Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis

INTRODUCTION — Pertussis, also known as "whooping cough," is a highly contagious, acute respiratory illness caused by Bordetella pertussis. In the prevaccine era, the disease predominantly affected children <10 years of age and usually manifested as a prolonged cough illness with one or more of the classical symptoms: inspiratory whoop, paroxysmal cough, and post-tussive emesis [1].

Since the introduction of pertussis vaccines in the late 1940s, the epidemiology of reported pertussis infections has changed. In the United States in the 1990s, more than half of cases occurred in adolescents and adults [2]. Infected adolescents and adults serve as a reservoir for infection of infants and children in whom serious morbidity and mortality may occur. In adolescents and adults, symptoms and signs of pertussis are often nonspecific. Adults >65 years with pertussis are more likely than other adults to be hospitalized (14.8 percent of those infected) or to die from pertussis (accounting for 4.8 percent of all pertussis-related deaths) [3].

Clinical manifestations and diagnosis of pertussis in adolescents and adults will be reviewed here. Issues related to the pathogenesis, epidemiology, treatment, and prevention of pertussis in adults, as well as pertussis in infants and children, are discussed separately. (See "Pertussis infection: Epidemiology, microbiology, and pathogenesis" and "Pertussis infection in adolescents and adults: Treatment and prevention" and "Pertussis infection in infants and children: Clinical features and diagnosis" and "Pertussis infection in infants and children: Treatment and prevention".)

CLINICAL MANIFESTATIONS

Incubation period and spectrum of illness — The incubation period following exposure is typically 7 to 10 days but may be three weeks or longer [4]. This incubation period is considerably longer than that of common upper respiratory infections, such as the common cold (one to three days).

Many B. pertussis infections appear to be asymptomatic; in a systematic review of studies evaluating infection among household contacts of index cases, up to 56 percent of those with laboratory confirmed infection had no symptoms [5]. Symptomatic infection with B. pertussis in individuals without pre-existing immunity is characterized by three phases: the catarrhal phase, the paroxysmal phase, and the convalescent phase, as detailed below. In infected adolescents or adults with a history of prior infection or vaccine-induced immunity, classic symptoms may or may not occur.

Catarrhal phase — The catarrhal phase is the earliest phase of illness, lasting one to two weeks, and is characterized by nonspecific symptoms including generalized malaise, rhinorrhea, and mild cough. Slight temperature elevations may be present, but high fever is uncommon [6]. Two early clinical findings suggestive of pertussis are excessive lacrimation and conjunctival injection. Diagnostic tests are most accurate during this phase; however, the nonspecific clinical manifestations rarely lead to suspicion of pertussis. (See 'Approach to diagnosis' below.)

Paroxysmal phase — The paroxysmal stage begins during the second week of illness. The hallmark symptom, paroxysmal cough, is a series of severe, vigorous coughs that occur during a single expiration. Paroxysms often occur in rapid succession and can be quite distressing to patients (both children and adults) as well as caregivers [7,8]. Following a prolonged cough paroxysm, a vigorous inspiration causes the distinctive "whooping" sound. This sound is common in affected infants and small children due to the relatively small caliber of their trachea; it may also occur in adults. Post-tussive syncope or emesis can also occur during the paroxysmal phase.

The cough is present throughout the day and night and may be precipitated by acts such as yawning, stretching, laughing, yelling, or exercise. Cough may be worse at night and can be triggered by the inhalation of steam, mist, or other respiratory irritants. Patients often feel otherwise well and have few symptoms between cough paroxysms [6]. Untreated, the paroxysmal phase generally lasts two to three months then gradually transitions to the convalescent phase.

Convalescent phase — The convalescent phase is characterized by a gradual reduction in the frequency and severity of cough. It usually lasts one to two weeks but may be prolonged.

The total duration of all three phases is typically about three months but can last four months or longer.

Adolescents and adults — Clinical manifestations of pertussis in adolescents and adults are often less severe than in infants and children. Prior infection or immunization may attenuate the illness, but neither confers lifelong immunity. As a result, prolonged cough may be the only symptom in adolescents and adults [9]. The presence or absence of the classically described manifestations (ie, inspiratory whoop, paroxysmal cough, post-tussive emesis or syncope) is only modestly useful in determining whether prolonged cough represents pertussis in adolescents and adults.

Systematic reviews have shown that the presence of inspiratory whoop or post-tussive emesis increases the likelihood of pertussis, whereas the absence of paroxysmal cough decreases the likelihood [10-12]. Other symptoms may include sputum production, coryza, sweating episodes, and sore throat (table 1).

Several studies have shown that pertussis is responsible for a substantial portion of prolonged cough illnesses in adolescents and adults. Among adults with acute cough illness (defined as <28 days), the prevalence of pertussis infection is 3 percent; greater duration of cough at presentation (ie, >2 weeks) increased the likelihood of pertussis [13].

COMPLICATIONS — Complications of pertussis may be related to the infection itself (eg, pneumonia, otitis media) or the mechanical sequelae of the severe cough (eg, subconjunctival hemorrhage, development or exacerbation of abdominal wall hernia, rib fractures, urinary incontinence, or lumbar strain). Rarely, vigorous coughing may cause more serious problems, including intracranial hemorrhage, stroke due to carotid or vertebral artery dissection, and encephalopathy or seizures (presumed due to hypoxia).

In general, morbidity and mortality due to pertussis are most common in infants and young children (table 2). In adolescents and adults, the prolonged cough may result in substantial time lost from school or work as well as social isolation, sleep deprivation, or anxiety about an undiagnosed condition [14]. Asthma and tobacco use increase the severity of infection [14]. The risk of hospitalization in adults increases with age and is highest in individuals over 65 years [15,16]. A high proportion of adolescents and adults who are hospitalized with pertussis have underlying asthma or chronic obstructive pulmonary disease and exacerbation of these conditions is often the reason for hospitalization [16].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of cough is broad; the duration of illness is useful in narrowing the potential causes [17]. Cough that has been present less than three weeks is considered acute (as defined by the American College of Chest Physicians); cough present for three to eight weeks is classified as subacute; and cough present for more than eight weeks is chronic [18]. Many adolescents and adults with pertussis, particularly those with milder manifestations, first seek medical attention only after several weeks of coughing (ie, with a subacute or chronic cough illness).

The most common cause of acute cough is self-limited viral upper respiratory tract infection (eg, the common cold). Subacute cough often represents persistence of an acute respiratory infection (eg, viral or bacterial upper airway infections or lower respiratory tract infections, such as pneumonia). Common causes of cough include cigarette smoking, gastroesophageal reflux disease, asthma, postnasal drip, and angiotensin-converting enzyme inhibitors. (See "Causes and epidemiology of subacute and chronic cough in adults".)

DIAGNOSIS — Diagnosing pertussis in adolescents and adults requires a high index of suspicion. Early diagnosis is important as it can prevent the spread of infection, particularly in vulnerable populations (eg, infants and young children, adults who have not received booster vaccination, immunocompromised individuals). In addition, antibiotic treatment given in the early stages may shorten the duration of symptoms.

Given the variable and nonspecific symptoms of pertussis, microbiologic testing is needed to confirm the diagnosis for most patients (algorithm 1).

Underdiagnosis and delays in diagnosis are common. In one retrospective study, the diagnosis of pertussis was delayed by 12 days on average, with nearly two missed opportunities to make the diagnosis per patient. Delay was greater in patients ≥18 years old [19].

Approach to diagnosis — The clinical case definition advocated by the United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) is a cough illness lasting at least two weeks without an apparent cause, with one of the following symptoms: paroxysms of coughing, inspiratory whoop, or post-tussive emesis [20,21]. Further information can be found on the CDC website. In the setting of a pertussis outbreak or known close contact with a confirmed case, the presence of a cough lasting ≥2 weeks is sufficient for clinical diagnosis (even in the absence of other symptoms). In outbreaks, the sensitivity and specificity of this case definition for detecting culture-positive pertussis has been 84 and 63 percent, respectively [22].

In nonoutbreak settings, the choice of diagnostic tests (culture, polymerase chain reaction [PCR], serology) depends upon the duration of cough (figure 1) [23-25]:

●For patients with less than two weeks of cough in whom there is clinical concern for pertussis, perform both culture and PCR for B. pertussis (see 'Laboratory tools' below). The sensitivity of culture is highest during the first two weeks of illness.

●For patients with two to four weeks of cough, perform both culture and PCR. The sensitivity of culture declines after the first two weeks, but PCR remains useful up to four weeks since it can detect nonviable organisms. Both tests should be performed since the accuracy of PCR as a stand-alone diagnostic test requires further study. Serology may be a useful alternative to culture in this setting once it has been standardized and more widely available.

●For patients with more than four weeks of cough, only serology is useful.

The United States Centers for Disease Control and Prevention (CDC) Pertussis and Diphtheria Laboratory has developed its own PCR (multitarget) and serologic (antipertussis toxin immunoglobulin [Ig]G) assays to diagnose pertussis. In a study including more than 800 patients with cough, at least one diagnostic test was positive for B. pertussis in 14 percent of cases [26]. The sensitivity and specificity of PCR were 91 and 100 percent, respectively. PCR and culture were most sensitive when performed during the first two weeks of cough; serology was optimally sensitive after the second week of cough.

Patients with at least one test positive for pertussis, including patients with discordant test results (eg, positive culture with negative PCR, negative culture with positive PCR, or positive serology with negative PCR) should be presumed to have pertussis.

Confirmed and probable cases of pertussis are defined on the CDC website [20]. Confirmed and probable cases should be reported to local public health authorities. International outbreaks of pertussis should be reported to the appropriate WHO regional office [27].

Specimen collection — Specimens must be collected by swab or aspiration from the ciliated respiratory epithelium of the posterior nasopharynx where B. pertussis resides, rather than the anterior nares or throat (picture 1). A nasopharyngeal swab or aspirate should be obtained whenever possible [28]. Cotton-tipped or rayon swabs should not be used for obtaining culture specimens as they contain fatty acids that are toxic to B. pertussis. Instead, a calcium alginate or polyester (such as Dacron) swab with a flexible metal shaft should be used. For PCR specimen collection, polyester or rayon swabs should be used; cotton-tipped swabs and calcium alginate may interfere with the assay.

Obtaining a specimen from the posterior nasopharynx is uncomfortable for the patient, often leading to suboptimal specimen collection. Therefore, the patient should be educated about the importance of a properly obtained specimen and forewarned about the discomfort of the procedure. Proper specimen collection typically induces coughing or sneezing; therefore, the person obtaining the specimen should wear a protective face mask and gloves.

The CDC has developed short videos describing the proper collection of nasopharyngeal aspirate and swab specimens [29].

Technique-specific factors that reduce the sensitivity of culture include incorrect specimen collection technique, prolonged transport time to the laboratory, delayed specimen plating, and fastidious nature of the organism [6]. Immediate plating of the specimen is optimal but is not typically practical in clinical situations.

After specimen collection, use of a special transport medium (Regan-Lowe agar) rather than standard medium (such as modified Stuart's) will help to prevent loss of B. pertussis and overgrowth of other nasopharyngeal organisms. Even though Bordet-Gengou agar is the classic medium for isolating B. pertussis, Regan-Lowe agar is preferred by most laboratories because of its longer shelf life. Growth on culture media typically takes 7 to 10 days.

Laboratory tools — Microbiologic confirmation is needed to establish the diagnosis of B. pertussis infection as well as for public health surveillance and for outbreak investigations [6,30]. Bacterial culture and PCR are the most useful microbiologic tools; use of both of these together is the diagnostic approach recommended by the CDC [31].

Culture — Culture is the gold standard laboratory test for diagnosis of pertussis; sensitivity in clinical practice is only 20 to 80 percent, but it has excellent specificity (100 percent) (table 3). Patient-specific factors that reduce the sensitivity of culture include prolonged duration of illness by the time a specimen is collected, recent antibiotic use, and prior vaccination.

PCR testing — PCR is used for diagnosis of pertussis in most cases reported to the National Notifiable Diseases Surveillance System in the United States [15]; culture and direct fluorescent antibody testing were the main diagnostic tests employed in the early 1990s. PCR testing is more sensitive than culture as it may detect small numbers of viable and nonviable organisms; specificity is high. Primers from four chromosomal regions are employed: repeated insertion sequences (such as IS481, which is also present in lesser quantities in Bordetella holmesii and Bordetella bronchiseptica), the pertussis toxin gene (PT), the PT promoter region, and the adenylate cyclase gene (not specific to B. pertussis) [30,32].

PCR is not affected by previous antibiotic use, and results are typically available within one to two days. Compared with culture, PCR may increase the diagnostic yield three- to fivefold [33-36]. Disadvantages to PCR include its relatively high cost, more limited availability, and the potential for false-positive results [35]. There are no standardized protocols, reagents, or reporting formats for PCR testing.

The CDC recommends use of PCR together with culture for the diagnosis of pertussis [31].

The CDC provides information regarding best practices on the use of PCR for diagnosing pertussis.

Notably, molecular assays that detect multiple pathogens (multiplex tests) are increasingly available to clinicians. These assays permit a syndromic approach to testing, including for respiratory infections, and some multiplex respiratory panels detect B. pertussis [37]. However, the multiplex panels may be less reliable than a dedicated PCR test for B. pertussis [38].

Serology — Serologic testing is used primarily for epidemiologic or research purposes. It has become more widely available but remains hampered by lack of standardization [39].

Natural infection with B. pertussis results in production of IgA, IgG, and IgM antibodies to a variety of antigens; primary immunization induces mainly IgG and IgM antibodies [30]. Serologic testing typically involves comparing levels of pertussis antibodies (IgA or IgG to pertussis toxin [PT], filamentous hemagglutinin [FHA], pertactin [PRN], fimbriae, or sonicated whole organism) in acute and convalescent (more than four weeks after the acute sample is obtained) sera; a substantial change in the titers (typically a fourfold increase or more) suggests infection. Infection with other Bordetella species also induces antibodies to FHA, PRN, and the sonicated whole organism [40], and FHA antibodies are also induced by other bacteria (eg, H. influenzae, M. pneumoniae, and C. pneumoniae) [41], so these are not specific for B. pertussis. IgA and IgG antibodies to PT are most specific for the diagnosis of B. pertussis infection [30].

A practical problem with serologic testing is the timing of obtaining the acute phase specimen. In the setting of delayed collection of the acute phase specimen, antibody titers may have already peaked, and a further rise in the convalescent specimen may not be observed. Alternatively, a single sample titer above a designated threshold (typically IgG anti-PT ≥100 to 125 endotoxin units [EU]/mL) or decreases in antibody titers between the acute and convalescent titers may be diagnostic [42].

Single-specimen titers are useful in adolescents and adults who have not had recent Tdap immunization, but not in children since recent immunization can affect the results. Because the acellular pertussis vaccine contains pertussis toxin, recent booster vaccination also affects serologic testing results in adolescents and adults [43].

Other tests — Direct fluorescent antibody testing is inexpensive and provides rapid results but has poor sensitivity and specificity so is not recommended.

Pulsed-field gel electrophoresis is a DNA fingerprinting technique that may be useful for epidemiologic purposes (eg, community or nosocomial outbreaks), but its availability is limited [44-46].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pertussis".)

SUMMARY

●Transmission – Pertussis is highly contagious. The incubation period is typically approximately one week but may be three weeks or longer. (See 'Incubation period and spectrum of illness' above.)

●Phases of pertussis – Pertussis infection in individuals without immunity is characterized by three phases: the catarrhal phase, the paroxysmal phase, and the convalescent phase. (See 'Clinical manifestations' above.)

●Spectrum of illness – Adolescents or adults with a history of prior infection or vaccine-induced immunity often do not manifest classic clinical findings of pertussis. In these cases, the only symptom may be prolonged cough. Some pertussis infections may be asymptomatic. (See 'Incubation period and spectrum of illness' above and 'Adolescents and adults' above.)

●Clinical case definition – The clinical case definition of pertussis advocated by the United States Centers for Disease Control and Prevention and the World Health Organization is a cough illness lasting at least two weeks without clear cause and one of the following clinical findings (algorithm 1):

•Paroxysms of coughing

•Inspiratory whoop

•Post-tussive emesis

In the setting of an outbreak or known close contact with a confirmed case of pertussis, the presence of a cough lasting ≥2 weeks is sufficient for clinical diagnosis (even in the absence of other symptoms). (See 'Approach to diagnosis' above and 'Clinical manifestations' above.)

●Diagnostic approach – The choice of diagnostic test (culture, polymerase chain reaction [PCR], serology) depends to some degree upon the duration of cough (algorithm 1 and figure 1). (See 'Approach to diagnosis' above.)

•Culture and PCR for Bordetella pertussis are appropriate for patients with up to four weeks of cough; the sensitivity of culture is highest during the first two weeks of illness.

•For patients with more than four weeks of cough, only serology is useful, but the lack of a widely available, standardized test limits its use.

●Case confirmation – Confirmed cases of pertussis are defined as an acute cough illness of any duration and a positive B. pertussis culture or PCR. (See 'Approach to diagnosis' above.)