An overview of the pathogenesis of respiratory tract infections is presented in Chapter 69. It is important to keep in mind that upper respiratory tract infections may spread and become more serious because the mucosa (mucous membrane) of the upper tract is continuous with the mucosal lining of the sinuses, eustachian tube, middle ear, and lower respiratory tract.

Diseases of the Upper Respiratory Tract, Oral Cavity, and Neck

Pharyngitis, Tonsillitis, and Peritonsillar Abscesses

Pharyngitis and Tonsillitis.

Pharyngitis (sore throat) and tonsillitis are common upper respiratory tract infections affecting both children and adults. Acute pharyngitis is an illness that frequently causes people to seek medical care.

Clinical Manifestations.

Infection of the pharynx is associated with pharyngeal pain. Visualization of the pharynx reveals erythematous (red) and swollen tissue. Depending on the causative microorganism, either inflammatory exudate (fluid with protein, inflammatory cells, and cellular debris), vesicles (small blister-like sacs containing liquid) and mucosal ulceration, or nasopharyngeal lymphoid hyperplasia (swollen lymph nodes) may be observed.

Pathogenesis.

Pathogenic mechanisms differ and depend on the organism causing the pharyngitis. For example, some organisms directly invade the pharyngeal mucosa (e.g., Arcanobacterium haemolyticum), others elaborate toxins and other virulence factors at the site (e.g., Corynebacterium diphtheriae), and still others invade the pharyngeal mucosa and elaborate toxins and other virulence factors (e.g., group A streptococci [Streptococcus pyogenes]). Pathogenic mechanisms are reviewed in Part III according to various organism groups.

Epidemiology/Etiologic Agents.

Most cases of pharyngitis occur during the colder months and often accompany other infections, primarily those caused by viruses. Patients with respiratory tract infections caused by influenza types A and B, parainfluenza, coxsackie A, rhinoviruses, or coronaviruses frequently complain of a sore throat. Pharyngitis, often with ulceration, is also commonly found in patients with infectious mononucleosis caused by either Epstein-Barr virus or cytomegalovirus. Although less common, pharyngitis caused by adenovirus or herpes simplex virus is clinically severe. Finally, acute retroviral syndrome caused by human immunodeficiency virus 1 (HIV-1) is associated with acute pharyngitis.

Although different bacteria can cause pharyngitis or tonsillitis, the primary cause of bacterial pharyngitis is Streptococcus pyogenes (or group A beta-hemolytic streptococci). Viral pharyngitis or other causes of pharyngitis/tonsillitis must be differentiated from that caused by S. pyogenes, because pharyngitis resulting from S. pyogenes is treatable with penicillin and a variety of other anti-microbials, whereas viral infections are not. In addition, treatment is of particular importance because infection with S. pyogenes can lead to complications such as acute rheumatic fever and glomerulonephritis. These complications are referred to as poststreptococcal sequelae (diseases that follow a streptococcal infection) and are primarily immunologically mediated; these sequelae are discussed in greater detail in Chapter 15. S. pyogenes may also cause pyogenic infections (suppurations) of the tonsils, sinuses, and middle ear, or cellulitis as secondary pyogenic sequelae after an episode of pharyngitis. Accordingly, streptococcal pharyngitis is usually treated to prevent both the suppurative and nonsuppurative sequelae, as well as to decrease morbidity.

Although bacteria other than group A streptococci may cause pharyngitis, this occurs less often. Large colony isolates of groups C and G streptococci (classified as Streptococcus dysgalactiae subsp. equisimilis) are pyogenic streptococci with similar virulence traits as S. pyogenes; symptoms of pharyngitis caused by these agents are also similar to S. pyogenes. In contrast to S. pyogenes, these agents are rarely associated with poststreptococcal sequelae, namely glomerulonephritis and possibly rheumatic fever. Recent studies have demonstrated that these streptococci can exchange genetic information with S. pyogenes and thus potentially obtain virulence factors usually associated with S. pyogenes such as M proteins, streptolysin O, and superantigen genes. Arcanobacterium haemolyticum is also a cause of pharyngitis among adolescents. Examples of agents that can cause pharyngitis or tonsillitis are listed in Table 70-1.

TABLE 70-1

Examples of Bacteria That Can Cause Acute Pharyngitis and/or Tonsillitis

Organism	Disease	Relative Frequency
Streptococcus pyogenes	Pharyngitis/tonsillitis/rheumatic fever/scarlet fever	15% to 35%
Group C and G beta-hemolytic streptococci	Pharyngitis/tonsillitis	<3% to 11%
Arcanobacterium (Corynebacterium) haemolyticum	Pharyngitis/tonsillitis/rash	<1% to 10%
Neisseria gonorrhoeae	Pharyngitis/disseminated disease	Rare*
Corynebacterium ulcerans	Pharyngitis	Rare
Mycoplasma pneumoniae	Pneumonia/bronchitis/pharyngitis	Rare
Yersinia enterocolitica	Pharyngitis/enterocolitis	Rare
Human immunodeficiency virus-1	Pharyngitis/acute retroviral disease	Rare

^*Less than 1%.

Although H. influenzae, S. aureus, and S. pneumoniae are frequently isolated from nasopharyngeal and throat cultures, they have not been shown to cause pharyngitis. Carriage of any of these organisms, as well as Neisseria meningitidis, may have clinical importance for some patients. Cultures of specimens obtained from the anterior nares often yield S. aureus. The carriage rate for this organism is especially high among health care workers, and 10%-30% of the general population can be colonized with this microbe, depending on the population characteristics.

Vincent’s angina, also called acute necrotizing ulcerative gingivitis, or trench mouth, is a mixed bacterial-spirochetal infection of the gingival edge. The infection is relatively rare today, but it is considered a serious disease because it is often complicated by septic jugular thrombophlebitis, bacteremia, and widespread metastatic infection. Adults are more often affected than children; poor oral hygiene is a predisposing factor. Multiple anaerobes, especially Fusobacterium necrophorum, are implicated in this syndrome. Although Gram stain of a throat specimen is usually not predictive, in those patients with symptoms suggestive of Vincent’s angina, Gram stain reveals numerous fusiform, gram-negative bacilli, and spirochetes.

Peritonsillar Abscesses.

Peritonsillar abscesses are generally considered a complication of tonsillitis. This infection is most common in children older than 5 years of age and in young adults. It is important to treat these infections because they can spread to adjacent tissues, as well as erode into the carotid artery to cause an acute hemorrhage. The predominant organisms isolated in peritonsillar abscesses include non–spore-forming anaerobes, such as Fusobacterium (especially F. necrophorum), Bacteroides (including the B. fragilis group), and anaerobic cocci. Streptococcus pyogenes and viridans streptococci may also be involved.

Rhinitis

Rhinitis (common cold) is an inflammation of the nasal mucous membrane or lining. Depending on the host response and the etiologic agent, rhinitis is characterized by variable fever, increased mucous secretions, inflammatory edema of the nasal mucosa, sneezing, and watery eyes. With rare exceptions, rhinitis is typically associated with viral infections (20%-25%); some of these agents are listed in Box 70-1. Rhinitis is common because of the large number of different causative viruses, and reinfections may occur. Bacterial agents associated with rhinitis (10%-15%) include Chlamydia pneumoniae, Mycoplasma pneumoniae, and Group A streptococci.

Box 70-1 Viral Agents That Can Cause Rhinitis

Rhinoviruses

Coronaviruses

Adenoviruses

Parainfluenza and influenza viruses

Respiratory syncytial virus

Enterovirus

Miscellaneous Infections Caused by Other Agents.

Corynebacterium diphtheriae.

Pharyngitis caused by Corynebacterium diphtheriae is less common than streptococcal pharyngitis. After an incubation period of 2 to 4 days, diphtheria usually presents as pharyngitis or tonsillitis. Patients are often febrile and complain of sore throat and malaise (body discomfort). The hallmark for diphtheria is the presence of an exudate or membrane that is usually on the tonsils or pharyngeal wall. The gray-white membrane is a result of the action of diphtheria toxin on the epithelium at the site of infection. Complications occur frequently with diphtheria and are usually seen during the last stage of the disease (paroxysmal stage). The most feared complications are those involving the central nervous system such as seizures, coma, or blindness. Information as to how this organism causes disease is discussed in Chapter 69. Additional specifics regarding this organism are provided in Chapter 17.

Bordetella pertussis.

Although mass immunization programs have greatly reduced the incidence of pertussis, enough cases (because of outbreaks and regional epidemics) still occur. In 2010, the CDC reported 27,500 cases of pertussis. This increased number of identifiable cases may be due to improved awareness and improved diagnostic methods, such as nucleic acid-based testing. It is important that laboratories are capable of detecting, isolating, and identifying the organism, or the specimen should be referred to a reference laboratory.

Characteristically, pertussis, or whooping cough, is a prolonged disease (lasting as long as 6 to 8 weeks) marked by paroxysmal (sudden or intense) coughing.

Following an incubation period of 7 to 13 days, the patient with symptomatic infection develops upper respiratory symptoms, including a dry cough, fever, runny nose, and sneezing. After about 2 weeks, this may progress to spells of paroxysmal coughing. As these episodes worsen, the characteristic whoop, caused by attempted inspiration through an epiglottis undergoing spasm, begins. Vomiting may occur, and usually a lymphocytosis is present. This phase of the illness may last as long as 6 weeks. Bacterial culture for B. pertussis is effective using nasopharyngeal specimens during the first 2 weeks when symptoms are evident. Amplification and polymerase chain reaction may demonstrate positive results within 0-4 weeks of the onset of symptoms. However, positive results should be interpreted with caution and in correlation with patient signs and symptoms. More information regarding B. pertussis is provided in Chapter 37.

Klebsiella spp.

Rhinoscleroma is a rare form of chronic, granulomatous infection of the nasal passages, including the sinuses and occasionally the pharynx and larynx. Associated with Klebsiella rhinoscleromatis and Klebsiella ozaenae, the disease is characterized by nasal obstruction appearing over a long period, caused by tumor-like growth with local extension. K. ozaenae may contribute to another infrequent condition called ozena, characterized by a chronic, mucopurulent nasal discharge that is often foul smelling. It is caused by secondary, low-grade anaerobic infection.

Oral Cavity

Stomatitis

Stomatitis is an inflammation of the mucous membranes of the oral cavity. Herpes simplex virus is the primary agent of this disease, in which multiple ulcerative lesions are seen on the oral mucosa. These lesions are painful and can be found in the mouth and in the oropharynx. Herpetic infections of the oral cavity are prevalent among immunosuppressed patients.

Thrush

Candida spp. can also invade the oral mucosa. Immunosuppressed patients, including very young infants, may develop oral candidiasis, called thrush. Oral thrush can extend to produce pharyngitis or esophagitis, a common finding in patients with acquired immunodeficiency syndrome and in other immunosuppressed patients. Thrush is suspected if whitish patches of exudate on an area of inflammation are observed on the buccal (cheek) mucosa, tongue, or oropharynx. Oral mucositis or pharyngitis in the granulocytopenic patient may be caused by Enterobacteriaceae, S. aureus, or Candida spp. and is manifested by erythema, sore throat, and possibly exudate or ulceration.

Periodontal Infections

Types.

The three dental problems that may require culture and identification in a clinical laboratory include (1) root canal infections, with or without periapical abscess; (2) orofacial odontogenic infections, with or without osteomyelitis (inflammation of a bone) in the jaw; and (3) perimandibular space infections. Oral bacteria are clearly important in other dental processes, such as caries (destruction of the mineralized tissues of the tooth; a cavity), periodontal (tissues in, around, and supporting the tooth) disease, and localized juvenile periodontitis, but clinical laboratories are not involved in culturing in such cases.

Etiologic Agents.

The bacteriology is similar in all of these infections and involves primarily anaerobic bacteria and streptococci except for perimandibular space infections, which may also involve staphylococci and Eikenella corrodens in about 15% of patients. The streptococci are microaerobic or facultative and are usually alpha-hemolytic (particularly the Streptococcus anginosus group—see Chapter 15); they are usually found in 20% to 30% of dental infections.

Members of the Bacteroides fragilis group are found in root canal infections, orofacial odontogenic infections, and bacteremia secondary to dental extraction in 5% to 10% of patients. Anaerobic cocci (both Peptostreptococcus and Veillonella), pigmented Prevotella and Porphyromonas, the Prevotella oralis group, and Fusobacterium are found in about 20% to 50% of the three conditions mentioned, as well as in postextraction bacteremia. Infection with Actinomyces israelii may complicate oral surgery.

Salivary Gland Infections

Acute suppurative parotitis (inflammation of the salivary glands located under the cheek in front of and below the external ear) is seen in very ill patients, especially those who are dehydrated, malnourished, elderly, or recovering from surgery. It is associated with painful, tender swelling of the parotid gland; purulent drainage may be evident at the opening of the duct of the gland in the mouth. Staphylococcus aureus is the major pathogen but on occasion Enterobacteriaceae, other gram-negative bacilli, and oral anaerobes may play a role in infection. A chronic bacterial parotitis has been described involving Staphylococcus aureus. Less often, other salivary glands may be involved with a bacterial infection, usually because of ductal obstruction.

The mumps virus is traditionally the major viral agent involved in parotitis; however, since the advent of childhood vaccination, infection with mumps virus is rarely diagnosed. Influenza virus and enteroviruses may also cause this syndrome. Viral parotitis is typically diagnosed using serology. Infrequently, Mycobacterium tuberculosis may involve the parotid gland in conjunction with pulmonary tuberculosis.

Neck

Infections of the deep spaces of the neck are potentially serious because they may spread to critical structures such as major vessels of the neck or to the mediastinum, leading to mediastinitis, purulent pericarditis, and pleural empyema. Oral flora is responsible for these infections. Accordingly, the predominant organisms are anaerobes, primarily Peptostreptococcus, various Bacteroides, Prevotella, Porphyromonas, Fusobacterium spp., and Actinomyces. Streptococci, chiefly of the viridans variety, are also important. Staphylococcus aureus and various aerobic, gram-negative bacilli may be recovered, particularly from patients developing these problems in the hospital.

Scrofula is a tuberculous infection in the lymph nodes of the neck that may be associated with Mycobacterium tuberculosis, Mycobacterium scrofulaceum, or Mycobacterium avium. The characteristic signs and symptoms include painless swelling of the lymph nodes with the rare appearance of fever or ulcerations. Diagnosis may require bacterial culture of the lymph nodes, computed tomography (CT) of the neck, biopsy, and chest x-ray or PPD (purified protein derivative) testing associated with M. tuberculosis.

Diagnosis of Upper Respiratory Tract Infections

Collection and Transport of Specimens

Sterile, Dacron, or Rayon swabs with plastic shafts are suitable for collecting most upper respiratory tract microorganisms. Flocked swabs may also be used when available. If the swab remains moist, no further precautions need to be taken for specimens cultured within 4 hours of collection. After that period, transport medium is required to maintain viability and prevent overgrowth of contaminating organisms. Swabs for detection of group A streptococci (Streptococcus pyogenes) are the only exception. This organism is highly resistant to desiccation and remains viable on a dry swab for as long as 48 to 72 hours. These throat swabs can be placed in glassine paper envelopes for mailing or transport to a distant laboratory. Throat swabs are also adequate for recovery of adenoviruses and herpes viruses, Corynebacterium diphtheriae, Mycoplasma, Chlamydia, and Candida spp. Recovery of C. diphtheriae is enhanced by culturing both the throat and nasopharynx.

Nasopharyngeal swabs are better suited for recovery of Bordetella pertussis, Neisseria spp., along with several viruses including respiratory syncytial virus, parainfluenza virus, and the other viruses causing rhinitis. Optimum conditions for the collection and transport of specimens for viral detection or culture are described in Chapter 65. Although swabs made of calcium alginate are commonly used to collect nasopharyngeal specimens (excluding those specimens for chlamydia or viral culture), nasopharyngeal secretions collected by either aspiration or washing will improve recovery for Bordetella pertussis because a larger amount of material is obtained.

The type of swab used for collection is very important. For example, cotton swabs should never be used for culture because fibers contain fatty acids on the surface, which are capable of killing Bordetella. Calcium alginate or Dacron swabs are acceptable for obtaining nasopharyngeal swab specimens, with calcium alginate being optimal for culture. However, if polymerase chain reaction (PCR) is to be performed, Dacron or rayon swabs on plastic shafts are preferred. Specimens for B. pertussis ideally should be inoculated directly to fresh culture media at the patient’s bedside. If this is not possible, transport for less than 2 hours in 1% Casamino acid medium at room temperature is acceptable. If specimens are plated on the day of collection, Amies transport medium with charcoal is acceptable. If specimens are plated more than 24 hours after collection, Regan-Lowe or Jones-Kendrick transport medium is optimal; both contain charcoal, starch, and nutrients as well as cephalexin. If lengthy delays in transport are expected, transport of specimens in Regan-Lowe medium at 4°C is recommended.

Direct Visual Examination or Detection

A Gram stain of material obtained from upper respiratory secretions or lesions may not improve diagnosis. Yeast-like cells can be identified, which are helpful in identifying thrush, and the characteristic pattern of fusiform and spirochetes of Vincent’s angina may be visualized. Gram’s crystal violet (allowed to remain on the slide for 1 minute before rinsing with tap water) and the Gram stain can be used to identify the spirilla and fusiform bacilli of Vincent’s angina. However, if crystal violet is used, the smear should be very thin because everything will be intensely Gram positive, making a thick smear difficult to read. Additionally, spirilla and bacilli may be stained using a dilute solution of carbol fuchsin.

For causes of pharyngitis, Gram stains are unreliable. Direct smears of exudate from membrane-like lesions used to differentiate diphtheria from other causes are also not reliable or recommended.

Fungal elements, including yeast cells and pseudohyphae, may be visualized with a 10% potassium hydroxide (KOH) preparation, calcofluor white fluorescent stain, or periodic acid-Schiff (PAS) stain. Direct examination of material obtained from the nasopharynx of suspected cases of whooping cough using a fluorescent antibody stain (see Chapter 37) has been shown to yield some early positive results for detection of B. pertussis. However, direct fluorescent antibody (DFA) staining of nasopharyngeal secretions often lack sensitivity and specificity depending on the antibody used. Numerous studies have demonstrated that PCR-based assays for B. pertussis in nasopharyngeal secretions are superior to both DFA and culture. Various methods, including fluorescent antibody stain reagents, enzyme immunoassays, and nucleic acid amplification methods are also commercially available to detect numerous viral agents (see Chapter 65).

Improvement in the development of rapid methods for detection of group A streptococcal antigen or nucleic acid has obviated the need for culture of pharyngeal specimens. At least 40 commercial products are available to identify group A streptococcal antigens using membrane enzyme immunoassays or liposomal and optical immunoassay techniques. Although the specific procedures vary with the products, several generalizations can be made. Throat swabs are incubated in an acid reagent or enzyme to extract the group A specific carbohydrate antigen. Dacron swabs seem to be most efficient at releasing antigen, although other types of swabs may yield acceptable results. In laboratory comparisons between a rapid antigen method and conventional culture methods for detecting the presence of group A streptococci in throat swabs, the commercial kits have shown relatively acceptable (62% to more than 90%) sensitivity and specificity. Specimens with a negative direct antigen test for group A streptococci should be cultured (requires collection of specimen with two swabs) or confirmed using a nucleic acid method. Group A streptococci can be directly detected from pharyngeal specimens by nucleic acid testing using different molecular assay formats. The commercially available assay (Probe Group A Strep Direct Test (GAS Direct), Hologic-GenProbe, Inc., San Diego, California) that employs a nonisotopic, chemiluminescent, single-stranded DNA probe complementary to the rRNA target of the group A Streptococcus. The assay detects organisms directly from swab specimens by lysing the bacterial cells before amplification. Dacron swabs are acceptable for use with this assay. Sensitivities of the Gen-Probe Group A Strep Direct Test range from 91.7% to 99.3% when compared with culture. A rapid-cycle real-time PCR method, the Light Cycler Strep-A (Roche Applied Science, Indianapolis, Indiana), also detects S. pyogenes directly from throat swabs. Using this technology, 32 samples (including controls) can be tested per run in about 1.5 hours. Isothermol DNA amplification is also available for the detection of Group A Streptococcus from throat swabs (Illumigene Group A Streptococcus, Meridian Bioscience, Inc., Cincinnati, Ohio) and demonstrates sensitivity equal to the Group A Strep Direct test. See Chapter 8 for more information on isothermal DNA amplification.

Culture

Streptococcus pyogenes (Beta-Hemolytic Group A Streptococci)

Because the primary cause of bacterial pharyngitis in North America is Streptococcus pyogenes, most laboratories routinely screen throat cultures for this organism. Group A streptococci are usually beta-hemolytic, with less than 1% being nonhemolytic. Three variables must be taken into consideration regarding successful culture of group A streptococci from pharyngeal specimens: medium, atmosphere, and duration of incubation. Kellogg recommended four combinations of media and atmosphere of incubation for throat specimens; these are listed in Table 70-2. Regardless of the medium and atmosphere of incubation employed, culture plates should be incubated for at least 48 hours before reporting as negative for group A streptococci. In addition, the incubation of sheep blood agar in 5% to 10% CO₂ was strongly discouraged.

TABLE 70-2

Medium and Atmosphere for Incubation of Cultures to Recover Group A Streptococci from Pharyngeal Specimens

Media	Atmosphere of Incubation
Sheep blood agar	Anaerobic
Sheep blood agar with coverslip over the primary area of inoculation	Aerobic
Sheep blood agar with trimethoprim-sulfamethoxazole	5%-10% CO₂ or anaerobic

Drawbacks to culture include an extended incubation time of 24 to 48 hours for visible colony formation with additional manipulations of the beta-hemolytic organisms for definitive identification (see Chapter 15). If sufficient numbers of pure colonies are not available for identification, a subculture requiring additional incubation is necessary. By placing a 0.04-unit differential bacitracin filter paper disk, available commercially directly on the area of initial inoculation, presumptive identification of S. pyogenes can be made after overnight incubation (all of group A and a very small percentage of group B streptococci are susceptible). However, use of the bacitracin disk in the primary area of inoculation reduces the sensitivity and specificity of culture and identification of S. pyogenes. Sometimes growth of too few beta-hemolytic colonies or overgrowth of other organisms makes interpretation difficult. Therefore, using the bacitracin disk as the only method of identification of S. pyogenes is not recommended. New selective agars, such as streptococcal selective agar, have been developed that suppress the growth of almost all normal flora and beta-hemolytic streptococci except for groups A and B and Arcanobacterium haemolyticum. Direct antigen or nucleic detection tests or the PYR test (see Chapter 15) can also be carried out on isolated beta-hemolytic colonies.

Corynebacterium diphtheriae

If diphtheria is suspected, the physician must communicate this information to the clinical laboratory. Because streptococcal pharyngitis is included in the differential diagnosis of diphtheria and because dual infections do occur, cultures for Corynebacterium diphtheriae should be plated onto sheep blood agar or streptococcal selective agar, as well as onto special media for recovery of this agent. These special media include a Loeffler’s agar slant and a cystine-tellurite agar plate. Chapter 17 discusses the identification of the organism. Recovery of this organism is improved when culturing specimens from the throat and nasopharynx of potentially infected patients. In addition to culture, rapid toxigenicity assays, including immunoassays and polymerase chain reaction, may be used to assist in the diagnosis. Caution should be used when interpreting molecular assays, because positive results have been associated with related species of Corynebacteria.

Bordetella pertussis

Freshly prepared Bordet-Gengou agar was the first medium developed for isolation of Bordetella pertussis. However, because it was inconvenient to use, other media were subsequently developed (see Chapter 37). Today, Regan-Lowe or charcoal horse blood agar is recommended for use in diagnostic laboratories. Because the organisms are extremely delicate, specimens should be plated directly onto media, if possible. The yield of positive isolations from clinical cases of pertussis seems to vary from 20% to 98% depending on the stage of disease, previous treatment of the patient, age of the patient, and laboratory techniques. Due to the fastidious growth requirements, additional methods, including 16SrRNA sequencing and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) have proven effective. See Chapter 7 for a description of MALDI-TOF methodology.