Bordetella pertussis

History

The first epidemic of whooping cough was described in 1578 by de Baillou, who wrote the following: “The lung is so irritated that, in its attempt by every effort to cast forth the cause of the trouble, it can neither admit breath nor easily give it forth again. The sick person seems to swell up, and, as if about to strangle, holds his breath clinging in the midst of his jaws.” This vivid clinical description of whooping cough holds true to this day. In 1679, Sydenham gave this respiratory illness the name “pertussis,” meaning a violent cough of any type. The organism that causes whooping cough was discovered in 1900 by Bordet and Gengou. They described a new gram-negative bacillus (subsequently named Bordetella pertussis , after Bordet) that they had found in the sputum of a 6-month-old infant with whooping cough. By 1906, they had developed a culture medium to support the growth of the organism and described in detail its morphologic features and virulence characteristics. In 1943, Joseph Lapin, a pediatrician who worked in the whooping cough clinic at the Bronx Hospital in New York City, wrote an extensive monograph on the subject of pertussis.

Description of Pathogen

B. pertussis is the pathogen that causes whooping cough or pertussis. It is one of 10 known Bordetella species, namely, B. pertussis, B. parapertussis, B. bronchiseptica, ovine-adapted B. parapertussis, B. avium, B. hinzii, B. holmesii, B. trematum, B. petrii, and B. ansorpii. B. pertussis and B. parapertussis are the most common Bordetella species causing respiratory illnesses in humans. With improved molecular testing methods, polymerase chain reaction (PCR) assays can now distinguish between B. pertussis and B. holmesii and have detected B. holmesii in 0.1% to 20% of patients with pertussis-like symptoms. B. holmesii can colonize the respiratory tract but also can cause a pertussis-like syndrome. Unlike B. pertussis, B. holmesii can cause bacteremia or other nonpulmonary infections. Distinction between the two species can be through biochemical reactions, the distinctive brown pigment of B. holmesii, or use of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry.

Although B. pertussis strictly affects humans and has no known animal reservoir, many of the other Bordetella species are recognized primarily for the diseases they cause in animals. B. bronchiseptica causes kennel cough in dogs and cats, and human infections occur primarily in immunocompromised patients, often after exposure to animals. Ovine-adapted B. parapertussis causes respiratory tract infections in sheep. B. avium is a pathogen of poultry but has been isolated from the ear culture of a patient with chronic otitis media. Similarly, B. hinzii also colonizes the respiratory tract of poultry and has been isolated from the sputum of cystic fibrosis patients. It has been reported to cause bacteremia in immunocompromised and in immunocompetent patients and has been described as a cause of chronic cholangitis. B. trematum has been isolated from patients with wounds or otitis media. B. petrii, originally identified from an environmental source, has been isolated from patients with chronic infections. Finally, in 2005, a novel species of Bordetella, Bordetella ansorpii, was described after the isolation of a gram-negative bacillus from the purulent exudate of an epidermal cyst. 16S ribosomal RNA (rRNA) gene sequencing has revealed that this bacterium belongs to the Bordetella genus but is distinct from other Bordetella species. This species was subsequently isolated from an immunocompromised patient in the United Kingdom.

Bordetella species are small gram-negative coccobacilli. Some species are motile and, except for B. petrii, are strictly aerobic. All species possess catalase activity and oxidize amino acids but do not ferment carbohydrates. Bordetella organisms grow optimally at 35°C to 37°C. Bordetella species are fastidious because their growth can be inhibited by components commonly found in laboratory media. In addition, their rate of growth is inversely related to their degree of fastidiousness. B. pertussis is the most fastidious and slowest growing of the Bordetella species. Its growth is inhibited by fatty acids, metal ions, sulfides, and peroxides. Isolation of B. pertussis requires a medium containing charcoal, blood, or starch. Traditionally, Bordet-Gengou (BG) medium has been used and consists of a potato-starch base. Charcoal medium (Regan-Lowe [RL] medium), supplemented with glycerol, peptones, and horse or sheep blood, can also be used and may provide better isolation of B. pertussis than the BG medium.

Pathogenesis

B. pertussis infection and disease occur after four important steps: (1) attachment, (2) evasion of host defenses, (3) local damage, and (4) systemic manifestations.

Filamentous hemagglutinin (FHA) and fimbriae (FIM) are two major adhesins and virulence determinants for B. pertussis. FHA is a 220-kDa surface-associated and secreted protein, and FIM is a filamentous cell surface structure. They are required for tracheal colonization, are highly immunogenic, and are components of certain acellular pertussis vaccines. However, there is likely redundancy in the adhesion role of B. pertussis proteins, and it has been suggested that virulence factors such as pertactin (PRN) may mediate attachment in the absence of FHA. Pertussis toxin (PT) also acts as an adhesin and has specific recognition domains for human cilia.

Evasion of host defenses occurs primarily through adenylate cyclase toxin (ACT) and PT. ACT is a toxin secreted by B. pertussis that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which inhibits the migration and activation of phagocytes. It has also been shown to suppress T-lymphocyte activation and chemotaxis. PT, one of the most important virulence factors of B. pertussis, also targets the innate immune system of the lung by inactivating or suppressing G protein–coupled signaling pathways. PT has two components, the A subunit and the B subunit. The B (binding) subunit binds to the cell surface to enable adenosine diphosphate (ADP)–ribosylation of G proteins by the A (active) subunit, thereby altering the cell. Through this mechanism of action, PT delays the recruitment of neutrophils to the respiratory tract and targets airway macrophages to promote B. pertussis infection. The virulence factors of B. pertussis, such as PT, are encoded by the bvg (or vir ) gene. The bvg operon is composed of bvgA and bvgS, members of a two-component signal transduction system that controls the genetic state, or phase, of B. pertussis. There are virulent and avirulent phases, and their expression is regulated by environmental factors.

Original reports by Lapin described the local tissue damage caused by pertussis in the lung. The initial pulmonary lesion is a lymphoid hyperplasia of peribronchial and tracheobronchial lymph nodes. Necrosis and desquamation of the bronchial epithelium follow, with diffuse infiltrations by macrophages ( Fig. 230.1 ). Most of the damage to the ciliated epithelial cells is caused by tracheal cytotoxin (TCT). TCT is a disaccharide tetrapeptide derived from peptidoglycan, which triggers the production of an inducible nitric oxide (NO) synthase. The synthase produces NO, which ultimately kills the tracheal epithelial cells. The induction of the NO synthase is likely caused by the cytokine interleukin-1 (IL-1), generated in response to TCT. Dermonecrotic toxin (DNT), a 160-kDa heat-labile secreted toxin that activates intracellular Rho guanosine triphosphate (GTP)ases, may also have a role in local tissue damage. DNT was first discovered by Bordet and Gengou and derives its name from the characteristic skin lesion produced when injected into test animals.

Unlike other bacterial diseases, there are few systemic manifestations of B. pertussis infection because it does not enter the circulation and disseminate. B. pertussis is relatively sensitive to killing by serum in vitro. However, in vivo, even serum-sensitive strains can efficiently infect mice. B. pertussis has multiple mechanisms for avoiding antibody-mediated complement killing, including the expression of BrkA, a surface-associated protein belonging to the autotransporter secretion system. PT is the primary virulence determinant responsible for the systemic manifestations, of which the most prominent is leukocytosis with lymphocytosis. Other systemic responses include sensitization to histamine and serotonin and sensitization of the beta-islet cells of the pancreas. This latter effect leads to hyperinsulinemia with resultant hypoglycemia, particularly in young infants. Pertussis-associated encephalopathy is observed rarely ; some have suggested that it may be caused by the effect of PT on the central nervous system via monocyte chemoattractant protein-1 (MCP-1) overexpression. Fatal pulmonary hypertension has also been associated with pertussis in infants. Pathologic studies have demonstrated that, in addition to producing pulmonary vasoconstriction resulting from hypoxemia, pulmonary infection with B. pertussis triggers toxin-mediated leukocytosis, causing increased vascular resistance and subsequent refractory pulmonary hypertension.

In addition to the direct effects of these virulence factors in the lung, some believe that they modulate, in a more global fashion, the immune system itself. Studies investigating immunomodulation by B. pertussis have demonstrated skewing of the host immune response toward expansion of the Th17 subset of T lymphocytes, induced by the production of cytokine IL-23. The Th17 immune response may be protective against some other gram-negative bacterial respiratory pathogens but may also be associated with chronic autoimmune inflammation. Some have suggested that the chronic cough seen with B. pertussis infection may be explained by this autoimmune phenomenon, akin to asthma, although it has also been hypothesized to be a direct effect of mediators such as bradykinin released in response to tissue damage.

Epidemiology

Despite vaccination, pertussis disease continues to be a problem in the developing and developed world ( Fig. 230.2 ). According to the World Health Organization (WHO), an estimated 24.1 million cases and 160,700 deaths occurred in 2014 in children younger than 5 years because of B. pertussis. Case-fatality rates in developing countries may be as high as 3% in infants. WHO recommended that a pertussis incidence of less than 1 case per 100,000 population be achieved in Europe by 2000. Data from countries represented in the Global Pertussis Initiative (GPI) have indicated that this incidence has not yet been achieved.

Current Issues Regarding Resurgence of Pertussis

In recent years, a resurgence in pertussis has been reported in many countries worldwide. The reason for this resurgence is likely to be multifactorial. One of the key factors is the finding that neither natural pertussis infection nor immunization produces lifelong immunity to pertussis. Different pertussis vaccines have had varying rates of success over the years. In the 1990s, Canada experienced a resurgence of pertussis, primarily in young adolescents. This was a result of the low effectiveness of the whole-cell pertussis vaccine used between 1985 and 1998 in that country. This resulted in a “marching cohort” effect, or an increase each year in the age of peak incidence by 1 year, which revealed the existence of a susceptible cohort ( Fig. 230.3 ). This was addressed with universal immunization programs to vaccinate adolescents with a more effective acellular pertussis vaccine. However, despite a more effective acellular pertussis vaccine, pertussis outbreaks continue to be reported in young adults and in young children who recently completed a full pertussis vaccine series. In 2010, a large pertussis outbreak occurred in California, with the highest number of pertussis cases in more than 60 years. Second to children younger than 6 months, the highest disease rates were observed in fully vaccinated preadolescents (7–10 years of age), as observed by others. A case-control study of children 4 to 12 years of age who were PCR positive for pertussis, compared with PCR-negative and matched controls, demonstrated that PCR-positive children were more likely to have received the fifth DTaP (diphtheria toxoid, tetanus toxoid, acellular pertussis vaccine) dose earlier than controls, with an odds of acquiring pertussis increasing by an average of 42% per year. This suggests that immunity after acellular pertussis vaccination may begin to decline after 4 to 5 years, indicating that a booster dose may be appropriate. Epidemiologic studies have also shown that decreasing antibody levels to PT at a population level can precede large pertussis epidemics, although long-term memory B cells in vaccinated children may persist despite waning antibody levels and may provide protection against pertussis disease. Additional factors that may have contributed to the resurgence in reported pertussis include increased awareness and subsequent testing for pertussis with very sensitive molecular methods that can detect as little as one organism of B. pertussis , making it difficult to distinguish between colonization and disease (discussed further under “Carrier State”). Finally, it is possible that the bacterium itself has evolved and changed over time in response to vaccination practices; additional detail regarding strain variation among B. pertussis is included in the section “Molecular Diagnosis.”

Clinical Presentation

There is a spectrum of disease caused by B. pertussis infection, and its presentation will vary according to the patient's age, degree of immunity, use of antibiotics, and respiratory coinfection.