Diagnosis of group A beta-hemolytic streptococcal pharyngitis

DIAGN MICROBIOLINFECTDIS 1986;4:5S-15S

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ORIGINAL ARTICLES

Diagnosis of Group A Beta-Hemolytic Streptococcal Pharyngitis Use of Antigen Detection Tests Michael A. Gerber

Early diagnosis and prompt initiation of antibiatic therapy for group A beta-hemolytic streptococcal pharyngitis can shorten the duration of the clinical illness and reduce the period of infectivity. This in turn may expedite a patient's return to school or day care, as well as a parent's return to work. Antigen detection tests are available that can provide a rapid diagnosis of group A beta-hemolytic streptococcal pharyngitis and can facilitate the prompt initiation of antibiotic therapy. In addition, these antigen detection tests can provide a rapid exclusion of group A beta-hemolytic streptococcal pharyngitis and thereby prevent the initiation of unnecessary antibiotics in patients with nonstreptococcal pharyngitis. However, before throat cultures on blood agar plates are totally abandoned and completely replaced by antigen detection tests, a number of additional studies are needed. The consequences of false-negative and false-positive antigen detection tests need to be determined. The accuracy of the antigen detection test as performed in physicians' offices needs to be compared with traditional culture methods performed in physicians' offices and not with an "idealized" standard. Finally, investigations need to be initiated to determine the impact of different antigen detection tests on the revenues and work flow in various practice settings, as well as their direct impact on patient care.

INTRODUCTION The signs and s y m p t o m s of group A b e t a - h e m o l y t i c streptococcal (GABHS) pharyngitis are nonspecific, m a k i n g the clinical diagnosis of this disease, even for the most e x p e r i e n c e d p h y s i c i a n , difficult (Breese a n d Disney, 1954). Therefore, an a c c u r a t e diagnosis d e p e n d s on s o m e m e t h o d of bacteriologic confirmation. Breese a n d Disney (1954) first d e s c r i b e d the use of throat s p e c i m e n s cultured on sheep b l o o d agar plates in a p h y s i c i a n ' s office to confirm the diagnosis of GABHS pharyngitis. Over the past three decades, m a n y p h y s i c i a n s have i n c o r p o r a t e d this diagnostic test into their office routine. However, c u l t u r i n g throat swabs on blood agar plates has not been w i t h o u t p r o b l e m s . O n e of the most significant is the i n a b i l i t y of the throat culture to d i s t i n g u i s h b e t w e e n patients w i t h bona fide GABHS infections a n d patients w h o are m e r e l y streptococcal carriers. A n o t h e r i m p o r t a n t p r o b l e m has been the m i n i m u m time of 2 4 - 4 8 hr required to obtain the throat culture results. There has been a great deal of confusion in the past regarding the definition of

From the Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT. Address reprint requests to: Michael A. Gerber. M.D., Assistant Professor of Pediatrics, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06032. Received November 19, 1985; accepted November 26, 1985. 'it 1986 Elsevier Science Publishing Co.. Inc. 52 Vanderbilt Avenue, New York, NY 10017

13732-8893186/503.50

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streptococcal carriers and actual streptococcal infections. There is still disagreement about the definition of these terms. Most people, however, define a bona fide streptococcal infection as the presence of GABHS in the upper respiratory tract associated with a rise in streptococcal antibody titers, whereas streptococcal carriage is defined as the presence of GABHS in the upper respiratory tract in the absence of a rise in streptococcal antibody titers (Kaplan, 1980). It has been reported that as many as 50% of patients who present with acute pharyngitis and a positive throat culture for GABHS will not have a significant rise in streptococcal antibody titers and are presumably streptococcal carriers (Kaplan et al., 1971). This issue, however, is clouded by the fact that most patients with pharyngitis and a positive throat culture are treated with antibiotics. Several studies have demonstrated that appropriate antibiotic therapy suppresses the formation of streptococcal antibodies (Brink et al., 1951; Kilbourne and Loge, 1948). Other studies, however, have failed to demonstrate a significant effect of antibiotic therapy on the streptococcal antibody response in patients with GABHS pharyngitis (Kaplan et al., 1971: Siegel et al., 1961). Ethical considerations w o u l d p r e c l u d e the performance of an investigation in which streptococcal titers were measured in patients with GABHS pharyngitis while antibiotic therapy was withheld. Therefore, this controversy will probably never be completely resolved. However, streptococcal antibody titers measured in patients with GABHS pharyngitis who are receiving appropriate antibiotic therapy may not reflect the maximal potential antibody response in these patients.

Value of Early Diagnosis and Antibiotic Therapy of Group A Beta-Hemolytic Streptococcal Pharyngitis Although early diagnosis and prompt initiation of appropriate antibiotic therapy is not required for the prevention of rheumatic fever (Catanzaro et al., 1954), it can have other important clinical implications. For example, early diagnosis and prompt initiation of antibiotic therapy can minimize the spread of infection. Group A betahemolytic streptococcal pharyngitis is spread by secretions and droplets (Quinn, 1982) and the risk of an untreated patient with GABHS pharyngitis transmitting this organism to other children is very high. In one report, about 25% of the household contacts acquired GABHS within a few days after the index had been identified (Breese and Disney, 1956). Untreated patients often become asymptomatic in 3-4 days and upon return to normal activities become an occult source for spread to others (Brink et al., 1951), whereas 97% of treated patients become culture-negative within 24 hr of initiating antibiotic therapy (Randolph et al., 1985). Studies of the use of oral penicillin to control outbreaks of streptococcal infections in the armed forces (Bernstein et al., 1954) and in school populations (Poskanzer et al., 1956) have demonstrated the ability of antibiotic therapy to prevent the spread of GABHS from one individual to other susceptibles. In addition, an examination of the spread of GABHS within the family group demonstrated that the longer the delay in initiating antibiotic therapy for the index case the higher the secondary attack rate became (Breese and Disney, 1956). Therefore, early diagnosis and prompt initiation of appropriate antibiotic therapy could reduce the period of infectivity and minimize the risk of transmission. If antibiotic therapy can shorten the clinical course of GABHS pharyngitis in children, early diagnosis and prompt initiation of appropriate antibiotic therapy would be of value in reducing the morbidity of this disease. However, the effect of antibiotic therapy on the clinical course of GABHS pharyngitis in children has been a controversial issue. Some have questioned the impact of antibiotic therapy on the clinical course of GABHS pharyngitis citing investigations carried out at Warren Air Force Base in the early 1950s to support their position (Peter and Smith, 1977). In

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these studies, the rate of improvement in young adults with GABHS pharyngitis treated with penicillin, chlortetracycline, or oxytetracycline was only marginally greater than in comparable patients who did not receive antibiotic therapy. Antibiotic therapy initiated early in the course of the illness, however, appeared to have a more dramatic impact on the rate of recovery than antibiotics initiated at a later stage of the disease (Brink et al., 1951; Denny et al., 1953). In contrast Haight (1954) studied 208 naval recruits with epidemic scarlet fever and found that antibiotic therapy had a marked impact on the rate of recovery when compared with a placebo. Similarly, Brumfitt and Slater (1957) studied 82 servicemen hospitalized with endemic GABHS pharyngitis and found a statistically significant reduction in duration of fever and sore throat in patients treated with penicillin when compared with patients who were not treated. Although many practicing pediatricians have had the impression that antibiotic therapy has a dramatic impact on the clinical course of GABHS pharyngitis (Breese, 1978), with the exception of two recent, small investigations (Krober et al., 1985; Nelson, 1984), there have been no prospective studies of this issue performed in a pediatric population. We recently completed a randomized, placebo-controlled investigation in 194 children with proven GABHS pharyngitis (Randolph et al., 1985). After a throat culture had been obtained, each child was first evaluated for the presence of several predetermined signs and symptoms and was then randomized in a double-blind manner to receive penicillin V, cefadroxil, or placebo. Approximately 18-24 hr later, each patient returned for a reevaluation of their clinical status. Significantly fewer of the children who had received either penicillin or cefadroxil had persistence of objective signs (Figure 1) and subjective symptoms (Figure 2) than the children who had received placebo. In addition, the evaluating physician, parents, and patients all had the general impression that significantly more of the antibiotic-treated patients demonstrated an overall clinical improvement at the follow-up evaluation than the placebo-treated patients. Therefore, antibiotic therapy, particularly if initiated early, can have a dramatic impact on the clinical course of GABHS pharyngitis.

FEVER

CERVICAL ~ LYMPHADENITIS

PHARYNGEAL INJECTION

iii!:!i~:t (y)

O-

~

Before ~

Therapy

Penicillin~

Cefadroxil ~

Placebo

FIGURE 1. Patients with the presence of specific clinical signs before and after 24 hr of therapy. Adapted from Randolph et al., 1985. J Pediatr.

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SORE THROAT

HEADACHE

ABDOMINAL PAIN

1008~~0~ 40::::::::::::

20-

,:::::::, ]

Before Therapy

I~

Penicillirt

[]

Cefadro.il E ~ Placebo

FIGURE 2. Patients with the presence of specific clinical symptoms before and after 24 hr of therapy. Adapted from Randolph et al., 1985. J Pediatr.

The inherent delav in the throat culture procedure has led some physicians to initiate antibiotic therapy before knowing the results of the throat culture. Because the majority of children with acute pharyngitis do not have GABHS (Wannamaker, 1972), and will not benefit from antibiotic therapy (Randolph et al.. 1985), this approach will result in a large number of children receiving unnecessary antibiotics. Of additional concern is the fact that once antibiotic therapy has been initiated, some physicians are reluctant to discontinue it, even when the throat culture is later reported to be negative (Cochi et al., 1984; Holmberg and Faich, 1983). A rapid diagnostic test for GABHS could eliminate the temptation to initiate unnecessary and costly antibiotic therapy in these patients. On the other hand, a rapid diagnostic test could allow the early initiation of appropriate antibiotic therapy when indicated. By shortening the duration of the clinical illness and by reducing the period of infectivity, early antibiotic therapy of GABHS pharyngitis may not only allow the patient to return to school or day care 24-48 hr sooner than if therapy had been withheld until the results of the throat culture were known, but, in addition, may also allow a parent to return to work 24-48 hr sooner.

Antigen Detection Tests for the Rapid Identification of Group A Beta-Hemolytic Streptococcal Pharyngitis Directly From Throat Swabs One of the most exciting developments in recent years in the area of GABHS pharyngitis has been the appearance of commercial antigen detection tests (ADTs) for the rapid identification of GABHS directly from throat swabs. Although these ADTs may be more expensive than the blood agar culture (about $2.00 and about $0.50, respectively}, the advantage they offer over the traditional procedure is the speed with which they can provide results. Identification of GABHS with an ADT could allow the prompt initiation of specific antibiotic therapy, and rapid exclusion of GABHS pharyngitis could reduce the amount of unnecessary antibiotics that patients are receiving.

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Accuracy of Antigen Detection Tests for Group A Beta-Hemolytic Streptococcal Pharyngitis Compared With Blood Agar Plate Cultures The ADTs for GABHS that have received the most extensive evaluations are the Directigen Group A Strep Kit (Hynson, Westcott, and Dunning, Baltimore, MD) and the Culturette Brand Ten Minute Group A Strep ID Kit (Marion Scientific, Kansas City, MO). We recently performed an evaluation of these two tests (Gerber et al., 1984). Two pharyngeal swabs were collected simultaneously from patients between 2 and 16 yr of age with clinical findings suggesting GABHS pharyngitis. This procedure was then repeated in order to produce two sets of duplicate swabs for each patient. One swab was cultured on a sheep blood agar plate in the usual manner. The other swab was processed by one of the ADTs. Different people were responsible for reading the throat cultures and the ADT, and the person reading one was unaware of the results of the other. Of the 339 throat cultures performed, 108 (32%) were positive for GABHS. The Culturette Brand test had an 83% sensitivity, 99% specificity, 97% positive predictive value, and a 93% negative predictive value when compared with the simultaneously obtained throat culture. The Directigen test had an 84% sensitivity, 99% specificity, 99% positive predictive value, and a 93% negative predictive value. Several similar evaluations of these ADTs have produced similar results /Table 1) (Chang and Mohla, 1985; McCusker et al., 1984; Miller et al., 1984; Slifkin and Gil, 1984). Of the false-negative Directigen and Culturette Brand test results (negative ADT and positive throat culture) that we and others have observed, a large number occurred in patients who had <10 colonies of GABHS on their blood agar culture (1 + cultures) (Gerber et al., 1984: McCusker et al., 1984: Slifkin and Gil, 1984). When these 1 + cultures were not considered positive, the sensitivity of both the Directigen and Culturette Brand tests was 95%-100%. There has been much debate over the significance of throat cultures with <10 colonies of GABHS per plate. Some have suggested that most of these patients are merely streptococcal carriers and not truly infected (Breese et al., 1970; Stillerman and Bernstein, 1961), whereas others believe that the differentiation of patients with streptococcal infections from those who are carriers cannot be made on the basis of degree of positivity of the throat culture alone (Kaplan et al., 1971). If the majority of patients with negative ADT results and a 1 + TABLE 1. Comparison of Two Latex Agglutination Tests for the Detection of Group A Beta-Hemolytic Streptococci Directly From Throat Swabs With Blood Agar Cultures Directigen

Study

Sensitivity (%}

Specificity (%}

Culturette PPV (%1

NPV (%}

Slifkin and Gil

Sensitivity (%)

Specificity (%}

PPV

NPV

95

100

100

99

90

99

96

98

83 (95)

99

97

93

(lOO)o

(1984)

Chang and Mohla

(19851 Gerber et al. (1984) McCusker et al. (1984) Miller et al. (1984)

84 (95)

99

99

93

91 (97) 91 (100)

99

98

96

98

88

98

PPV, positive predictive value; NPV, negative predictive value. °Sensitivity if cultures with <10 colonies of group A beta-hemolytic streptococci per plate are not considered positive.

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positive throat culture were carriers, then the sensitivity of these diagnostic tests, in terms of identifying bona fide streptococcal infections, would be much higher. We recently compared the results of the Culturette Brand test with blood agar plate cultures in 272 children with acute pharyngitis, 219 (81%) of whom had positive throat cultures for GABHS (Gerber et al., unpublished data). Patients with a positive throat culture had acute blood specimens drawn and were instructed to return in 4 wk at which time convalescent specimens were obtained. All serum specimens were stored at -70°C and later analyzed simultaneously in pairs for antistreptolysin O (ASO) and antideoxyribonuclease B (ADB) titers. We found that the Culturette Brand test had a sensitivity of 89%, a specificity of 96%, a positive predictive value of 99%, and a negative predictive value of 67%, which is similar to previous reports. Approximately 50% of the false-negative Culturette Brand test results occurred in children with 1 + positive throat cultures and when these 1 + cultures were not considered positive, the sensitivity of the Culturette Brand test was 93% and the negative predictive value was 80%. Of the 22 children with false-negative Culturette Brand tests from whom serologic data were available, eight (36%) were shown to have bona fide streptococcal infections as evidenced by a positive throat culture and a significant rise in ASO or ADB titers. Of a randomly selected subgroup of 45 children with truepositive Culturette Brand tests (positive ADT and positive throat culture), 20 (44%) were shown to have bona fide streptococcal infections. Therefore, the percentage of patients with false-nega!ive ADT who had bona fide streptococcal infections was not significantly different from the percentage of patients with true-positive ADT who had bona fide streptococcal infections. These findings support the concept that the differentiation of patients with streptococcal infections from those who are carriers cannot be made on the basis of degree of positivity of the blood agar plate culture alone. Furthermore, they suggest that some of the patients with false-negative ADTs for GABHS have bona fide streptococcal infections and are not merely streptococcal carriers. In fact, as previously noted, because of the possible effect of antibiotic therapy, the antibody response we observed may not reflect the maximal potential antibody response in these patients. All of the studies of the accuracy of the new ADT for GABHS pharyngitis have used the sheep blood agar plate culture as performed in a reference laboratory as the standard against which these tests have been evaluated. However, the majority of primary care physicians in this country are performing blood agar plate cultures in their own offices (Arthur et al., 1984). Earlier studies have demonstrated that when duplicate throat swabs are simultaneously obtained from children with acute pharyngitis and one swab is processed on a blood agar plate in a physician's office while the other swab is processed on a blood agar plate in a reference laboratory, the physician's cultures identify only 80%-85% of the isolates of GABHS identified on the reference laboratory's cultures (Battle and Glasgow, 1971; R0senstein et al., 1970). A more legitimate evaluation would compare the results of the new ADTs as performed in a physician's office with the results of the blood agar plate culture as performed in a physician's ofrice. If the ADT performed in a physician's office can identify 90% of the GABHS identified in a reference laboratory (Gerber et al., 1984), but the blood agar plate culture in a physician's office can identify only 80% of the GABHS identified in a reference laboratory (Battle and Glasgow, 1971), then the ADT may actually be more sensitive than the blood agar plate culture in this particular setting. Consequences of False-Negative and False-Positive Antigen Detection Test Results Another important issue in evaluating these new ADTs for GABHS pharyngitis is the percentage of false-negative and false-positive test results than can be tolerated. To address this question, one first needs to consider the consequences of a false-

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negative or false-positive ADT result for GABHS pharyngitis. A false-negative test could result in a missed opportunity to shorten both the clinical course of the pharyngitis and the period of infectivity. Of potentially greater importance is the fact that a child with GABHS pharyngitis who is not properly diagnosed and treated because of a false-negative ADT result is at risk of developing acute rheumatic fever. The exact magnitude of this risk is not known. However, with the incidence of rheumatic fever in this country at 0.6 cases per 100,000, this risk would appear to be extremely small (Land and Bisno, 1983). In 1961, the risk in untreated Chicago school children with GABHS pharyngitis was 0.39% (Siegel et al., 1961), and although the current risk is probably much lower, this figure can be used to calculate a m a x i m u m risk. Using this figure and a false-negative rate for the ADT of 10%, rheumatic fever would occur in fewer than one of 2,500 cases of GABHS pharyngitis if the ADT alone were used to make this diagnosis (10% times 0.39%). A false-positive ADT for GABHS pharyngitis, on the other hand, could result in unnecessarily missed school or day care for the patient and missed work for a parent, as well as an unnecessary course of antibiotic therapy. Given a rate of penicillin anaphylaxis of no more than 0.025% (Rudolph and Price, 1973) and a false-positive rate of 5%, there would be less than one case of anaphylaxis per 80,000 patients treated on the basis of the ADT alone, which could be attributed to unnecessary antibiotic therapy.

Practical Applications of Antigen Detection Tests for Group A Beta-Hemolytic Streptococcal Pharyngitis Few of the investigations of the ADTs for GABHS pharyngitis have critically examined the practicality of these tests in a physician's office or the potential impact of these tests on patient care in the office setting. For example, we found the Directigen test to be practical for use in a diagnostic microbiology laboratory. However, because of its complexity, the need for special equipment and supplies, and the fact that it requires 75 min to perform, we found this test impractical for routine use in a large pediatric office. In contrast, we found the Culturette Brand test, because of its simplicity, the absence of special equipment or supplies, and the fact that it requires 15 min to perform, practical for use both in a diagnostic microbiology laboratory and in a large pediatric office (Gerber et al., 1984). Large group practices with laboratory technicians or nurses who can perform these tests repeatedly throughout the day could take full advantage of them by performing the procedure while the patient waits for the results. In contrast, solo or small group practices may lack the personal required to incorporate these tests into their office routine. For these practices, running specimens in batches either once or twice a day may provide a reasonable alternative. Additional investigations in this area are needed.

Additional Questions Regarding Antigen Detection Tests for Group A BetaHemolytic Streptococcal Pharyngitis There are several other questions regarding these ADTs for GABHS pharyngitis that need to be addressed in future investigations. For example, although not associated with nonsuppurative sequelae such as acute rheumatic fever or acute glomerulonephritis (Hill et al., 1969), several localized outbreaks of pharyngitis have been attributed to group C and G beta-hemolytic streptococci (Benjamin and Perriello, 1976: McCue, 1982). Is the fact that these tests cannot identify episodes of pharyngitis due to group C or group G beta-hemolytic streptococci an important shortcoming? Recently, patients have been described with pharyngitis due to nonhemolytic group A streptococci, identified with ADT but not on blood agar plates (Hull and Wolsh,

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1985). Nonhemolytic group A streptococci have previously been reported to be responsible for a localized outbreak of acute rheumatic fever (James and McFarland, 1971). Will ADTs be able to identify a large number of episodes of pharyngitis due to nonhemolytic group A streptococci that would have gone unrecognized with blood agar cultures? Recently, several patients have been described who had positive ADT but only alpha-hemolytic streptococci on their throat cultures. All had received a nonprescription decongestant-antihistamine within I hr of having their throat culture taken. Further testing revealed that the alpha-hemolytic streptococci were group A and that the decongestant-antihistamine could reversibly convert the beta-hemolytic strains of group A streptococci into alpha-hemolytic strains in vitro (Southern et al., unpublished data). Will ADTs for GABHS be able to identify a large number of episodes of pharyngitis due to GABHS that would have gone unrecognized with blood agar cultures because of the effect of previously administered decongestantantihistamine or antiseptic mouthwashes? Finally, how long after the initiation of appropriate antibiotic therapy will an initially positive ADT for GABHS remain positive? CONCLUSION Early diagnosis and prompt initiation of appropriate antibiotic therapy for GABHS pharyngitis can shorten the duration of the clinical illness and can reduce the period of infectivity. This in turn may expedite a patient's return to school or day care, as well as a parent's return to work. Antigen detection tests are available that can provide a rapid diagnosis of GABHS pharyngitis and can facilitate the prompt initiation of appropriate antibiotic therapy. In addition, these ADTs can provide a rapid exclusion of GABHS pharyngitis and thereby prevent the initiation of unnecessary antibiotics in patients with nonstreptococcal pharyngitis. However, before throat cultures on blood agar plates are totally abandoned and completely replaced by ADTs, a number of additional studies need to be performed. Further attempts should be made to determine the consequences of false-negative and false-positive ADTs. The accuracy of the ADTs as performed in physicians' offices need to be compared with blood agar plate cultures as performed in physicians' offices and not with an "idealized" standard. Finally, investigations need to be performed to determine the impact of different ADTs on the revenues and work flow in various practice settings, as well as their direct impact on patient care. REFERENCES

Arthur JD, Bass JW. York WB (1984) How is suspected streptococcal pharyngitis managed? Postgrad Med 75:241. Battle CV. Glasgow LA (1971) Reliability of bacteriologic identification of beta-hemolytic streptococci in private offices. Am ] Dis Child 122:134. Benjamin JT. Perriello VA Jr (1976) Pharyngitis due to group C hemolytic streptococci in children. I Pediatr 89:254. Bernstein SH, Feldman VA, Harper OF, et al. (1954) Observations in Air Force recruits of streptococcal diseases and their control with orally administered penicillin. I Lab Clin Med 44:1. Breese BB, Disney FA (1954) The accuracy of diagnosis of beta streptococcal infections an clinical grounds. I Pediatr 44:670. Breese BB, Disney FA (1956) Factors influencing the spread of beta-hemolytic streptococcal infections within the family group. Pediatrics 17:834. Breese BB, Disney FA, Talpey WB, et al. (1970) Beta-hemolytic streptococcal pharyngitis. The clinical and epidemiologic importance of the number of organisms found in cultures. Am ] Dis Child 119:18.

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Breese BB (1978) Pharyngitis and scarlet fever. In Beta Hemolytic Streptococcal Disease. Eds., BB Breese, CB Hall. Boston: Houghton Mifflin, pp 65-78. Brink WR, Rammelkamp CH Jr, Denny FW, et al. (1951) Effect of penicillin and aureomycin on the natural course of streptococcal tonsilitis and pharyngitis. Am l Med 10:300. Brumfitt W, Slater JDH (1957) Treatment of acute sore throat with penicillin: a controlled trial in young soldiers. Lancet i:8. Cantanzaro El, Stetson CA, Morris AJ, et al. (1954) Symposium on rheumatic fever and rheumatic heart disease: the role of the streptococcus in the pathogenesis of rheumatic fever. Am l Med 17:749. Chang MJ, Mohla C (1985) Ten-minute detection of group A streptococci in pediatric throat swabs, l Clin Microbiol 21:258. Cochi S, Fraser DW, Hightower AW, et al. (1984) Diagnosis and treatment of streptococcal pharyngitis: survey of U.S. medical practitioners. In Pharyngitis: Management in an Era of Declining Rheumatic Fever. Ed,, ST Shulman. New York: Praeger, pp 73-94. Denny FW, Wannamaker LW, Hahn EO (1953) Comparative effects of penicillin, aureomycin and terramycin on streptococcal tonsillitis and pharyngitis. Pediatrics 11:7. Gerber MA, Spadaccini L), Wright LL, et al. (1984) Latex agglutination tests for the rapid identification of group A streptococci directly from throat swabs. I Pediatr 105:702. Haight TH (19541 Erythromvcin. therapy of respiratory infections. Controlled studies on the comparative effect of ervthromvcin and penicillin on scarlet fever. I Lab Clin Med 43:15. Hill HR, Caldwel] GG, Wilson E, et al. (1969) Epidemic of pharyngitis due to streptococci of Lancefield group G. Lancet ii:371. Holmberg SD, Faich GA (1983) Streptococcal pharyngitis and acute rheumatic fever in Rhode Island. lAMA 250:2307. Hull KH, Wolsh ]J (1985) Use of three screening methods for detecting streptococcal pharyngitis. Program and Abstracts of the 85th Annual Meeting of the American Society for Microbiology (March 3-7, 1985) p 336. lames L, McFarland RB (1971) An epidemic of pharyngitis due to a non-hemolytic group A streptococcus at Lowry Air Force Base. N Engl I Med 284:750. Kaplan EL, Top FH (r, Dudding BA, et al. (1971) Diagnosis of streptococcal pharyngitis: differentiation of active infection from the carrier state in the symptomatic child, l Infect Dis 123:490. Kaplan EL (1980) The group A streptococcal upper respiratory tract carrier state: an enigma, l Pediatr 97:337. Kilbourn ED, Loge JP (1948) The Comparative effect of continuous and intermittent penicillin therapy on the formation of antistreptolysin in hemolytic streptococcal pharyngitis, l Clin Invest 27:418. Krober MS, Bass JW, Michels GN (1985) Streptococcal pharyngitis: placebo-controlled doubleblind evaluation of clinical response to penicillin therapy, lAMA 253:1271. Land MA, Bisno AL (1983) Acute rheumatic fever: a vanishing disease in suburbia, lAMA 249:895. McCue JD (1982) Group G streptococcal pharyngitis: analysis of an outbreak at a college, lAMA 248:1333, McCusker JI, McCoy EL, Young CL, et al. (1984) Comparison of Directigen Group A Strep Test with a traditional culture technique for detection of group A beta-hemolytic streptococci, l Clin Microbiol 20:824. Miller JM, Phillips HL, Graves RK, et al. (1984) Evaluation of the Directigen Group A Strep Test kit. l Clin Microbiol 20:846. Nelson JD (1984) The effect of penicillin therapy on the symptoms and signs of streptococcal pharyngitis, Pediatr Infect Dis 3:10. Peter G, Smith AL (1977) Group A streptococcal infections of the skin and pharynx. N Engl l Med 297:365. Poskanzer DC, Feldman HA, Beadenkopf WG, et al. (1956) Epidemiology of civilian streptococcal outbreaks before and after penicillin prophylaxis. A m I Public Health 46:1513, Quinn RW (1982) Streptococcal infections. In Bacterial Infections of Humans. Epidemiology and Control. Eds., AS Evans, HA Feldman. New York: Plenum, pp 525-552.

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Randolph MF, Gerber MA, DeMeo KK, et al. (1985} The effect of antibiotic therapy on the clinical course of streptococcal pharyngitis, l Pediatr (in press). Rosenstein BJ, Markowitz M. Gordis L (19701 Accuracy of throat cultures processed in physicians' offices. I Pediatr 76:606, Rudolph AN, Price EV (1973) Penicillin reactions among patients in venereal disease clinics: a national survey, lAMA 223:499. Siegel AC, Iohnson EE, Stollerman GH (1961] Controlled studies of streptococcal pharyngilis in a pediatric population. 1. Factors related to the attack rate of rheumatic fever. N Engl ! Med 265:559. Slifkin M. Gil GM (1984) Evaluation of the Culturette Brand Ten-Minute Group A Strep ID technique. I Clin Microbiol 20:12. Stilterman M. Bernstein SH (1961} Streptococcal pharyngitis: evaluation of clinical sw~drolnes in diagnosis. Am l Dis Child 101:476. Wannamaker LW {1972) Perplexity and precision in the diagnosis of streptococcal pharyngitis. A m I Dis Child 124:352.

DISCUSSION Dr. W a s h i n g t o n : M u c h of the focus has been relative to false-negative antigen tests versus the n u m b e r of colonies. One of my associates, Dr. John Anhalt, has been exploring an a d d i t i o n a l variable, that is the interval between the taking of the throat swab and its testing for' antigen. In the Directigen system, for those swabs y i e l d i n g 50 colonies or greater, those that were tested i m m e d i a t e l y versus those that were tested after a several hour d u r a t i o n of storage s h o w e d major differences in sensitivity. For example, those that were tested i m m e d i a t e l y s h o w e d a sensitivity of 70% versus nearly 90% for stored swabs. Dr. Gerber: Under what c o n d i t i o n did that storage occur? Was it in nutrient m e d i a or transport broth? Dr. W a s h i n g t o n : They were stored in the Culturette system at room temperature. Dr. Gerber: How do you e x p l a i n growth in a n o n n u t r i e n t m e d i u m ? Dr. W a s h i n g t o n : I have no idea. It's a curious p h e n o m e n o n that we h a p p e n e d on a c c i d e n t a l l y in our initial evaluation of that system. Whether there is some multiplication of organisms in that " n o n n u t r i e n t system" or w h e t h e r the storage c o n d i t i o n s s i m p l y allow the antigen to become more available is not k n o w n at this time. W h e n this observation is translated to the office setting w h e r e i m m e d i a t e testing is the objective, then the false-negative rate may increase. Dr. F a c k l a m : What do you c o n s i d e r the " s t a n d a r d " throat culture? W o u l d you comment on the use of selective m e d i a and anaerobic incubation? Are we c o m p a r i n g antigen detection systems with a n o n s t a n d a r d i z e d reference test? Dr. Gerber: The problem, as you are well aware, is that there is no universal s t a n d a r d procedure. This was one of the reasons that I m a d e the plea to c o m p a r e these antigen detection tests as performed in a p h y s i c i a n ' s office with the cultures s i m i l a r l y performed. In this study, we used nonselective m e d i a and aerobic i n c u b a t i o n although, as Dr. Schwartz m e n t i o n e d , if we had used anaerobic incubation, we p r o b a b l y w o u l d

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have increased the yield of group A streptococcus on the culture. If we had used selective media, I suspect that we also would have increased the yield. I don't believe there are many physicians, however, who are using either selective media or anaerobic incubation in their offices, which is why we opted for the nonselective media and aerobic incubation. If you ask 10 people how they do throat cultures, you would probably get 10 different answers.