YH Yang, XZ Shen

Introduction

Group A beta-haemolytic streptococcal (GABHS) infections have always been an important part of paediatric practice. During the 30 years before the 1980s, accurate diagnosis and prompt therapy have caused a remarkable decrease in the incidence of serious sequelae, both suppurative and nonsuppurative, of these infections. As a result, physicians and public health authorities have become less vigilant about GABHS infections.^1,2

The reemergence of outbreaks of rheumatic fever in the late 1980s and early 1990s has altered this complacent attitude.^1-4 The increasing report of GABHS bacteraemia, sepsis and a toxic shock-like syndrome (TSS) has prompted public health authorities, epidemiologists and basic scientists to reexamine the problem. Although it appeared that there was no absolute increase in the number of cases of GABHS pharyngitis, there certainly was an apparent increase in the incidence of serious infections and sequelae. Many of the young physicians are now faced with conditions they have never experienced before and do not know how to properly address the issue.

A current assessment of the epidemiology and management of virulent GABHS infections and their sequelae had been discussed in the United States.^1-7 This review will introduce recent data on the epidemiology, diagnosis and management of GABHS infections, with special reference to pharyngitis.

Epidemiology of GABHS Infections

During the previous 40 years severe GABHS infections and their nonsuppurative complications such as rheumatic fever and glomerulonephritis had become uncommon.⁸ The concern about GABHS infections was heightened when outbreak of rheumatic fever occurred in the early 1980s,⁹ followed by reports of severe, systemic GABHS disease and complications such as scarlet fever and toxic shock-like syndrome.^10,11

1. Pharyngitis

There is no population-based data on the incidence of GABHS pharyngitis. Experience in the United States suggests that there has been little change in the incidence over the past 25 years.¹² It is likely that any apparent increase is actually due to a more frequent use of throat cultures in recent years which leads to an increase in the number of GABHS carriers being identified. In view of the widespread use of antibiotics for pharyngitis, one would have expected a decline in the incidence of these infections.

One change during the past 20 years has been the specific M serotypes isolated from patients with GABHS infections. Studies from the Centers for Disease Control and Prevention in United States suggested that M type 4 and 12 had decreased significantly. M types 1, 3, and 18 however accounted for a larger proportion of isolates from 1980 to 1988 when compared with isolates obtained between 1973 and 1979.¹³ M types 1, 3, and 18 are believed to be strains with increased virulence. It should be noted that these strains can also cause pharyngitis in patients who have either mild or no symptoms. Among the patients with rheumatic fever 75% had either mild or no proceeding symptoms of pharyngitis.¹⁴ These findings suggested that GABHS upper respiratory infections as well as scarlet fever are milder illnesses than in the past and require throat cultures for bacteriological confirmation.

OF inhibition test and M typing is used to analyse GABHS isolates in Beijing Children's Hospital.¹⁵ Of the 110 isolates, M types 68 and 75 accounted for 66.7%. All of the M68 strains were isolated from patients with pharyngitis and scarlet fever. These results suggest that there is a different distribution of M serotypes between China and other countries.

2. Rheumatic fever

Rheumatic fever and its sequelae, rheumatic heart disease, continue to be major public health problems in underdeveloped countries of the world. Marcus described over 700 operative procedures for rheumatic mitral valve disease over a 3-years period in a hospital of Soweto, South Africa.²

Outbreaks of rheumatic fever were reported in the United States between 1987 and 1990, after the incidence had fallen from 20 to less than 1 per 100,000 population over 20 years.⁹ The reasons most often given to account for the sharp decline include widespread use of penicillin, better methods of diagnosis and improved access to health care.² There were several unusual epidemiologic features of these recent outbreaks.^2,16 Most occurred within a 5-year period in widely separated geographic areas involving "open" communities such as schools, hospitals, and especially military institutions. The patients affected were mainly middle class children living in suburban and rural areas. Except the outbreaks in military institutions, they were not preceded by any clinically or epidemiologically apparent increase in GABHS infections. GABHS recovered from the patients and family members were mainly M type 3 and 18, the same serotypes associated with past outbreaks. It is not clear whether the epidemic rheumatogenic serotypes also pay a significant role in endemic rheumatic fever. A report of type-specific antibody measurement from Chile suggested that a well-known rheumatogenic serotype, M type 5, emerged as predominant.¹⁷

3. Impetigo

Studies during the 1960s and 1970s showed that in more than one-half of the cultures from nonbullous impetigo GABHS was present either alone or in combination with Staphylococcus aureus.^18,19 In the 1980s Staphylococcus aureus has become the organism found in 70-80% of patients with skin infections either alone or with GABHS, but the isolation of both organisms has been reported in a smaller percentage of patients than in the past.²⁰ Our study showed that only about 5% of the patients with impetigo in Beijing was caused by GABHS (Yang YH, et al. unpublished data). These etiologic changes have implications on the treatment of skin infections. The GABHS isolated from pyoderma were usually M types 49, 55 and 57, of which some were nephritogenic.

4. Glomerulonephritis

Acute poststreptococcal glomerulonephritis has the same sharp decline in incidence as rheumatic fever, but showed no resurgence. The widely recognized nephritogenic M types 12 and 49 are still prevalent.²¹ The decline in nephritis may be caused by recent changes in the nephritogenic potential of strains of type 12 or changes in the susceptibility of the host. There is no evidence that nephritis can be prevented by penicillin treatment. Nephritis continues to occur in other parts of the world, especially tropical regions where impetigo is common. The possibility of reemergence in the near future cannot be excluded.²

5. Invasive diseases

Since the late 1980s, there were increasing reports of severe GABHS infections associated with toxic shock syndrome (TSS), bacteraemia, acute respiratory distress syndrome and death in 30% of patients.^2,3,22-25 Isolates of GABHS from patients with invasive diseases have been predominantly strains of M type 1, 3, 12 and 28 which produce pyrogenic exotoxin A (SPEA) and/or B (SPEB), as well as proteinase.^23,24 It has been postulated that these substances may be associated with increased virulence. Recently we isolated a M type 76 strain from a fatel case with sepsis and TSS in Beijing, which is not a common type associated with streptococcal TSS (strepTSS).²⁶

The clinical spectrum of invasive GABHS infections include bacteraemia, sepsis, necrotizing fasciitis, pyomyositis, malignant scarlet fever, and strepTSS. Reports of strepTSS began to appear at about the same time as increased reports of GABHS sepsis.^27-29 The source of infection in strepTSS is usually the skin or soft tissues. The condition is characterized by rapid development of shock, multiorgan system failure and a high mortality rate. The upper respiratory tract is not the portal of entry for most patients with strepTSS. The ability to prevent invasive streptococcal diseases is limited. The reasons for the change in pathogenic potential of these strains are not clear. It has been shown that a serotype can become more virulent by acquiring new genetic material such as pyrogenic gene.²

Diagnosis of GABHS Pharyngitis

Because the signs and symptoms of GABHS pharyngitis can be nonspecific, an accurate clinical diagnosis often remain difficult even for experienced physicians.

Therefore, it has become standard practice to distinguish GABHS pharyngitis from the large number of patients who have pharyngitis caused by other (usually viral) agents. The use of throat swab culture to confirm the presence of GABHS has been praticised for about 40 years.³⁰ The large majority of cases of acute rheumatic fever are preventable by accurate identification of patients with GABHS pharyngitis followed by effective antimicrobial therapy. It is important for clinicians to note that a large fraction (70-80%) of patients with complaint of sore throat does not have GABHS infection and hence does not require antibiotic therapy. Abuse of antibiotics is a very serious problem especially in Asian countries. This abuse was severe in China and interfered with proper determination of etiology of bacterial diseases.³¹ Antibiotics are associated with the risk of adverse reactions and certainly can be costly, particularly for many of the recently introduced agents. That abuse of antibiotics has potential consequences for society has been emphasized by the recent emergence of multiply resistant bacteria in many countries.^4,32

When school-aged children present in late winter or spring with acute onset of fever, sore throat, headache, abdominal pain, exudative pharyngitis and tender anterior cervical lymph nodes one can diagnose acute GABHS pharyngitis on clinical grounds.³³ However, most patients with GABHS pharyngitis lack some of these "classical" features. Therefore, diagnostic laboratory tests such as throat culture or rapid antigen detection tests are necessary. When certain typical signs and symptoms of acute upper respiratory viral infection are present, the clinician who performs a diagnostic test for GABHS is much more likely to identify a chronic pharyngeal carrier of GABHS than a patient with acute streptococcal pharyngitis. Chronic GABHS carriers appear to be at little or no risk for development of acute rheumatic fever or invasive diseases.⁴

The reliability of throat culture is subject to several technical variables of which the most important one may be the technique of swabbing the patient's pharyngeal and tonsillar regions. Some studies have demonstrated that a single throat culture is likely to be 90-97% sensitive in detecting the presence of GABHS. The overall discordance rate for all throat cultures is approximately 1-2%.³⁴ Many individuals with "false negative" throat cultures are likely to harbour only very small numbers of GABHS in the pharynx, and most are likely to be chronic GABHS carriers rather than truly infected patients. Anaerobic incubation may increase the yield of GABHS by approximately 3-6%. ft is not clear whether this increased number of patients identified represent those with GABHS pharyngitis or those with chronic GABHS carriage. Therefore, routine anaerobic incubation is probably not necessary in clinical practice.³⁵

Some have suggested that the use of selective media in which trimethoprim/sulfamethoxazole is incorporated into sheep blood agar may enhance the recovery of GABHS.³⁶ The use of the bacitracin disc for presumptive identification of GABHS is widespread and an acceptable technique.³⁷ In general the subcultured plates will be sent to reference laboratories for further identification by specific serogrouping procedures such as Lancefield's capillary precipitation or agglutination methods.

The clinical use of rapid antigen detection tests enables more timely therapeutic decision based on the results. All of these tests involve an extraction step for releasing GABHS cell wall carbohydrate and identification of its presence by an immunologic reaction, usually by latex agglutination. However, the sensitivity of these assays, i.e. their ability to detect true positives, is variable and not sufficiently high to be relied upon to exclude the presence of GABHS. Even if other methodology like enzyme immunoassay³⁸ and the optical immunoassay³⁹ has been used for these tests, it remains unproved at present whether such is associated with improved performance. The advantage of the rapid diagnostic tests is the speed of obtaining a result. Rapid antigen tests must have end points that are as objective as possible to prevent bias from affecting the results. They must be subjected to routine quality control activities to ensure reliability.⁴

Management of GABHS Pharyngitis

The goals of optimal management of infections caused by GABHS include clinical improvement, microbiologic cure, prevention of suppurative and nonsuppurative complications and prevention of transmission of the infection.^5,6 Introduction of sulfonamides and later penicillins had resulted in microbiologic and clinical cure of many of these infections. Current recommendations for oral penicillins, cephalosporins and macrolides that are effective in vitro and capable of eradicating GABHS from the pharynx in children are an extrapolation from the results of the use of procaine penicillin in peanut oil for treating young adults.⁴⁰

GABHS remain uniformly susceptible to all penicillins and cephalosporins. No evidence of resistance has been identified.^6,32 A combination of procaine penicillin with the benzathine salt may reduce the incidence of severe local reactions.⁶ Penicillin V administered two to four times a day is now the preferred oral penicillin regimen.⁴¹

A number of oral cephalosporins including cephalexin, cefadroxil, cefaclor, cefixime, cefuroxime axetil, cefprozil, loracarbef and cefpodoxime, demonstrate clinical and microbiologic efficacy for therapy of GABHS pharyngitis. They are alternatives to penicillin especially for patients who are allergic to penicillin. Some investigators reported significantly improved clinical results with the cephalosporins and demonstrated higher rates of eradication of GABHS from the oropharynx.^42-44 The significance of these data, though widely discussed, has remained uncertain. The broader spectrum of activity of the cephalosporins, including their efficacy against beta-lactamase producing strains may be a reason for their increased microbiologic cure rates. Nevertheless, there are concerns regarding alteration of the bacterial flora of the mouth and intestinal tract. The cost effectiveness of cephalosporins in reducing the number of relapses and recurrence has not been fully investigated.⁵

Erythromycin has been considered the antibiotic of choice for patients with GABHS pharyngitis who are allergic to penicillin. But erythromycin-resistant strains of GABHS have been identified in Finland,⁴⁵ Sweden,⁴⁶ Germany,⁴⁷ Japan⁴⁸ and China.⁴⁹ The azalides clarithromycin and azithromycin have a spectrum of activity similar to that of erythromycin but are associated with less gastrointestinal side-effects. Recent study showed that resistance appeared to be uncommon with clarithromycin.⁵⁰

Most strains of GABHS are susceptible in vitro to sulfonamides and trimethoprim-sulfamethoxazole. Sulfadiazin is effective as prophylaxis against GABHS for patients who are allergic to penicillin. But all sulfonamides, including trimethoprim-sulfamethoxazole, are ineffective for therapy of pharyngitis caused by GABHS.^5,51 Clindamycin has remained effective for treatment of patients with GABHS pharyngitis.

What to do with a patient who, after a course of antibiotic therapy for GABHS pharyngitis, remains symptomatic or has a positive throat culture for GABHS is a common problem facing the practicing paediatrician. Treatment failures have traditionally been classified as either "clinical" or "bacteriologic".⁶

An analysis of clinical failure is complicated by a number of confounding issues: (1) GABHS pharyngitis is a self-limited illness even without therapy;^52,53 (2) diagnosis is empirical in the absence of isolation of the infecting strain of GABHS; (3) investigators are not "blinded" when performing the clinical evaluation. Therefore, the focus is limited to bacteriologic treatment failures which can be classified as either "true" or "apparent". "True" bacteriologic treatment failure refers to the inability of appropriate antibiofic therapy to eradicate the specific strain of GABHS causing an acute episode of pharyngitis. "Apparent" bacteriologic failure reflect a variety of circumstances.

Patients who have become streptococcal carriers are the most common source of "apparent" bacteriologic treatment failure. During winter and spring in temperate climates, as many as 20% of asymptomatic school-aged children are GABHS carriers who are unlikely to spread the GABHS to their close contacts and are at very low risk for developing suppurative or nonsuppurative complications.^54,55 Presumably a similar proportion of school age children with viral pharyngitis are also streptococcal carriers. It is difficult to prospectively distinguish these children from children with acute GABHS pharyngitis. Because penicillin is less effective in eradicating GABHS carriage, these enrolled carriers are frequently misclassified as penicillin treatment failures.⁵⁶ "Apparent" bacteriologic failures can also occur when newly acquired GABHS isolates are mistaken as the original infecting strain of GABHS. This acquisition can be with either a different or the same serotype of GABHS. Finally poor compliance in taking the antibiotic can also produce "apparent" bacteriologic treatment failure.

Several explanations for "true" bacteriologic failure with penicillin therapy for acute GABHS pharyngitis have been proposed. It has been suggested that GABHS may have become more resistant to penicillin, but there is no evidence to support this hypothesis and no penicillin-resistant strain of GABHS has yet been identified. It has also been suggested that some strains of GABHS have developed penicillin tolerance i.e. a discordance between the concentrations of penicillin required to inhibit and to kill the organisms. The clinical role of penicillin tolerance in GABHS pharyngitis treatment failure has not been established.^57,58 Other species of bacteria present in the normal pharyngeal flora can interfere with the colonization and growth of GABHS in the upper respiratory tract and influence the outcome of penicillin treatment.^59-61 Finally, it has been suggested that a variety of normal pharyngeal flora produce beta-lactamase that may contribute to penicillin treatment failure by local inactivation of the penicillin in the upper respiratory tract.^58,62 The reported incidence of bacteriologic treatment failures with oral penicillin has been increasing in recent years.⁶³

Summary

What has been made evident by the reemergence of severe GABHS diseases and penicillin treatment failures is that antibiotics alone cannot completely control these conditions. Other approaches, such as immunization need to be explored. There is much more to be learned about GABHS infections throughout the world.

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