Disease
B. pertussis causes whooping cough (pertussis).
Important Properties
B. pertussis is a small, coccobacillary, encapsulated gram negative rod.
Pathogenesis & Epidemiology
B. pertussis, a pathogen only for humans, is transmitted by airborne droplets produced during the severe coughing episodes. The organisms attach to the ciliated epithelium of the upper respiratory tract but do not invade the underlying tissue. Decreased cilia activity and subsequent death of the ciliated epithelial cells are important aspects of pathogenesis.
Pertussis is a highly contagious disease that occurs primarily in infants and young children and has a worldwide distribution. The number of cases has declined in the United States because use of the vaccine is widespread. However, outbreaks of pertussis during the years 2005, 2010, and 2012 have led to concern about waning immunity to the vaccine and to the recommendation that an additional booster immunization be given (see “Prevention”).
The following several factors play a role in the pathogenesis:
(1) Attachment of the organism to the cilia of the epithelial cells is mediated by a protein on the pili called filamentous hem agglutinin. Antibody against the filamentous hemagglutinin inhibits attachment and protects against disease.
(2) Pertussis toxin stimulates adenylate cyclase by catalyzing the addition of adenosine diphosphate ribose—a process called ADP-ribosylation—to the inhibitory subunit of the G protein complex (Gi protein). This results in prolonged stimulation of adenylate cyclase and a consequent rise in cyclic adenosine monophosphate (AMP) and in cyclic AMP-dependent protein kinase activity. This results in edema of the respiratory mucosa that contributes to the severe cough of pertussis. The toxin also has a domain that mediates its binding to receptors on the surface of respiratory tract epithelial cells. It is an A-B subunit toxin. Pertussis toxin also causes a striking lymphocytosis in the blood of patients with pertussis. The toxin inhibits signal transduction by chemokine receptors, resulting in a failure of lymphocytes to enter lymphoid tissue such as the spleen and lymph nodes. Because the lymphocytes do not enter lymphoid tissue, there is an increase in their number in the blood (see the discussion of chemokines in Chapter 58). The inhibition of signal transduction by chemokine receptors is also caused by ADP-ribosylation of the Gi protein.
(3) The organisms also synthesize and export adenylate cyclase. This enzyme, when taken up by phagocytic cells (e.g., neutrophils), can inhibit their bactericidal activity. Bacterial mutants that lack cyclase activity are avirulent.
(4) Tracheal cytotoxin is a fragment of the bacterial peptidoglycan that damages ciliated cells of the respiratory tract. Tracheal cytotoxin appears to act in concert with endotoxin to induce nitric oxide, which kills the ciliated epithelial cells.
Clinical Findings
Whooping cough is an acute tracheobronchitis that begins with mild upper respiratory tract symptoms followed by a severe paroxysmal cough, which lasts from 1 to 4 weeks. The paroxysmal pattern is characterized by a series of hacking coughs, accompanied by production of copious amounts of mucus, that end with an inspiratory “whoop” as air rushes past the narrowed glottis. Despite the severity of the symptoms, the organism is restricted to the respiratory tract and blood cultures are negative. A pronounced leukocytosis with up to 70% lymphocytes is seen. Although central nervous system anoxia and exhaustion can occur as a result of the severe coughing, death is mainly due to pneumonia.
The classic picture of whooping cough described above occurs primarily in young children. In adults, B. pertussis infection often manifests as a paroxysmal cough of varying severity lasting weeks. The characteristic whoop is often absent, leading to difficulty in recognizing the cough as caused by this organ ism. In the correct clinical setting, adults with a cough lasting several weeks (often called the 100-day cough) should be evaluated for infection with B. pertussis.
Laboratory Diagnosis
The organism can be isolated from nasopharyngeal swabs taken during the paroxysmal stage. Bordet-Gengou1 medium used for this purpose contains a high percentage of blood (20%–30%) to inactivate inhibitors in the agar. Identification of the isolated organism can be made by agglutination with specific antiserum or by fluorescent antibody staining. However, the organism grows very slowly in culture, so direct fluorescent antibody staining of the nasopharyngeal specimens can be used for diagnosis. Polymerase chain reaction-based tests are rapid, specific, and highly sensitive and should be used if available.
Isolation of the organism in patients with a prolonged cough is often difficult. Serologic tests that detect antibody in the patient’s serum can be used for diagnosis in those patients.
Treatment
Azithromycin is the drug of choice. Note that azithromycin reduces the number of organisms in the throat and decreases the risk of secondary complications but has little effect on the course of the disease at the “prolonged cough” stage because the toxins have already damaged the respiratory mucosa. Supportive care (e.g., oxygen therapy and suction of mucus) during the paroxysmal stage is important, especially in infants.
Prevention
There are two types of vaccines: an acellular vaccine containing purified proteins from the organism and a killed vaccine containing inactivated B. pertussis organisms. The acellular vaccine contains five antigens purified from the organism. It is the vaccine currently used in the United States.
The main immunogen in this vaccine is inactivated pertussis toxin (pertussis toxoid). The toxoid in the vaccine is pertussis toxin that has been inactivated genetically by introducing two amino acid changes, which eliminates its ADP-ribosylating activity but retains its antigenicity. It is the first vaccine to contain a genetically inactivated toxoid. The other pertussis antigens in the vaccine are filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3. The acellular vaccine has fewer side effects than the killed vaccine but has a shorter duration of immunity. Outbreaks of pertussis are attributed to “waning immunity,” a manifestation of the short duration of vaccine induced immunity.
The pertussis vaccine is usually given combined with diphtheria and tetanus toxoids (DTaP) in three doses beginning at 2 months of age. A booster at 12 to 15 months of age and another at the time of entering school are recommended. Because outbreaks of pertussis have occurred among teenagers, a booster for those between 10 and 18 years old is recommended. A pertussis booster dose is recommended for adults as well. To protect newborns, pregnant women should receive pertussis vaccine. Antipertussis IgG will pass the placenta and protect the newborn.
The killed vaccine is no longer used in the United States because it is suspected of causing various side effects, including postvaccine encephalopathy at a rate of about one case per million doses administered. The killed vaccine is in use in many countries other than the United States.
Azithromycin is useful in prevention of disease in exposed, unimmunized individuals. It should also be given to immunized children younger than 4 years who have been exposed because vaccine-induced immunity is not completely protective.
