a Department of General Practice, University Medical Center, Utrecht; b Department of Medical Microbiology and Infectious Diseases, Isala Clinics, Zwolle; c National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Abstract |
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Introduction |
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Materials and methods |
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All 280 GAS-positive adult patients with an acute sore throat (7 days) who participated in our penicillin-intervention trial6 were included. Eighty-seven GAS-positive children, described in our first report,5 were also included. These patients were allocated randomly to one of three regimens: (i) penicillin V for 7 days; (ii) penicillin V for 3 days followed by placebo for 4 days; or (iii) placebo for 7 days.
Endpoints
Patients kept a diary to record the degree of pain and impairment of daily activities. They were considered to have a delayed recovery if they still perceived pain or a severe impairment of their daily activities at day 5. A complication was noted if the treatment code had to be broken because of a deteriorating condition, most often an (imminent) quinsy.6 As no serological investigation was carried out, the complications we found could only be suspected to be poststreptococcal.
Bacteriology
Each throat sample was cultured semiquantitatively on 5% sheep blood agar and an ssA agar plate (Becton Dickinson, Leiden, The Netherlands). Both types of agar plate were incubated anaerobically at 35°C for 48 h. Pinpoint catalase-negative, Gram-positive cocci in chains were serogrouped. ß-Haemolytic streptococci were classified according to whether there was no growth, sporadic growth (110 colonies) or 1+ (low), 2+ (medium) or 3+ (high) colony counts (growth into the initial, second, and third inoculation area, respectively). Serogroup A isolates were investigated at the National Institute of Public Health and the Environment, Bilthoven, The Netherlands, for T-serotyping and M and exotoxin gene A and C typing as described previously.5
Data analysis
Associations were determined using odds ratios with 95% confidence intervals, computed by logistic regression analysis. P values of 0.05 were considered significant. The following possible confounding baseline characteristics were examined in a bivariate model: age; sex; smoking habits; asthma/chronic obstructive pulmonary disease (COPD) or diabetes mellitus; a history of tonsillectomy; a documented history of pharyngitis in the previous 6 months; number of household members; system of healthcare insurance (as an indicator of socioeconomic status); urbanization; absence from school or work; prior duration of pain; and degree of pain and impairment of daily activities. To adjust for confounders, baseline characteristics with a P value of
0.20 in the bivariate analysis were entered into a multivariate model, together with treatment allocation and the four streptococcus-related factors. These four factors were (i) T1M1 and T3M3 versus all other subtypes; (ii) speA exotoxin gene present versus absent; (iii) speC exotoxin gene present versus absent; and (iv) colony counts of 3+ versus colony counts of less than 3+.
The multivariate logistic regression analyses tested the association between the streptococcus-related factors and the two endpoints [delayed recovery versus normal recovery (patients with a complication were excluded) and, in a separate analysis, complications versus normal recovery (patients with delayed recovery were excluded)]. A final multivariate logistic regression analysis tested the association between the streptococcus-related factors and a combination of the two endpoints.
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Results |
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Placebo treatment (P < 0.001), increasing age (P < 0.001) and a high initial grade of pain (P = 0.01) were associated with a delayed recovery, while placebo treatment (P < 0.001), increasing age (P = 0.05) and a low number of household members (P = 0.05) were associated with a complication.
High colony-count streptococci were isolated in 329 (90%) patients; T1M1 was isolated in 15 (4%), T3M3 in 24 (7%), speA exotoxin gene in 90 (25%) and speC exotoxin gene in 217 (59%) patients. The speA exotoxin gene was isolated in all but one of the T1M1 and T3M3 strains. Neither of these streptococcal characteristics was associated with a delayed recovery or a complication of GAS pharyngitis after adjustment for treatment allocation and the confounding baseline characteristics mentioned above (Table). The combination of both endpoints, i.e. delayed recovery and complications, resulted in similar findings.
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Discussion |
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Our results should be interpreted with caution, as the subgroups having T1M1 or T3M3 and colony counts of less than 3+ were small, thus resulting in wide confidence intervals. Furthermore, the bacteriological methods employed were not conventional at the time of the study. These methods have now been absorbed into a recent issue of the Manual of Clinical Microbiology, however.8 In our low-risk population of pharyngitis patients, the streptococcal factors were not associated with virulence. In contrast, the same streptococcal factors did show such an association in a population having invasive streptococcal infections: in a nationwide surveillance in The Netherlands,9 the prevalence of T1M1 and T3M3 subtypes was 48% in patients with streptococcal toxic shock syndrome and 21% in patients without the syndrome, while the prevalence of speA exotoxin gene was 59% and 33% and that of the speC exotoxin gene 34 and 48%, respectively. During this surveillance, only 11% of the isolates cultured from patients who retrospectively did not match the definition of invasive streptococcal disease consisted of T1M1 or T3M3 subtypes.9 We found the same prevalence of these subtypes in our sore throat population in about the same period and in a well-defined area. Host-related factors play an important role in determining whether or not an infection with Streptococcus pyogenes will lead to invasive disease. This disease is often (in about half of cases) associated with an underlying disorder, such as diabetes mellitus, COPD or malignancy, and usually occurs in an older age group than streptococcal pharyngitis.3,4,9 However, because the proportion of T1M1 and T3M3 strains in invasive streptococcal disease is much higher than that in non-invasive disease, the virulence properties of these strains, promoting invasion and toxicity, also appear to play a role. In our sore throat patients, however, potentially virulent strains did not predict a deterioration in the course of streptococcal pharyngitis. High GAS colony counts did not predict such a deterioration either, although in a previous study we found them to be associated with active disease when compared with healthy controls.5 In conclusion, unless there is a local epidemic of invasive streptococcal disease10 or rheumatic fever, general practitioners do not need to look for potentially virulent strains in patients suffering from streptococcal pharyngitis.
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Notes |
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References |
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3 . Johnson, D. R., Stevens, D. L. & Kaplan, E. L. (1992). Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. Journal of Infectious Diseases 166, 37482.[ISI][Medline]
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5 . Zwart, S., Ruijs, G. J., Sachs, A. P., van Leeuwen, W. J., Gubbels, J. W. & de Melker, R. A. (2000). Beta-haemolytic streptococci isolated from acute sore-throat patients: cause or coincidence? A casecontrol study in general practice. Scandinavian Journal of Infectious Diseases 32, 37784.[ISI][Medline]
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9 . Schellekens, J. F., Schouls, L., van Silfhout, A., Elzenaar, K., Brunings, H., Ten Broek, H. et al. (1995). The resurgence of group A streptococcal disease; characteristics of invasive infections in the Netherlands, 19931995. Nederlands Tijdschrift voor Medische Microbiologie 4, 7883.
10 . Cockerill, F. R., MacDonald, K. L., Thompson, R. L., Roberson, F., Kohner, P. C., Besser-Wiek, J. et al. (1997). An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. Journal of the American Medical Association 277, 3843.[Abstract]
Received 4 May 2000; returned 2 October 2000; revised 30 November 2000; accepted 30 November 2000