Pertussis ( Bordetella pertussis and Bordetella parapertussis )

Etiology

Bordetella pertussis is the cause of epidemic pertussis and the usual cause of sporadic pertussis. Bordetella parapertussis is an occasional cause of sporadic pertussis that contributes significantly to total cases of pertussis in Eastern and Western Europe, but increasingly has been detected during regional pertussis outbreaks in the United States. B. pertussis and B. parapertussis are exclusive pathogens of humans and some primates. Bordetella holmesii , first identified as a cause of bacteremia in immunocompromised hosts without cough illness, also is reported to cause pertussis-like cough illness in small outbreaks in healthy persons. Bordetella bronchiseptica is a common animal pathogen. Occasional reports in humans describe a variety of body sites involved, and cases typically occur in immunocompromised persons or young children with intense exposure to animals. Protracted coughing (which in some cases is paroxysmal) is attributable sporadically to Mycoplasma, parainfluenza viruses, influenza viruses, enteroviruses, respiratory syncytial virus (RSV), or adenoviruses.

Epidemiology

The World Health Organization (WHO) estimated that in 2008, 16 million cases of pertussis and 195,000 childhood deaths occurred worldwide, 95% of which were in developing countries. The WHO also estimated that 82% of infants worldwide received 3 doses of pertussis vaccine and that global vaccination against pertussis averted 687,000 deaths in 2008. Before vaccination was available, pertussis was the leading cause of death from communicable disease among U.S. children <14 yr old, with 10,000 deaths annually. Widespread use of whole cell pertussis vaccine (DTP) led to a >99% decline in cases. After the low U.S. number of 1,010 cases reported in 1976, there was an increase in annual pertussis incidence to 1.2 cases per 100,000 population from 1980 through 1989, with epidemic pertussis in many states in 1989–1990, 1993, and 1996. Since then, pertussis has become increasingly endemic, with shifting burden of disease to young infants, adolescents, and adults. By 2004, the incidence of reported pertussis in the United States was 8.9 cases per 100,000 in the general population and approximately 150 per 100,000 in infants <2 mo old, with 25,827 total cases reported, the highest since 1959. A total of 40 pertussis-related deaths were reported in 2005, and 16 were reported in 2006; >90% of these cases occurred in infants.

Prospective and serologic studies suggested that pertussis is underrecognized , especially among adolescents and adults, in whom the actual number of U.S. cases is estimated to be 600,000 annually. A number of studies documented pertussis in 13–32% of adolescents and adults with cough illness for >7 days. Responding to these changes in epidemiology, tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis antigens ( Tdap ) was recommended in 2006 for 11-12 yr olds and was aimed to enhance control. With >70% uptake of Tdap in adolescents, the burden of disease in young adolescents fell commensurately, but without evidence of protection of the community (herd) of young infants, older adolescents, and adults. An epidemiologic shift has occurred due to substantial and rapid waning of protection following both DTaP and Tdap in the aging cohort of children and adolescents who were not primed with DTP (whole cell) vaccine, which was no longer used in the United States after 1997. The >42,000 cases of pertussis and 20 deaths reported in 2012 were the highest numbers in >50 yr. A shift in disease burden was observed among 7-10 yr olds in 2010, 13-14 yr olds in 2012, and 14-16 yr olds in 2014, as the cohort of solely DTaP-vaccinated cohort aged.

Neither natural disease nor vaccination provides complete or lifelong immunity against pertussis reinfection or disease. Subclinical reinfection undoubtedly contributed significantly to immunity against disease ascribed previously to both vaccine and prior infection. The resurgence of pertussis can be attributed to a variety of factors, including partial control of pertussis leading to less continuous exposure as well as increased awareness and improved diagnostics. Rapidly waning vaccine-induced immunity and pathogen adaptation are most important currently. Although the DTaP series is protective short-term, vaccine effectiveness wanes rapidly, with estimates of only 10% protection 8.5 yr after the 5th dose. Tdap protection also is short-lived, with efficacy falling from >70% initially to 34% within 2-4 yr. Divergence of circulating strains from vaccine strains began with the introduction of DTP, but with the exclusive use of acellular pertussis vaccines, pertactin-deficient strains emerged and have become dominant in countries where these vaccines are used. Pertactin-deficient B. pertussis was first reported in the United States from a Philadelphia infant case collection from 2008 to 2011. The Centers for Disease Control and Prevention (CDC) subsequently reported the earliest U.S. isolate from 1994 and rapid dominance of pertactin-deficient strains in the United States since 2010. Despite the role of pertactin as a bacterial virulence factor, illness severity in infants with pertactin-deficient B. pertussis is similar to that of pertactin-producing strains. Until development of new pertussis vaccine(s), pertussis will continue to be endemic, with cycling epidemics.

Pathogenesis

Bordetella organisms are small, fastidious, gram-negative coccobacilli that colonize only ciliated epithelium. The exact mechanism of disease symptomatology remains unknown. Bordetella species share a high degree of DNA homology among virulence genes. Only B. pertussis expresses pertussis toxin (PT), the major virulence protein. PT has numerous proven biologic activities (e.g., histamine sensitivity, insulin secretion, leukocyte dysfunction). Injection of PT in experimental animals causes lymphocytosis immediately by rerouting lymphocytes to remain in the circulating blood pool but does not cause cough. PT appears to have a central, but not a singular, role in pathogenesis. B. pertussis produces an array of other biologically active substances, many of which are postulated to have a role in disease and immunity. After aerosol acquisition, filamentous hemagglutinin , some agglutinogens (especially fimbriae [Fim] types 2 and 3), and the 69-kDa pertactin (Prn) protein are important for attachment to ciliated respiratory epithelial cells. Tracheal cytotoxin, adenylate cyclase, and PT appear to inhibit clearance of organisms. Tracheal cytotoxin, dermonecrotic factor, and adenylate cyclase are postulated to be predominantly responsible for the local epithelial damage that produces respiratory symptoms and facilitates absorption of PT. Both antibody and cellular immune responses follow infection and immunization. Antibody to PT neutralizes toxin, and antibody to Prn enhances opsonophagocytosis. Disease as well as DTP appear to drive a mixed cellular and antibody (Th1) immunologic response, while DTaP and Tdap drive a narrow antibody-dominant (Th2) response.

Pertussis is extremely contagious , with attack rates as high as 100% in susceptible individuals exposed to aerosol droplets at close range. High airborne transmission rates were shown in a baboon model of pertussis despite vaccination with the acellular vaccine. B. pertussis does not survive for prolonged periods in the environment. Chronic carriage by humans is not documented. After intense exposure as in households, the rate of subclinical infection is as high as 80% in fully immunized or previously infected individuals. When carefully sought, a symptomatic source case can be found for most patients; usually a sibling or related adult.

Clinical Manifestations

Classically, pertussis is a prolonged disease, divided into catarrhal, paroxysmal, and convalescent stages. The catarrhal stage (1-2 wk) begins insidiously after an incubation period ranging from 3-12 days with nondistinctive symptoms of congestion and rhinorrhea variably accompanied by low-grade fever, sneezing, lacrimation, and conjunctival suffusion. As initial symptoms wane, coughing marks the onset of the paroxysmal stage (2-6 wk). The cough begins as a dry, intermittent, irritative hack and evolves into the inexorable paroxysms that are the hallmark of pertussis. A well-appearing, playful toddler with insignificant provocation suddenly expresses an anxious aura and may clutch a parent or comforting adult before beginning a machine-gun burst of uninterrupted cough on a single exhalation, chin and chest held forward, tongue protruding maximally, eyes bulging and watering, face purple, until coughing ceases and a loud whoop follows as inspired air traverses the still partially closed airway. Posttussive emesis is common, and exhaustion is universal. The number and severity of paroxysms escalate over days to a week and remain at that plateau for days to weeks. At the peak of the paroxysmal stage, patients may have >1 episode hourly. As the paroxysmal stage fades into the convalescent stage (≥2 wk), the number, severity, and duration of episodes diminish.

Infants <3 mo old do not display the classic stages. The catarrhal phase lasts only a few days or is unnoticed, and then, after the most insignificant startle from a draft, light, sound, sucking, or stretching, a well-appearing young infant begins to choke, gasp, gag, and flail the extremities, with face reddened. Cough may not be prominent, especially in the early phase, and whoop is infrequent. Apnea and cyanosis can follow a coughing paroxysm, or apnea can occur as the only symptom (without cough). Both are more common with pertussis than with neonatal viral infections. The paroxysmal and convalescent stages in young infants are lengthy. Paradoxically, in infants, cough and whooping may become louder and more classic in convalescence. “Exacerbations” of paroxysmal coughing can occur throughout the 1st yr. of life with subsequent respiratory illnesses; these are not a result of recurrent infection or reactivation of B. pertussis.

Adolescents and previously immunized children have foreshortening of all stages of pertussis. Adults have no distinct stages. Classically, adolescents and adults describe a sudden feeling of strangulation followed by uninterrupted coughs, feeling of suffocation, bursting headache, diminished awareness, and then a gasping breath, usually without a whoop. Posttussive emesis and intermittency of paroxysms separated by hours of well-being are specific clues to the diagnosis. At least 30% of adolescents and adults with pertussis have nonspecific cough illness, distinguished only by duration, which usually is >21 days.

Findings on physical examination generally are uninformative. Signs of lower respiratory tract disease are not expected unless complicating secondary bacterial pneumonia is present. Conjunctival hemorrhages and petechiae on the upper body are common.