TONSILLOPHARYNGITIS IN ADULTS
Specific Etiologies of Pharyngitis
Nonbacterial Potentially Treatable Pathogens
Summary of Evaluation and Treatment
Tonsillopharyngitis (more simply, pharyngitis) is a common complaint characterized by inflammation of the mucous membranes of the throat. Erythema is generally present, but exudate is variably noted. Less commonly, ulceration or a membrane can be seen. Up to 40 million office visits are made annually by persons of all ages because of this illness, primarily during colder seasons, and it may account for up to 100 million days lost from work each year. Many patients and clinicians are aware of the importance of group A b-hemolytic streptococci (Streptococcus pyogenes) as a cause of pharyngitis, and concern for this pathogen must be a major focus in the management of sore throat. It is also felt to be the only commonly encountered pathogen for which treatment is clearly indicated. However, numerous other potentially treatable causes of this illness exist, and most cases of pharyngitis in adults are not caused by S. pyogenes. Table 1-1 lists some etiologies that need to be considered in the differential diagnosis of pharyngitis in adults. Patients who are immunosuppressed may be infected with additional pathogens—for example, enteric gram-negative bacilli or mixed anaerobes (granulocytopenia) and Candida albicans (T cell-mediated immunosuppression, HIV infection). Furthermore, HIV itself may be a cause of pharyngitis.
Table 1-1. Notable causes of pharyngitis in adults and percentages of cases
The clinical presentation of pharyngitis is usually a soreness in the throat. Dysphagia may also be noted, and if the uvula is involved, a rather discomforting feeling of a “lump” when swallowing may be felt. A major responsibility of all clinicians is to distinguish treatable from untreatable disease and to recognize potential complications. An important component of this process is the history. As an example, a sexual history may help define the likelihood of Neisseria gonorrhoeae pharyngitis, whereas an immunization history will help define the possibility of diphtheria. Risk factors for HIV infection should always be assessed. A patient’s inability to manage secretions or severe dysphagia should alert the clinician to epiglottitis or abscess. Constitutional symptoms are variable. In many instances, initial assessment will not allow differentiation among etiologies. Streptococcal and adenoviral pharyngitis are commonly accompanied by significant fever; chills may also be present. The onset is generally abrupt, and patients are ill. Physical examination reveals pharyngeal erythema, and exudate is noted in at least 50% of cases. Exudate is uncommon in rhinovirus, coxsackievirus, and herpes simplex virus pharyngitis. Anterior cervical adenopathy often exists with streptococcal infection. Alternatively, the presence of posterior cervical adenopathy, laryngitis, diarrhea, or rhinorrhea generally indicates a viral etiology, and these symptoms have a negative predictive value of about 80% for disease caused by S. pyogenes. Infectious mononucleosis is often associated with severe pharyngitis, but other evidence of this disease is often present.
Gram’s stain of pharyngeal exudate is an underemployed test that may be useful in determining the etiology of pharyngitis. In trained hands, groupable streptococci can be identified. The presence of polymorphonuclear leukocytes suggests bacterial or adenoviral infection. Additionally, although little literature exists, experience should allow differentiation of Neisseria species, Haemophilus influenzae, and Corynebacterium species (C. diphtheriae or C. hemolyticum). Infection with Epstein-Barr virus (EBV) is often associated with exudative pharyngitis; however, Gram’s stain demonstrates only mixed organisms and no polymorphonuclear leukocytes. In the presence of EBV, Gram’s stain demonstrating polymorphonuclear leukocytes suggests a confounding bacterial infection, usually with S. pyogenes.
A complete physical examination may help to identify the infection; splenomegaly or generalized lymphadenopathy with EBV, S. pyogenes with scarlet fever, C. hemolyticum with scarlatiniform or urticarial rash, adenovirus with conjunctivitis, N. gonorrhoeae with rectal or genital disease or disseminated infection, and Mycoplasma pneumoniae with pneumonia.
An immediate goal in the evaluation of pharyngitis is to detect cases caused by S. pyogenes. Although culture for S. pyogenes remains the gold standard for diagnosis, antigen testing of material from the tonsillopharyngeal area is the most expeditious means of identifying the organism. It is sensitive (80% to 90%) and specific (>95%) and provides information while the patient is still in the office. The test results may be adversely affected if performed by unskilled personnel. A positive test result should prompt therapy. A negative test result should be followed by formal culture for this and possibly other bacterial pathogens, based on epidemiologic information. The easiest method is to swab the throat simultaneously with two swabs. If the first swab (for antigen detection) is negative, the second can be formally cultured. It is extremely important to sample the posterior pharynx and tonsils because yields from the tongue, gums, buccal mucosa, and other areas are far lower. H. influenzae, C. hemolyticum, and N. gonorrhoeae require special media and will not be identified by standard culture techniques or antigen-detection systems. Thus, when they are suspected, the clinician must communicate directly with the microbiology laboratory to access appropriate media and techniques.
A recent survey of board-certified pediatricians was conducted to determine actual practice patterns for the management of presumed streptococcal pharyngitis. Rapid tests were employed by about 64% of respondents, whereas 85% employed cultures. Only 42% of physicians in the survey employed the protocol of rapid test followed by culture if the result of the rapid test was negative. A third of physicians routinely discontinued antibiotics if studies for S. pyogenes were negative. Patients who are known to be immunosuppressed by virtue of underlying disease or therapy should be evaluated for other potential pathogens. Alternatively, persons who are demonstrated to have unusual etiologies or fail to respond to standard therapy may require evaluation for underlying diseases. For example, a patient with oral thrush should be evaluated for infection with HIV unless another risk factor is known. Similarly, when a patient has severe, unresolving pharyngitis, a CBC should be performed to assess for EBV or granulocytopenia.
Specific Etiologies of Pharyngitis
Streptococci remain the most commonly identified cause of sore throat. S. pyogenes is the most common and important of these organisms, but other groupable streptococci, including groups C and G, have been implicated. These may be associated with large food-borne or respiratory droplet outbreaks. However, only S. pyogenes is associated with rheumatic fever. Group C streptococcal pharyngitis has also been associated with glomerulonephritis. Reasons to treat S. pyogenes pharyngitis include (a) relief of symptoms, (b) prevention of spread, (c) prevention of immunologic sequelae, and (d) prevention of local suppurative complications. Rheumatic fever complicates S. pyogenes infections of the throat and can be prevented by administration of an appropriate antimicrobial agent within 8 to 9 days of disease onset. There is no evidence that poststreptococcal glomerulonephritis is preventable by use of antimicrobial agents. The most common local suppurative complication is peritonsillar abscess. Typical presentation is that of ongoing, generally unilateral pharyngitis and constitutional symptoms, often associated with dysphagia and the presence of a mass on digital palpation around the tonsil. In adults, retropharyngeal abscess is uncommon because lymphatic drainage from the tonsils does not flow in this direction. Peritonsillar abscess requires drainage for cure. If employed early, antimicrobial agents shorten the course of pharyngitis caused by S. pyogenes but have not been shown to alter that of group C or G streptococcal infection.
Penicillin remains the agent of choice for streptococcal pharyngitis, and a single dose of IM benzathine penicillin (1.2 million U) often suffices and ensures compliance. However, this regimen may be sensitizing and is accompanied by a bacteriologic failure rate of up to 20%. Thus, many clinicians prefer penicillin V potassium. Current recommendations for this agent are 250 to 500 mg thrice daily. Numerous studies demonstrate, however, that compliance with a regimen of this length is poor. Some data demonstrate that only 8% of patients continue to take medication by day 9. Treatment for less than 10 days is associated with fewer bacteriologic cures. Other agents that can be employed include first-generation cephalosporins, erythromycin, and clindamycin. Agents that include azithromycin, cefuroxime, cefpodoxime, and cefixime have been successfully employed for less than 10 days of treatment, but the author continues to recommend a full therapeutic course. Antimicrobial agents that should not be used for streptococcal pharyngitis include trimethoprim-sulfamethoxazole (TMP-SMX), sulfonamides, quinolones, and tetracyclines; their activity against S. pyogenes is less favorable.
Routine reculturing of the throat following therapy is not indicated, except perhaps in patients with prior rheumatic fever or rheumatic heart disease. After therapy, approximately 10% of patients continue to harbor S. pyogenes (representing asymptomatic carriage), and in the absence of symptoms this should not be a reason to repeat therapy or for the physician or patient to panic (“streptomania”). Reasons for ongoing or rapidly recurrent illness despite apparently appropriate therapy with penicillin include (a) deep-seated infection within tonsillar crypts, (b) simultaneous presence of a b-lactamase-producing organism (e.g., Staphylococcus aureus) that antagonizes penicillin therapy, and (c) noncompliance. If rapid recurrence or lack of response is demonstrated, repeated treatment with a b-lactamase-stable agent for up to 3 weeks usually suffices. Appropriate choices include clindamycin or amoxicillin-clavulanate.
Infection caused by group G streptococci is clinically indistinguishable from that associated with S. pyogenes. The likelihood of suppurative complications is unknown, and the impact of therapy on spread has not been formally established. Therapy has not been demonstrated to alter symptomatology. Group C streptococci may cause endemic or epidemic disease and may be associated with up to 6% of cases of sore throat. Symptoms associated with group C streptococci are similar to but generally less severe than those seen with S. pyogenes infection. Occasional cases of poststreptococcal glomerulonephritis have been associated with these organisms, and elevations of antistreptolysin O titer occur. Need for therapy is undetermined, but clinicians generally treat in a manner similar to that used for S. pyogenes pharyngitis.
Pharyngitis associated with H. influenzae has been reported infrequently but is probably underdiagnosed. A recent review suggests that it may be the second most commonly noted bacterial cause of pharyngitis. Most cases are probably associated with nontypeable, nonencapsulated strains. In adults, clinical presentation is generally subacute, with throat soreness predominating over constitutional symptoms. Examination reveals mild pharyngeal erythema, usually without exudate or cervical adenopathy, and the clinician may initially suspect viral disease. Suppurative complications are rare. In the absence of therapy, symptoms linger for weeks. Therapy with an agent active against H. influenzae (e.g., second-generation cephalosporins, doxycycline, or TMP-SMX) results in rapid resolution of symptoms. The need to employ an agent with activity against b-lactamase-producing strains is uncertain. Throat cultures need to be plated specifically for H. influenzae because neither rapid antigen-detection tests nor routine cultures on blood agar can identify this organism.
C. hemolyticum accounts for approximately 2% of cases of pharyngitis, and infection with this organism occurs primarily in teenagers and young adults. Occasionally, it may be isolated in association with groupable streptococci. The organism is susceptible to penicillin and erythromycin, but data fail to demonstrate its routine eradication following therapy. Clinically, disease typically is associated with tonsillopharyngitis. Exudates or membranes may be noted, and the disease may mimic diphtheria in this regard. Several days after throat complaints, a rash develops in 40% to 50% of patients that may be urticarial or scarlatiniform and can also be confused with a drug eruption. A toxin produced by C. hemolyticum is thought to be the cause of rash. Relapse may occur, and optimal therapy is unknown.
Gonococcal pharyngitis is an important consideration in all persons who are sexually active and is statistically correlated with oral sex. It has been best described in prostitutes, service men, and male homosexuals. In high-risk populations, positive cultures may be noted in up to 6% of patients. Documentation requires culturing on special media under carbon dioxide; thus, routine cultures for group A b-hemolytic streptococci will fail to isolate this pathogen. Disease is often asymptomatic but may be associated with erythema or exudate. Lymphadenitis and constitutional symptoms are uncommon. However, the pharynx may still serve as a nidus for disseminated disease. Therapy with 250 mg of ceftriaxone IM as a single dose is effective and should usually be accompanied by therapy for chlamydial infection. Spectinomycin may not be effective for pharyngeal gonococcal infection.
Currently, fewer than five cases of diphtheria are reported in the United States annually. In several outbreaks noted in the 1970s, disease occurred almost entirely in nonimmunized populations. The organism is noninvasive, and most morbidity and mortality is associated with complications resulting from toxin production. The disease should be suspected in patients representing populations unlikely to have been immunized: selected religious sects, immigrants from Third World countries, and people of lower socioeconomic status. Clinical presentation generally involves the upper respiratory tract. Seropurulent nasal discharge may be noted in the absence of pharyngeal complaints. Pharyngitis may occur and is associated with exudative or membranous changes that involve the soft palate and uvula. Onset is often rapid and in the early stage resembles other forms of exudative pharyngitis. Within days, a membrane forms, which turns from white to dark. Extent of membrane correlates with severity of disease, which may involve the larynx and trachea.
Antimicrobial therapy with penicillin or erythromycin is preferred and probably limits the spread of disease and aids in terminating toxin production. Standard doses of antimicrobial agents are employed for 14 days, and patients require strict isolation until cultures are proved negative on several occasions. Patients identified as carriers should also be treated, although eradication may be difficult.
The mainstay of therapy is diphtheria antitoxin, a horse-derived hyperimmune antiserum. It should be administered early in management, generally in doses of 20,000 to 100,000 U IM or IV, depending on the extent, severity, and duration of disease.
Nonbacterial Potentially Treatable Pathogens
Mycoplasma pneumoniae and Chlamydia pneumoniae have been associated with pharyngitis, although it is generally unlikely that the clinician will make a specific etiologic determination. A recent investigation suggests that almost 10% of patients with sore throat will harbor M. pneumoniae, and a similar percentage (8%) was associated with C. pneumoniae. Infections with both were more common than infection with S. pyogenes. Cases of M. pneumoniae and C. pneumoniae infection could not be clinically differentiated from those caused by S. pyogenes, and about 33% demonstrated pharyngeal exudates. Although lower respiratory infection, such as pneumonia, has been associated with both M. pneumoniae and C. pneumoniae, pharyngitis may be the sole manifestation of disease. Antibiotics active against these pathogens include the newer quinolones, erythromycin, clarithromycin, azithromycin, and tetracyclines. However, clinical experience is limited, and these agents may not affect the length of disease or likelihood of complications. Additionally, quinolones should generally not be employed in patients less than 18 years old, and quinolones and tetracyclines may not be satisfactory agents for disease associated with S. pyogenes.
Viruses, including EBV, cytomegalovirus (CMV), HIV, adenovirus, herpes simplex virus, coxsackievirus, and respiratory syncytial virus, have been implicated in tonsillopharyngitis in adults. In most instances, the diagnosis becomes one of exclusion. EBV and adenovirus are often associated with pharyngeal exudate, and infection with these agents can mimic bacterial disease. EBV may be associated with other clinical manifestations, and a CBC can provide useful information. In up to 50% of cases, EBV pharyngitis can be complicated by infection with S. pyogenes, and in the presence of EBV infection, many clinicians associate severe pharyngitis with the presence of both pathogens. Gram’s stain and culture of pharyngeal exudate often can clarify the situation. When EBV or CMV is considered, neither ampicillin nor amoxicillin should be employed because of the risk for severe dermatitis. This feature is the result of a toxic rather than an allergic reaction to the antimicrobial agents. Thus, use of these products after clinical recovery is not contraindicated.
Herpes simplex virus and coxsackievirus are often associated with oral vesicular or ulcerative eruptions. The former most commonly involves the anterior mouth, whereas the latter is more commonly located posteriorly. Ulcerative or vesicular lesions are uncommon with bacterial infections, and their presence should make the clinician suspect a virus or another process, such as oral erythema multiforme.
Summary of Evaluation and Treatment
Adults who present with a complaint of sore throat should undergo a thorough history and physical examination to identify epidemiologic features that may help identify etiology. Risk factors for HIV and a sexual history should be obtained. Information about outbreaks of streptococcal disease may be available from local health departments. Acute onset associated with pharyngeal exudates, anterior cervical adenopathy, and fever is commonly associated with S. pyogenes infection, and therapy based on these findings is reasonable. When available, a Gram’s stain of pharyngeal exudate can provide immediate practical information to guide initial antimicrobial decision making. In the consideration of S. pyogenes pharyngitis, a rapid strep test should be performed. If the result is negative, a specimen should be sent for cultural confirmation. Patients with risk factors for N. gonorrhoeae infection should be appropriately cultured. Adolescents and young adults may be infected with EBV, M. pneumoniae, or C. pneumoniae. The first can be assessed by CBC or monospot, or both, whereas consideration of the other two agents (generally suspected by failure to respond to penicillin and lack of other identified pathogen) may necessitate empiric antimicrobial therapy. (R.B.B.)
Bisno AI, et al. Diagnosis and management of group A streptococcal pharyngitis: a practice guideline. Clin Infect Dis 1997;25:574–583.
This document represents a comprehensive guide to the diagnosis and treatment of S. pyogenes pharyngitis. Recommendations for testing, choices of test, and therapeutic alternatives are provided. A comprehensive table depicting etiologic agents for pharyngitis is provided. The authors favor 10-day courses of therapy, despite the availability of data recommending shorter ones.
Carroll K, Reimer L. Microbiology and laboratory diagnosis of upper respiratory tract infections. Clin Infect Dis 1996; 23:442–448.
The authors review the preferred methods for the diagnosis of several upper respiratory infections, including group A b-hemolytic streptococcal pharyngitis. They point out the pitfalls of diagnosis, which can include sampling error. They also review the indications and limitations of the rapid tests for detection of S. pyogenes. The usual laboratory is not geared for the routine diagnosis of unusual pathogens, and the clinician needs to communicate directly with laboratory personnel if these are suspected to be present.
Crawford G, Brancato F, Holmes KK. Streptococcal pharyngitis: diagnosis by Gram stain. Ann Intern Med 1979;90:293–297.
In the hands of persons experienced in interpreting Gram’s stains, this method provided excellent early information for the diagnosis of streptococcal pharyngitis. The authors note that patients with other diagnoses (C. hemolyticum, Vincent’s angina) can also be identified in a similar manner. This inexpensive and rapid test should be utilized in patients with exudative pharyngitis, as it can provide useful information for a variety of etiologies.
Hofer C, Binns HJ, Tanz RR. Strategies for managing group A streptococcal pharyngitis. A survey of board-certified pediatricians. Arch Pediatr Adolesc Med 1997; 151:824–829.
The authors received responses to a survey of 510 pediatricians. Only 42% routinely employed both a rapid strep test and culture, and fewer than 30% routinely discontinued antibiotics if results of tests for S. pyogenes were negative. Penicillin or a derivative was employed as standard therapy by the vast majority of respondents.
Krober MS, Bass JW, Michels GN. Streptococcal pharyngitis. Placebo-controlled double-blind evaluation of clinical response to penicillin therapy. JAMA 1985;253:1271–1274.
Although penicillin treatment for group A b-hemolytic streptococcal pharyngitis has been recommended for many years, its efficacy in producing clinical improvement has been debated. This well-performed study in children is one of just a few in the literature documenting that early administration of penicillin is associated with enhanced clinical improvement when compared with placebo.
Miller RA, Brancato F, Holmes KK. Corynebacterium hemolyticum as a cause of pharyngitis and scarlatiniform rash in young adults. Ann Intern Med 1986;105:867–872.
In this investigation, 0.4% of throat cultures yielded C. hemolyticum (compared with 8.3% for S. pyogenes). Most cases occurred in patients 10 to 20 years old, and about 50% of cases were associated with bilateral cervical lymphadenopathy. Most patients demonstrated a rash that was often pruritic. Gram’s stain of pharyngeal exudate often allowed a presumptive diagnosis, but ancillary tests were generally of little value. Penicillin or erythromycin appeared to accelerate clinical improvement.
Pichichero ME, Cohen R. Shortened course of antibiotic therapy for acute otitis media, sinusitis, and tonsillopharyngitis. Pediatr Infect Dis J 1997;16:680–695.
The authors review available data regarding courses of therapy considered shorter than standard for three common upper respiratory infections. For tonsillopharyngitis, numerous studies have compared various agents with classic 10-day penicillin treatment. Although many are associated with equivalent clinical outcomes, penicillin treatment for less than 10 days does not satisfactorily eradicate the organism. Several cephalosporins and macrolides do appear to be equivalent in both clinical and microbiologic outcomes.