OVERVIEW: What every practitioner needs to know

Pertussis is an acute respiratory tract infection caused by Bordetella pertussis and typified by a protracted paroxysmal cough illness. B. pertussis is the sole cause of epidemic pertussis and the usual cause of sporadic pertussis. Neither the disease nor immunization provides lifetime protection. Currently, worldwide prevalence is dampened only by continuous use of immunization.

Are you sure your patient has pertussis? What should you expect to find?

The key symptoms of disease in adolescents and adults are:

  • Cough illness that is escalating (rather than plateauing or improving) after the first week of illness
  • Paroxysmal nature of cough (greater than 75% of patients)—explosive bursts of coughing, all on one breath with intervening minutes or hours without cough
  • Posttussive emesis (approximately 50% of patients)
  • Posttussive whoop (less than or equal to 40% of patients)
  • Aura of suffocation at beginning of cough episode
  • Absence of fever or flu-like symptoms (headache, myalgia, and malaise) at onset of illness or at cough escalation
  • Mild sneezing and congestion, only in the first week of illness
  • Protracted course of cough (more than 28 days in greater than 50% of patients)

The key symptoms of disease in infants aged less than 3 months are:

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  • Short (less than or equal to 3 days) catarrhal (congestion, rhinorrhea, sneezing) stage. Then heralding symptoms are:

    gagging, gasping, choking

    cyanosis, apnea, “apparent life-threatening event”

  • Paroxysmal cough is universal; it can occur in infants hospitalized for symptoms listed above, only several days after the heralding event, or in less affected/older infants as the reason for coming to medical attention.
  • Posttussive emesis is universal.
  • Posttussive whoop is universal, but first occurs during convalescence in very young infants.
  • Absence of fever or systemic illness.
  • Protracted course (greater than 6 weeks) with exaggerated paroxysmal coughing with subsequent viral upper respiratory tract infections (URTIs) through the first year of life.

Key physical findings in uncomplicated pertussis are:

  • Afebrile, well-appearance between cough episodes
  • Sudden anxious look and explosive burst of coughing on one breath, with flushed face, protruding tongue, and watering eyes
  • Petechiae of conjunctiva or the skin of the upper body
  • Normal respiratory rate
  • Absence of rales, wheezing, or other lower respiratory tract abnormalities

How did the patient develop pertussis? What was the primary source from which the infection spread?

The primary source and mode of acquisition
  • Humans are the sole source of B. pertussis, in whom infection is confined to ciliated epithelium.
  • Cough-generating airborne droplets are the vehicle of transmission.
  • Pertussis has an almost 100% contagion rate for unimmunized individuals in close contact.
  • A coughing adult family/extended family member is the source for pertussis in greater than 80% of infants.
  • Coughing adolescents and adults are the source of sporadic school and community outbreaks of pertussis, with the specific source-per-patient less commonly identified.
The underlying principles of the current epidemiology of pertussis
  • Neither disease nor infection provides lifetime immunity.
  • When pertussis was common (prevaccine era), frequent subclinical re-infections boosted immunity (leading to the misconceptions of prolonged immunity from a first episode).
  • Pertussis immunization provides protection against clinical disease (defined as at least 2 weeks of cough illness with paroxysms, whoop, or posttussive), which is incomplete (approximately 80%) and short lived (waning 3 to 5 years postimmunization).
  • People born since 1999 will have received only acellular pertussis vaccines, for which vaccine immunity wanes rapidly.
  • Partial but incomplete control of B. pertussis through immunization has led to 1) ongoing circulation of the organism; and 2) large groups of susceptible people, the degree of which depends on time since last pertussis-containing vaccination in preschool-aged children (diphtheria and tetanus toxoids and acellular pertussis vaccine, DTaP) or since administration of the tetanus, diphtheria, and pertussis vaccine (Tdap) in adolescents or adults.
  • Young infants are especially vulnerable because of low passive antibody levels (unless the infant’s mother received Tdap during this pregnancy), and during the hiatus before active antibody forms to DTaP, which is given only at when the infant is aged 2 months.

Which individuals are of greater risk of developing pertussis?

Individuals at risk of pertussis
  • People of all ages and health status are susceptible to pertussis.
  • The opportunity for exposure is broad and there is no marked seasonality.
  • In prospective studies, approximately 20% of cough illnesses of greater than 2 weeks’ duration in adults are due to pertussis.
  • Pertussis should be considered in any individual with a cough illness that is escalating after 1 week of illness, and especially if it is associated with paroxysms, posttussive vomiting, or whoop.
  • People who are unimmunized are at highest risk of infection (and frequently are sources for school outbreaks).
  • People whose vaccine protection has waned are at increased risk (especially children aged at least 9 years and prior to Tdap at 11 or 12 years, adolescents greater than 3 years past Tdap, adults, and the elderly who have not received Tdap).
  • Infants aged less than 3 months (whose mothers have not received Tdap during this pregnancy) have the highest age-related incidence of reported disease (greater than 100 cases per 100,000 population) and risk of severe, sometimes fatal, outcome.

Beware: there are other diseases that can mimic pertussis:

Other causes of protracted cough illness
  • Adenoviruses, parainfluenza and influenza viruses, enteroviruses, and respiratory syncytial virus can cause a predominantly cough illness. The prodrome in viral illnesses (fever, malaise, myalgia, and sore throat) usually is identifiable and frequently these infections, unlike B pertussis, lead to multiple-mucous-membrane involvement (e.g. marked nasal congestion, conjunctivitis, pharyngitis, laryngitis, and wheezing); ill contacts have URTI symptoms more than cough, and usually are ill concurrently.
  • Mycoplasma pneumoniae can cause prolonged cough illness in adolescents and adults that can be difficult to distinguish from pertussis clinically. Prodrome of fever, headache, and sore throat would distinguish Mycoplasma, as would rales on auscultation of the chest; ill contacts usually had symptoms more than 2 weeks before or after the patient’s.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • A complete blood count can be useful in infants, or older unimmunized children, as absolute lymphocytosis and thrombocytosis sometimes can be distinctive (e.g., lymphocytes greater than 50,000/mm3 and platelets greater than 500,000/mm3).
  • Complete blood count, tests of inflammation (e.g. C-reactive protein or erthrocyte sedimentation rate), and biochemical and hepatic studies are expected to be normal in previously immunized children or adolescents, or adults with pertussis.
  • A culture or a polymerase chain reaction (PCR) test of posterior nasopharyngeal secretions for B. pertussis confirms the diagnosis, usually is positive in infants with pertussis, but is positive infrequently in adolescents and adults with pertussis (less than 25% positive results), and only in the first 7 to 10 days of illness.
  • Serologic testing for immunoglobulin (Ig) G antibody to pertussis toxin (PT) is the most sensitive and specific diagnostic test in adolescents and adults. Low levels of antibody due to immunization can be confounding; but rise over weeks, or a single high anti-PT IgG greater than 90EU/mL, in a standardized assay confirms pertussis. A resting anti-PT IgG level greater than 50EU/mL at least 3 years after immunization is suggestive of pertussis. Antibodies to other antigens (e.g. filamentous hemagglutinin [FHA], pertactin [PRN], or fimbriae [FIM]) or anti-PT IgA or IgM lack sensitivity, specificity, or both and should not be performed.
  • A culture or PCR test for Mycoplasma confirms Mycoplasma infection. Serum anti-Mycoplasma IgM lacks sensitivity, specificity, or both. Seroconversion of anti-Mycoplasma IgG affords specific but impractical confirmation. A cold agglutinin response is expected only in older children or adults with pneumonia syndromes. Dual infection with B. pertussis and M. pneumoniae is described.
  • In practice, a patient with an escalating cough after 1 week of illness, with other typical feature(s) of pertussis, who lacks other virus- or Mycoplasma-like signs and symptoms usually should be managed as for pertussis. If early in the second week, a PCR test may confirm the diagnosis; if coming up to the third week after onset of illness, a high anti-PT IgG level would be expected, and confirmatory. In community outbreaks of pertussis-like illness, it is important to attempt to confirm at least some cases in order to manage contacts, and to heighten suspicion in other patients with cough illness.
  • It also is important in highly symptomatic adults to confirm pertussis in order to predict the duration of cough, and to avoid costly and nonbeneficial diagnostic procedures or therapies.

Results that confirm the diagnosis

See earlier in this chapter.

What imaging studies will be helpful in making or excluding the diagnosis of pertussis?

  • A chest radiograph should be ordered only when clinical findings suggest a lower respiratory tract infection, in order to exclude another diagnosis (e.g. primary pneumonia) or a complication of pertussis, such as secondary bacterial pneumonia (present in 13 to 25% of young infants hospitalized for pertussis, but infrequently in adolescents or adults).

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has pertussis, what therapies should you initiate immediately?

Key principles of therapy:

  • Antimicrobial therapy is given empirically to patients in whom pertussis is likely. If given early in the course of illness (especially in infants), there may be symptomatic benefit. Therapy is always given, however, unless symptoms have been present for at least 21 days, to halt contagiousness.
  • Postexposure prophylaxis (PEP) is given to close contacts regardless of age or immunization status if seen within 21 days of their last exposure to the disease. PEP always is given urgently to contacts:

    at risk of severe pertussis (young infants)

    pregnant or postpartum women

    to those who care for infants aged more than 12 months or pregnant women (e.g. health care personnel, home or childcare workers)

  • B. pertussis is susceptible in vitro to erythromycin, newer macrolides, fluoroquinolones, third-generation cephalosporins, and carbapenems. Ampicillin, rifampicin, and trimethoprim-sulfamethoxazole are only modestly active in vitro; first- and second-generation cephalosporins are not active.
  • Doses and durations of therapy are the same for treatment or PEP.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Treatment options are summarized in Table I.

Table I.
Agent Agea
1–5 months ≥
6 months through adulthood
Primary agents
Azithromycin 10mg/kg once daily for 5 days 10mg/kg (max 500mg) once on day 1; then 5mg/kg (max 250mg) once on days 2 to 5
Erythromycin 40–50mg/kg/day divided four times a day for 14 days 40–50mg/kg/day (max 2g/day) divided four times a day for 14 days
Alternative agent
TMP-SMX At ≥ 2 months, TMP 8mg/kg/day; SMX 40mg/kg daily divided twice a day for 14 daysb TMP 8mg/kg/day (max 320mg/day); SMX 40mg/kg/day (max 1,600mg/day) divided twice a day for 14 days

a Infants aged less than 1 month should be treated or given postexposure prophylaxis using only azithromycin 10mg/kg/once daily for 5 days; erythromycin has been associated with idiopathic hypertrophic pyloric stenosis (IHPS) in neonates. The risk following azithromycin appears to be lower. The risk of pertussis always outweighs theoretical concern for IHPS following azithromycin.

b TMP-SMX, trimethoprim-sulfamethoxazole; contraindicated at age <2 months.

2. Other key therapeutic modalities

  • Management of infants aged less than 3 months almost always requires hospitalization to observe the cadence of symptoms, the ability of self-rescue at the end of a paroxysm, and to intervene expertly anticipating apnea, respiratory failure, or secondary complications.
  • Management of older infants, children, and adults rarely requires hospitalization unless there is severe underlying neuromuscular, respiratory, or cardiac disorder.
  • Avoidance of sudden noise, bright lights, and dry or polluted air is key to diminishing cough episodes (sudden startle can precipitate life-threatening paroxyms in infants). Feedings should be small in volume and frequent.
  • No clinical benefit is provided by antitussive medications, corticosteroids, bronchodilator therapy, or intravenous Ig therapy. The sedative effect of antitussive medications in young children is dangerous.

What complications could arise as a consequence of pertussis?

What should you tell the family about the patient’s prognosis?

Complications
  • Complications in adolescents and adults occur in less than 10% of cases and include secondary bacterial pneumonia/otitis media/sinusitis.
  • Complications in young infants include those above in up to 25% of cases.
  • Apnea or secondary pneumonia can lead to respiratory failure and requirement for intubation, sedation, and artificial ventilation.
  • Progressive pulmonary hypertension is a severe and frequently fatal complication of pertussis in very young infants.
  • Young infants with severe pertussis should be managed where there is a pediatric intensive care unit on site and where personnel are knowledgeable and skilled in management and possible interventions (e.g., plasmaphoresis, exchange transfusion) for infants with respiratory compromise and pulmonary hypertension.
Prognosis
  • Prognosis is excellent in previously healthy infants aged more than 3 months, and in older children and adults without underlying compromising conditions.
  • The course of pertussis in young infants usually is clear within 48 hours of hospitalization, with utilization of a detailed cough record. Most will have reached the peak of disease and exhibit good self-rescue at the end of paroxysms. Parents are educated about optimal home care and advised on the lengthy course of cough illness. Medical monitoring at home is not recommended.
  • Prognosis for very young infants who require intubation is guarded, with prognosis for those intubated pre-emptively because of apnea before hypoxia being excellent, for those intubated for respiratory failure due to secondary pneumonia intermediate, and those who develop pulmonary hypertension poor.

What-if scenarios:

N/A

How do you contract pertussis and how frequent is this disease?

Epidemiology
  • Worldwide, there continue to be 50 million cases of pertussis annually, causing 300,000 deaths. In the United States in the prevaccine era, pertussis was an inescapable part of early childhood and was the leading cause of death from communicable disease among children aged less than 14 years. A peak of 9,000 deaths was recorded in 1923 and 260,000 cases were recorded in 1934. Following widespread use of whole-cell pertussis vaccine (DPT) in the later 1940s, incidence fell 100-fold (to 0.5 cases per 100,000 population in 1981). The lowest number of cases (1,010) and deaths (7) were reported in 1976. Reactogenicity of DPT and concerns of the United States populace about adverse events led to the development of more purified, acellular pertussis vaccines (DTaPs), which have been used exclusively in the United States since 1997, in a five-dose series beginning at 2 months of age with the last reinforcing dose given at 4 to 6 years of age.
  • By the 1990s, the incidence of pertussis in the United States was increasing. It became clear that the reservoir of B. pertussis changed from young children in the prevaccine era, to young adolescents and adults in the postvaccine era. By 2004 to 2005, approximately 25,000 cases of pertussis were reported annually. Studies using active surveillance and serologic methods for diagnosis have shown that the number of actual cases is more than 10-times the number of reported cases. In two prospective studies between 1995 and 2005 using extensive methodology to confirm pertussis, the annual incidence of cough illness due to pertussis was estimated to be 370 cases per 100,000 population in adolescents and 450 cases per 100,000 population in adults.
  • The increase in pertussis in the United States is multifactorial, but is primarily due to partial control of circulation of B. pertussis (yielding fewer opportunities for constant infection/boosting), waning immunity following last dose of DTaP before 7 years of age, failure to vaccinate, and failure of vaccine. Very young infants are unduly susceptible for the first time in history (incidence of approximately 200 cases per 100,000 population in 2004; incidence of 575 cases per 100,000 population in Hispanic infants aged less than 6 months in the California epidemic in 2010) because of low maternal antibody levels resulting in inadequate transplacental protection.
  • In 2006, Tdap (tetanus toxoid, reduced content diphtheria toxoid, reduced content acellular pertussis antigens) was introduced in the United States for universal use at 11 to 12 years of age and subsequently for all adults of any age who previously had not received Tdap, and to replace one decennial dose of tetanus-diphtheria (Td) vaccine in adults. There was a temporal decrease in the number of cases annually. Unfortunately, immunity following Tdap wanes rapidly, especially in people who received only acellular vaccine (DTaP) in early childhood.

What pathogens are responsible for this disease?

N/A

How do these pathogens cause pertussis?

Pathogenesis
  • B. pertussis organisms are acquired by inhalation and have strict tropism for ciliated epithelium of the respiratory tract. Attachment is mediated by several surface molecules, including PRN, FHA, and FIM. Tracheal cytotoxin impairs cilia, and PT and adenylate cyclase impair leukocyte function. PT plays a central but not singular role in pertussis. PT is a complex bacterial toxin, composed of six subunits with an A protomer responsible for biologic activity and a B protomer directing binding and cellular entry of the A subunit. PT has multiple biologic effects, one of which is to cause lymphocytosis by preventing migration from the blood pool.
  • B. pertussis is uniquely an infection of humans and other primates. The exact pathogenesis is not well understood. Experimental infection in baboons has enlightened transmissibility and vaccine protection.
  • There is no serologic marker of protection from pertussis. US licensed acellular pertussis vaccines include PT, FHA, PRN and antigens; FIM composition varies.
  • Degree of lymphocytosis (a manifestation of PT) correlates with severity of pertussis in young infants. Leukoaggregation in pulmonary vasculature is found at autopsy in fatal cases associated with pulmonary hypertension.
  • There is no evidence of direct central nervous system effects of B. pertussis or toxin. Autopsies in fatal cases with encephalopathy show hypoxic-ischemic changes likely due to respiratory compromise.
  • Pertussis is predominantly a mucosal infection. Immunity wanes 5 to 10 years following disease and sooner following acellular vaccines.
  • Evidence does not favor a causal relationship of DPT with encephalopathy. Genetic testing of alleged cases of vaccine-induced encephalopathy has shown SCN1A mutations (Dravet syndrome) in the majority.

What other clinical manifestations may help me to diagnose and manage pertussis?

N/A

What other additional laboratory findings may be ordered?

N/A

How can pertussis be prevented?

Routine vaccine recommendations of the Advisory Committee on Immunization Practices of the Centers for Diseases Control and Prevention and the Committee on Infectious Diseases of the American Academy of Pediatrics
  • A five-dose series of DTaP at 2, 4, 6, and 12 to 18 months of age, and 4 to 6 years of age.
  • A single dose of Tdap at 11 to 12 years of age.
  • A single dose of Tdap for older adolescents and all people of any age who have not received Tdap previously.
  • A single dose of Tdap for all pregnant women, during each pregnancy, preferably between 27 and 36 weeks of gestation, to provide passive antibody protection for very young infants (who are at high risk of severe disease, sometimes with fatal outcome.
  • Repeated dose of Tdap is not recommended for any person of any age, except pregnant women as stated above.
Vaccine recommendations in special circumstances
  • Children aged 7 through 10 years who were under- or unimmunized with DTaP, should be given a single dose of Tdap (and further doses of Td if needed for catch-up).
  • Children and adults who are contacts of a case of pertussis should be brought up-to-date with appropriate pertussis vaccines by age: DTaP for those aged less than 7 years; Tdap for those 10 years of age and older and adults of any age (including those aged 65 years or older) who previously have not received Tdap.
  • The cocoon strategy applies the recommendations above urgently to diminish potential exposure of newborn infants to B. pertussis. This strategy includes

    Tdap immediately postpartum for women who previously have never received Tdap.

    Tdap during each pregnancy (see “Routine vaccine recommendations” above).

    DTaP or Tdap as for underimmunized ot contacts of a case (see “Vaccine recommendations in special circumstances” above).

  • Tdap should replace Td when Td is indicated for tetanus prophylaxis following injury in those who have not received Tdap previously.
Considerations for determining the length of the interval between Td and Tdap

When Tdap is indicated (as in all recommendations above—except for tetanus prophylaxis), there is no required or recommended minimum interval since last receipt of Td; Tdap should be given.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Kretsinger, K, Broder, KR, Cortese, MM. “Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel”. MMWR Recomm Rep. vol. 55. 2006. pp. 1-37. (Evidence of burden of disease, immunogenicity safety of Tdap, and recommendations for use in adolescents and adults. Preferred interval of 5 years since last Td-containing vaccine.)

“America Academy of Pediatrics Commitee on Infectious Diseases. Prevention of pertussis among adolescents: recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine”. Pediatrics. vol. 117. 2006. pp. 965-78. (Evidence of burden of disease, immunogenicity, and safety of Tdap and recommendations for use in adolescents. Preferred interval of 5 years since last Td-containing vaccine. The American Academy of Pediatrics recommended in 2006 that pregnant adolescents be given Tdap because of the burden of disease in adolescents and the high risk of pertussis in infants of adolescent mothers.)

“Outbreaks of respiratory illness mistakenly attributed to pertussis—New Hampshire, Massachusetts, and Tennessee 2004–2006”. MMWR Morb Mortal Wkly Rep. vol. 56. 2007. pp. 837-42. (Caution regarding use of nonstandardized pertussis PCR test.)

“Best practices for health care professionals on the use of polymerase chain reaction (PCR) for diagnosing pertussis”. 2012. (Guidance for best practices in PCR test methodology to optimize sensitivity and specificity.)

“Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010”. MMWR Morbid Mortal Wkly Rep. vol. 60. 2011. pp. 13-15. (Evidence and recommendation to remove any minimum interval between Td-containing vaccine and Tdap; use of Tdap for those aged 7 to 10 years who were under- or unimmunized with DTaP; extension of Tdap recommendation to those with close contact with infants aged less than 12 months to include those aged 65 years or older.)

“Additional recommendations for use of tetanus toxoid, reduced-content diptheria toxoid, and acellular pertussi vaccine (Tdap)”. Pediatrics. vol. 128. 2011. pp. 809-12. (Evidence and recommendation to remove any minimum interval between Td-containing vaccine and Tdap; use of Tdap for those aged 7 to 10 years who were under- or unimmunized with DTaP; extension of Tdap recommendation to those with close contact with infants aged less than 12 months to include those aged 65 years or older.)

“Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women – Advisory Committee on Immunization Practices (ACIP), 2012”. MMMWR Morb Mortal Wkly Rep. vol. 62. 2013. pp. 131-135. (Updated recommendations for use of Tdap during each pregnancy (preferably between 27 and 36 weeks gestation.)

Dabrera, G, Amirthalingam, G, Andrews, N. “A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infanns in England and Wales, 2012-2013”. Clin Infect Dis. 2014. (Evidence that maternal Tdap protects infants less than 8 weeks of age from pertussis).

Witt, MA, Arias, L, Katz, PH. “Reduced risk of pertussis among persons ever vaccinated with whole cell pertussis vaccine compared to recipients of acellular pertussis vaccines in a large US cohort”. Clin Infect Dis. vol. 56. 2013. pp. 1248-1254. (Evidence that shows poorer protection over time against clinical pertussis when acellular pertussis vaccine was used in the primary series, compared with whole cell vaccine).

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