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Title: Streptococcal tonsillopharyngitis in children

ETIOLOGY AND CLINICAL CLUES — Acute infectious pharyngitis in children and adolescents is caused by a variety of agents . The frequency of each pathogen varies according to the age of the child, season, and geographic area.
Bacteria — Streptococcus pyogenes (group A Streptococcus, GAS) is the most common cause of bacterial pharyngitis in children and adolescents. A number of other bacteria can cause acute pharyngitis but do so much less frequently than GAS.
Group A Streptococcus — GAS accounts for 15 to 30 percent of all cases of pharyngitis in children between the ages of 5 and 15 years . In temperate climates, the incidence peaks during the winter and early spring. GAS pharyngitis is seen most frequently in school-age children but may occur in younger children, especially if they have contact with school-age children [5,6]. In a meta-analysis, the pooled prevalence of GAS among children (<18 years) who presented to an outpatient clinic or emergency department with sore throat was 37 percent (95% CI 32-43 percent) . The prevalence among children <5 years was 24 percent (95% CI 21-26 percent).

Unfortunately, there is no single sign or symptom that reliably identifies GAS pharyngitis . In children older than three years, GAS pharyngitis typically has an abrupt onset. Fever, headache, abdominal pain, nausea, and vomiting may accompany the sore throat, which can lead to poor oral intake . Additional features may include exudative pharyngitis, enlarged tender anterior cervical lymph nodes, palatal petechiae, an inflamed uvula, and scarlatiniform rash . Symptoms usually resolve spontaneously in three to five days.

In children <3 years — Streptococcal infections usually manifest with atypical symptoms in children younger than three years of age . Instead of a well-defined episode of pharyngitis, they may have protracted symptoms of nasal congestion and discharge, low-grade fever, and tender anterior cervical adenopathy. This GAS symptom complex is called \\\"streptococcosis\\\". Infants younger than one year may present with fussiness, decreased appetite, and low-grade fever. They often have older siblings or day care contacts with GAS infection.
Clinical features suggestive of viral etiology include concurrent conjunctivitis, coryza, cough, hoarseness, anterior stomatitis, discrete ulcerative lesions, viral exanthems, and/or diarrhea .The majority of cases of acute pharyngitis in children and adolescents are caused by viruses. However, depending upon the season, as many as 35 to 40 percent of cases are caused by group A Streptococcus (GAS). It is important to determine which cases are caused by GAS, since GAS is the most common pathogen that requires antimicrobial therapy. 

Most clinicians prescribe symptomatic measures for children with pharyngitis that is not caused by GAS. Symptoms usually resolve promptly, and the infection is ascribed to a virus. In the occasional child with more persistent symptoms or with epidemiologic clues to specific etiologies, specific diagnostic testing may be necessary. 


IDENTIFYING GAS PHARYNGITIS — The major task when evaluating children and adolescents with pharyngitis is to determine if group A Streptococcus (GAS) is the cause. There are several important reasons to identify and treat children with acute pharyngitis due to GAS. These include:

●Prevention of overuse use of antibiotics
●Reduction in duration and severity of symptoms
●Prevention of suppurative complications and acute rheumatic fever
●Prevention of disease transmission


Clinical predictors — There is no single sign or symptom that reliably identifies GAS pharyngitis [3,8-10]. In a meta-analysis, the following individual findings increased the probability of GAS pharyngitis to >50 percent in children with sore throat, but could not be used for definitive diagnosis :

●Scarlatiniform rash (
●Palatal petechiae
●Pharyngeal exudate
●Vomiting
●Tender cervical nodes
Constellations of symptoms and epidemiologic features have been used to develop clinical scores in an attempt to predict the likelihood that a throat culture will be positive for GAS 

One such system gives one point for each of the following :

●Age (5 to 15 years)
●Season (late fall, winter, early spring)
●Evidence of acute pharyngitis (erythema, edema, and/or exudates) on physical examination
●Tender, enlarged (>1 cm) anterior cervical lymph nodes
●Middle-grade fever (between 101 and 103ºF)
●Absence of usual signs and symptoms associated with viral upper respiratory tract infections
In a patient with a score of six, the likelihood of a positive throat culture is approximately 85 percent . However, in a patient with a score of five, the likelihood falls to 50 percent. Other scoring systems have been devised [31,33,34], but none with sufficient sensitivity and specificity to eliminate the need for microbiologic testing in children and adolescents .

Who should be tested? — The diagnosis of GAS pharyngitis in children and adolescents should be confirmed microbiologically (with throat culture or rapid antigen detection test [RADT] for GAS) before treatment is initiated. Treatment of GAS pharyngitis is discussed separately.

Factors to be considered in the decision to perform microbiologic testing for GAS include age, clinical signs and symptoms, season of year, and exposure to an individual with GAS. In addition, it is important to identify GAS in children who are contacts of individuals with a history of acute rheumatic fever (ARF) or poststreptococcal glomerulonephritis (PSGN) to minimize the risk of recurrence.

We recommend NOT performing microbiologic testing for GAS in children and adolescents with manifestations suggestive of viral illness (eg, coryza, conjunctivitis, hoarseness, anterior stomatitis, discrete ulcerative lesions or vesicles, diarrhea) 

We suggest microbiologic testing for GAS in the following children and adolescents

●Those with evidence of acute pharyngitis (erythema, edema, and/or exudates) on physical examination and absence of signs and symptoms of viral infections
●Children with symptoms of GAS and exposure to an individual with GAS at home or school, or a high prevalence of GAS infections in the community
Although GAS pharyngitis is uncommon in children younger than two to three years of age (they have fewer epithelial cell attachment sites in the throat), such children may develop GAS infection, typically manifest with prolonged nasal discharge, tender anterior cervical adenopathy, and low-grade fever . Microbiologic testing may be warranted for symptomatic young children, particularly if they have been exposed to contacts with GAS infection.

Which test? — The diagnosis of GAS pharyngitis can be confirmed by a positive throat culture or RADT for GAS. For children and adolescents in whom microbiologic testing for GAS is necessary, we suggest initial testing with a standard throat culture; if throat culture results will not be available for more than 48 hours, we suggest RADT. Otherwise, we suggest RADT only for children with a streptococcal score of ≥5 (ie, those most likely to have a positive culture) 

This approach, rather than initial testing with RADT, places a high value on cost effectiveness. Most children who require microbiologic testing do not have GAS pharyngitis and will have a negative RADT. Since negative RADT must be confirmed with throat culture, using RADT as the initial test commits the majority of children who are tested to be tested with both RADT and throat culture. Limiting RADT to those children in whom it is likely to be positive and performing throat cultures in the remainder minimizes the number of children who require both tests .

Between 5 and 21 percent of children between 3 and 15 years of age are pharyngeal carriers of GAS . Unfortunately, neither RADT nor throat culture can differentiate patients with acute GAS pharyngitis from GAS carriers with intercurrent viral illness]. Nonetheless, the use of RADT or throat culture to confirm the presence of GAS in the pharynx before initiation of antimicrobial therapy helps to minimize the overuse of antibiotics .

Throat culture — Throat culture is the reference standard for the diagnosis of acute pharyngitis due to GAS. For children and adolescents in whom microbiologic testing for GAS is necessary, we suggest initial testing with a standard throat culture; if throat culture results will not be available for more than 48 hours, we suggest RADT.

Throat culture also can identify other bacteria that cause pharyngitis less commonly than GAS (eg, group C and group G streptococci, A. haemolyticum).  However, most laboratories do not routinely identify these pathogens in throat cultures unless specifically requested to do so.

When performed properly, the sensitivity of throat culture is 90 to 95 percent for GAS .

Serology — True streptococcal infection may be confirmed by measurement of antistreptococcal antibody titers (eg, antistreptolysin O, antideoxyribonuclease B, hyaluronidase, streptokinase, or nicotinic acid dehydrogenase) However, the antibody response does not occur until two to three weeks after the onset of infection and therefore is not helpful in the diagnosis of acute pharyngitis . In addition, the antibody response is frequently aborted by early and appropriate antibiotic therapy.

Serologic testing for GAS may be necessary to confirm previous infection in patients who are being evaluated for ARF or PSGN but is not helpful in managing patients at the time of clinical presentation.

Specimen collection — The key to optimizing detection of GAS in clinical specimens is appropriate collection and transport of the sample:
●Specimens should be obtained before initiation of antimicrobial therapy, since a single dose of antibiotics can result in a negative culture.
●If RADT is to be performed, we suggest that the throat be swabbed with two swabs simultaneously. One is used for RADT; if RADT is positive, the second swab can be discarded. If RADT is negative, the second swab can be used for standard culture.
●Specimens should be obtained by vigorous swabbing of both tonsils (or tonsillar fossae in patients who have undergone tonsillectomy) and the posterior pharynx. The swab(s) should be moved into and out of the mouth without touching the tongue or the buccal mucosa. The importance of obtaining an adequate specimen cannot be overstated; the sensitivity of both culture and RADT correlate with inoculum size .

TREATMENT — Antimicrobial therapy is warranted for patients with symptomatic pharyngitis if the presence of group A streptococci (GAS) in the pharynx is confirmed by culture or rapid antigen detection testing (RADT). The approach to establishing the diagnosis of acute streptococcal pharyngitis is discussed in detail separately.

Antimicrobial therapy may also be administered to mitigate the clinical course of pharyngitis due to group C and group G streptococci. The approach to antibiotic selection is as outlined in the following sections. However, treatment need not continue for 10 days since acute rheumatic fever is not a complication of infection due to these organisms; five days of treatment is sufficient

In general, antimicrobial therapy is of no proven benefit for treatment of pharyngitis due to bacteria other than Streptococcus (with the exception of relatively rare infections caused by other bacterial pathogens such as Corynebacterium diphtheriae and Neisseria gonorrhoeae). Such therapy unnecessarily exposes patients to the expense and potential hazards of antimicrobial drugs and contributes to the emergence of antibiotic-resistant bacteria.

Timing of therapy — If clinical and/or epidemiologic factors point to a high index of suspicion for GAS pharyngitis while laboratory results are pending, it is appropriate to initiate empiric antimicrobial therapy. However, if laboratory testing does not confirm the diagnosis of GAS pharyngitis, antimicrobial therapy should be discontinued.

In the natural history of GAS pharyngitis, the incubation period is two to four days. Fever and constitutional symptoms usually resolve within three to four days, even in the absence of antimicrobial therapy [17]. Clinical improvement has been observed up to 48 hours sooner in patients receiving penicillin versus placebo within the first two days of illness .

Treatment is warranted for patients with negative rapid antigen detection testing but subsequent positive culture results whose symptoms are resolving, in order to reduce the likelihood of transmission.

There is some concern that early therapy may suppress host antibody response and thereby increase risk for recurrent pharyngitis. In a study of 142 children with presumed GAS pharyngitis, those treated with penicillin at the initial office visit had a higher incidence of recurrent infection than those for whom treatment was delayed at least 48 hours (recurrent infection occurred eight times more frequently) .

Antibiotics for group A Streptococcus — Antibiotic options for treatment of GAS pharyngitis include penicillin (and other related agents including ampicillin and amoxicillin), cephalosporins, macrolides, and clindamycin [20]. Sulfonamides, fluoroquinolones, and tetracyclines should NOT be used for treatment of GAS pharyngitis because of high rates of resistance to these agents and their frequent failure to eradicate even susceptible organisms from the pharynx.

Intramuscular penicillin is the only therapy that has been shown to prevent initial attacks of rheumatic fever in controlled studies . These studies were performed with penicillin G procaine in oil containing aluminum monostearate; this preparation has since been supplanted by penicillin G benzathine. There are data suggesting that penicillin G benzathine is effective for primary prevention of rheumatic fever, although they are not definitive . Other antimicrobials have been shown to effectively eradicate GAS from the upper respiratory tract, and it is assumed that such eradication is a surrogate for efficacy in primary prevention of rheumatic fever.

Resistance — Antimicrobial resistance has not been a significant issue in the treatment of GAS. No clinical isolate of GAS has demonstrated penicillin resistance, likely due to the organism\\\'s lack of altered penicillin-binding proteins and/or inefficient gene transfer mechanisms for resistance . However, streptococcal strains tolerant to penicillin (eg, strains inhibited but not killed by penicillin in vitro, with ratio of minimum bactericidal concentration to minimum inhibitory concentration [MIC] of ≥32) have been described . The clinical significance of such strains is not clear; they have been isolated in the setting of outbreaks in which penicillin treatment failure was observed, but there was no difference in failure rates among tolerant and susceptible strains. 

There have been reports of relatively high levels of resistance to macrolide antibiotics in some regions of the United States and Asia; given the increasing use of macrolides for treatment of upper and lower respiratory tract infections, clinicians should be cognizant of local patterns of antimicrobial resistance .

Selection — Oral penicillin V is the agent of choice for treatment of GAS pharyngitis given its proven efficacy, safety, narrow spectrum, and low cost . The appropriate duration is 10 days of therapy; dosing is outlined in the Table . This approach is extrapolated from studies performed in the 1950s demonstrating that treatment of streptococcal pharyngitis with intramuscular penicillin prevents acute rheumatic fever 

Amoxicillin is often used in place of oral penicillin in children, since the taste of the amoxicillin suspension is more palatable than that of penicillin. Some data suggest that oral amoxicillin may be marginally superior to penicillin, most likely due to better gastrointestinal (GI) absorption . In addition, amoxicillin has activity against one-third of the common pathogens that cause otitis media (which presents concurrently with GAS tonsillopharyngitis in up to 15 percent of children, particularly those under four years of age). Dosing is outlined in the Table .

Intramuscular penicillin G benzathine (single dose) may be administered to patients who cannot complete a 10-day course of oral therapy or to patients at enhanced risk for rheumatic fever (eg, those with history of previous rheumatic heart disease and/or living in crowded conditions). Injections of benzathine penicillin provide bactericidal levels against GAS for 21 to 28 days. The addition of procaine penicillin alleviates some of the discomfort associated with benzathine injections and may favorably influence the initial clinical response. The preferred product in children is the combination of 900,000 units of benzathine penicillin G plus 300,000 units of procaine penicillin (Bicillin C-R 900/300). Dosing is outlined in the Table (table 3).

Cephalosporins are acceptable alternatives in patients with recurrent GAS infection but are not recommended as first-line therapy in national guidelines . Cephalosporins have demonstrated better microbiologic and clinical cure rates than penicillin; these differences appear to be greater among children than adults, and some favor use of first-generation cephalosporins as first-line therapy in this group. However, second- and third-generation cephalosporins may facilitate development of antibiotic resistance and are not favored as first-line therapy 

Antibiotic therapy directed against beta-lactamase–producing upper respiratory tract flora (such as amoxicillin-clavulanate) remains controversial and is not indicated in patients with acute pharyngitis, although it would be effective .

For patients with penicillin hypersensitivity, cephalosporins (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone) may be used , in the absence of history of life-threatening allergic reaction to penicillin; cross reactivity with penicillin is not likely for later-generation cephalosporins.. Macrolides (clarithromycin, azithromycin, or erythromycin) are an acceptable alternative for penicillin-allergic patients, depending on local resistance patterns [29,32-37]. For the rare patient with an erythromycin-resistant strain of GAS who is unable to tolerate beta-lactam agents, clindamycin is an appropriate choice .

Duration — In general, the conventional duration of oral antibiotic therapy to achieve maximal pharyngeal GAS eradication rates is 10 days, even though patients usually improve clinically within the first few days of treatment. Five days of therapy with cefpodoxime, cefdinir, or azithromycin is an acceptable alternative approach, with rates of bacteriologic and clinical cure of streptococcal pharyngitis comparable with that of the conventional 10-day course of penicillin . Three injections of ceftriaxone on sequential days (or every other day) are needed for optimal eradication.


Follow-up — Patients with GAS pharyngitis should have improvement in clinical symptoms within three to four days of initiating antibiotic therapy. Patients are considered no longer contagious after 24 hours of antibiotic therapy [16]. Patients may return to daycare, school, camp, or work after 24 hours of antibiotics.

Failure to observe a clinical response to antibiotics should prompt diagnostic reconsideration or the possibility of a suppurative complication. If acute streptococcal pharyngitis was diagnosed by rapid testing, the result may represent a false-positive finding; if the diagnosis was made by culture, the patient may be a pharyngeal carrier whose symptoms are likely attributable to an alternate process. 

In general, test of cure is not necessary for asymptomatic patients or their close contacts following completion of a course of antimicrobial therapy. The majority of patients with GAS remaining in their upper respiratory tracts after completing a course of antimicrobial therapy are asymptomatic Streptococcus carriers .

However, follow-up test of cure is appropriate testing for asymptomatic index patients and their asymptomatic household contacts in the following circumstances:

●Individuals with history of rheumatic fever
●Individuals who develop acute pharyngitis during an outbreak of acute rheumatic fever or acute poststreptococcal glomerulonephritis 
●Spread of GAS among several family members
Asymptomatic patients and asymptomatic household contacts in the above circumstances with positive laboratory results should receive a standard course of antimicrobial therapy with one of the agents outlined above. Repeat treatment should be administered with an agent with greater beta-lactamase stability than the previous agent . If a penicillin was used for initial therapy, repeat treatment with amoxicillin-clavulanate or a first-generation cephalosporin may be used; if initial treatment was with a first-generation cephalosporin, a second- or third-generation cephalosporin may be used. First-generation cephalosporins regimens include cephalexin and cefadroxil; second generation regimens include cefprozil, cefuroxime, and cefaclor; third-generation cephalosporins include cefdinir, cefpodoxime, and cefixime. 

Recurrent infection — In the setting of recurrent acute pharyngitis with positive repeat diagnostic testing, there are several possible explanations :

●Persistence of Streptococcus carriage in the setting of viral infection
●Nonadherence with the prescribed antimicrobial regimen
●New infection with GAS acquired from household or community contacts
●Treatment failure (eg, repeat episode of pharyngitis caused by the original infecting strain); treatment failure is rare.
In the setting of a second episode of acute pharyngitis with positive repeat diagnostic testing, a repeat course of treatment is appropriate . Repeat treatment should be administered with an agent with greater beta-lactamase stability than the previous agent 

If adherence is uncertain, intramuscular penicillin G benzathine may be chosen as the second course of therapy. If a full course of penicillin was completed as initial therapy, a first-generation cephalosporin (such as cephalexin, cefadroxil) may be used; if a first-generation cephalosporin was used for initial therapy, a second- or third-generation cephalosporin (such as cefpodoxime, cefdinir) may be used. Alternative agents include amoxicillin-clavulanate or clindamycin.

PREVENTION

Carriers — In general, group A Streptococcus (GAS) resides in the oropharynx of Streptococcus carriers in the absence of host immunologic response to the organism. In temperate climates during the winter and spring, up to 20 percent of asymptomatic school-aged children may be carriers. About 25 percent of asymptomatic individuals in the households of index patients harbor GAS in their upper respiratory tracts. Streptococcal carriage may persist for many months. 

Carriers may demonstrate evidence of GAS in the upper respiratory tract during an episode of viral pharyngitis, suggesting acute streptococcal pharyngitis. In these circumstances, clinically distinguishing viral from streptococcal pharyngitis can be difficult. Useful clues may include patient age, season, local epidemiology, and the nature of presenting signs and symptoms. In addition, pharyngeal strep carriers tend to have low antistreptolysin O (ASO) titers; they may be just above detectable. 

Streptococcus carriers are unlikely to spread the organism to close contacts and are at very low risk for developing suppurative complications or acute rheumatic fever . Moreover, eradication of GAS from the upper respiratory tract of carriers is much more difficult than eradication of GAS from patients with acute infection . In general, except for the circumstances described above, Streptococcus carriers do not require antimicrobial therapy. 

Prophylaxis — Continuous antimicrobial prophylaxis is only appropriate for prevention of recurrent rheumatic fever in patients who have experienced a previous episode of rheumatic fever. 

Vaccination — There is no vaccine against GAS available for clinical use, although development of this preventive measure is under investigation . An important area of uncertainty is whether vaccine-induced antibodies may cross-react with host tissue to produce nonsuppurative sequelae in the absence of clinical infection.


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