Pertussis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.

Pertussis, also known as whooping cough, is a highly contagious infectious disease caused by the bacterium Bordetella pertussis, a Gram-negative, aerobic, non-motile coccobacillus. The incidence of pertussis is approximately 1.5 to 3.0 per 100,000 individuals, with approximately 5,000 to 7,000 cases reported annually. Pertussis is primarily a toxin-mediated disease. It is highly contagious and is usually transmitted to the human host by direct contact with aerolized mucus of infected individuals. Risk factors in the development of pertussis include no or incomplete vaccination against pertussis, exposure to infected individuals, infants or children < 5 years of age, and immunocompromised status. The clinical course of the illness is divided into three stages: catarrhal, paroxysmal, and convalescent. If left untreated, the majority of patients develop low-grade fever and coryza (runny nose, occasional cough) for 1-2 weeks, followed by paroxysmal fits of whooping cough that may last 1-6 weeks, before finally recovering from the disease. Compared with children, adolescents and adults usually experience a milder course of the disease, and the characteristic whooping cough may be absent. Unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for developing severe infection and life-threatening complications and death. Prognosis is generally excellent, but unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for severe and life-threatening complications and death. Complications of pertussis may include apnea, pneumonia, otitis media, pneumothorax, refractory pulmonary hypertension, and seizure. Pertussis is usually suspected based on clinical findings and confirmed by either nasopharyngeal culture, polymerase chain reaction (PCR), or serology. The mainstay of treatment of pertussis is antibiotic therapy with either a macrolide or trimethoprim-sulfamethoxasole. Post-exposure prophylaxis may be recommended among high-risk individuals. The primary prevention method for pertussis is vaccination with multiple doses of the DTaP vaccine during childhood and adolescence/adulthood. Patients who had been infected with pertussis or who have received vaccination against pertussis in the past may be re-infected in the future, but typically experience a milder course of the disease.

The first description of Pertussis dates back to the 12th century. The earliest outbreaks of pertussis were recognized by Bahaodwole Razi in 1502 in Persia and by Guillaume de Baillou in 1578 in France. Bordetella pertussis was first isolated by Jules Bordet and Octave Gengou in 1906. Bordet and Gengou developed the first vaccine and serological test for Pertussis. In the 1940s, Grace Elderling, Loney Gordon, and Pearl Kendrick combined diphtheria and tetanus with the pertussis and develop the first combination DTP vaccine. In response to adverse side effects of DTP, a safer acellular DTaP vaccine was created in Japan in 1981.

Pertussis is primarily a toxin-mediated disease. Bordetella pertussis is highly contagious and is usually transmitted to the human host by direct contact with aerolized mucus of infected individuals. B. pertussis attaches to the cilia of the respiratory epithelial cells, proliferates and produces virulence factors that paralyze the cilia, and causes inflammation of the respiratory tract, which interferes with the clearing of pulmonary secretions. B. pertussis utilizes virulence factors – including pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae (FIM), adenylate cyclase toxin (ACT), tracheal cytotoxin (TCT), lipooligosaccharide (LOS), and dermonecrotic toxin (DNT) – to attach, proliferate, and and evade the host immune system.^[1][2]

Bordetella pertussis is a Gram-negative, aerobic, non-motile, non-spore-forming coccobacillus. It is the pathogen responsible for pertussis (whooping cough). Unlike B. bronchiseptica, B. pertussis is not motile. Humans are the only known reservoir for B. pertussis. The lipopolysaccharide-containing outer membrane of B. pertussis is unique and contains a different phosphate composition from other bacterial outer membranes.

Pertussis must be differentiated from other causes of cough, dyspnea, and coryza, such as asthma, pneumonia, bronchiolitis, croup, common cold, cystic fibrosis, foreign body aspiration, gastroesophageal reflux disease, and sinusitis.

In the United States, the incidence of pertussis is approximately 1.5 to 3.0 per 100,000 individuals, with approximately 5,000 to 7,000 cases reported annually. The incidence of pertussis is thought to be on the rise due to the decline in vaccination rate and diminished herd immunity. Infants and young children < 5 years of age are more commonly infected with pertussis than adults. There is no gender predilection for the development of pertussis. Pertussis-related deaths are rare, but are more common in developing countries, among infants < 6 months of age, and among adult patients with significant co-morbidities.

Risk factors in the development of pertussis include no or incomplete vaccination against pertussis, exposure to infected individuals, infants or children < 5 years of age, and immunocompromised status.

The clinical course of the illness is divided into three stages: catarrhal, paroxysmal and convalescent. If left untreated, the majority of patients develop low-grade fever and coryza (runny nose, occasional cough) for 1-2 weeks, followed by paroxysmal fits of whooping cough that may last 1-6 weeks, before finally recovering from the disease. Compared with children, adolescents and adults usually experience a milder course of the disease, and the characteristic whooping cough may be absent. Unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for developing severe infection and life-threatening complications and death.^[3] Complications of pertussis include apnea, pneumonia, seizure, and death. Prognosis is generally excellent, but unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for severe and life-threatening complications and death.

Initially, symptoms of pertussis include cough, sneezing, and runny nose. After one to two weeks, the cough changes character, and patients typically experience whooping cough, which are paroxysms of violent coughing followed by an inspiratory “whooping” sound.

The physical examination of a patient with pertussis is usually unremarkable. Low grade fever, cyanosis, and conjunctival hemorrhages may be observed. Involvement of the lower respiratory tract indicates another underlying or concomitant process.

Several laboratory tests may be used to diagnose pertussis. Culture, obtained by nasopharyngeal swab, is considered the gold standard for diagnosis. Other tests that can be performed include polymerase chain reaction (PCR) and serology.

Chest radiography is usually unremarkable among patients with pertussis. Possible findings include atelectasis and lymphadenopathy.

Pertussis can also be diagnosed using direct flourescent antibody (DFA) and pulsed-field gel eletrophoresis tests.

The mainstay of treatment of pertussis is antibiotic therapy. Early treatment is essential: individuals aged >1 year should be treated within 3 weeks of cough onset, infants aged <1 year and pregnant women (especially near term) should be treated within 6 weeks of cough onset. The recommended antimicrobial agents for treatment of pertussis are macrolides. Trimethoprim-sulfamethoxasole is an alternative in those who do not tolerate macrolide antibiotics.^[4]

The primary prevention method for pertussis is vaccination using the DTaP vaccine. Five doses are recommended in children, with a booster dose recommended during adolescence/adulthood using a similar vaccine with smaller concentrations of diphtheria and pertussis toxoids known as Tdap.^[5]

Patients who had been infected with pertussis or have received vacccination against pertussis in the past may be re-infected (milder symptoms upon re-infection). Effective measures of secondary prevention include post-exposure antibiotic prophylaxis for individuals who are considered high-risk for developing the disease or having serious complications. Antibiotic prophylaxis regimens are similar to those used for treatment, and vary with the individual’s age.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Luke Rusowicz-Orazem, B.S.; Serge Korjian M.D.

The first description of pertussis dates back to the 12th century. The earliest outbreaks of pertussis were recognized by Bahaodwole Razi in 1502 in Persia and by Guillaume de Baillou in 1578 in France. Bordetella pertussis was first isolated by Jules Bordet and Octave Gengou in 1906. Bordet and Gengou developed the first vaccine and serological test for Pertussis. In the 1940s, Grace Elderling, Loney Gordon, and Pearl Kendrick combined diphtheria and tetanus with the pertussis and develop the first combination DTP vaccine. In response to adverse side effects of DTP, a safer acellular DTaP vaccine was created in Japan in 1981.

• The earliest description of Pertussis dates back to the 12th century.
• The characteristic whooping cough was often described as “the kink” or “the kindhoest”.^[1]
• In 1502, the first outbreak of Pertussis was reported by the Persian Physician Bahaodowle Razi in the Persian Empire.^[2]
• In 1578, pertussis outbreak was first reported in Paris by French physician Guillaume de Baillou.^[1]
• Bordetella pertussis was first isolated in 1906 by Belgian biologists Jules Bordet and Octave Gengou.

• Jules Bordet and Octave Gengou developed the first vaccine and serological test for pertussis following the discovery of the Bordetella pertussis organism.
• In 1942, American scientists Grace Eldering, Loney Gordon, and Pearl Kendrick combined the whole-cell pertussis vaccine with diphtheria and tetanus toxoids to generate the first DTP combination vaccine.
• In 1981, an acelluar vaccine was created in Japan and was added in 1992 to the DTP Vaccine to create the DTaP vaccine. Compared with the DTP vaccine, the DTaP vaccine had a much smaller rate of adverse side effects.^[3]

• The highest recorded annual incidence of pertussis occurred in 1934 when more than 260,000 cases were reported.
• The incidence of reported pertussis disease declined substantially in the 1940s as use of whole-cell DTP vaccines became widespread.
• By 1970, the reported incidence had declined greater than 99%, only 1,010 cases were reported in 1976.
• A rise in the incidence of pertussis was observed in the early 1980s reported pertussis, and cyclical peaks in incidence occurred in 1983, 1986, 1990, and in 1993.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.; Aditya Govindavarjhulla, M.B.B.S. [2]

Pertussis is primarily a toxin-mediated disease. Bordetella pertussis is highly contagious and is usually transmitted to the human host by direct contact with aerolized mucus of infected individuals. B. pertussis attaches to the cilia of the respiratory epithelial cells, proliferates and produces virulence factors that paralyze the cilia, and causes inflammation of the respiratory tract, which interferes with the clearing of pulmonary secretions. B. pertussis utilizes virulence factors – including pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae (FIM), adenylate cyclase toxin (ACT), tracheal cytotoxin (TCT), lipooligosaccharide (LOS), and dermonecrotic toxin (DNT) – to attach, proliferate, and and evade the host immune system.^[1][2]

• Humans are the only reservoir for Bordatella pertussis, and the incubation period is approximately 10 days (range from 1 week to 3 weeks).
• Infection occurs through direct contact with the aerosolized mucus of infected individuals, usually during coughing and sneezing. The bacterium adheres to the ciliated epithelium of the nasopharynx and proliferates in the lower respiratory system.

• The bacterium produces toxins (virulence factors) that paralyze the cilia, and cause inflammation of the respiratory tract, which interferes with the clearing of pulmonary secretions.
• Bordetella pertussis has tropism for pulmonary tissue and rarely disseminates to other organs.
• The steps involved in the pathogenesis of pertussis include the following:

• Inoculation
• Attachment to the respiratory epithelium
• Proliferation
• Production of virulence factors (toxins)
• Evasion of host immune cells
• Tissue destruction

Bordetella pertussis produces multiple antigenic and biologically active virulence factors responsible for the clinical manifestations of pertussis. These virulence factors include:^[1][2]

• Pertussis toxin (PT)

• PT undergoes ADP-ribosylation of G proteins to disrupt signal transduction in host cells.^[2]

• Filamentous hemagglutinin (FHA)

• Suface protein responsible for the interaction and adhesion between host cells and Bordetella pertussis.^[2]
• FHA is a component of the acellular DTaP vaccine.

• Adenylate cyclase toxin (ACT)

• ACT delivers an adenylate cyclase domain into the host cell and increases the intracellular cAMP concentration.^[2]
• Following cAMP delivery, phagocyte activity is inhibited, and phagocytes undergo apoptosis.

• Pertactin (PRN)

• PRN defends Bordetella pertussis against the host neutrophils (immunomodulation).^[2]
• PRN is a component of the acellular DTaP vaccine.

• Tracheal cytotoxin (TCT)

• TCT is responsible for the death of host respiratory cells using intracellular IL-1 and nitric oxide.^[2]

• Lipooligoosaccharide (LOS)

• Unique outer membrane component that is thought to play a role in clinical manifestations of pertussis.^[2]
• Unknown virulence mechanism.

• Dermonecrotic toxin (DNT)

• DNT de-aminates signaling proteins (similar mechanism to Pasteurella multicida leukotoxin).

• Fimbriae (FIM)

• Surface appendages to adhere to host cells and avoid host immune cells (immunomodulation).^[2]
• FIM is a component of the acellular DTaP vaccine.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Yazan Daaboul, M.D.; Serge Korjian M.D.

Bordetella pertussis is a Gram-negative, aerobic, non-motile, non-spore-forming coccobacillus. It is the pathogen responsible for pertussis (whooping cough). Unlike B. bronchiseptica, B. pertussis is not motile. Humans are the only known reservoir for B. pertussis. The lipopolysaccharide-containing outer membrane of B. pertussis is unique and contains a different phosphate composition from other bacterial outer membranes.

• Kingdom: Bacteria
• Phylum: Proteobacteria
• Class: Betaproteobacteria
• Order: Burkholderiales
• Family: Alcaligenaceae
• Genus: Bordetella
• Species: B. pertussis

• The genome of B. pertussis consists of 1 circular chromosome and plasmids.

• The circular chromosome contains 3867 genes and 4,086,189 nucleotides.^[1]
• The IncP-1 beta plasmid pBP136 carries 46 ORFs and contains 41,268 bp nucleotides.^[1]

• B. pertussis is a Gram-negative, aerobic, non-spore forming coccobacillus.
• Compared with Bordetella bronchiseptica, B. pertussis is non-motile.
• It contains an outer membrane, an inner membrane, and a periplasmic space between the 2 membranes.^[2]
• The rough lipopolysaccharide on the outer membrane (also called lipooligosaccharide) contains a phosphate composition (containing lipid X) that is different from other bacterial lipopolysaccharides (containing lipid A). The B. pertussis outer membrane is thus a distinguishing feature of B. pertussis.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.; Aditya Govindavarjhulla, M.B.B.S. [2]; Luke Rusowicz-Orazem, B.S.

Pertussis must be differentiated from other causes of cough, dyspnea, and coryza, such as asthma, pneumonia, bronchiolitis, croup, common cold, cystic fibrosis, foreign body aspiration, gastroesophageal reflux disease, and sinusitis.

• Pertusis must be differentiated from other respiratory and cardiac diseases that can cause the same clinical manifestations like cough and dyspnea. These diseases include bronchiolitis, COPD, pneumonia, congestive heart failure, diffuse idiopathic neuroendocrine cell hyperplasia, tuberculosis, asthma, foreign body aspiration, pulmonary embolism and Harmann-Rich syndrome.^{[1][2][3][4][5]}

• Pertussis must be differentiated from other causes of cough, dyspnea, and coryza, such as:^[18]
• Asthma
• Pneumonia (typical or atypical)
• Influenza
• Bronchiolitis (e.g. RSV infection)
• Chlamydia
• Common cold (e.g. rhinovirus infection)
• Croup
• Foreign body aspiration
• Gastroesophageal reflux disease
• Sinusitis (allergic or infectious)
• Tuberculosis
• Cystic fibrosis
• Interstitial pneumonitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Aditya Govindavarjhulla, M.B.B.S. [2]; Serge Korjian M.D.

In the United States, the incidence of pertussis is approximately 1.5 to 3.0 per 100,000 individuals, with approximately 5,000 to 7,000 cases reported annually. The incidence of pertussis is thought to be on the rise due to the decline in vaccination rate and diminished herd immunity. Infants and young children < 5 years of age are more commonly infected with pertussis than adults. There is no gender predilection for the development of pertussis. Pertussis-related deaths are rare, but are more common in developing countries, among infants < 6 months of age, and among adult patients with significant co-morbidities.

• In the United States, the incidence of pertussis is approximately 1.5 to 3.0 per 100,000 individuals, with approximately 5,000 to 7,000 cases reported annually.
• Incidence of pertussis has increased steadily since the 1980s despite the availability of vaccination. It is thought that the decline in vaccination rate and diminished herd immunity may, at least in part, be responsible for the rise of the incidence.

• Pertussis is responsible for approximately 20-40 million deaths worldwide.
• The majority of pertussis-related deaths occur in Africa and Southeast Asia.
• Pertussis-related death is rare, but is more common among infants < 6 months of age and among adult patients with significant co-morbidities.

• Pertussis may infect individuals of all age groups.^[1]
• Infants and young children < 5 years of age are more commonly infected with pertussis than adults.^[1]

^{*Total age incidence per 100,000 calculated from 32,861 cases with age reported.
Table adapted from 2014 Final Pertussis Surveillance Report – Centers for Disease Control and Prevention.[2]}

• There is no gender predilection for the development of pertussis.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Luke Rusowicz-Orazem, B.S.; Serge Korjian M.D.

Risk factors in the development of pertussis include no or incomplete vaccination against pertussis, exposure to infected individuals, infants or children < 5 years of age, and immunocompromised status.

Risk factors in the development of pertussis include the following:

• No or incomplete vaccination
• Exposure to infected individual (usually within 5 feet)
• Infants and children < 5 years of age
• Significant pulmonary co-morbidities (e.g. asthma)
• Immunocompromised status

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.; Aditya Govindavarjhulla, M.B.B.S. [2]; Rim Halaby, M.D. [3]

The clinical course of the illness is divided into three stages: catarrhal, paroxysmal and convalescent. If left untreated, the majority of patients with clinical manifestations of pertussis develop low-grade fever and coryza (runny nose, occasional cough) for 1-2 weeks, followed by paroxysmal fits of whooping cough that may last 1-6 weeks, before finally recovering from the disease. Compared with children, adolescents and adults usually experience a milder course of the disease, and the characteristic whooping cough may be absent. Unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for developing severe infection and life-threatening complications and death.^[1] Complications of pertussis include apnea, pneumonia, seizure, and death. Prognosis is generally excellent, but unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for severe and life-threatening complications and death.

• The clinical course of the illness is divided into three stages: catarrhal, paroxysmal and convalescent.
• Pertussis has an insidious onset with catarrhal symptoms that are indistinguishable from those of minor respiratory tract infections.
• The cough, which is initially intermittent, becomes paroxysmal. In typical cases paroxysms terminate with inspiratory whoop and may be followed by post-tussive vomiting. Paroxysms of cough, which may occur more at night, usually increase in frequency and severity as the illness progresses and typically persist for 2 to 6 weeks or more.
• The illness can be milder and the characteristic “whoop” may be absent in children, adolescents and adults who were previously vaccinated. After paroxysms subside, a nonparoxysmal cough can continue for 2 to 6 weeks or longer.
• Unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for developing severe infection and life-threatening complications and death.

Shown below is a table summarizing the main clinical findings in each stage.^[1]

^{Timeline of pertussis clinical manifestations. Retrieved from Centers of Disease Control and Prevention (CDC) [2]}

Pertussis may cause serious and potentially life-threatening complications, especially among infants and young children. Patients who are not fully vaccinated are more predisposed to developing pertussis-related complications.^[3][4][5]

• Sleep apnea (most common)
• Epistaxis
• Pneumonia
• Otitis media
• Pneumothorax
• Refractory pulmonary hypertension
• Urinary incontinence
• Hernia
• Rectal prolapse
• Rib fracture
• Seizures
• Subdural hematoma
• Encephalopathy

• Unvaccinated or incompletely vaccinated infants younger than 12 months of age have the highest risk for severe and life-threatening complications and death.^[1]
• Treatment with an effective antimicrobial agent the infectious period but does not generally alter the outcome of the disease.
• When treatment is initiated during the catarrhal stage, symptoms may be less severe.
• Among adolescents and adults, pertussis is generally less severe, and the characteristic whooping cough is less frequently described.^[1]

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