WHOOPING COUGH (PERTUSSIS)
• Primarily a toxin-mediated disease
• Incubation period 7 to 10 days (range 4 to 21 days)
• Insidious onset, similar to the common cold with nonspecific cough
• Catarrhal stage: 1 to 2 weeks
• Paroxysmal cough stage: 1 to 6 weeks
• Convalescence: weeks to months
• Nasopharyngeal culture—gold standard
• Vaccination is key for prevention.
• Early treatment eradicates the organism from secretions, decreasing transmission, and may shorten the course of the illness.
• Macrolides are the treatment of choice, specifically azithromycin (Zithromax).
Pertussis, or whooping cough, is an acute infectious disease caused by the bacterium Bordetella pertussis. Outbreaks of pertussis were first described in the 16th century, and the organism was first isolated in 1906.
In the 20th century, pertussis was one of the most common childhood diseases and a major cause of childhood mortality in the United States. In 1932, an outbreak of whooping cough hit Atlanta, Georgia, and a pediatrician by the name of Leila Denmark began her study of the disease. In partnership with Emory University and Eli Lilly & Company, she developed the first pertussis vaccine. Before the availability of the pertussis vaccine in the 1940s, more than 200,000 cases of pertussis were reported annually. Since widespread use of the vaccine began, incidence has decreased more than 80% compared with the prevaccine era.
Worldwide, it is estimated that there are about 16 million pertussis (whooping cough) cases and about 195,000 pertussis deaths in children per year. Despite generally high coverage with childhood pertussis vaccines, pertussis is one of the leading causes of vaccine- preventable deaths worldwide. Most deaths occur in infants who are either unvaccinated or incompletely vaccinated. The World Health
Organization (WHO) estimates that in 2008, global vaccination against pertussis prevented approximately 687,000 deaths. The year 2012 was the peak year in which there were 48,277 reported cases in the United States, which drew the attention of the public health community.
Through vaccination efforts and education, in 2015, reported cases in the United States dropped to 20,762 people.
Pertussis is a human disease. There is no animal, insect source, or vector. Adolescents and adults are an important reservoir for B. pertussis and are often the source of infection for infants.
Transmission most commonly occurs by the respiratory route through contact with respiratory droplets or by contact with airborne droplets of respiratory secretions. Transmission occurs less frequently by contact with freshly contaminated articles of an infected person as the bacteria does not survive long outside of the reservoir. Pertussis is highly communicable, as evidenced by secondary attack rates of 80% among susceptible household contacts. Persons with pertussis are most infectious during the catarrhal period and the first 2 weeks after cough onset (Figure 1).
FIGURE 1 Changes in pertussis reporting by state from 2013 to 2014.
B. pertussis is a small, aerobic, gram-negative rod. pertussis produces multiple antigenic and biologically active products, including pertussis toxin (PT), filamentous hemagglutinin (FHA), agglutinogens, adenylate cyclase, pertactin, and tracheal cytotoxin. These products are responsible for the clinical features of pertussis disease, and an immune response to one or more produces immunity following infection. Immunity following B. pertussis infection does not appear to be permanent.
Pertussis is primarily a toxin-mediated disease. The bacteria attach to the cilia of the respiratory epithelial cells, produce toxins that paralyze the cilia, and cause inflammation of the respiratory tract, which interferes with the clearing of pulmonary secretions. Pertussis antigens appear to allow the organism to evade host defenses, in that lymphocytosis is promoted but chemotaxis is impaired. Until recently it was thought that B. pertussis did not invade the tissues. However, recent studies have shown the bacteria to be present in alveolar macrophages.
The steps in pathogenesis are:
- Tissue tropism/attachment
- Proliferation and production of virulence factors
- Evasion/modulation of host defenses
- Local and systemic cell and tissue dysfunction/damage
- Clearance and resolution of symptoms or chronic infection or death
PT is important but not essential, and its adenosine diphosphate (ADP)-ribosylation of heterotrimeric G proteins affects signal transduction (disrupts function) in many cell types. The resulting biological effects include induction of lymphocytosis, alteration in insulin secretion, and enhancement of sensitivity to histamine and other mediators.
This large surface protein can participate in the interaction of B. pertussis with host cells and exerts immunomodulatory effects; thus it is appropriately classified as an adhesion.
Pertactin (PRN) can contribute to bacterium–host cell interaction as an adhesin. PRN was found to have a role in defense against neutrophils (polymorphonuclear neutrophils), suggesting immunomodulation with consequences similar to those of adenylate cyclase toxin.
These surface appendages, similar to those in other bacteria, function as adhesins and make up several of the agglutinogens, which are the basis for Bordetella serotyping.
Adenylate Cyclase Toxin
This toxin delivers an adenylate cyclase domain into host cells, where it increases cyclic adenosine monophosphate (cAMP) levels, resulting in inhibition of phagocyte function and activation of apoptosis in some cell types. Adenylate cyclase toxin is a critical virulence factor.
This disaccharide-tetrapeptide, derived from peptidoglycan, kills respiratory epithelial cells in vitro by a complex mechanism involving intracellular interleukin-1 and nitric oxide.
The whole clinical course of the illness can typically last from 30 to 90 days and is divided into three stages. The incubation period of pertussis is commonly 7 to 10 days but can range anywhere from 4 to 21 days.
The first stage, the catarrhal stage, is similar to the symptoms of the common cold and characterized by sneezing, low-grade fever, rhinitis, and a mild, occasional cough. This cough gradually becomes more severe over 1 to 2 weeks, which transitions to the second, or paroxysmal, stage.
It is during the paroxysmal stage that the diagnosis of pertussis is usually suspected. Typically the patient has paroxysms or “fits” of numerous rapid coughs, apparently due to irritation of the tracheal- bronchial tree. Owing to the length and force of the paroxysm, a long deep inspiratory effort is usually accompanied by a distinctive high- pitched “whoop.” Children and young infants usually appear very ill and distressed during these occurrences. Posttussive vomiting and exhaustion commonly follow the episode. Between attacks, the patient may not appear ill. Paroxysmal attacks occur more frequently at night, with an average of 15 attacks per 24 hours. During the first 1 or 2 weeks of this stage, the attacks increase in frequency, remain at the same level for 2 to 3 weeks, and then gradually decrease. The paroxysmal stage usually lasts 1 to 6 weeks but may persist for up to 10 weeks.
In the convalescent stage, recovery is gradual. The cough becomes less paroxysmal and disappears in 2 to 3 weeks. However, paroxysms often recur with subsequent respiratory infections for many months after the onset of pertussis.
Adolescents, adults, and children partially protected by the vaccine may become infected with B. pertussis but may have milder disease than infants and young children. Pertussis infection in these persons may range from being asymptomatic to having classic pertussis symptoms.
The most common complication and the cause of most pertussis- related deaths is secondary bacterial pneumonia. Young infants are at highest risk for acquiring pertussis-associated complications.
Neurologic complications such as seizures and encephalopathy may occur as a result of hypoxia or possibly from the toxin itself.
Neurologic complications of pertussis are more common among infants. Other less serious complications of pertussis include otitis media, anorexia, and dehydration. Complications resulting from pressure effects of severe paroxysms include pneumothorax, epistaxis, subdural hematomas, hernias, and rectal prolapse.
In 2008 through 2011, a total of 72 deaths from pertussis were reported to the Centers for Disease Control and Prevention (CDC). Children 3 months of age or younger accounted for 60 (83%) of these deaths.
Most healthy older children and adults fully recover, but those with comorbid conditions have a higher risk of morbidity and mortality.
Infection in newborns is particularly severe. Pertussis is fatal in an estimated 1.6% of hospitalized U.S. infants younger than 1 year of age. First-year infants are also more likely to develop complications, such as pneumonia (20%), encephalopathy (0.3%), seizures (1%), failure to thrive, and death (1%). This is perhaps the result of the ability of the bacterium to suppress the immune system. Pertussis can cause severe paroxysm-induced cerebral hypoxia, and 50% of infants admitted to hospitals suffer apneas.
The diagnosis of pertussis is based on a characteristic clinical history (cough for more than 2 weeks with whoop, paroxysms, or posttussive vomiting), as well as a variety of laboratory tests (culture, polymerase chain reaction [PCR], and serology).
An elevated white blood cell count with a lymphocytosis is usually present in classical disease of infants. The absolute lymphocyte count is usually greater than 10,000 and often reaches 20,000. However, lymphocytosis is not absolute. Chest radiographs may show peribronchial consolidation, interstitial edema, or variable atelectasis.
Culture is considered the gold standard laboratory test and is the most specific of the laboratory tests for pertussis. However, fastidious growth requirements make B. pertussis difficult to culture. The yield of culture can be affected by specimen collection, transportation, and isolation techniques. Specimens from the posterior nasopharynx, not the throat, should be obtained. Isolation rates are highest during the first 2 weeks of illness (catarrhal and early paroxysmal stages). Since adolescents and adults have often been coughing for several weeks before they seek medical attention, it is often too late for culture to be useful.
PCR is a rapid test and has excellent sensitivity. PCR tests vary in specificity, so obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time there is suspicion of a pertussis outbreak. Results should be interpreted along with the clinical symptoms and epidemiologic information. PCR should be tested from nasopharyngeal specimens taken at 0 to 3 weeks following cough onset, but may provide accurate results for up to 4 weeks of cough in infants or unvaccinated persons. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining false-negative results
Serologic testing could be useful for adults and adolescents who present late in the course of their illness, when both culture and PCR are likely to be negative. Generally, serologic tests are more useful for diagnosis in later phases of the disease.
Because direct fluorescent antibody testing of nasopharyngeal secretions has been demonstrated in some studies to have low sensitivity and variable specificity, such testing should not be relied on as a criterion for laboratory confirmation.
All positive test results should be reported to the local health department.
Early treatment of pertussis is very important. The earlier a person, especially an infant, starts treatment the better. If treatment for pertussis is started early in the course of illness, during the first 1 to 2 weeks before coughing paroxysms occur, symptoms may be lessened. Clinicians should strongly consider treating prior to receiving test results if clinical history is strongly suggestive or the patient is at risk for severe or complicated disease (e.g., infants). If the patient is diagnosed late, antibiotics will not alter the course of the illness, and even without antibiotics, the patient should no longer be spreading pertussis.
Antibiotic therapy eradicates the organism from secretions, thereby decreasing communicability, and if initiated early, it will modify the course of the illness. Recommended first-line antibiotics are macrolides:
- Azithromycin (Zithromax)1
- Clarithromycin (Biaxin)1
- Erythromycin (Ery-Tab)
- Trimethoprim-sulfamethoxazole (less effective)1
Persons with pertussis are infectious from the beginning of the catarrhal stage through the third week after the onset of paroxysms (multiple, rapid coughs) or until 5 days after the start of effective antimicrobial treatment.
Postexposure Antimicrobial Prophylaxis
The CDC supports targeting postexposure antibiotic use to persons at high risk of developing severe pertussis and to persons who will have close contact with those at high risk of developing severe pertussis.
A reasonable guideline is to treat persons older than 1 year of age within 3 weeks of cough onset and infants younger than 1 year of age and pregnant women (especially near term) within 6 weeks of cough onset. A course of antibiotics should be administered to close contacts within 3 weeks of exposure, especially in high-risk settings. Use the same doses as in the treatment schedule.
The primary method of prevention for pertussis is vaccination. Refer to the CDC recommended immunization schedule for details.
Evidence is insufficient to determine the effectiveness of antibiotics in those who have been exposed but are without symptoms. Preventive antibiotics, however, are still frequently used in those who have been exposed and are at high risk of severe disease (such as infants).
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1 Not FDA approved for this indication.