Pertussis (Whooping Cough)

1. Introduction

Pertussis, commonly known as whooping cough, is a highly contagious acute respiratory tract infection. Historically a major cause of childhood mortality, it remains a significant public health problem despite widespread vaccination. The term "pertussis" means "intense cough," which describes the hallmark clinical feature of the disease,. While the incidence declined dramatically following the introduction of whole-cell vaccines, a resurgence has been observed in recent years, attributed largely to the transition to acellular vaccines and waning immunity.

2. Etiology

2.1. Causative Agents

The primary etiologic agent is Bordetella pertussis, a small, fastidious, gram-negative, aerobic, pleomorphic coccobacillus,. It is an exclusive pathogen of humans.

Other species in the genus can cause a similar, though usually milder, pertussis-like illness:

• Bordetella parapertussis: Causes 5–20% of clinical cases. It does not produce pertussis toxin (PT), which explains the milder clinical course and absence of lymphocytosis,,.
• Bordetella holmesii: Increasingly identified in outbreaks and can cause pertussis-like symptoms in adolescents and adults,.
• Bordetella bronchiseptica: Primarily an animal pathogen but can infect immunocompromised humans,.

2.2. Antigenic Structure and Virulence Factors

B. pertussis produces numerous biologically active components that serve as virulence factors and immunogens,.

1. Pertussis Toxin (PT): The major virulence protein expressed only by B. pertussis. It is an A-B toxin that ADP-ribosylates G proteins, leading to lymphocytosis, insulin secretion, and histamine sensitivity,,.
2. Filamentous Hemagglutinin (FHA): A large surface protein facilitating attachment to ciliated respiratory epithelium,.
3. Pertactin (PRN): An outer membrane protein that promotes adhesion and resists neutrophil-mediated clearance,.
4. Fimbriae (FIM): Types 2 and 3 are the main agglutinogens involved in attachment,.
5. Adenylate Cyclase Toxin (ACT): Enters phagocytes and inhibits their function (chemotaxis and killing) by raising cAMP levels,.
6. Tracheal Cytotoxin (TCT): Causes ciliostasis and extrusion of ciliated epithelial cells,.

3. Pathogenesis

Pertussis is primarily a toxin-mediated disease localized to the respiratory tract, although systemic effects occur due to absorbed toxins. The incubation period is typically 7–10 days.

3.1. Attachment and Colonization

Infection is initiated by the inhalation of aerosol droplets containing bacteria. The organisms attach specifically to the cilia of the respiratory epithelial cells of the nasopharynx, trachea, and bronchi. This attachment is mediated by adhesins, primarily FHA, FIM, PRN, and the B-oligomer of PT,.

3.2. Evasion of Host Defenses

Once attached, the bacteria evade host immunity through several mechanisms:

• Adenylate Cyclase Toxin (ACT) and PT paralyze host phagocytes (neutrophils and macrophages) and inhibit their migration to the site of infection,.
• PT impairs the recruitment of lymphocytes to the lymphoid tissue, trapping them in the vasculature, which results in the characteristic leukocytosis with absolute lymphocytosis seen in B. pertussis infection,.

3.3. Local Tissue Damage

The proliferation of bacteria and release of toxins lead to significant local pathology:

• Tracheal Cytotoxin (TCT) causes direct damage to ciliated epithelial cells, leading to ciliostasis (paralysis of cilia) and sloughing of cells.
• The loss of ciliary function combined with thick, tenacious mucus production leads to obstruction of small airways. This predisposes the patient to atelectasis and secondary bacterial pneumonia,.
• Necrotizing bronchiolitis and intra-alveolar hemorrhage may occur in severe cases.

3.4. Systemic Effects (Toxin-Mediated)

Although the bacteria rarely invade the bloodstream, PT is absorbed and causes systemic manifestations.

• Hyperinsulinemia: PT stimulates pancreatic islet cells, occasionally causing hypoglycemia.
• Pulmonary Hypertension: In young infants, extreme leukocytosis (driven by PT) can lead to leukocyte aggregates in the pulmonary vasculature, causing severe, often fatal, pulmonary hypertension and cardiogenic shock,,.
• Cough: The mechanism of the paroxysmal cough is not fully understood (the "cough toxin" remains unidentified), but it may involve bradykinin and toxin-mediated sensitization of cough receptors.

4. Complications

Complications are most severe in infants, particularly those unimmunized or partially immunized.

4.1. Respiratory Complications

• Pneumonia: This is the most common cause of death (responsible for >90% of fatalities in infants). It can be primary (viral) or secondary (bacterial superinfection with S. pneumoniae or S. aureus),.
• Apnea: Common in infants <6 months, often preceding the cough. It is a major indication for hospitalization,.
• Pulmonary Hypertension: A life-threatening complication in young infants characterized by extreme leukocytosis (>50,000–100,000/mm³), hypoxemia, and cardiovascular collapse,.
• Others: Atelectasis, otitis media,.

4.2. Neurologic Complications

• Seizures: Occur in 1–2% of infants, usually due to hypoxia from coughing paroxysms or apnea, but occasionally due to hyponatremia (SIADH) or toxin effects,.
• Encephalopathy: Rare (0.2–0.5%), likely due to cerebral hypoxia or hemorrhage. It can lead to permanent sequelae,.
• Cerebral Hemorrhage: Resulting from increased intracranial pressure during paroxysms.

4.3. Mechanical Complications

The force of the paroxysmal cough increases intrathoracic and intra-abdominal pressure, leading to:

• Subconjunctival hemorrhages and epistaxis,.
• Hernias (umbilical, inguinal) and rectal prolapse,.
• Pneumothorax and subcutaneous emphysema,.
• Ulceration of the frenulum of the tongue,.

4.4. Nutritional

• Severe weight loss and dehydration due to post-tussive vomiting and feeding difficulties.

5. Prevention of Pertussis

Prevention strategies rely on vaccination, chemoprophylaxis, and isolation.

5.1. Active Immunization

Universal vaccination is the cornerstone of control.

• Primary Series: Three doses of DTP-containing vaccine starting at 6 weeks of age (6, 10, 14 weeks in India; 2, 4, 6 months in the US),.
• Boosters: Recommended at 15–18 months, 4–6 years, and 11–12 years (Tdap),.
• Maternal Immunization: Administration of Tdap to pregnant women during every pregnancy (optimally 27–36 weeks) is crucial. It facilitates the transplacental transfer of antibodies to protect the infant during the vulnerable first few months of life (before their own vaccination series begins),. This strategy is 80–91% effective in preventing pertussis in infants <2 months.

5.2. Chemoprophylaxis

Post-exposure prophylaxis is recommended for all household contacts and high-risk close contacts (e.g., infants, pregnant women, immunocompromised) regardless of immunization status,.

• Drug of Choice: Azithromycin (10 mg/kg/day for 5 days) or Erythromycin (40–50 mg/kg/day for 14 days),.
• Timing: Should be administered within 21 days of cough onset in the index case to be effective.

5.3. Isolation

Patients should be placed on droplet precautions. Isolation is required for 5 days after the initiation of effective antibiotic therapy. If untreated, the patient is considered contagious for 21 days (3 weeks) after the onset of paroxysmal cough,.

6. Comparison of Whole Cell (wP) and Acellular (aP) Pertussis Vaccines

The shift from whole-cell to acellular vaccines has highlighted significant trade-offs between safety (reactogenicity) and durability of protection.

6.1. Composition and Mechanism

• Whole Cell (wP): Suspensions of the entire killed B. pertussis organism. They contain thousands of antigens (proteins, LPS). They induce a robust Th1 and Th17 immune response, similar to natural infection, which is crucial for mucosal immunity and long-term memory,,.
• Acellular (aP): Contain purified components of the bacteria (PT, FHA, PRN, and FIM). Available as 1, 2, 3, or 5 component vaccines. They primarily induce a Th2 (antibody-dominant) response, which is less effective at clearing mucosal infection and generating long-term memory,,.

6.2. Comparison Table: wP vs. aP Vaccines

6.3. Detailed Analysis of Differences

A. Efficacy

• wP: Historically, effective wP vaccines reduced pertussis incidence by >99%. Efficacy varies by manufacturer but is generally high for potent vaccines.
• aP: Initial efficacy of multicomponent (3-5) aP vaccines is comparable to wP (approx. 80–85%). However, 1 or 2 component vaccines are less efficacious.

B. Duration of Protection (Waning Immunity)

• The "Waning" Problem: The most critical difference is the durability of immunity. Immunity following aP vaccination wanes significantly faster than wP vaccination.
• Data: Studies show that 5 years after the last dose, children vaccinated with aP have a significantly higher risk of pertussis compared to those primed with wP,.
• Mechanism: This is attributed to the "Linked-Epitope Suppression" and the type of T-cell response. aP vaccines induce a Th2 response that does not generate adequate long-term memory or mucosal immunity, unlike the Th1/Th17 response induced by wP and natural infection,. Consequently, aP-vaccinated individuals can become colonized and transmit the infection (asymptomatic carriers) even if they do not develop severe disease.

C. Adverse Events (Reactogenicity)

• wP: Known for high reactogenicity due to the presence of endotoxin (LPS).
  • Common: Fever, injection site redness, swelling, pain, fussiness (up to 50% of recipients),.
  • Moderate/Severe: Persistent crying (>3 hours), high fever (>40.5°C), and Hypotonic-Hyporesponsive Episodes (HHE) (collapse/shock-like state) occur rarely but are frightening to parents.
  • Neurologic: Historically linked to encephalopathy, but large-scale studies (e.g., NCES) and IOM reviews concluded there is no causal relation between wP and permanent neurologic damage; the vaccine may trigger the first seizure in children predisposed to epilepsy,.
• aP: Developed specifically to address the safety concerns of wP.
  • General: Significantly lower rates of fever, local reactions, and fussiness.
  • Specific Reaction: Extensive Limb Swelling (swelling of the entire thigh/arm) is a specific reaction associated with the 4th and 5th doses of aP vaccines, occurring in 2–3% of children. It resolves spontaneously without sequelae,.

6.4. Current Consensus

Due to the rapid waning of immunity and the lack of mucosal protection (herd immunity) offered by aP vaccines, the World Health Organization (WHO) and many experts recommend that countries currently using wP (like India) should continue to use wP for the primary series to ensure robust initial priming and longer-lasting protection,. aP is preferred for boosters in adolescents and adults (Tdap) or for children with a history of severe reactions to wP.