in nonsuppurative complications. #Atypical symptoms may resemble the common cold [13]. +Typical symptoms are sore throat, headache, and fever. serologic responses do not occur until several weeks after the clinical presentation. Accordingly, they cannot be helpful at the time of the acute visit. Another way to identify streptococcal carriers is to evaluate children for microbiologic failure after treatment with an appropriate antimicrobial agent. In a study of an outbreak of GAS in a closed community in the 1970s, Gastanaduy et al, performed throat cultures and serology on over 300 individuals [8]. Nearly 20% of 132 patients who were treated with either oral penicillin or intramuscular benzathine penicillin continued to harbor the same strain of GAS in their throats after a course of treatment. In addition, nearly half of the children who experienced a microbiological treatment failure continued to have a positive throat culture with an identical strain after a second, and 42% were positive after a third course of penicillin. Furthermore, among the patients who failed treatment, only 8% had overt symptoms of pharyngitis. This observation and the fact that the few patients who were true treatment failures did have a serologic response suggest that the majority of patients, who are adherent to an appropriate antimicrobial regimen and nonetheless experience microbiologic failure, are in fact GAS carriers [9]. In the clinical setting, the carrier state is usually suspected in the child with closely spaced symptomatic recurrences of GAS pharyngitis. The most practical method of identifying carriers is to perform a test of cure shortly after an effective course of therapy has been delivered. The asymptomatic child with a positive throat culture for GAS under these conditions is very likely to be a carrier. Before identifying a child as a carrier by this method, the clinician should be confident that treatment failure is not due to nonadherence to therapy. Epidemiology of the Carrier State There has been much interest in definingtherateofcarriage of GAS in the throats of ill and healthy children. However, the rates of carriage of GAS vary greatly depending on the population studied and how carriers are defined. For instance, in an office-based setting, throat cultures were obtained from well children ages 2 16 years, children with

3 338 DeMuri and Wald sore throat, and children recently treated with penicillin for a positive throat culture [10]. As expected, well children had the lowest rate of positive throat cultures (2.5%). Children presenting with sore throat and those recently treated with penicillin were positive 4.4% and 11.3% of the time, respectively. Studies that determine the efficacy of antimicrobial agents give us another estimate of carrier rates. Because carriers may be defined as treatment failures, the percentage of children who harbor GAS after treatment will provide an estimation of the carrier rate. In these studies, 5% 25% of children are carriers [11, 12]. School-based studies provide yet another perspective on carriage. A recent 4-year longitudinal study of children in an elementary school setting provided useful insights into the carrier state [13]. Throat cultures were performed on the children twice a month and during every respiratory illness. At any given time, the mean prevalence of carriers was approximately 16%, and over 40% of children were classified as carriers at least once during the 4-year study period. Over half of the carriers switched emm types during the study period, and most of the acquisitions of these new emm types were not associated with any clinical symptoms. Children in this study carried GAS for an average of 10.8 weeks, with a maximum duration of carriage of 127 weeks. Recently, a meta-analysis of studies reporting GAS infection and carrier rates in the past 35 years was performed [14]. The analysis included clinic and emergency department sites from around the world in both symptomatic and asymptomatic patients. In children who had clinical symptoms of pharyngitis, the prevalence of GAS detected in the throat was 37%. In children who lacked clinical symptoms, GAS was detected 12% of the time. In both groups, children who were younger than 5 years had lower rates of GAS detection. Overall, asymptomatic carriage of GAS is common, especially among school-aged children. The rate of carriage depends highly on the methods of the study, particularly how carriers are defined. In surveys of asymptomatic children, the rate is approximately 2% 5%, whereas in children who experience microbiological treatment failure, the rate is 5% 25%. Lastly, in school surveys, the carriage rates are between 8% and 40%. Pathogenesis of the Carrier State Several theories have been proposed to explain the pathogenesis of the carrier state in children exposed to GAS (Table 1). The first theory is that some of the normal bacterial flora of the pharynx and tonsils produce β-lactamase that shields GAS from the effects of penicillins. This theory has been based on studies that have detected Table 1. Proposed Pathogenetic Mechanisms for Carriage of GAS Effects of the pharyngeal microbiome (a) β-lactamase-producing flora (b) Absence of inhibitory flora Internalization of GAS into epithelial cells Production of biofilms Development of antimicrobial tolerance Abbreviation: GAS, group A streptococcal. β-lactamase-producing bacteria and detectable levels of β-lactamase in the pharynx and tonsillar tissues of patients with GAS. Bacteria such as Bacteroides species, Staphylococcus aureus, Moraxella, and Haemophilus have been associated with GAS treatment failures and carriers in some studies. In addition, several studies have shown that antimicrobials directed at β-lactamase-producing organisms have higher GAS eradication rates than penicillin [15 20]. However, this theory has been controversial and conflicting results are reported in other investigations that have found no association between the presence of β-lactamase-producing organisms and penicillin treatment failure nor higher eradication rates with β-lactamase-stable antimicrobials [21 24]. Other authors have suggested that certain bacteria have an inhibitory effect on the establishment of GAS colonization in the pharynx [25]. Brook at al demonstrated a higher rate of recovery of α-hemolytic streptococci, non-hemolytic streptococci, and Prevotella and Peptostreptococcus species from the tonsillar surfaces of children who were not GAS carriers than in those who were asymptomatic carriers [17]. This hypothesis is supported by studies of the use of probiotics such as Lactobacillus and α-streptococci to prevent colonization of GAS in vitro and in vivo [26 33]. However, it is noteworthy that these latter studies were done in the context of children with apparent recurrent pharyngitis. Other theories have proposed that GAS are capable of evading treatment and establishing residence in the pharynx secondary to their ability to become internalized in epithelial cells. In in vitro models of infection, it has been demonstrated that GAS are internalized into epithelial cells and survive intracellularly despite exposure to penicillin. Strains that have been associated with persistence in patients after antibiotic therapy are more likely to be sequestered intracellularly [34, 35]. Additional evidence for this hypothesis comes from biopsies of tonsils of asymptomatic carriers from whom over 70% of tonsils have GAS detected intracellularly [36, 37]. Another potential explanation for treatment failure and thus persistence of GAS in the pharynx is the ability of many strains of GAS to produce biofilms in vitro. This

4 The Group A Streptococcal Carrier State Reviewed 339 process permits the organism to survive antibiotic concentrations greater than 10 times the minimal inhibitory concentration of the organism. Furthermore, the formation of biofilms seems to be related to the ability of GAS to internalize into epithelial cells (as noted above), which also allows the organism to evade antibiotic treatment [38 40]. Lastly, lack of response to penicillin in carriers has been hypothesized to be the phenomenon of tolerance, in which bacteria survive despite levels of antibiotic above their minimal inhibitory concentration. Early studies suggested that most strains of GAS isolated from patients who failed penicillin exhibited tolerance in vitro [41 43]. However, there has been disagreement in the literature as to a uniform method of detecting tolerance, and subsequent studies have failed to verify the role of tolerance in treatment failure and the carrier state [20, 44 47]. Importance of the Carrier State When considering the implications of the carrier state, several important questions arise. Does being a carrier convey a risk for nonsuppurative complications such as acute rheumatic fever or post-streptococcal glomerulonephritis? Do carriers serve as a source of transmission of GAS to others in the community? Does pharyngeal carriage of GAS place the carrier at risk for severe invasive disease? How does the carrier state confuse the diagnosis of pharyngitis in the acute care setting? It has long been recognized that GAS carriers have little or no risk for acute rheumatic fever. These observations were first made in 1935 and were based mainly on antibody titers to ASO [48]. It was observed that patients who had had acute rheumatic fever had significant rises in ASO titers, whereas those patients who had GAS isolated from the pharynx but did not develop rheumatic fever did not. Since carriers have been defined historically as not developing an antibody response to ASO, it has been concluded that they are not at risk for acute rheumatic fever. The second observation in carriers comes from studies on the latent period between isolation of GAS from the throat and the development of symptoms. In a group of Air Force recruits, it was observed that the majority (92%) of individuals who developed acute rheumatic fever did so within 1 month of acquiring GAS in the pharynx [49]. Because carriers would theoretically harbor GAS for a much longer period of time, it was then surmised that carriers would be at little risk for acute rheumatic fever. One observational study suggests that carriers also have a low risk of glomerulonephritis [50]. The carrier of GAS has been considered to be ineffective as a transmitter of infection. This belief was derived in part from a study of outbreaks of GAS in institutionalized children in the 1930s and 1940s [51]. In this study of 4 major outbreaks, it was determined that the source of GAS was not from known carriers in the institution but rather from serotypes recently introduced to the population. Several minor outbreaks, with less than 10% of children becoming infected, were secondary to strains known to be harbored by carriers. This discovery led investigators to conclude that although infection from carriers can occur, it is substantially less likely than transmission from a child with active infection. Also, in a study of military recruits, Wannamaker [52] observed the risk of transmission from military recruits following new acquisition of GAS in the pharynx. Those recruits who carried GAS for more than 2 weeks were much less likely to transmit the organisms to others. Most importantly, children who are carriers are asymptomatic with regard to respiratory symptoms (cough or coryza) for the majority of time that they are carriers, which dramatically reduces the likelihood of spread of GAS to the environment. When a carrier does develop respiratory symptoms secondary to a communityacquired virus, transmission is more likely. The role of carriers in invasive disease is not entirely clear. Although GAS may be found in the pharynx of patients with invasive infection at the time of presentation, it is usually not possible to determine whether the patient was a carrier before infection or was more recently colonized or infected. However, a common model for respiratory pathogens that cause systemic disease is that if invasive disease is going to occur, it does so within days of acquisition [53]. GAS carriage is commonly found among close contacts of patients with invasive infections. In a study of 17 patients with invasive infection, GAS was detected in the pharynx of 27% of close contacts of the index patient [54]. In a case-control study of children with invasive GAS disease, (1) invasive disease was associated with the presence of other children in the home and (2) in another outbreak setting there was an increase in carriage rates of the invasive GAS strain among school-aged children in the community [55, 56]. It is most likely that the carriers served as a reservoir of infection for the patient with invasive disease [54, 56]. Perhaps the most significant impact of the carrier state is the confusion it may cause in the evaluation of the patient with symptoms of acute pharyngitis. This confusion arises when the carrier acquires a respiratory virus and presents with sore throat. An important strategy to minimize this issue is for the practitioner to avoid testing children with prominent nasal symptoms and cough for GAS infection. However, some community-acquired viruses target the pharynx. When the clinician performs a rapid antigen detection test or throat culture, it will be positive because the patient is a carrier and yet a virus is the actual cause of the pharyngitis. The positive test will be interpreted as

5 340 DeMuri and Wald an acute streptococcal infection, and an antibiotic will be prescribed unnecessarily. In the clinical setting, there is no practical way to differentiate the carrier from the person with acute infection. Assuming there are 10 million cases of streptococcal pharyngitis per year in the United States, and the carrier rate is 15%, 1.5 million of these patients will be carriers who do not require treatment [57 59]. This unintended overuse of antimicrobials may have a significant public health impact because it may promote the development of antibiotic resistance, result in adverse events, and add to healthcare costs. Treatment of the Carrier State: Evidence and Controversies Two important questions arise when a GAS carrier has been identified. (1) Does treatment eradicate carriage? (2) Is eradication of benefit to the patient or to the population? Six trials of treatment of the carrier state have been reported in the medical literature (Table 2) [20, 60 64]. In reviewing these trials, it is important to consider how the carrier state is defined and under what circumstances the study was done. Azithromycin (12 mg/kg per day for 5 days) was studied in an uncontrolled trial in school children who were contacts of a case of invasive GAS disease; the overall eradication rate was 91% [61]. Tanz et al [62] found an eradication rate of 92% with oral clindamycin (10 days) vs 55% with benzathine penicillin in carriers defined as children who experienced microbiologic failure after penicillin treatment. It is important to note that both of these studies were performed over 10 years ago, and recent investigations have shown a rising rate of resistance of GAS to the macrolides and clindamycin. In the setting of a community outbreak, amoxicillin-clavulanate (10 days) and dicloxacillin (10 days) had a 91% and 50% eradication rate, respectively [20, 60]. Finally, rifampin (4 days) in combination with penicillin demonstrated a rate of eradication of 55% 100% [62 64]. Although several antimicrobial regimens are variably effective in eradicating GAS carriage, the question remains as to the benefit of treatment to the patient. If there is no risk of nonsuppurative sequelae and the risk of transmission to others is low, it would appear that there may be little to gain by treating carriers. Published guidelines, based on expert opinion, generally recommend against identifying and treating carriers except for the following special situations: (1) a local outbreak of acute rheumatic fever, invasive GAS disease, or poststreptococcal glomerulonephritis; (2) an outbreak of GAS pharyngitis in a closed or semiclosed community; (3) family or personal history of acute rheumatic fever; (4) multiple episodes of GAS pharyngitis occurring in a family for many weeks despite appropriate treatment; and (5) when tonsillectomy is being considered only because of GAS carriage [9, 65]. One important reason to consider eradication of carriage is to avoid confusion when the patient presents with subsequent episodes of symptomatic pharyngitis. This situation may be particularly important in the patient who presents with apparent, closely spaced, recurrent episodes of GAS pharyngitis early in the respiratory season. If the etiology of the carrier s symptoms is a viral infection, then the patient will continue to receive unnecessary treatment because a rapid antigen detection test or throat culture will likely be positive repeatedly. Furthermore, because carriers are not precluded from acquiring new emm types while they are carriers, they may indeed be at risk of acute rheumatic fever if a new acquisition occurs. Thus, carriers should be tested and treated as if they have new GAS infection when they have symptomatic episodes of pharyngitis, especially without viral symptoms, and a test is positive for GAS. Finally, repeated episodes of pharyngitis accompanied by a positive test for GAS may cause much consternation among parents and patients. The patient may have missed Table 2. Studies of the Treatment of GAS Carriers Study Carrier Definition Study Setting Control Drug Eradication Rate (%) Study Drug Morita et al [60] Asymptomatic School None - Azithromycin 91 contacts Tanz et al [61] Treatment failures Outpatient clinics Benzathine 55 Clindamycin 92 and ED penicillin + rifampin Smith et al [20] Treatment failures Community Penicillin V 17 Dicloxacillin 50 outbreak Kaplan et al [59] Treatment failures Community Penicillin V 29 Amoxicillin-clavulanate 91 outbreak Chaudhary et al [63] Serological Outpatient clinics Penicillin V 71 Penicillin + rifampin Tanz et al [62] Treatment failures Outpatient clinics and ED Abbreviations: ED, emergency department; GAS, group A streptococcal. *A group that received no treatment had a 23% eradication rate in this study. Benzathine penicillin* 30 Benzathine penicillin + rifampin Eradication Rate (%)

6 The Group A Streptococcal Carrier State Reviewed 341 significant time in school or childcare, the parent may have missed work, and invasive procedures such as tonsillectomy may be requested by parents or primary care providers. An attempt at eradicating carriage may provide reassurance in this scenario. CONCLUSIONS Despite decades of research, the GAS carrier state remains poorly understood. A working definition used in some clinical trials and practical to clinicians is the patient who harbors GAS in the pharynx after adherence to an appropriate antibiotic for an episode of pharyngitis presumed to be caused by GAS. Streptococcal carriers are common in school-age populations, representing 10% 15% of children in most surveys. Carriers have little risk for nonsuppurative complications of GAS and though they may possibly transmit the organism to others, the degree of communicability is less than from acutely infected individuals. 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