Moffet’s Pediatric Infectious Diseases: A Problem-Oriented Approach
4th Edition

Chapter 2
Nose and Throat Syndromes
Definitions and Classifications
“Upper respiratory infection,” often abbreviated URI, is a collective term. It has the same kind of meaning as “lower respiratory infection,” i.e., it includes several anatomic syndromes. URI has become a lay term like “strep throat” or “flu.”
The term “URI” is an oversimplification. The clinical skill of a physician is related to the ability to make specific diagnoses, which are based on discrimination and distinction between shades of differences, not on oversimplifications. In general, the best diagnosticians have a large number of possible anatomic syndromes to consider. The use of the collective term URI when a more specific diagnosis is possible implies unnecessarily superficial thinking.
In a study of emergency room visits, the diagnostic terms “common cold” and “rhinitis” were rarely used by the physicians, whereas the term URI was common.1 Perhaps this was because the patient really had a more severe syndrome, sometimes referred to as the “uncommon cold,” which may include acute bronchitis or some other diagnosis the vague term URI covers.1
Two syndromes are often misdiagnosed as upper respiratory infections. The first is a systemic syndrome, manifested by relatively high fever and general symptoms such as headache and fever, but with a normal physical examination. It is useful to classify such illnesses in diagnostic terms that emphasize the fever, such as “fever without localizing signs,” as described in Chapter 10. This term is much more descriptive than “viral syndrome,” an unsophisticated phrase that usually implies fever but is vague, assumes the etiology, and lacks an anatomic component.
The second misdiagnosed syndrome is distinguished by prominent respiratory symptoms (i.e., cough and sore throat) with a moderate to high fever or with generalized weakness. It is useful to classify such illnesses as influenza-like, as described in Chapter 7. Unfortunately, these distinctions between upper respiratory illnesses, systemic febrile illnesses, and influenza-like illnesses are not widely accepted, and medical communications continue to be hampered by the lumping of a variety of separable syndromes into the category of URI or “viral syndrome.”
This chapter includes the common cold syndrome, purulent rhintis, and pharyngitis (see Box 2-1). Other respiratory syndromes are discussed in Chapters 7 and 8. Dental infections, gingivitis, stomatitis, and tongue infections are discussed in Chapter 4.
Common Cold Syndrome
The common cold syndrome was defined in adults as a self-limited illness, with watery nasal discharge, nasal stuffiness, occasionally a scratchy throat, sneezing, chills, burning eyes and nasal membranes,
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and mild muscle aches. Cough may be present but is usually not prominent. Significant fever, defined as an oral temperature of 102°F (38.9°C) or higher, is unusual, especially in the older child. Common cold syndrome may reasonably be considered a rhinosinusitis. The lining of the sinuses is contiguous with the nasal mucosa and typically becomes inflamed during the course of a common cold.2
Possible Etiologies
Rhinoviruses
The most frequent cause of the common cold syndrome in adults and probably in teenagers is infection with one of the approximately 100 serotypes of rhinovirus. Reinfection with the same serotype can occur but is usually less symptomatic.3 Unlike most other human viruses, rhinoviruses are temperature sensitive. They grow best at 33°C, about the temperature of the nasal mucosa, and growth is inhibited gradually at increasing temperatures. In vitro, most rhinoviruses do not grow well at 37°C, which is the reason they do not usually cause lower respiratory infection. It has been reported, however, that certain rhinoviruses can and do cause lower respiratory infection in some individuals,4 and also that infection of the upper respiratory tract with a rhinovirus commonly induces wheezing in patients with asthma.5
Inoculation of susceptible volunteers with a rhinovirus results in an illness that begins about the first day after inoculation and lasts about 7 days. The virus continues to be recoverable from the nasopharynx for about 1–2 weeks. More than 90% of adult volunteers had nasal discharge, nasal obstruction, and inflamed nasal mucosa, and about 50% had sneezing and cough. About 10–30% of adults with the common cold syndrome will have a rhinovirus detected when proper cultures are done.
Coronaviruses
At least two serotypes of these viruses are causes of the common cold syndrome. Experimental infection in adult volunteers produced an illness similar to that caused by rhinoviruses. The incubation period is about 24 hours longer, and the duration of illness is generally 2–3 days shorter. Headache was reported by 85% of volunteers infected with coronavirus 229E versus about half of those infected with rhinovirus.6 These viruses are difficult to detect in the laboratory.7 They have been estimated to cause about 10% of adult upper respiratory infections. They are named for their appearance in electron micrographs as spheres with crownlike, petal-shaped projections. Coronavirus colds are most frequent in young children and gradually decrease in frequency throughout life.8 Reinfection can occur. Wheezing is frequently present.7
Other Viruses
Summer “colds” are often mild infections with enteroviruses, which do not particularly cause diarrhea but do cause fevers, often with mild rhinitis or cough.
Mycoplasmas
Mycoplasma pneumoniae infection, as detected by monitoring of infants and young children, typically is asymptomatic.9 When symptomatic, there can be mild rhinitis and cough, reasonably classified as a “common cold syndrome.” More severe illness associated with M. pneumoniae infection is discussed in Chapter 7.
Modified Viral Infection (Reinfection)
In adults, many illnesses diagnosed as the common cold are probably modified infection caused by viruses that produce a mild illness on reinfection and a more severe disease on primary infection. The most common of these is respiratory syncytial virus, which circulates in epidemics yearly, and to which human adult volunteers can be productively infected repeatedly.10,11 Influenza and the parainfluenza viruses can also cause this phenomenon. Adenoviruses and enteroviruses (Coxsackie and echoviruses) are also occasionally recovered from adults with illnesses resembling the common cold.
Prodrome of a More Serious Infection
Some serious infections, such as bronchiolitis, pneumonia, or meningitis may begin with symptoms resembling those of the common cold. In the case of bronchiolitis, the cold symptoms are part of the natural course of the disease. As for meningitis, the common cold syndrome may, in fact, be a risk factor for its development, due to disruption of the nasal mucosal barrier.12
Allergic Rhinitis
This condition closely resembles the common cold syndrome of infectious etiology. It can occur as
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early as the first month of life, especially if the baby is allergic to cow’s milk,13 but is rare in infancy. Mouth breathing, nasal rubbing, recurrent episodes of nasal bleeding, family or personal history of asthma or atopic dermatitis, seasonal episodes, and nasal eosinophilia support the diagnosis of allergic rhinitis.14,15
Nonallergic Rhinitis with Eosinophilia Syndrome (NARES)
Children 6–12 years of age may also have this syndrome, although it is usually associated with adults.16 The syndrome is characterized by perennial rhinitis, negative allergy skin tests, normal serum immunoglobulin E (IgE), and nasal eosinophilia. It is a vasomotor rhinitis, with pale, boggy, edematous nasal mucosa, and usually responds to topical corticosteroids.
Nasal Polyps
Multiple and bilateral nasal polyps can be the presenting manifestation of cystic fibrosis, whether or not the obstruction or rhinorrhea respond to antiallergic therapy.17
Diagnostic Plan
Usually, no diagnostic studies are necessary or useful for the evaluation of a patient with the common cold syndrome.
Treatment
Antibiotics
Studies in college students, military recruits, and children have repeatedly documented the lack of efficacy of antibiotics in the treatment of the common cold.18,19,20 A Cochrane database review of prospective placebo-controlled trials concluded that antibiotic treatment of the common cold produces no clinical benefit.21 This is an expected outcome because bacteria do not cause the disease. Common cold is only occasionally complicated by secondary bacterial infection, and prophylaxis against this unusual occurrence is not effective.22 Worse, the overuse of antibiotics in clinical pediatrics is a major contributing factor for the emergence of antimicrobial resistance in bacteria. Multiple studies have identified recent antibiotic use as a risk factor for invasive disease with resistant pneumococci.23 Parental desire for antibiotics is not an indication for their use in this benign, self-limited illness. Unfortunately, surveys show that although almost all physicians understand this concept, about half of them routinely prescribe antibiotics anyway.24
Cough Medications
Cough is not in itself an indication for cough suppression. Antitussive medicines are usually not necessary in the common cold but may be helpful for selective cases if the cough is not useful to raise sputum, interferes significantly with sleep, or precipitates vomiting. Severe or protracted coughing should make the physician rethink the diagnosis of common cold syndrome. Asthma is particularly underdiagnosed in this setting, as common cold can trigger an exacerbation of reactive airways disease (see Chapter 7). When needed, dextromethorphan is almost as potent an antitussive as codeine, but it is not addictive. Studies proving the antitussive effect of dextromethorphan in children are lacking. Parents should be educated about the fact that most of the combination cough medications that are available over-the-counter contain other drugs not necessary for treatment of the cough, which can produce significant side effects. Nonsensical combinations are also marketed, such as guaifenesin (thins mucus to make it easier to expectorate) and dextromethorphan (stops the cough that would expel the thinned mucus). Generally, stopping a cough requires a larger dose of dextromethorphan (0.5–1.0 mg/kg) than is recommended on the bottle. Attempting to achieve this dosage in combination syrups is likely to lead to overdosage of one of the other ingredients. Physicians should recommend the simplest formulations available if they choose to medicate cough at all.
Decongestants
Nose drops, nasal sprays, and oral decongestants may provide temporary relief of nasal obstruction. However, excessive use of nose drops can produce sensitization or rebound vasodilation (rhinitis medicamentosa). Several prospective, placebo-controlled studies of antihistamine-decongestant combinations in children have shown no measurable efficacy.25,26 The younger the child, the less likely these medicines are to be effective. No study has ever shown clinical improvement in a child less than age 3 years with the use of these medications. Despite this, physicians continue to recommend over-the-counter antihistaminedecongestant medications,
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which have the potential to produce frightening and even life-threatening side effects.27
Expectorants
Drugs such as guaifenesin are intended to reduce the viscosity of sputum. They are unnecessary in the treatment of the uncomplicated common cold. Even in acute bronchitis their value is not clearly established. They may be of some benefit in the treatment of chronic bronchitis in adults. Toxic effects of iodides include acne and goiter. Iodides are contraindicated during pregnancy and breastfeeding, because they can produce goiter in the infant.
Antihistamines
The symptoms of the common cold are caused by virus replication and by the host immune response to the virus, not by histamine release. However, some patients can get partial relief from nasal congestion by the drying effects of antihistamines, a nonspecific side effect of these medications. A metaanalysis of all the prospective, placebo-controlled trials of antihistamines in common cold syndrome concluded “the primary literature offers little support for the use of antihistamines in the common cold.”28 Antihistamines may also produce sedation, decreased bladder tone, and rare severe reactions. If the cough is productive of sputum, the drying effect of antihistamines is undesirable.
Vitamin C
At present, the efficacy of vitamin C is not proved. It has been most highly touted as a preventive, rather than a treatment. A review in the British Journal of Nutrition of the six largest vitamin C supplementation studies (studies that used dosages of 1 g/day or greater) showed no reduction in the incidence of common cold in recipients of vitamin C.29 This analysis included over 5,000 episodes. The relative risk of contracting a cold while on high-dose vitamin C was seen to be 0.99 (95% confidence interval 0.93–1.04). Adverse effects of high-dose vitamin C, other than stomach upset, are uncommon. The urine is acidified, however, which can lead to increased excretion of oxalic acid (a metabolic byproduct of ascorbic acid); this, in turn, can cause urinary tract calculi in predisposed individuals. Other than cost, perhaps the most important disadvantage is that this therapy may encourage people to use excessive doses of other, nonwater-soluble vitamins, some of which are exceedingly toxic.
Zinc Gluconate
A prospective study in adults with community-acquired common cold syndrome showed that subjects who received zinc gluconate lozenges every 2 hours for the duration of their colds recovered 3 days sooner, had half as many days with cough, one third fewer days of hoarseness and headache, two days less nasal drainage, and one third the duration of sore throat as compared with subjects in the placebo group.30 There was no difference in resolution of fever, muscle aches, scratchy throat, or sneezing. Side effect profiles were impressive, with 20% of subjects experiencing nausea and 80% complaining of bad-taste reactions. The mechanism of action of zinc is unknown. An attempt to translate the adult experience into a pediatric population was unsuccessful.31 No benefits of zinc gluconate have yet been demonstrated in childhood. The side effects, however, were preserved.
Other Therapies
Various other therapies have been tried, including anticholinergic nasal sprays, mast cell stabilizers, steroids, and new anti-viral agents active against enteroviruses including the rhinoviruses. Table 2-1 is a summary of these trials, along with the zinc trial mentioned above. The most effective therapy with the lowest side effect profile is probably nasal irrigation with warm salt water, but this has not been well studied. Commercial saline nasal sprays may not be entirely innocuous; most contain benzalkonium chloride, which is toxic to white blood cells in vitro.
Prevention
Vaccines
The need for rhinovirus vaccines, if indeed one exists, is based primarily on the frequency, rather than the severity, of rhinovirus infections. The large number of serotypes of rhinovirus, coupled with the fact that not all colds are due to rhinovirus infection, make a “common cold vaccine” impractical.
Avoid Exposure
Avoidance of exposure is not a practical measure within a family, although handwashing and not
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sharing glassware, silverware, etc. may be helpful. Attack rates for rhinovirus infection within a family are high but irregular.
TABLE 2-1. TRIALS OF TREATMENTS FOR THE COMMON COLD SYNDROME
DRUG DOSING DESIGN RESULTS SIDE EFFECTS COMMENTS REF.
Zinc 13 mg q 2hr PRDBPCTa Duration of cold sxs Nausea 20%; bad taste 80% High price to pay? 1
Ipatropium bromide 1–2 sprays per nostril qid PRDBPCT ↓Nasal d/c (30%) Bloody mucus (12%), dryness Saline spray helped, too 2
Pirodavir (antiviral) 2 mg i.n. 6 times/d for 5 days PRDBPCT ↓virus shedding; no sx relief Dryness, bloody mucus, bad taste Fancy drug without efficacy 3
Clemastine fumarate 1.34 mg po q 12 hr for 4 days PRDBPCT ↓Runny nose, ↓sneezing on days 2–4 Dryness   4
Na Cromoglycate 20 mg powder or 5.2 mg spray q 2hr for 2 days, then quid for 5 days PRDBPCT ↓Duration; ↓severity on last several days None   5
Prednisone 20 mg tid for 5 days PRDBPCT No effect; ↑virus titers Negliglble Worthless and potentially dangerous 6
Antihistamines Many trials Many designs Little or no benefit Dryness, sedation More side effects than effects  
Note: None of these trials was performed in children.
aProspective, randomized, double-blind, placebo-controlled trial.
Source: 1Mossad SB, et al. Ann Intern Med 1996;125:81–88; 2Hayden FG, et al. Ann Inten Med 1996;125:89–97; 3Hayden FG, et al. Antimicrob Agents Chemother 1995;39: 290–294; 4Gwaltney JM, et al. Clin Infect Dis 1996;22; 656–662; 5Aberg N, et al. Clin Exper Allergy 1996;26: 1045–1050; 6Gustafson LM, et al. J Aller Clin Immunol 1996;97: 1009–1014.
Rhinoviruses can be transmitted by self-inoculation of the nose or conjunctivae with the fingers.32 As nonenveloped, hard protein-shelled viruses, they can survive on environmental surfaces and fomites for prolonged periods. These viruses can be spread by large aerosol particles33 but not usually by droplet nuclei, which implies that the virus is not likely to be spread beyond 6 feet by air. An instructional program on handwashing and germs decreased the incidence of respiratory infections in a day-care setting.34
Purulent Rhinitis and Nasal Abscess
Purulent rhinitis is an objective diagnosis that implies the presence of thick nasal discharge, usually yellow to green in color. This diagnosis does not imply the presence of bacterial infection. Even if exudate has been cleaned off, the nostrils usually appear crusted. Fever may be present but is usually not greater than 102°F (38.9°C). Excoriation around the nostril may be present.
This diagnostic classification should be used as a preliminary descriptive diagnosis only when there are no findings to suggest sinusitis or otitis. Most children for whom purulent rhinitis is the only finding are younger than 5 years. Purulent or febrile rhinitis usually has been specifically excluded from studies of antibiotic value in uncomplicated upper respiratory infections.
It is not unusual for nasal discharge to change from watery early in the course of a common cold to more viscous and yellow to green 4–7 days after the onset. This is part of the natural history of the common cold syndrome. The mucus changes color because of the influx of lymphocytes, which are there to lyse infected cells and clear the infection. Thus, the appearance of thickened and possibly colored nasal discharge is a good sign, usually heralding recovery from the cold within 3–4 days. The
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child usually feels quite well by this time. Parents and physicians alike seem to believe that green mucus is tantamount to a bacterial infection that must be treated with antibiotics, but no study has ever shown a correlation between the color of nasal secretions and the presence of bacteria. Despite this fact, in one study 97% of physicians admitted to routinely prescribing antibiotics for “purulent rhinitis” of any duration.24
Sometimes, however, persistent purulent rhinitis is caused by bacterial infection of the sinuses. Often, it is the nasal mucosa or adenoidal lymphoid tissue that is the source of the pus. Bacterial sinusitis can be a reasonable diagnosis in cases when the nasal discharge persists for 10–14 days without improvement (See section on sinusitis, Chapter 5.)
Possible Etiologies
Group A Beta-hemolytic Streptococcus
This organism typically produces a thin, slightly bloody discharge. If there is a slow-healing excoriation about the nostril, Group A beta-hemolytic streptococcus is a likely etiology.35
Streptococcus pneumoniae
With this organism, also called the pneumococcus, the discharge is usually green and thick. If the discharge is protracted, or signs of sinusitis are present (fever, facial pain, periorbital swelling), the patient may respond to a course of therapy with amoxicillin.
Sinusitis
This diagnosis should be considered in any patient with purulent nasal discharge and is discussed in detail in Chapter 5.
Uncommon Causes
A foreign body should be considered in young children, especially if the discharge is unilateral and/or foul smelling. Nasal diphtheria is a rare cause of purulent rhinitis. A membrane is sometimes seen, and slight bleeding is often present. Allergic rhinitis is unlikely to produce a purulent discharge. Viral infections, such as those with adenoviruses, might produce purulent discharge, but this has not been documented. Purulent rhinitis without sinusitis caused by other bacteria, such as H. influenzae or Staphylococcus aureus, is difficult to document, because recovery of such normal flora on culture may be coincidental.
Diagnostic Plan
The nose should be examined carefully to exclude the presence of a foreign body. Occasionally, culture of the discharge to exclude Group A streptococcal infection may be indicated. Radiologic studies such as sinus x-rays or computed tomographic scans are usually not helpful.
Treatment
Many physicians use antibiotics to treat purulent rhinitis. Only a small prospective study of purulent rhinitis has been done, which indicated no benefit of cephalexin over placebo, with about 35 children in each group.36 In a carefully controlled study of minor respiratory infections of children, true purulent rhinitis was observed as a complication in only 5 of about 670 patients.37 Thickening and discoloration of mucus near the end of a common cold occurs with much greater regularity. In general, observation without treatment is indicated for patients with green nasal discharge unless the presence of Group A streptococci (which can be confirmed by culture) or a concomitant diagnosis of sinusitis is strongly suspected.
Complications
Acute purulent otitis media or sinusitis may occur as a complication of purulent rhinitis. The frequency of these complications is unknown, because no prospective study of purulent rhinitis has been done.
Nasal Septal Abscess or Hematoma
A history of a nasal furuncle or minor trauma is sometimes present in these cases.38 Dental infections can be a source.39 The swelling is usually bilateral and appears to arise medially. Fever and nasal obstruction are present, but the nasal discharge is usually serous rather than purulent.
Needle aspiration for confirmation and culture and surgical drainage are indicated.40
A nasal septal hematoma can be associated with bacteria without an abscess.41 Hematomas can become infected and produce purulent drainage. The hematoma should be evacuated as an urgent procedure to prevent erosion of the nasal septal cartilage.
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Pharyngitis
The terms “tonsillitis,” “tonsillopharyngitis,” and “pharyngitis” are often used interchangeably. In this section, the more general term “pharyngitis” is used for brevity, as the tonsils may have been removed. Pharyngitis is best defined by objective evidence of inflammation of the pharynx, such as exudate, ulceration, or definite erythema. Redness of the throat may occur as part of the general redness of all mucous membranes in a patient with fever. Therefore, a diagnosis of pharyngitis is not justified when the pharynx is no redder than the rest of the oral mucosa or if there is only slight injection of the pharynx.
The symptom of sore throat should be distinguished from the clinical diagnosis of pharyngitis, which should be based on the evidence of definite signs on physical examination. “Sore throat” often refers to tracheal irritation, as can often be demonstrated by asking the patient to point to the location of the soreness. In tracheitis, the patient usually points to the trachea in the midline with one finger. In pharyngitis, the patient typically points with one hand, using the thumb and forefinger to point to the tonsillar nodes.
Diagnostic Approach
It is important to get a thorough look at the pharynx with a good light using whatever restraint is necessary. The pharyngeal examination can be one of the more unpleasant parts of the physical examination, and there seems to be a tendency to rationalize a cursory look. Exudate, which usually resembles a thin layer of milk or cream on the surface, should be distinguished from cryptic debris, which is shiny, yellow-tinted, hard, and smooth and forms a cast of the tonsillar crypts. A cast of debris can be carefully picked out of the crypts, but this is not advisable. Submucosal spherical white areas may be seen, which give the tonsils the appearance of raw ground beef—red with white spheres mixed throughout. These white submucosal areas are not exudate but probably are nodules of lymphoid hyperplasia.
The palate, buccal mucosa, gums, and tongue should be examined for erythema or ulcers. The size and tenderness of the anterior (tonsillar) and posterior cervical nodes should be noted. Careful examination should be done for generalized lymphadenopathy, splenomegaly, liver tenderness, and edema of the eyelids or upper malar area, all of which suggest infectious mononucleosis. Absence of a heart murmur or dependent edema should be noted for their relevance to rheumatic fever and glomerulonephritis. Vital signs, including blood pressure, should be recorded. Poor quality of the heart sounds raises the question of diphtheritic myocarditis.
Anatomic Classification
Exudative Pharyngitis
The definition of exudative pharyngitis is the presence of a white or gray scum on the surface of the tonsils or pharynx. This scum resembles milk and is readily wiped off without producing bleeding. White material seen in the tonsillar crypts is usually cryptic debris, not exudate.
Ulcerative Pharyngitis
The criterion for ulcerative pharyngitis is the presence of circular or oval shallow ulcers on the soft palate, tonsillar area, or posterior pharynx. Herpangina is an older term still used for this syndrome, discussed later.
Membranous Pharyngitis
This is defined by the presence of a membrane (also called a pseudomembrane) on the tonsils, palate, or other part of the pharynx. It is defined as a gray-white layer of materials that can be peeled from the pharynx, usually leaving the surface underneath bleeding. Membranous pharyngitis is rare. In the United States, the cause is rarely diphtheria, which typically occurs in unimmunized children. Instead, most cases are due to infectious mononucleosis, particularly in teenagers and young adults.
Uvulitis
Uvulitis is uncommon. It can be associated with serious disease or can be an isolated finding. Several patterns have been recognized.42,43,44 Uvulitis can occur in conjunction with streptococcal or other severe pharyngitis. In this case, the uvula is very red and swollen, as are the tonsils and the rest of the pharynx.
Uvulitis can also represent an extension of the acute inflammatory process of epiglottitis, so laryngeal or obstructive signs should be noted. A lateral soft-tissue roentgenogram of the neck might be indicated, as described in the section on epiglottitis. Isolated uvulitis has also been reported to occur with bacteremia due to Haemophilus influenzae type
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b (Hib) without epiglottitis. Since the advent of the conjugated Hib vaccine, epiglottitis and bacteremia due to this agent have become vanishingly rare in the United States. Prior to the routine use of this vaccine, Hib bacteremia occurred primarily in younger patients and produced high fever and toxicity. Uvulitis due to Group A streptococcal infection, in contrast, is more common in school-age children, and does not cause respiratory distress or high fever.
Other causes of uvulitis include acute uvular edema.44 This can be an allergic reaction, so that the uvula is more swollen than red. Antihistamines have been recommended to shorten the course of this type of uvulitis.
Throat Culture
The most important and practical decision about pharyngitis is whether it is caused by the Group A streptococcus (S. pyogenes). The throat culture is a useful guide in this decision, but the clinician should make the final judgment as to its significance. Culturing for bacteria other than beta-hemolytic streptococci is unnecessary and usually more expensive.
The value of the throat culture has been clearly established by controlled clinical studies done in physicians’ offices during the 1950s. Valuable studies were done by Breese, Stillerman, and others, who demonstrated that throat cultures are extremely useful for the prevention of rheumatic fever and therefore can be regarded as the gold standard for office practice. Rapid methods for the detection of Group A streptococcal antigen are discussed later.
The standard method for throat cultures, which has been best studied and is in longest use, is swabbing the symptomatic patient’s throat, inoculating a sheep blood-agar plate, and streaking it with a flamed wire loop to separate the colonies.45 Breese, Stillerman, and others have found this method sufficiently sensitive to identify those outpatients who needed antibiotic therapy to prevent complications. The principal variables involved with this method include use of clinical judgment to decide which patients to culture and which plates with few or questionable beta-hemolytic colonies to ignore. The more carefully one attends to the first question, the easier the second question is to answer. Indiscriminate testing of patients who lack objective evidence of pharyngitis leads to a decreased percentage of positive tests, and, more crucially, to an increased number of false-positive test results.46 For this reason, the practice of allowing patients to have a “throat culture only” outpatient visit, during which the patient is not seen by a physician, is discouraged.
The standard throat culture method outlined above has been practical and accurate to the degree that acute rheumatic fever is virtually never observed by those physicians in private practice who use it as a guide to the diagnosis and treatment of streptococcal pharyngitis.
Etiologic Classification
For practical purposes, pharyngitis can be classified as streptococcal or nonstreptococcal on the basis of a conventional throat culture for beta-hemolytic streptococci. “Group A streptococci” and “beta-hemolytic streptococci” are two phrases that, although not synonymous, will be used interchangeably in this chapter, because beta-hemolytic streptococci that cause pharyngitis are almost always Group A.
The throat culture is primarily useful to exclude the diagnosis of streptococcal pharyngitis.47 The recovery of beta-streptococci on throat culture does not prove a streptococcal infection; infection is usually defined by a streptococcal antibody titer rise (which may be partially inhibited by early antibiotic therapy). Although Group A streptococci may not always be the cause of the pharyngitis when found in the throat, their recovery from the throat is infrequent enough using office culture methods that a positive throat culture in a patient with pharyngitis is both a convenient and a practical basis for defining streptococcal pharyngitis. The carrier rate depends on many variables, discussed later in this section.
Frequency of Streptococcal Pharyngitis
Streptococcal pharyngitis is a common disease in children. In one study of school-age children, beta-hemolytic streptococcus was the most frequent cause of moderate to severe pharyngitis and the most common cause of fever greater than 101°F (38.4°C).48 The frequency of beta-hemolytic streptococci as a cause of pharyngitis is closely related to age. In children less than 3 years of age, severe exudative pharyngitis was usually not streptoccocal in one study.49 The exact reason why Group A streptococcal pharyngitis is not common in infants and young children is not well understood. Children less than 3 years of age who have school-age siblings may be at higher risk. Certainly they should
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have throat cultures if they have suggestive symptoms and older siblings or adults in the family have compatible illnesses or positive throat cultures. Clinical experience suggests that young children have a somewhat different pattern of illness, with fewer symptoms referable to the throat. It is not uncommon for a young child to not complain of throat pain at all, but rather to have headache, abdominal pain, fever, nausea and vomiting, or some combination of these symptoms. Streptococcal pharyngitis is certainly not unheard of in young children. One study of children with pharyngitis indicated that 17% of those less than 1 year, 19% of those 1–2 years, and 35% of those 2–3 years of age had Group A streptococci recovered.50 Young adults without exposure to children, and older adults also do not frequently contract Group A streptococcal pharyngitis. However, a study of adults presenting to an emergency room with pharyngitis indicated that it is worthwhile to culture those patients with fever or exudates.51
Laboratory Methods
Throat Culture
Swabbing the tonsillar area for inoculation of a sheep blood-agar plate is the practical specific method for recognition of streptococcal pharyngitis. Nasal cultures need not be done and are much less sensitive than are throat cultures for the detection of Group A streptococci if the patient has pharyngitis. Viral culture of the throat is not a practical method for early diagnosis of viral pharyngitis. Viral agents causing pharyngitis are more likely to be recovered from a swab of the deep nasopharynx. Occasionally, viral throat cultures will have educational value for late confirmation of a clinical diagnosis.
FIGURE 2-1 Effect of various treatments on mean rise in ASO titer in children with moderate or severe group A streptococcal pharyngitis. (Redrawn from Moffet HL et al: Antimicrobial Agents and Chemotherapy- 1963. © 1964, American Society for Microbiology)
Antistreptolysin O Titer
Serologic methods are also of no practical value in determining whether pharyngitis is streptococcal or not. A rise in antistreptolysin O (ASO) titer takes 3–6 weeks or longer, and waiting that long without antibiotic therapy increases the risk of acute rheumatic fever. Antibiotic therapy tends to prevent a rise in ASO titer, but if a rise occurs in spite of antibiotic therapy, this can be taken as accurate evidence of a streptococcal pharyngitis. Sometimes it is asserted that failure to develop an antibody titer rise is evidence that a patient was a streptococcal carrier and that the pharyngitis had some other cause. However, carriers should not be defined in this way, because the ASO titer is suppressed by antibiotic therapy, and more so by early treatment and larger doses (Fig. 2-1).52,53,54
The ASO titer may be useful to demonstrate that a recent unrecognized and untreated streptococcal
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infection has occurred in a patient with suspected acute rheumatic fever, as discussed in Chapter 18. However, it is neither necessary nor advisable to use ASO titers to follow the antibody response of patients with streptococcal pharyngitis who are adequately treated with antibiotics.
Antigen Detection Methods
Group A streptococcal antigen tests that detect the presence of streptococci in throat swabs are now widely available and are being used with increasing frequency in the routine evaluation of children with pharyngitis.
The most relevant problem of these rapid antigen tests is whether the sensitivity is sufficient. Studies show that most commercially available antigen detection kits have a sensitivity of about 90% compared with conventional throat culture techniques, especially if cultures with fewer than 10 colonies are considered negative.55 However, many children with fewer than ten colonies of Group A streptococci on throat cultures will have a rise in their titer of antistreptococcal antibodies if untreated. This has led many clinicians to back up rapid antigen detection methods with conventional culture. Children with positive antigen tests are treated, and those with negative tests are not treated unless their throat culture becomes positive. Newer rapid antigen tests that utilize an optical immunoassay (OIA) may actually be more sensitive than traditional culture,56 but are not yet widely available (in this study Todd-Hewitt broth culture was used as the gold standard). In a recent study, polymerase chain reaction was as sensitive as culture and much more so than antigen testing.57 However, this test takes longer than rapid antigen testing and is not yet widely available.
The consequences of having rapidly available results in the office are important. The patient (or patient’s family) is often interested in obtaining a rapid diagnosis so that therapy can begin as soon as possible. There is also a psychological benefit from obtaining a diagnosis on the day of the visit. Enthusiasm for these tests needs to be tempered by remembering that (1) streptococcal pharyngitis is a self-limited disease, in which the symptoms are modulated somewhat but not eliminated by antibiotic therapy, (2) there is no increased risk of nonsuppurative complications by delaying therapy until the throat culture results are available, and (3) early institution of therapy against Group A streptococcus may ameliorate the patient’s antibody response, which may predispose to more frequent reinfection.58
The gold standard against which all these rapid antigen tests are measured is the usual office procedure of using a sheep blood-agar plate streaked on the surface and cultured in ordinary incubator temperature without CO2 or anaerobic conditions. False-negative cultures may be obtained when throats are too gingerly or rapidly swabbed, or when the patient has had a recent dose of an antibiotic.
Nonspecific Laboratory Methods
These studies are of little value in the etiologic diagnosis of pharyngitis. Throat smears are of no value in making an etiologic diagnosis of any type of pharyngitis, and are likely to be misleading in the diagnosis of diphtheria because “diphtheroids” are frequently seen. Owing to an effective vaccine, diphtheria has become so rare that there are few technicians, bacteriologists, or pathologists who see it often enough to maintain competence in reading smears for corynebacteria. The interpretation of smears for diphtheria is frequently false positive.
White blood cell counts are often equivocal and are of no specific value in ruling in or out the diagnosis of streptococcal disease. The presence of lymphocytosis or atypical lymphocytes may aid in the diagnosis of infectious mononucleosis. High white blood cell counts may occur in viral, as well as in Group A streptococcal, pharyngitis.
C-reactive protein or other measures of inflammation are of no value in distinguishing streptococcal from viral pharyngitis.59
Reasons to Do Throat Cultures
Throat cultures for streptococci are recommended, especially for school-age and preschool children, when the following conditions are present:
  • Pharyngitis without hoarseness or significant cough, especially with fever
  • Febrile cervical adenitis
  • Illnesses with definite fever but no apparent focus of infection, especially if headache, abdominal pain, vomiting without diarrhea, or a scarlatiniform rash are present
  • Symptomatic family contacts of patients with streptococcal pharyngitis.60 Asymptomatic family contacts should not be cultured.
TABLE 2-2. FINAL CLINICAL DIAGNOSES IN 230 CONSECUTIVE ADMISSIONS TO A CHILDREN’S HOME INFIRMARY OF SCHOOL-AGE CHILDREN WITH AN ORAL TEMPERATURE OF 101°F OR HIGHER
CLINICAL DIAGNOSIS NUMBER % WITH + TCc FOR GASd
Pharyngitis 128 79
Otitis media 18 28
FWLSa 59 19
LRIb 13 8
Other 12 0
Total 230  
a Fever without localizing signs.
b Lower respiratory infections.
c Throat culture
d Group A streptococcus
Source: Moffet HL, Cramblett HG, Smith A. Group A streptococcal infections in a children’s home; II. Clinical and epidemiologic patterns of illness. Pediatrics 1964;33:11–17.
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As shown in Table 2-2, both otitis media and fever without localizing signs are associated with Group A streptococci significantly more frequently than they are seen in a normal control group. The office throat culture is a simple and inexpensive way to detect concurrent streptococcal pharyngitis. In patients with obvious acute otitis media that requires treatment with antibiotics (see Chapter 5), throat culture may be omitted because the antibiotics that treat otitis media also treat streptococcal pharyngitis.
Methods for Throat Culture
Personnel charged with obtaining throat cultures must be trained in the proper technique in order to derive useful information. A single cotton-tipped swab is used to swab the patient’s tonsillar area. Refrigerating the swab overnight or retaining it at room temperature for several hours does not significantly reduce the accuracy of the method.61 “False-negative” results where two consecutive cultures reveal one positive and one negative result are usually found in patients with small numbers of colonies and probably have little if any clinical significance.48,52
Anaerobic incubation or incubation in CO2 may yield a slightly greater frequency of positive cultures for Group A streptococci.62 However, the simpler, practical methods described above have been sufficiently sensitive for prevention of rheumatic fever by detecting streptococcal pharyngitis in office practice.45 Selective media for Group A streptococci are available, but their increased sensitivity has not been proved necessary in office practice.
FIGURE 2-2 Comparison of size of hemolysis zone produced by beta-hemolytic streptococci with that produced by hemolytic S. aureus.
As mentioned above, after inoculation onto a sheep blood-agar plate, the culture should be streaked with a flamed wire loop. Beta-hemolysis can often be recognized after 12–16 hours of incubation at 37°C. The area of hemolysis is large compared with the colony size (Fig. 2-2). The plate should be reexamined for beta-hemolytic colonies after an additional 24 hours at room temperature, since this will detect approximately 10% of the additional positive cultures. Non-Group A beta-hemolytic streptococci are not inhibited by a bacitracin disk placed on the plate at the time of inoculation (Fig. 2-3).
FIGURE 2-3 Group A streptococci are inhibited by bacitracin, but other groups of streptococci are not.
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Although there are more sensitive methods for the recovery of Group A streptococci, the above method is sensitive enough for practice purposes and avoids identifying small numbers of Group A streptococci in well individuals. The simple surface streaking method has a long history of successful discrimination between normal children and those at risk for acute rheumatic fever.45
Non-Group A Streptococcal Pharyngitis
The fact that beta-hemolytic streptococci other than Group A can cause streptococcal pharyngitis has been well established for at least 25 years. The primary basis of this evidence is food-borne outbreaks, where one of the non-Group A streptococci has contaminated food, particularly milk, and resulted in an outbreak of pharyngitis. Such outbreaks have confirmed that Group C or Group G streptococci can cause pharyngitis.63 Of course, outbreaks of Group A streptococcal infection due to contaminated foodstuffs have also been reported, usually when food was contaminated by someone with active Group A streptococcal pharyngitis.64 One outbreak of food-borne Group A streptococcal pharyngitis secondary to foodstuff contaminated by a cook with an infected hand wound has been reported.65
Group B streptococci also have a statistical relation with pharyngitis.66 Because Groups C, G, and B can also be normal pharyngeal flora, it is still not known whether it is important to look for these organisms in nonoutbreak situations, or whether penicillin therapy should be given when they are recovered from the throat. A reasonable solution is that if on throat culture a patient with pharyngitis has streptococci that are not bacitracin sensitive, a recheck of the patient’s symptoms should be done; if the patient is still sick, one could consider using penicillin, which may afford some symptomatic relief. However, it should be emphasized that there is no risk of acute rheumatic fever after non-Group A streptococcal pharyngitis.
Interpretation of Throat Culture
Carrier Rates
Interpretation of positive throat cultures is occasionally complicated by the fact that the isolation of Group A streptococci from the throat does not necessarily imply infection. The frequency of Group A streptococcal carriage in normal children has varied from study to study and is a function of the sensitivity of the culture method and the relative certainty of the patient’s being “normal.”45 In a private practice, where the certainty that an individual was “normal” was great, Group A streptococci were recovered from 3–5% of children.45,67 In a study in a children’s home in which children were under close supervision, about 8% of normal children with nonpharyngeal disease had positive cultures with more than 10 colonies of Group A streptococci (see Table 2-2).48 In surveys of schoolchildren, in which many have had a recent unreported illness, the recovery rate of Group A streptococci has usually been about 10–40% but has been as high as an average of 30% of “normal” (nonsick) individuals.45
The high carrier rates found in surveys of schoolchildren is best explained by use of excessively sensitive methods for recovery of Group A streptococci, use of multiple cultures, failure to assess the normality of the children by history and physical examination, and detection of a high convalescent carrier rate in a lower socioeconomic group that often did not seek medical care for illness.45 The lower carrier rates of about 5–10% or less by Breese, Moffet, McCracken, and others reflect use of a single culture and careful screening to exclude convalescent individuals.45,48,68
Numbers of Colonies
In general, there is a correlation between the number of colonies of Group A streptococci found on throat culture and the clinical and laboratory findings of the patient. That is, the fewer the colonies on the culture plate, the less likely the patient is to have had recent or severe clinical pharyngitis, a typable Group A streptococcus, or an ASO titer rise. However, some patients with a severe pharyngitis do have fewer than 10 colonies; in one series, 33% of patients with fewer than 10 colonies had an ASO titer rise.69 Another study revealed that 82 (29%) of 279 children with fewer than 10 colonies of beta-hemolytic streptococci had a typable organism, and one third of these 82 children had an ASO titer rise (Table 2-3). Thus, about 10% of children with fewer than 10 colonies will have both a typable Group A streptococcus and an ASO titer rise. Yet another study gave even a higher estimate: about half of patients with 10 or fewer colonies had a rise in ASO or anti-DNAse B titer.53
Sometimes there may be only two or three colonies of beta-hemolytic organisms and the organism
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cannot be isolated on subculture to test bacitracin sensitivity. A repeat culture may clarify the situation and often reveals no Group A streptococci.70 In this situation, withholding of antibiotics is usually reasonable.
TABLE 2-3. TYPABILITY AND ASO TITER RISE AS A FUNCTION OF NUMBER OF COLONIES OF BETA-HEMOLYTIC STREPTOCOCCI IN UNTREATED CHILDREN STUDIED AT CHILDREN’S MEMORIAL HOSPITAL, CHICAGO, 1956–1968
  NUMBER OF COLONIES TOTAL PATIENTS PATIENTS WITH ASO TITER RISE (%)
Group A typable <10 82 27 (33)
>10 343 176 (51)
Group A nontypable <10 125 30 (24)
>10 338 143 (42)
Not Group A <10 72 13(18)
>10 39 130 (30)
(Siegel AC, Johnson E, Loeffen M, Yarashus D; unpublished data.)
Streptococcal Pharyngitis
Objective evidence of pharyngitis and a throat culture positive for beta-hemolytic streptococci is the most practical basis for the presumptive diagnosis of streptococcal pharyngitis.
Importance
Nonsuppurative Complications
Streptococcal pharyngitis is important because a few untreated patients develop acute rheumatic fever and some patients with acute rheumatic fever suffer permanent damage to the heart valves. Thus, the most important reason for treating streptococcal pharyngitis is to prevent rheumatic fever and rheumatic heart disease. Relief of symptoms can usually be obtained with acetaminophen and gargling with warm water. Early therapy with antibiotics also provides a slightly more rapid improvement in symptoms, but antibiotic treatment need not be regarded as an urgent way to relieve symptoms.
Another nonsuppurative complication of streptococcal pharyngitis is acute glomerulonephritis. This complication is not prevented by treatment of the pharyngitis with antibiotics. These two complications are immunologically mediated, not caused by direct extension of infection.
Two interesting but rare nonsuppurative complications that have been associated with Group A streptococcus infection are: (1) poststreptococcal reactive arthritis (PSRA) and (2) pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Patients with PSRA develop asymmetric, nonmigratory arthritis primarily involving the large joints, one to several weeks after streptococcal pharyngitis. Other features of acute rheumatic fever are absent.71 Although usually not associated with long-term sequelae, about 5% of patients with PSRA have subsequently developed carditis, prompting some experts to recommend penicillin prophylaxis for up to 1 year in these patients.72
The theory behind the second of these syndromes, PANDAS, is that in some patients, streptococcal infection triggers exacerbation of extant obsessive-compulsive disorders (OCD) or tic disorders. This is believed to be mediated through the same mechanism that causes Sydenham’s chorea.73 Children prone to this usually have a known OCD or tic disorder, but sometimes latent OCD is uncovered by streptococcal infection. Treatment of the infection typically results in resolution of symptoms. The link between Group A streptococcus infection of the pharynx and OCD or tic disorder in these patients is not yet firmly established. Therefore, although the authors of original study73 believe that patients with severe or frequent symptoms may require prophylactic treatment, there does not yet seem to be a clear indication for long-term anti-streptococcal prophylaxis. The questions concerning PANDAS, its possible link to streptococcal infection,
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and the role of antibiotic therapy in this syndrome remain to be answered by prospective clinical trials.
Although the cause of Kawasaki disease is not known, up to 25% of patients with Kawasaki disease have a preceding Group A streptococcus infection.74 At the least, there can be some overlap in the clinical symptomatology of streptococcal infection (especially with toxin-producing strains) and Kawasaki disease. Clinicians should certainly not exclude the possibility of Kawasaki disease in the patient with concomitant or recent streptococcal pharyngitis.75 (See Chapter 11 on rash syndromes.)
Suppurative Complications
Direct purulent extensions of streptococcal pharyngitis include:
  • Otitis media (discussed in Chapter 5)
  • Sinusitis or mastoiditis (discussed in Chapter 5)
  • Peritonsillar cellulitis or abscess, which should be considered when one tonsil is larger and pushed toward the midline, with or without lateral deviation of the uvula. An abscess is difficult to distinguish clinically from cellulitis. Peritonsillar infections are discussed later in this chapter
  • Retropharyngeal abscess, an uncommon syndrome that typically produces difficulty swallowing and may be confused with epiglottitis (discussed in Chapter 6)
Clinical Diagnosis
Presumptive Diagnosis
The presumptive clinical diagnosis of streptococcal pharyngitis can be based on probability using epidemiologic and historical factors and observations from the physical examination. The following findings increase the probability that the pharyngitis is streptococcal:
  • Scarlatiniform rash
  • Fever greater than 101°F (38.4°C), definite exudate, and definite pharyngeal edema
  • Tender tonsillar nodes, palatal petechiae, and edema of the uvula
  • Frontal headache, abdominal pain, vomiting (especially in younger patients)
  • Age 5–16 years
  • Exposure to a sibling or other contact with known streptococcal pharyngitis
  • High frequency of streptococcal pharyngitis in the community at the time the patient is seen.
Conversely, the following findings decrease the likelihood that the pharyngitis is due to Group A streptococci:
  • Concurrent common cold-like symptoms, including runny nose, nasal stuffiness, hoarseness, or cough
  • Conjunctivitis
  • Absence of fever
  • Nonspecific (i.e., nonscarlatiniform) rash
  • Hepatomegaly or splenomegaly.
The above features assist the clinician in deciding whether to test for streptococcal pharyngitis; they are neither sufficiently sensitive nor specific to enable an accurate diagnosis without confirmation by throat culture.
Natural History of Streptococcal Pharyngitis
If a school-age child is seen very early in the course of streptococcal pharyngitis, tonsillar exudate may not yet be present (see Fig. 2-4). If the child is seen late in the course, the fever and redness of the pharynx may be gone, and only old exudate may remain. The clinical diagnosis becomes much less accurate after a day or two of illness.
Using clinical features to make the presumptive diagnosis of streptococcal pharyngitis, the physician can often decide to begin antibiotic treatment on the basis of a positive rapid streptococcal antigen test. Opting for conventional throat culture and awaiting its results is appropriate. Patients with negative rapid streptococcal antigen tests should almost never be treated with antibiotics pending results of conventional throat culture. Treatment of patients who have negative rapid antigen tests occasionally leads to confusing and expensive complications; a series of inappropriate laboratory tests may further alter the natural history and obscure a diagnosis that would have otherwise become apparent. One of the authors was recently consulted on a patient who, after being treated inappropriately for streptococcal pharyngitis despite a negative rapid antigen test, developed a moderately severe rash that was mistaken for Rocky Mountain spotted fever (RMSF) at an emergency treatment facility. An inappropriate serologic test for RMSF was ordered, which directed the physicians even further from the actual diagnosis, which was acute Epstein-Barr virus infection (see Chapter 3).
Treatment can be delayed 24 hours while awaiting throat culture results without any greater risk of either suppurative or nonsuppurative complications.
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In fact, treatment may be delayed by several days without increasing the risk of acute rheumatic fever.76 Therefore, the decision to treat presumptively should be based on: (1) unavailability of a rapid antigen test, and (2) a high likelihood that waiting for culture results will lead to an untreated child.
FIGURE 2-4 Average course of streptococcal pharyngitis in school-age children over the first 3 days of illness, based on illnesses observed by Dr. Moffet twice a day during a 3-year period. Symptomatic therapy (aspirin, gargling) was given the first day, and antibiotics were begun on the second day. (Moffet HL et al: Pediatrics 1964;33:11–17)
Treatment
Purpose
Antibiotic therapy is traditionally regarded as having the primary goal of prevention of suppurative and nonsuppurative complications. As was shown in military recruits in the 1950s, acute rheumatic fever can be reduced in frequency to about 0.02% in antibiotic-treated patients compared with about 2–3% in untreated controls.77 Patients who developed rheumatic fever despite antibiotic therapy still had streptococci present in their throats after treatment.78 Therefore, in many subsequent studies, eradication of the organism from the throat was equated with the adequacy of various antibiotic regimens.
During the 1950s and 1960s, treatment of streptococcal pharyngitis was intended to prevent rheumatic fever. It was recognized that fever and sore throat did improve, as could be shown statistically.79 However, one frequently heard the statement that therapy did not change the natural history of streptococcal pharyngitis very much, and this concept became incorrectly altered to mean treatment did not change symptoms at all.
These studies have now been repeated in children.58,80,81,82 It is not surprising to see that children, like recruits, do have statistically significant reduction of symptoms in the first 48–72 hours of penicillin treatment when compared with placebo or no treatment. However, it should be noted that those studies generally withheld antipyretics or other symptomatic therapy. Treatment of streptococcal pharyngitis also decreases the communicability of the infection to others. More than 80% of children will become culture negative for Group A streptococcus within 24 hours of the initiation of appropriate antibiotic therapy and, thus, may return to school or daycare thereafter.83
American Heart Association Recommendations
A committee of the American Heart Association (AHA) has made recommendations for the treatment of streptococcal pharyngitis based primarily on efficacy in eliminating organisms from the throat, as well as on efficacy in preventing acute rheumatic fever.72 The AHA continues to recommend
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10 days of oral penicillin V as the drug of choice for acute streptococcal pharyngitis. Several studies have suggested that shorter courses of oral cephalosporins are equally effective at eradicating the organism from the pharynx,84,85 but studies proving protection against subsequent rheumatic fever are lacking, and these antimicrobial agents are considerably more expensive than penicillin. Group A streptococcus remains exquisitely sensitive to penicillin, and no penicillin-resistant Group A streptococcus strains have yet been detected.
Recommended Doses
The dose recommended by the AHA since 1984 has been oral penicillin V 125 mg or 250 mg three or four times a day for a full 10 days for adults or children.72 Studies have demonstrated, however, equal eradication rates with the same total daily dose of penicillin V but given in divided doses twice a day, and compliance is likely to be better.86 Some people feel that because, on a twice-a-day schedule, one missed dose makes the therapy effectively a once-a-day regimen, prescribing the medication three times a day provides an extra measure of safety. For intramuscular (one injection) benzathine penicillin, the dose is 1.2 million units for adults and 600,000 units for children less than 60 lbs. For children, 900,000 units of benzathine penicillin combined with 300,000 units of procaine is satisfactory. Intramuscular penicillin has the advantage that compliance with the regimen is assured. However, there are several disadvantages to this regimen. First is that the eradication rate of IM penicillin therapy is lower than most people think it is (approximately 79%).87 Second, the administration of IM penicillin carries the risk of Hoigne’s syndrome if it is inadvertently administered intravenously. Because IM penicillin is opaque and viscous, a moderate amount of blood may be drawn up into the syringe and not be detectable to the person administering the drug.88 Hoigne’s syndrome is a very dramatic, albeit harmless, reaction in which the patient may fall or flop down to the floor and make erratic body movements that resemble those of a fish out of water. Psychosis and true seizures may occur.89 In the majority of cases the patient recovers spontaneously. Patients who have experienced Hoigne’s syndrome are likely to be labeled “penicillin-allergic,” although the syndrome is a nonallergic reaction to procaine; these patients may safely be administered penicillin or penicillin derivatives when they are needed. If IM penicillin is inadvertently administered into an artery, worse complications may occur, including distal tissue necrosis.88
Penicillin-allergic patients may be treated with erythromycin estolate at 30 to 40 mg/kg/day or erythromycin ethyl succinate at 40 mg/kg/day in divided doses two to four times per day for 10 days.
Carriers
The 1995 recommendations are liberal about not treating carriers: “Chronic streptococcal carriers usually do not need to be identified or treated with antibiotics. However, a difficult diagnostic problem arises when symptomatic upper respiratory tract viral infections develop in carriers. Because it is impossible to distinguish carriers from infected individuals, a single course of appropriate antibiotic therapy should be administered to any patient with pharyngitis and evidence of Group A streptococcus” infection.72 Streptococcal carriers are not at risk for rheumatic fever, and are definitively not like “typhoid Mary.” That is to say, carriers are not regarded as important reservoirs for the spread of streptococcal infection.
If, in some special circumstances, it is decided to eradicate the carrier state, clindamycin alone or rifampin plus penicillin can be used. In one study, clindamycin 20 mg/kg/day divided TID for 10 days eradicated carriage in 24 (92%) of 26 patients; by comparison, IM penicillin plus rifampin (20 mg/kg/day divided BID for 4 days) was effective in only 12 (55%) of 22 patients.90
Duration
The usual recommendation of 10 days of oral therapy is based on studies of eradication of the streptococcus, since no study has been done to determine the attack rate of rheumatic fever if shorter courses of penicillin are used.91 It is assumed, and rationally so, that eradication of the organism is a reasonable surrogate for the prevention of rheumatic fever. In one study, one million units of oral penicillin twice a day for 5 days failed to eradicate the organism in about 40% of men, compared with a failure rate that approximated zero when the same total dose was given for 10 days. There was persistence of the carrier state in 70–80% of untreated controls. Thus, the longer therapy of 10 days is the conventional recommendation.
Antibiotics other than Penicillin
Sulfonamides should not be used for the treatment of streptococcal pharyngitis. In one study, the frequency
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of acute rheumatic fever after therapy of streptococcal pharyngitis with sulfadize was about 5%, not significantly different from that of an untreated control group of 264 individuals, of whom 11 (4%) developed rheumatic fever.92 Trimethoprim-sulfamethoxazole (TMP-SMX) will not eradicate infection. As many as 20% of Group A streptococci are resistant to tetracycline, so it should not be used for therapy of streptococcal pharyngitis.93 In the United States, an increasing percentage of Group A streptococcal isolates are resistant to erythromycin,94 which is likely a consequence of increasing macrolide use.95 Any of the oral cephalosporins is effective at eradicating Group A streptococcal infections of the throat, and some of them have a better eradication rate than that of penicillin, but they are more expensive, have a higher side effect profile, and have not been clinically proven to be otherwise advantageous. A single large-scale trial in children comparing a 10-day course of oral penicillin with a 5-day course of other antimicrobials in the treatment of culture-confirmed streptococcal pharyngitis has been published.96 In this trial, 4,782 children were randomized, in a 1:2 ratio, to receive either 10 days of penicillin or 5 days of a different antimicrobial agent (amoxicillin/clavulanate, ceftibuten, cefuroxime axetil, loracarbef, clarithromycin, or erythromycin). Patients were followed for 12 months thereafter. Clinical response and acute eradication rates were similar. Of the 4,782 subjects enrolled, acute rheumatic fever (ARF) developed in only three, all of whom were in one of the 5-day treatment groups.96 This difference was not statistically significant; however, because of the low baseline incidence of ARF, even a study of this size is insufficiently powered to detect a difference between the two groups.
Amoxicillin, though frequently used, has no microbiologic benefit over penicillin and is more expensive. Practitioners used to say they preferred amoxicillin because it could be given three times a day versus the four times a day regimen of penicillin; with studies showing successful eradication of Group A streptococci with thrice- and even twice-a-day penicillin therapy, that particular argument in favor of amoxicillin is no longer relevant. The last remaining point of discussion seems to be that amoxicillin is more palatable, and thus more likely to be taken. As no drug is effective if it is not ingested, amoxicillin may be considered in cases where the child is likely to be averse to taking penicillin. Ampicillin is also not better than penicillin, and has the disadvantages of more frequent side effects, including diarrhea and rash. If used empirically, or when the culture is negative for Group A streptococci, the cause of the pharyngitis may be Epstein-Barr virus. In that case, ampicillin (and, to a lesser extent, amoxicillin) may cause an extensive maculopapular rash.
Recurrences
Clinical recurrences are best defined as pharyngitis and a positive culture within 30 days of starting therapy. Recurrence of the same type is usually not possible to distinguish from a new infection with a new type, because typing is not readily available. Bacteriologic recurrences are best defined as a positive follow-up culture within 30 days without clinical disease. This could also be called treatment failure but is not known to be associated with an increased risk of acute rheumatic fever if the treatment was appropriate.
Clinical or bacteriologic recurrences are relatively frequent (5–15%) after oral antibiotic therapy, depending on the dose and type of antibiotics used. Even intramuscular benzathine penicillin has a significant recurrence rate (about 20% of the same serotype). A “false” recurrence (recovery of a non-Group A streptococci) can be recognized by testing for bacitracin resistance. Ordinarily, reculture after therapy is not advisable except in patients with a history of rheumatic fever or rheumatic heart disease. However, some authorities recommend a follow-up culture as a precaution if the patient is given oral therapy and is judged unlikely to take the full course of antibiotics. There is no reason to obtain routine follow-up throat cultures except in patients not likely to comply with oral therapy.
Clinical recurrences should probably be treated with clindamycin or an oral cephalosporin, either of which is more effective than oral or intramuscular penicillin in such circumstances.97 Erythromycin, once an effective second choice, is a less desirable choice because an increasing percentage of streptococcal isolates are erythromycin resistant.
Causes of Streptococcal Recurrences
  • Nonadherence. Because the symptoms of the disease are likely to disappear before 10 days passes, with or without antibiotic therapy, and because adherence to an antibiotic regimen when fully recovered from an illness is difficult, failure to complete the entire 10-day course of
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    oral antibiotic therapy is fairly common. Nonadherence with the 10-day penicillin regimen is certainly a cause of bacteriologic treatment failures. It has not been shown, however, that nonadherence is a cause of streptococcal recurrences.98
  • Typability. Several studies have shown a recurrence rate of about 20% if the original isolate was typable and about 10% if it was not.98
  • Presence of beta-lactamase-producing anaerobic bacteria. Cultures of tonsils removed at tonsillectomy have indicated that beta-lactamase-producing anaerobes, especially Bacteroides species, can often be grown.99 It has been shown by a number of studies that antibiotics such as erythromycin, and clindamycin are more effective than beta-lactam antibiotics at eradicating Group A streptococci and in the treatment of a clinical recurrence of streptococcal pharyngitis. Beta-lactamase producing bacteria were more frequently recovered from children who fail penicillin therapy for Group A streptococci than in patients who did not fail therapy.100 Further confirmation of this theory that beta-lactamase producers might be important was derived from a study of the clinical efficacy of penicillin, erythromycin, and clindamycin. Although such studies have not yet involved large numbers, it does appear that patients treated with clindamycin are more likely to have the Group A streptococci eradicated than are patients treated with erythromycin, who, in turn, are more likely to have the beta-streptococci eliminated than are patients treated with penicillin.101 Some of this effect may be due to the fact that clindamycin achieves much higher tissue levels than do beta-lactam antibiotics. Given the side-effect profile of clindamycin, as well as the uncertain clinical significance of this phenomenon, penicillin remains the drug of choice for an initial episode of Group A streptococcal pharyngitis.
  • Penicillin-tolerant Group A streptococci. One of the theoretical explanations for recurrent Group A streptococcal infections after treatment with penicillin is that penicillin only inhibits, but does not kill, some strains of the organism. This theory is well established for Group B streptococci, where it applies to perhaps 5% of such isolates. In a study of the applicability of this theory to recurrent Group A streptococcal infections, there appeared to be an increased frequency of penicillin-tolerant streptococci in the recurrent cases.102 However, further studies of the possible role of penicillin-tolerant Group A streptococci have not indicated that this is a clinically significant factor.103 In addition, tolerance to penicillin among Group A streptococcus isolates is rare. Therefore, the possible role of tolerance as a cause of recurrences is not established.104
  • Presence of penicillin-resistant staphylococci. In the laboratory, penicillinase-producing Staphylococcus aureus protect Group A streptococci from the effects of penicillin.105 This observation led to the hypothesis that the same effect might occur in patients with streptococcal pharyngitis, leading to recurrences. However, the bacteriologic recurrence rate does not appear to correlate with the presence of penicillinase-producing S. aureus in the throat.99,106 Therapy with a penicillinase-resistant antibiotic such as nafcillin or cephalexin results in less frequent recurrences than does penicillin treatment, but the difference is not statistically significant.99,106 Thus, treatment with the more expensive penicillinase-resistant penicillin is not indicated.
  • Reinfection with the same serotype from the patient’s toothbrush. There are no clinical studies to show that this is a factor in recurrences. However, one study did show that toothbrushes may harbor the offending Group A streptococci for up to 15 days after the patient has been treated for streptococcal pharyngitis.107
Culture of Contacts
Other family members may also have a positive culture, but these contacts are unlikely to have been a source of recurrent infection. Speculation about the role of contacts in recurrent streptococcal pharyngitis has led some clinicians to culture even family pets. One study showed that culturing pets residing in the household is unlikely to yield a positive culture; no group A beta-hemolytic streptococci were recovered from any body site in a total of 230 dogs and cats.108 The evidence favors regrowth of the patient’s original serotype for one of the reasons above; only testimonial anecdotes support contacts as a source of reinfection.
Management of Recurrences
  • Make sure that recurrences are truly streptococcal infections, and that you are not just culturing Group A streptococcus from a carrier with a series of viral pharyngitides. Clinical features
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    of illness that suggest viral infection, i.e., cough, hoarseness, runny nose, indolent onset, etc. can be helpful. It may also be useful to obtain a throat culture on the patient when he is entirely asymptomatic to verify the carrier status.
  • Confirm that recurrences are caused by Group A streptococci by sending the isolate to a laboratory that can identify Group A by agglutination methods.
  • On the second or third clinical recurrence, use clindamycin instead of oral or intramuscular penicillin.
  • Give the patient with multiple recurrences a prophylaxis regimen similar to that used for prevention of acute rheumatic fever for approximately 3 months.109 During this period, if the patient takes the medication as instructed, the physician can reassure the parents, based on a large body of controlled studies of rheumatic fever prevention, that the child is not at risk for rheumatic fever. Episodes of pharyngitis that occur during penicillin prophylaxis are likely to be viral in origin.
  • Consider a tonsillectomy for selected patients who have recurrent streptococcal pharyngitis. This may be, in the long run, less expensive than multiple courses of antibiotics and treatment visits, although the physician should take into consideration the size of the tonsils and the severity of the illness.
  • Have the patient dispose of his or her toothbrush and buy a new one sometime just before therapy is completed. Although there is no evidence that this will change the recurrence rate, the fact that many toothbrushes still harbor the same isolate as the one that caused the pharyngitis suggests that it may be helpful.107
Tonsillectomy
A prospective study has been done of the effect of tonsillectomy on severe recurrent pharyngitis with documented fever or cervical adenopathy or exudate or a positive culture for Group A streptococci.110 After tonsillectomy (with or without adenoidectomy), there were moderately but significantly fewer throat infections than in children without tonsillectomy (who also had fewer infections than before admission to the control group). Some patients with frequent tonsillitis before tonsillectomy become patients with frequent pharyngitis after tonsillectomy.
Prevention
History of Rheumatic Fever
Daily oral penicillin or monthly benzathine penicillin injection is effective in the prevention of streptococcal infections. This type of prophylaxis is used almost exclusively for patients who have probably had rheumatic fever,111 but it has been used in situations where there is a high risk of infection, such as military camps.
Management of Exposed Family Contacts
Family contacts should generally not be cultured unless they develop signs and symptoms suggestive of streptococcal pharyngitis. If there is a history of rheumatic fever in the family, parents and siblings should be cultured 2–3 days after the index patient has begun to receive antibiotic therapy, and should be treated if the culture is positive, even in the absence of symptoms.112 Alternatively, reliable families, even with a history of rheumatic fever, may be cultured only when they develop symptoms.113
Severe PANDAS
Some children with frequent or severe PANDAS (discussed earlier) have been managed with antibiotic prophylaxis identical to that given to patients with a history of acute rheumatic fever, although with unproven benefit. Other therapies, such as immune globulin, remain investigational. These patients should be managed by an infectious diseases specialist in concert with a pediatric neurologist.
Axioms
The diagnosis and management of streptococcal pharyngitis is complex and controversial. There are conflicting studies regarding laboratory detection as well as practical guides to treatment. Axioms for the practitioner are provided in Box 2.
Peritonsillar Cellulitis or Abscess
Peritonsillar abscess can be defined as a collection of pus lateral to the tonsil that pushes the tonsil toward the midline. These abscesses are usually the result of severe tonsillitis. Peritonsillar cellulitis also displaces the tonsil medially but consists of edema and engorged mucosa without pus formation. The distinction between peritonsillar cellulitis and abscess can be difficult to make. Placing a needle into
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the swollen area and aspirating for pus is the traditional way of distinguishing the two; in recent years, investigators have studied intraoral sonography and computed tomographic scans as alternative methods. Computed tomography (CT) scans differentiate the two conditions with ease;114 intraoral sonography, when tolerated, is also useful in this regard.115 It is not entirely clear, however, that either of these methods yields results superior to those obtained by the old-fashioned methods. A review of 43 consecutive cases of clinically diagnosed peritonsillar abscess in children ages 7–8 years showed positive aspirate results in 76%; in 87% of these patients the abscess resolved; 6% each required two aspirations and immediate tonsillectomy.116 If the disease is detected early enough, neither biopsy nor surgical drainage is necessary.
Both of these entities are more frequent in teenagers and adults, perhaps a result of intense focal antigen-antibody reaction after years of making various streptococcal antibodies. In one study, the age range was 11–73 years, with half being 25 years or younger.117
Clinical Diagnosis
Usually, there is fever and painful swallowing. The patient may speak in a muffled “hot potato” voice. There may be ear pain and trismus on the affected side.118 Trismus and painful swallowing result from inflammation abutting the muscles of mastication. Toxicity or neck swelling raises the question of extension down the neck. Age less than 12 years and trismus are more frequent in cellulitis; age 13 or older, dysphagia, and drooling are more common in abscess.119
Bacteria
Group A, non-Group A, alpha-hemolytic, and Group D streptococci are frequent.119 The most common aerobic isolates are Streptococcus pyogenes (Group A streptococcus), Streptococcus milleri group, and viridans Streptococci.120 Anaerobes may be more frequent than aerobes, especially in older adolescents and adults. Fusobacterium spp. and Prevotella spp. are most frequent, followed by Actinomyces, Peptostreptococcus, and others. Many patients have mixed infections. Mouth organisms like Eikenella corrodens are sometimes seen.121 H. influenzae and S. aureus are not common.122,123 Throat cultures are often negative, but cultures of the tonsillar needle aspirate may grow GAS or many of the above bacteria.124
Treatment
For ambulatory patients early in the course of the infection, oral clindamycin or amoxicillin/clavulanate is a rational choice. For hospitalized children, intravenous clindamycin is effective against streptococci, staphylococci, and almost all throat anaerobic bacteria. Ticarcillin/clavulanate or ampicillin/sulbactam are reasonable alternatives. One study showed that all but one isolate in a series of 53 abscesses contained bacteria that were sensitive to either penicillin or metronidazole, and recommended the combination of the two.125 There is no consensus, however, on the optimal treatment for patients with peritonsillar abscess. Herzon published
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an exhaustive review of the management of peritonsillar abscess that used a cohort study of 123 patients, a national survey of management practices of otolaryngologists, and a meta-analysis in order to devise guidelines.126 The conclusions were that: (1) needle aspiration should be used as the initial surgical drainage procedure for all patients who do not have indications for abscess tonsillectomy, and (2) antibiotic regimens for these patients should include penicillin. Intravenous penicillin has been used for years, but no direct comparative trials of penicillin to clindamycin have been performed. In one small, prospective trial, intramuscular procaine penicillin was as effective as ampicillin/sulbactam at effecting a cure. All patients underwent peroral drainage.127 High doses of penicillin are needed to achieve good tonsillar tissue concentrations.123
Complications
Fatal necrotizing fasciitis of the neck has been reported in adults after late treatment.128 Rarely, mediastinitis or other deep neck space infections may occur.129 Lemierre’s disease, also known as postanginal sepsis, is a rare condition associated with Fusobacterium necrophorum infection of the deep tissues of the neck in which intermittent bacteremia and septic embolization occur secondary to infection of the jugular vein (discussed later).130
Tonsillectomy
The need for tonsillectomy during the acute phase of the illness, or after recovery to prevent recurrences is the subject of some debate. Many otolaryngologists do routine tonsillectomy for all patients with peritonsillar abscess, because of a reported 15% recurrence rate. It turns out that in the United States, the recurrence rate is only 10%, which is significantly different from the rest of the world (p > 0.02).126 A large abscess compromising the airway may require urgent drainage. Approximately 30% of patients will have a relative indication for immediate, or “quinsy” tonsillectomy.126 If a tonsillectomy is to be performed, prospective data show that performing it immediately is technically simpler, associated with fewer working days lost (in adult patients), and less intraoperative blood loss.131
The majority of patients are not that sick, and really have peritonsillar cellulitis, which responds to intravenous antibiotics. In one review, only one of 41 patients who had needle drainage had a recurrent peritonsillitis.132 Another study comparing incision and drainage with needle aspiration found the advantages of needle aspiration alone outweighed its acceptably low failure rate.133
Nonstreptococcal Pharyngitis
Nonstreptococcal pharyngitis can be defined as objective evidence of pharyngitis and a throat culture negative for beta-hemolytic streptococci. Ulcerative pharyngitis and membranous pharyngitis are special anatomic types of pharyngitis and are discussed in later sections.
It is a very common error to recover a microorganism from the throat of a patient with pharyngitis and say it is the cause. Many case reports of unusual causes of pharyngitis represent coincidental recovery of the agent. Recovery is less likely to be coincidental if there is bacteremia. However, statistical studies comparing normal controls and patients with pharyngitis are necessary to prove an association, as discussed in Chapter 1. Even experimental production of pharyngitis by inoculation of an agent may not be confirmed by epidemiologic studies, as exemplified by M. hominis, discussed below.
“Sore throat” is not pharyngitis and may be caused by trauma, allergy, and tracheal irritation from respiratory viruses, smoking, or inhalation of other irritants.134 This section deals with definitive pharyngitis, as determined by objective observations on physical examination.
Possible Etiologies
Adenoviruses
These viruses are the most frequent cause of nonstreptococcal pharyngitis in young children (Box 3).135,136,137 There are more than thirty respiratory serotypes of this virus, but most infections are caused by types 1–7.
Nasal obstruction or discharge and cough are often present. Conjunctivitis is sometimes seen. In some patients, a small pulmonary infiltrate, with or without evidence of pneumonia on physical examination, may be seen. Mild to moderate abdominal pain, with some loose stools, is occasionally present, as is otitis media (Fig. 2-5). A rash, usually lasting fewer than 3 days, may be observed. The rash is usually maculopapular but may rarely be petechial.
The tonsils frequently have flecks of superficial exudate or white spherical areas beneath their mucosal surfaces but occasionally have a necrotic-appearing exudate resembling that seen with infectious
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mononucleosis. Typically in these cases the child is less than 5 years of age.
Adenovirus also causes a very specific syndrome known as pharyngoconjunctival fever.138 Patients present with abrupt onset of pharyngitis, mild to moderate conjunctivitis, and fever. The pharyngitis is exudative in about a third of patients. Eye complaints are less than might be expected based on the appearance of the palpebral conjunctivae, which usually have a granular appearance. In severe cases, the appearance mimics subconjunctival hemorrhage. Fever to greater than 39°C (102.2°F) occurs in 50% of patients, and is accompanied by headache. The febrile episodes last from 4 to 7 days, and total duration of illness may approach 14 days.138
Herpes Simplex
Although more commonly associated with gingivostomatitis in toddlers, primary infection with herpes simplex type 1 may produce a sore throat with redness and sometimes a tonsillar exudate.139 Typical ulcerations or bleeding may not appear until a day or two after the onset and may not be observed at all if the patient is not reexamined after the first visit (Fig. 2-6). Many teenagers reach college without neutralizing antibodies to this herpesvirus.140
FIGURE 2-5 Adenovirus pharyngitis is usually associated with conjunctivitis. Minimal pneumonia, otitis media, mild diarrhea, febrile convulsion, or leukocytosis with a predominance of neutrophils can be present.
Herpes simplex type 2 can cause exudative pharyngitis as well as ulcerative pharyngitis in individuals with oral-genital contact.141,142
Coxsackie and Echoviruses
These viruses typically produce ulcerative pharyngitis but are sometimes recovered from patients without vesicular or ulcerative lesions.136,143 They may produce ulcerative lesions in the context of hand, foot, and mouth disease (see Chapter 11). Coxsackie B virus sometimes produces a definite pharyngitis along with several days of high fever. Exudate is uncommon in this situation.144 Echovirus is sometimes associated with a definite pharyngitis.145
Parainfluenza Viruses
Usually, these viruses produce only a mild pharyngitis associated with a more prominent cough and
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bronchitis. The frequency with which parainfluenza viruses are associated with pharyngitis is not clear, because most studies have combined patients with rhinitis, bronchitis, and pharyngitis.
FIGURE 2-6 Typical course of ulcerative pharyngitis caused by herpes simplex virus. (Moffet HL, et al: J Pediatr 1968;73:51–60)
Influenza Virus
This virus may produce pharyngeal erythema, but usually there is an additional Group A streptococcal infection if tonsillar exudate is present.146 The sore throat observed with influenza virus infection is usually tracheal as opposed to pharyngeal.147 The complaint of sore throat is usually out of proportion to the objective evidence seen on physical examination.
Respiratory Syncytial Virus
Although not usually thought of as a virus that causes pharyngitis, a review of 20 years of outpatient respiratory syncytial virus infection found that almost 70% of patients infected with this virus had pharyngitis on physical examination.148 It is possible that some or all of these children had redness of the pharynx secondary to irritation from cough. Cough, wheezing, and tachypnea are usually more prominent clinical signs.
Epstein-Barr Virus
After 10 years of age, heterophile-positive infectious mononucleosis is a common cause of severe exudative pharyngitis, as discussed later in this chapter and in Chapter 3. The heterophile test is often false negative before the age of 10 years. Nonstreptococcal febrile exudative pharyngitis was associated with a positive heterophile antibody test in only 3 (3%) of 93 younger children with nonstreptococcal pharyngitis in one study,136 although some of these children may have had Epstein-Barr Virus (EBV) infections. EBV infection causing pharyngitis may be less common in children less than 10 years of age, although an insufficient amount of study has been performed in this age group. Acute EBV infection may be diagnosed by EBV serology at any age.
Mycoplasmas
Mycoplasma hominis is capable of causing exudative pharyngitis when experimentally inoculated into adult volunteers.149 Mycoplasma pneumoniae may cause a mild pharyngitis in younger children, and a more pronounced pharyngitis in older children and young adults, usually associated with headache and cough.
Tularemia
Oropharyngeal tularemia is a very rare cause of nonstreptococcal pharyngitis. The pharyngitis and cervical adenopathy resemble those of streptococcal pharyngitis.150,151 Alternatively, patients may have a membrane indistinguishable from that of diphtheria.
Gonococcus
“Sore throat” is a frequent symptom of gonorrhea in individuals with oral-genital contact, but exudative
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pharyngitis is not common. The frequency of Neisseria gonorrheae as a cause of pharyngitis has not been established by studies that exclude other causes, so that recovery of gonococcus from the throat may be coincidental to the pharyngitis, just as the presence of Group A streptococcus can be coincidental.152
Chancroid (Haemophilus ducreyi infection) also can be added to the list of causes of pharyngitis in persons with an orogenital exposure history.153
Anaerobes
Because anaerobes are normal inhabitants of the oropharynx, it is more difficult to prove a causative association between their isolation and the presence of pharyngitis. Bacteroides melaninogenicus is probably a relatively rare cause of pharyngitis.154 It may produce a beta-lactamase that interferes with the penicillin therapy of streptococcal pharyngitis, as previously described. Fusobacterium species can be a rare cause of severe exudative pharyngitis with cellulitis of the neck and septic emboli.155
Diphtheria
Corynebacterium diphtheriae infection has become rare because of immunization, but should always be considered a possible cause of nonstreptococcal exudative pharyngitis. Early in the illness, the typical pseudomembrane may not be present. Usually, however, diphtheria produces a pseudomembrane on the soft palate, uvula, tonsil, or posterior pharynx. If such a membrane is present, the diagnosis should be “membranous pharyngitis,” thus greatly limiting the etiologic possibilities, as described later in this chapter.
Arcanobacterium hemolyticum
Arcanobacterium hemolyticum has been reported to cause pharyngitis, occasionally with a scarlet fever-like rash in teenagers and young adults.156 It is recovered more frequently from patients with acute pharyngitis than it is from controls. It has also been demonstrated that patients mount an antibody response to this organism following an episode of pharyngitis from which it was recovered.157 In longitudinal studies, Arcanobacterium hemolyticum is isolated from approximately 2–3% of patients with acute pharyngitis.158 Despite its resemblance to streptococcal pharyngitis, illness caused by A. hemolyticum is self-limited, and nonsuppurative complications do not occur.
Mumps
This virus occasionally produces pharyngitis.159 However, the clinical diagnosis is usually based on minimal erythema. Pharyngitis may also be assumed to be present because the parotid or submandibular swelling is mistaken for cervical adenitis.
Measles
In classic measles, oral mucous membrane erythema may be prominent. In this case, the physician should recognize that the pharyngeal redness is of the same degree as that seen in all of the oral mucosa and that significant conjunctivitis and prominent cough are also present.
Other Microorganisms
Candida albicans is sometimes recovered from older children with severe pharyngitis, but it is probably coincidental.
Staphylococcus aureus, Streptococcus pneumoniae, fusiform bacteria, and spirochetes are agents that have not been proven to be causes of pharyngitis but are often coincidentally recovered from patients.
Chlamydia trachomatis has been implicated in pharyngitis by serologic studies performed in adults,160 but these reports lacked important clinical details. This agent is probably not a cause of pharyngitis.161
In milk-borne yersiniosis involving all age groups, only adults were noted to have fever and pharyngitis with a throat culture positive for Yersinia enterocolitica.162,163
Noninfectious Causes
Rarely, lymphoma in teenagers presents as an exudative pharyngitis.117
Diagnostic Plan and Treatment
If the throat culture is negative for beta-hemolytic streptococci, few further diagnostic studies are useful except in special clinical circumstances. A slide test for infectious mononucleosis may be indicated for older children, or EBV serology for younger ones with suspicion of EBV infection. Viral cultures (e.g., for adenovirus) are occasionally of interest, especially in the immunocompromised host. Patients with risk factors for other agents, i.e., ingestion of undercooked meat (tularemia), history of orogenital contact (gonorrhea), should be evaluated for
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those specific diseases. This entails notifying the microbiology laboratory so that specimens are plated on proper media. Conventional throat cultures for Group A streptococcus will not detect the gonococcus. Tularemia is diagnosed by serology, as culturing the organism is hazardous to laboratory personnel.
No specific treatment is of value for nonstreptococcal pharyngitis except as noted earlier. In general, observation and the avoidance of unnecessary antibiotics are all that is necessary.
Postanginal Sepsis (Lemierre’s Syndrome)
Rarely, pharyngitis is complicated by extension of the infection into the adjacent veins, with septic thrombophlebitis beginning in the tonsillar vein. This postanginal sepsis (also called Lemierre’s syndrome) can occur in normal children (especially teenagers) as well as in immunocompromised children.130,155,164,165 Lemierre’s syndrome is classically associated with Fusobacterium necrophorum, although other anaerobes that are part of the normal flora, such as Bacteroides or Eikenella are occasionally reported.
Physical findings include severe pharyngitis, tender tonsillar nodes, and tenderness and swelling along the lateral aspect of the sternocleidomastoid muscle (over the internal jugular vein).164 The septic portion of the disease may follow the pharyngitis by 4–8 days. Therefore, in many cases, the pharyngitis may have resolved before the patient seeks medical care.165 Septic pulmonary emboli may occur, as can septic embolization to abdominal organs, muscles, or joints. The knees and hips are the most commonly infected joints.165 Ampicillin-sulbactam is reasonable empiric antibiotic therapy pending blood culture results, as Eikenella species are uniformly resistant to clindamycin.166 Metronidazole retains good activity against most penicillin-resistant anaerobes, and may be added. All Fusobacterium species are sensitive to penicillin, and intravenous penicillin G is the drug of choice once the bacterium has been isolated and definitively identified.
Recurrences of Nonstreptococcal Pharyngitis
A frustrating problem to family and physician, recurrent nonstreptococcal pharyngitis remains a puzzle, primarily because of the difficulty of identifying an infectious cause or a host defect. Is this something we can now name as a syndrome (i.e., recurrent nonstreptococcal pharyngitis) with the causes yet to be found?
An increasingly recognized cause of pharyngitis, although it usually presents as fevers of uncertain etiology, is the syndrome known as periodic fever, adenitis, pharyngitis, and apthous stomatitis (PFAPA).167 Not all of the features need to be present to make the diagnosis. The most consistent feature is a fever that is truly “periodic,” i.e., comes and goes at a fixed interval, usually 28 days. Most patients have some degree of pharyngitis and adenitis, and may wrongly be treated as if they have recurrent streptococcal infection, especially if cultures are not routinely obtained. Fevers are usually high and the symptoms last 4 to 5 days and then spontaneously disappear. The etiology of this syndrome is still not known; information about treatment, prognosis, and differential diagnosis are contained in Chapter 10 on fever syndromes.
Ulcerative Pharyngitis and Herpangina
Ulcerative pharyngitis is defined by ulcerations or vesicular lesions on the soft palate, anterior tonsillar fauces, or posterior pharynx. If glossitis or gingivostomatitis is present, the patient probably has herpetic gingivostomatitis (see Chapter 4). Thus, the diagnosis of ulcerative pharyngitis implies absence of erythematous, swollen, or bleeding gums and buccal mucosa.
“Herpangina” is a term first used in 1920 to describe pharyngitis with small vesicular lesions in the posterior pharynx. This term is still frequently used and now usually refers to any kind of vesicular or ulcerative pharyngitis.168 Herpangina occurs almost exclusively in the summer or fall when Coxsackie and echoviruses are prevalent. Nodular pharyngitis without vesicles has been called acute lymphonodular pharyngitis,169 and has been attributed to Coxsackie A virus. When ulcerative or vesicular stomatitis occurs with a vesicular or papular rash on the hands and/or feet, it is called hand, foot, and mouth disease (classically due to Coxsackie A16), and is discussed further in Chapter 11.
Possible Etiologies
Coxsackie A Virus
Because this virus grows poorly in cell culture, mouse inoculation is required to recover it. Coxsackie A virus is probably the most common cause of ulcerative pharyngitis.170 Lesions begin shortly
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after the onset of fever, and may be papular at first, but quickly become vesicular and then ulcerative. By the time patients come to medical attention the lesions are usually ulcerative. There are often only a few lesions, from one to about 15, and they are small, 1–2 mm in diameter with surrounding erythema. The most common site is the anterior tonsillar pillar, but ulcers may occur anywhere in the mouth. Sometimes so-called hand, foot, and mouth syndrome really involves only the mouth; occasionally the rash on the hands and feet is seen without concomitant oral lesions. This syndrome is in general mild and self-limited, and lasts for 4–6 days. As the rash resolves, there is often fine desquamation of the papular lesions.
Herpes Simplex
In these cases, the ulcerations on the soft palate or pharynx are usually larger (3–8 mm in diameter) than those produced by Coxsackie A virus. If mouth or circular lip ulcers are also present, the cause is probably herpes simplex virus (Fig. 2-7). In one study of university students, ulcerative pharyngitis was the usual presentation of herpes simplex virus (HSV) infection, and only one-fourth of them also had anterior lesions of the mouth or lips.171 Reactivation of HSV1 usually produces lip lesions (“cold sores”) at any age. A history of genital exposure is probably more helpful in the diagnosis of HSV2 pharyngitis than is the actual appearance of the throat.
FIGURE 2-7 Circular ulcers on the palate, lip, and tongue of a child with herpes simplex virus infection.
Other Causes
Coxsackie B viruses and echoviruses can also produce an ulcerative or vesicular pharyngitis that is indistinguishable from that caused by Coxsackie A virus.169,172 There is some evidence that Coxsackie B virus infection is becoming more common in recent years.173 Other enteroviruses, including poliovirus, can produce similar lesions, and this enanthem has been noted in both sporadic and epidemic poliomyelitis.174 Corynebacterium ulcerans is a rare cause of ulcerative pharyngitis.175 The disease is a zoonosis, and is seen in patients with animal contact or a history of consumption of contaminated raw milk. Primary syphilis can produce an ulcer of the tonsil, usually without fever, and with an appearance “suspicious” of a primary chancre.176,177
Diagnostic Plan
Antigen Detection
Often, the diagnosis of herpetic stomatitis is a clinical one, but herpes simplex antigen can be detected with a slide agglutination test,178 or the virus can be cultured readily from active lesions when the diagnosis is in doubt. Virus isolation from any herpesvirus group-induced disease is maximized by sampling fresh (not crusted) lesions, and by rapid, cold transport and quick tissue culture inoculation. Polymerase chain reaction (PCR) can also be used to detect HSV DNA with high sensitivity and specificity.179
Virus Culture
Ulcerative pharyngitis is typically caused by a virus. Throat cultures for Group A streptococci can be obtained when there are signs and symptoms suggestive of a coexisting streptococcal infection. Cultures for virus may be of educational value but are rarely practical. Sometimes they give retrospective reassurance to the patient. Coxsackie A virus, the usual cause of ulcerative pharyngitis, is unlikely to be recovered unless suckling mice are injected
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with the specimen, and this is both too expensive and too impractical to justify its use in the diagnosis of pharyngitis. Enteroviral PCR can be performed on throat swabs, but this technology is not yet widely available and offers little clinical benefit for this self-limited illness.180
Serum Antibodies
Serologic diagnosis is not practical for Coxsackie or echovirus infection. Paired sera could be obtained in an attempt to demonstrate herpes simplex virus infection, but this is seldom clinically useful.
Treatment
For the most part, symptomatic therapy is all that is required. Investigational antienteroviral agents may eventually be commercially available, but will probably not be indicated for these self-limited infections. Treatment of HSV pharyngitis is discussed under therapy for HSV gingivostomatitis in Chapter 4.
Membranous Pharyngitis
Membranous pharyngitis can be defined as a definite membrane over the tonsils, pharynx, soft palate, or uvula. Bleeding is typical when the membrane is peeled off, as can be done with a swab or tongue blade. “Membrane” is used here as a synonym for “pseudomembrane” for convenience. In reality, there is a fundamental difference, in that pseudomembranes do not have a true epithelial layer.
FIGURE 2-8 Diphtheritic membrane on the soft palate and uvula. (Kallick CA et al.: Ill Med J 1970;137:505–512)
Possible Etiologies
Infectious Mononucleosis
A membranous pharyngitis in the United States today is most likely to be caused by infectious mononucleosis, discussed in Chapter 3.
Diphtheria
Even though the disease is rare in the United States, diphtheria should be regarded as the presumptive cause of membranous pharyngitis in an unimmunized individual. There is a substantial group of parents who are now withholding vaccinations for their children either for religious or sociopolitical reasons. In addition, diphtheria has become common in the former Soviet Union, so the diagnosis should be suspected in patients with membranous pharyngitis and an appropriate travel history.
The incubation period is 2–5 days.181 Typically the membrane is gray to black, depending upon how much blood it contains. It bleeds easily. It usually begins on the tonsils and spreads toward the uvula.181 If the membrane extends over the soft palate and uvula, diphtheria is a much more likely diagnosis than infectious mononucleosis (Fig. 2-8).
Additional findings that suggest diphtheria include cervical adenitis with severe swelling of the neck (bullneck diphtheria); tachycardia, hypotension, or arrhythmia, which suggest myocarditis (this complication may occur as early as 3–5 days after the onset of illness); and proteinuria, secondary to the effect of the toxin on the kidneys. Palatal paralysis, which reflects a local effect of the toxin,
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may also occur in the first week of illness. Involvement of the nose, with a visible membrane or bleeding, or involvement of the larynx or trachea, resulting in croupy cough or stridor, occasionally coexists with the membranous pharyngitis.
Myocarditis may result in cardiogenic shock or congestive heart failure.182,183 Occasionally, the development of electrocardiographic findings consistent with myocarditis is the best evidence available for the diagnosis of diphtheria when cultures have been negative. Late complications include most frequently a reversible polyneuritis, which involves the motor nerves and is usually symmetric.184 Cutaneous diphtheria is manifested by a scaling rash or by ulcers with clearly demarcated edges. Most isolates are nontoxigenic.
Other Causes
Membranelike exudate has been described rarely in presumed viral or streptococcal pharyngitis. The exudate that forms after an adenotonsillectomy may resemble a membrane. Arcanobacterium hemolyticum has been reported to produce infections strongly mimicking diphtheria.185 Rarely, other corynbacterium species (such as C. pseudodiphtheriticum or C. ulcerans) cause the clinical syndrome known as diphtheria. Oropharyngeal tularemia is a rare cause of membranous pharyngitis that can be indistinguishable from that of diphtheria.186
Diagnostic Plan
Tests for Infectious Mononucleosis
A slide test or serology for EBV infection should be done immediately, although they may not become positive until later. The peripheral blood should be examined for atypical lymphocytes. In the vaccinated child with no history of travel to an area of diphtheria endemicity, infectious mononucleosis is the likely cause.
Immunization History
Written evidence of recent adequate immunization against diphtheria does not exclude the diagnosis but makes it much less likely. It should be remembered that because the vaccine is a toxoid, it does not protect against nontoxigenic strains, which can cause infection but usually produce a disease that is not as severe. Prognosis for the patient with diphtheria is better if he or she is fully immunized.187
Throat Smear
Diphtheroids are species of Corynebacterium other than Corynebacterium diphtheriae that can be found in the throat of normal persons, so the diagnosis of diphtheria should not be based on a stain of a throat smear. Even the presence of typical-appearing organisms is not diagnostic of diphtheria. Fluorescent antibody methods may be useful if the antiserum is specific and proper controls are done. Considerable confusion may result if cross-reactions are reported as weakly positive, such as may occur with many other throat organisms found in patients without diphtheria.
Throat Culture
The diphtheria bacillus can be recognized by the appearance of its colonies on special media (tellurite or Tinsdale), but these media are often not immediately available. Fortunately, the organism also grows satisfactorily on sheep blood agar or chocolate agar plates. The toxigenicity of a diphtheria bacillus can be determined by several tests, which must be done in a reference laboratory. The essential test of virulence is the production of toxin.
Public Health Importance
The laboratory confirmation of a clinically suspected case of diphtheria is of great public health importance. Respiratory diphtheria is now rare in the United States, with only 49 cases reported from 1980 through 1999. However, toxigenic C. diphtheriae is occasionally isolated from cutaneous lesions, particularly in certain Native American communities. Cutaneous diphtheria can serve as both a reservoir and a source, and may be more important than is oropharyngeal carriage as a factor in some outbreaks.188 One case of diphtheria usually leads to vigorous public health measures to prevent further spread. Many contacts are cultured and given diphtheria toxoid boosters. If there is clinical suspicion of early disease, antitoxin (horse serum) is given, and this is frequently associated with serum sickness. Therefore, bacteriologic confirmation of the first suspected cases is very important.
Outbreaks of respiratory diphtheria occurred in 1970 in Austin and San Antonio, Texas; Miami, Florida; and Chicago.189 Cutaneous diphtheria was a reservoir for respiratory diphtheria in the Seattle, Washington area in the late 1970s.190 The single most important factor in the public health problem posed by diphtheria is that approximately 50–60%
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of adults in the United States are not up-to-date on their booster immunizations.191 Immunity to diphtheria wanes, and boosters are required every 10 years.
In the acute situation, public health officials will not proceed with measures necessary to control an outbreak unless there is bacteriologic confirmation of suspected cases. “Epidemic” is the word that appears to be necessary in order to mobilize people to get booster immunizations.
Treatment
Airway
Patients with a pharyngeal membrane should have laryngoscopy or bronchoscopy with the physician ready to provide an airway, if needed.192 Orotracheal intubation is one way of securing an emergency airway. However, tracheotomy will usually be advisable after intubation.
Antitoxin
If the clinical diagnosis is diphtheria, administration of antitoxin should never be delayed while awaiting laboratory confirmation. Antitoxin is able to neutralize free toxin and toxin that is adherent to cells, but cannot reverse the effects of toxin that has already entered cells. Therefore, both morbidity and mortality of diphtheria are related to the length of the delay in receiving antitoxin. In severe cases, antitoxin may need to be given intravenously, because of the delayed onset of action when given intramuscularly.193 A test for allergy to the product, as described in the package circular, should be done before use, because it is a horse serum product.
Other Therapy
Some authorities recommend digoxin if congestive heart failure occurs, but it must be given cautiously.189 Antibiotic therapy has minimal effect on the clinical progression and should never be used as a substitute for antitoxin. However, antibiotics decrease communicability. The disease is usually not communicable 48 hours after antibiotics are given. Oral erythromycin or intramuscular procaine penicillin G are given for 14 days. In a study in Thailand, corticosteroids failed to prevent or modify myocarditis or neuritis.194
Management of Contacts
With the assistance of public health authorities, household contacts of a patient with a clinical suspicion of diphtheria should be examined and cultured without awaiting final laboratory confirmation of the index patient’s culture. Contacts with signs suggestive of diphtheria should be treated with diphtheria antitoxin and parenteral penicillin (or erythromycin if they are penicillin allergic). All contacts of a patient with probable diphtheria, regardless of immunization status, should be treated with oral erythromycin for 7 days or intramuscular benzathine penicillin (1.2 million units for adults; 600,000 units for children less than 6 years of age), immunized with diphtheria toxoid, and undergo daily surveillance for clinical evidence of diphtheria or for the diphtheria organism, which presumably is present.195 Cultures should be obtained at 1 day and 2 weeks after treatment. If surveillance is not possible, the unimmunized household contacts should also be given diphtheria antitoxin.195
All individuals with positive cultures should be isolated (see section on isolation, below). Even if asymptomatic, they should be treated with antitoxin because of the significant risk of serious disease, particularly myocarditis. Antitoxin should not be withheld while awaiting culture results if the diagnosis of diphtheria is strongly suspected on clinical grounds, regardless of immunization history. In a 1978 survey of children in Chicago, only 75% of those less than 10 years of age who had received three diphtheria toxoid vaccinations had protective levels of antibodies in their serum.196
Isolation Procedures
Droplet precautions are recommended for patients and carriers with pharyngeal diphtheria until at least two cultures of nose and throat are negative. Patients with cutaneous diphtheria require contact precautions. All medical personnel caring for patients with diphtheria should be up-to-date on diphtheria booster immunizations. Cultures of medical care personnel are neither necessary nor recommended. Diphtheria toxoid boosters are usually given to adequately immunized adults only at 10-year intervals. However, when an outbreak is present in a community with a large unimmunized population, diphtheria toxoid is usually given on a mass basis without individualization.
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