Pertussis, also known as whooping cough, is a highly contagious bacterial respiratory infection caused by Bordetella pertussis, a Gram-negative pathogen that colonizes the ciliated epithelium of the human respiratory tract [1]. The disease is characterized by severe paroxysmal coughing fits, often culminating in a high-pitched "whoop" during inhalation, and can persist for weeks or even months—earning it the colloquial name "the 100-day cough" [2]. It primarily spreads through respiratory droplets when infected individuals cough or sneeze, making it particularly transmissible in close-contact settings such as households and schools [3]. While pertussis can affect people of all ages, it poses the greatest risk to infants under six months, who are more likely to develop life-threatening complications such as apnea, pneumonia, encephalopathy, and even death [4]. Vaccination remains the cornerstone of prevention, with the DTaP vaccine administered in early childhood and the Tdap vaccine used for booster doses in adolescents and adults [5]. Crucially, maternal immunization during pregnancy has been shown to significantly reduce neonatal morbidity and mortality by transferring protective IgG antibodies transplacentally [6]. Despite widespread vaccination programs, pertussis has re-emerged globally due to factors such as waning immunity from acellular vaccines, the circulation of antigen-deficient strains like pertactin-negative Bordetella pertussis, and gaps in vaccine coverage [7]. Diagnosis is most reliable via polymerase chain reaction (PCR) testing during the catarrhal phase, while treatment typically involves macrolide antibiotics such as azithromycin to reduce transmission and severity [8]. Public health strategies, including cocooning (vaccinating close contacts of infants), robust epidemiological surveillance, and timely outbreak response, are essential to controlling the spread of this re-emerging infectious disease [9].
Etiology and Pathogenesis
Pertussis, or whooping cough, is caused by the Gram-negative bacterium Bordetella pertussis, which specifically colonizes the ciliated epithelium of the human respiratory tract [1]. This pathogen is non-spore-forming, non-motile, and does not belong to the normal respiratory flora, making it an obligate human pathogen with no known environmental reservoir [4]. Transmission occurs primarily through respiratory droplets expelled when infected individuals cough, sneeze, or speak, allowing the bacteria to be inhaled by close contacts within a range of approximately one meter [3]. The disease is most contagious during the catarrhal phase, which resembles a common cold, often leading to undetected spread in households, schools, and other close-contact settings [13].
Key Virulence Factors and Mechanisms of Pathogenicity
The pathogenesis of pertussis is driven by a suite of highly specialized virulence factors that enable Bordetella pertussis to adhere to respiratory epithelium, evade host immunity, and cause tissue damage. These mechanisms are particularly effective in vulnerable populations such as infants, whose immature immune systems are less capable of mounting an effective defense.
The primary virulence factor is pertussis toxin (PT), an AB5 exotoxin. The S1 subunit of PT catalyzes the ADP-ribosylation of inhibitory G proteins (Gαi/o), disrupting cellular signaling pathways and leading to unregulated activation of adenylate cyclase and a sustained increase in intracellular cyclic AMP (cAMP) levels [14]. This disruption impairs key immune functions such as chemotaxis, phagocytosis, and antigen presentation, facilitating immune evasion [15]. Additionally, PT induces massive lymphocytosis by interfering with the migration of lymphocytes from the bloodstream to lymphoid tissues, prolonging bacterial persistence in the respiratory tract [16].
Another critical factor is the adenylate cyclase toxin (ACT), which binds to phagocytes via the CR3 integrin receptor (αMβ2) and is internalized [17]. Once inside the cell, the catalytic domain generates high concentrations of cAMP, which suppresses phagocytic activity, inhibits the production of reactive oxygen species, and dampens the release of pro-inflammatory cytokines [18]. This immunosuppressive effect allows B. pertussis to survive in the hostile respiratory environment and can also induce apoptosis in immune cells, further depleting local defenses [19].
Adherence to the respiratory epithelium is mediated by surface adhesins, including filamentous hemagglutinin (FHA), pertactin (Prn), and fimbriae (Fim). FHA binds to receptors on ciliated cells, such as a 90 kDa glycoprotein, and also possesses immunomodulatory properties by inducing the production of the anti-inflammatory cytokine IL-10, which suppresses the host immune response [20]. This adherence is a prerequisite for colonization and allows the localized action of bacterial toxins [21].
The tracheal cytotoxin (TCT), a fragment of bacterial peptidoglycan, directly damages respiratory epithelial cells. TCT causes ciliostasis (paralysis of cilia), destruction of ciliated cells, and stimulates the release of nitric oxide, leading to epithelial necrosis [22]. This damage compromises the mucociliary clearance mechanism, a primary defense of the respiratory tract, thereby promoting bacterial persistence and increasing the risk of secondary infections [21].
B. pertussis also possesses a type III secretion system (T3SS), which injects effector proteins, such as BteA, directly into the host cell cytoplasm [24]. These effectors induce cytotoxicity and cell death, primarily by disrupting intracellular calcium homeostasis, and are crucial for establishing initial colonization and evading immune detection [25].
Clinical Progression Linked to Pathogenic Mechanisms
The clinical course of pertussis mirrors the action of these virulence factors. The disease progresses through three distinct phases: catarrhal, paroxysmal, and convalescent.
In the catarrhal phase (1–2 weeks), symptoms are mild and resemble a common cold, including rhinorrhea, mild cough, and low-grade fever. This phase coincides with bacterial adherence and the initial production of toxins like PT, which begin to subvert the host's immune response, allowing for progressive colonization [26].
The paroxysmal phase (2–6 weeks) is marked by severe, uncontrollable coughing fits. This is driven by the cumulative damage to the respiratory epithelium from TCT, ACT, and the T3SS, leading to intense inflammation and irritation. In infants, this phase is particularly dangerous and may manifest without the classic "whoop" but instead with apnea, cyanosis, and post-tussive vomiting [27]. The high rate of complications in infants, such as pneumonia, respiratory failure, and encephalopathy, is directly linked to their immunological immaturity and the overwhelming effects of these toxins [28].
The final convalescent phase involves a gradual decrease in cough frequency and intensity, although the cough can persist for weeks or months, especially if triggered by subsequent respiratory infections. This prolonged recovery is a consequence of the extensive epithelial damage that must be repaired by the host [29].
Clinical Presentation and Disease Progression
Pertussis, caused by the Gram-negative bacterium Bordetella pertussis, progresses through three distinct clinical phases: catarrhal, paroxysmal, and convalescent. The disease typically lasts for several weeks to months, earning it the colloquial name "the 100-day cough" [2]. Its presentation varies significantly by age, with infants under six months facing the most severe outcomes, while adolescents and adults often exhibit milder, atypical symptoms that complicate early diagnosis.
Clinical Symptoms and Disease Stages
The hallmark of pertussis is a severe, persistent cough that evolves in intensity and character over time. The illness begins with non-specific, cold-like symptoms during the catarrhal phase, lasting approximately one to two weeks. During this stage, patients experience rhinorrhea, nasal congestion, mild cough, and low-grade fever [31]. This phase is highly contagious, as the bacteria actively colonize the ciliated epithelium of the respiratory tract, but the non-specific symptoms often lead to misdiagnosis as a common upper respiratory infection [32].
As the disease advances into the paroxysmal phase, which typically lasts two to six weeks, the cough becomes more severe and characteristic. Patients experience intense, repetitive coughing fits known as paroxysms, which can occur more frequently at night. These paroxysms are often followed by a high-pitched, inspiratory "whoop" as the individual gasps for air, a sound that gives the disease its common name [31]. The forceful coughing can lead to post-tussive vomiting, facial flushing or cyanosis due to oxygen deprivation, and extreme fatigue [29]. In children, these episodes may be so violent that they result in temporary apnea or even rib fractures.
The final stage, the convalescent phase, can extend for several weeks or months. During this period, the frequency and severity of coughing paroxysms gradually decrease. However, the cough may persist and can be re-triggered by subsequent respiratory infections [29]. The prolonged nature of the cough underscores the significant morbidity associated with pertussis, even after the infectious period has ended.
Atypical Presentation in Infants and Young Children
Infants, particularly those under six months of age, often present with an atypical and more dangerous form of pertussis. Many do not develop the classic "whoop" and instead may exhibit apnea—episodes of breathing cessation—as their primary symptom [3]. This makes pertussis a medical emergency in neonates, as apnea can lead to bradycardia and even cardiac arrest [37]. Other signs in infants include difficulty breathing, cyanosis, feeding problems, and lethargy. Due to their immature immune systems and lack of complete vaccination, infants are at the highest risk for severe complications such as pneumonia, encephalopathy, and death [4].
Differences in Adolescents and Adults
In contrast, adolescents and adults who have been previously vaccinated or had prior exposure often experience a milder, atypical form of pertussis. The "whoop" is absent in more than half of adult cases, and the disease may be mistaken for chronic bronchitis, asthma, or a prolonged viral cough [39]. The primary symptom is a persistent, spasmodic cough lasting more than two weeks, which may be accompanied by post-tussive vomiting or a sensation of choking [40]. This atypical presentation is a major contributor to the underdiagnosis and delayed treatment of pertussis in older populations, allowing them to act as silent reservoirs and sources of transmission to vulnerable infants [9].
The clinical progression of pertussis is thus a spectrum, ranging from life-threatening apnea in unvaccinated infants to chronic cough in adults. This variability necessitates a high index of clinical suspicion, especially in the context of community outbreaks or known exposure, to ensure timely diagnosis and intervention. The waning immunity from both vaccination and prior infection contributes to the cyclical nature of pertussis epidemics, highlighting the need for booster doses of the Tdap vaccine in adolescents and adults to protect the broader community, particularly the most vulnerable [42].
Diagnosis and Laboratory Testing
Accurate and timely diagnosis of pertussis is critical due to its high transmissibility and potential for severe complications, particularly in infants. The diagnostic approach relies on a combination of clinical suspicion and laboratory confirmation, with the choice of test depending on the stage of illness, patient age, and vaccination status. The most reliable methods include polymerase chain reaction (PCR), bacterial culture, and serology, each with distinct advantages and limitations [43].
Laboratory Methods for Confirming Bordetella pertussis Infection
Polymerase Chain Reaction (PCR)
PCR, particularly real-time PCR, is the most sensitive and specific method for diagnosing pertussis, especially during the early stages of infection [43]. It detects the genetic material of Bordetella pertussis in nasopharyngeal swab specimens, allowing for rapid identification and differentiation from related species such as B. parapertussis using specific primers targeting regions like the pertussis toxin promoter or porin genes [45]. PCR is highly effective during the catarrhal phase and early paroxysmal phase, when bacterial load in the upper respiratory tract is highest [46]. In infants under three months, urgent PCR testing has become an essential tool in pediatric emergency departments, enabling rapid diagnosis, prompt initiation of antibiotic therapy, and prevention of unnecessary hospitalizations [47].
Bacterial Culture
Bacterial culture of B. pertussis from a nasopharyngeal swab is considered the gold standard for diagnosis due to its high specificity, as it allows for the isolation of live strains for epidemiological studies and susceptibility testing [48]. However, its sensitivity is significantly lower than PCR, particularly if the sample is collected after the first or second week of symptoms or if the patient has already received antibiotics [49]. Culture requires strict transport and growth conditions, including specialized media such as Bordet-Gengou or Regan-Lowe supplemented with blood and cycloheximide, and results can take 7 to 14 days to become available [50]. Due to these limitations, culture use has declined in routine clinical practice, although it remains valuable for surveillance purposes [51].
Serology
Serology, particularly the detection of IgG antibodies against pertussis toxin (IgG-PT), is useful in the later stages of the disease, beyond 3–4 weeks of symptom onset, when bacterial load is low and PCR may yield negative results [52]. However, interpreting serological results can be complex due to prior vaccination, which also induces antibodies against pertussis toxin. Therefore, it is recommended to collect two serum samples at least 2–4 weeks apart to demonstrate seroconversion or a significant rise in antibody titers [53]. In vaccinated children, ELISA techniques for IgG-PT must be interpreted cautiously and in clinical context [54].
Optimal Timing and Reliability of Diagnostic Methods
The reliability of pertussis diagnostic tests varies significantly depending on the stage of illness:
| Stage of Illness | Most Reliable Method | Rationale |
|---|---|---|
| Catarrhal phase (1–2 weeks) | PCR | Highest bacterial load in respiratory tract; PCR sensitivity exceeds 90% [55]. |
| Paroxysmal phase (2–6 weeks) | PCR (early), Serology (late) | PCR remains useful in the first half, but sensitivity declines. Serology becomes positive from the third week onward [52]. |
| Convalescent phase (>6 weeks) | Serology | PCR is no longer useful; IgG-PT serology peaks and can confirm recent infection [53]. |
| Infants <3 months | Urgent PCR | High morbidity and mortality; atypical clinical presentation; need for rapid diagnosis to initiate treatment and isolation [58]. |
Practical Considerations for Sample Collection and Interpretation
For optimal results, the nasopharyngeal swab for PCR or culture should be collected using a flexible flocked or dacron swab (never cotton), preferably within the first two weeks of cough onset [48]. For culture, the sample should be transported in Regan-Lowe medium or similar, while for PCR, viral transport medium or sterile buffer is appropriate [45]. Prior vaccination does not contraindicate any test but may interfere with serological interpretation [61].
In summary, real-time PCR is the most sensitive and specific diagnostic method for Bordetella pertussis infection, particularly in the early stages of disease. Culture, while less sensitive, retains value for surveillance. Serology is essential in late-stage cases, though interpretation requires caution in vaccinated individuals. A strategic combination of these methods based on clinical timing enables accurate and timely diagnosis, which is crucial for clinical management and epidemiological surveillance of pertussis [55].
Treatment and Management
The treatment and management of pertussis focus on reducing symptom severity, preventing complications, and interrupting transmission, particularly in vulnerable populations such as infants and young children. Early intervention is critical to improve outcomes and limit the spread of Bordetella pertussis within households and communities.
Antibiotic Therapy and Pharmacological Management
Antibiotic treatment is a cornerstone of pertussis management, primarily aimed at eradicating the causative bacterium, Bordetella pertussis, and reducing infectivity. Macrolide antibiotics are the first-line agents for treatment, with azithromycin being the preferred choice, especially in pediatric patients [8]. Azithromycin offers a favorable safety profile and shorter treatment duration compared to other macrolides, making it particularly suitable for infants under six months of age, who are at the highest risk of severe complications [64]. Alternative macrolides include clarithromycin and erythromycin, although erythromycin is associated with a higher risk of adverse effects such as infantile hypertrophic pyloric stenosis and gastrointestinal intolerance [65].
The recommended treatment durations are as follows: a 5-day course for azithromycin, 7 days for clarithromycin, and 14 days for erythromycin [66]. Antibiotics are most effective when initiated during the catarrhal phase or within the first three weeks of paroxysmal coughing, as they can reduce the duration of symptoms and prevent transmission. However, even if administered later in the disease course, antibiotics are still indicated to eliminate bacterial carriage and halt further spread [67]. For patients with documented macrolide resistance, which has been reported in regions such as China, trimethoprim-sulfamethoxazole serves as an effective alternative [68].
Hospitalization and Supportive Care
Hospitalization is frequently required for infants and young children, particularly those under six months of age, due to their heightened risk of life-threatening complications such as apnea, pneumonia, and encephalopathy [69]. Key criteria for hospitalization include age under six months, especially if the vaccination schedule is incomplete; episodes of apnea or cyanosis; significant respiratory distress; dehydration or inability to maintain oral intake; and the presence of severe complications like pulmonary hypertension or extreme leukocytosis (>100,000 cells/μL) [70]. In the hospital setting, supportive care is paramount and may include continuous monitoring of respiratory status, administration of supplemental oxygen, and intravenous fluid therapy to address dehydration resulting from frequent vomiting and feeding difficulties [50].
For critically ill patients, advanced interventions such as mechanical ventilation may be necessary to manage respiratory failure. The duration of hospitalization varies depending on the severity of illness but typically continues until the patient demonstrates stable respiratory function, adequate oral intake, and resolution of major complications [72]. Isolation protocols are implemented during the initial phase of treatment to prevent nosocomial transmission, with patients considered non-contagious after completing at least five days of appropriate antibiotic therapy [9].
Home Care and Symptom Management
For older children and adolescents with milder disease, outpatient management is often feasible with careful home care. Families should be advised to create a calm and quiet environment to minimize triggers for coughing paroxysms, which can be precipitated by stimuli such as loud noises, crying, or feeding [74]. Positioning the child in a semi-Fowler’s position (slightly upright) during coughing episodes can aid breathing and reduce the risk of aspiration [75]. The use of a cool-mist humidifier may help soothe irritated airways and reduce cough frequency, though warm vaporizers are discouraged due to burn risks [3].
Maintaining hydration is essential, as persistent vomiting can lead to dehydration. Caregivers should offer small, frequent amounts of fluids, including water, oral rehydration solutions, or breast milk [77]. Feeding should be done in small, frequent meals to minimize post-tussive emesis. Breastfeeding is strongly encouraged as it provides both nutritional and immunological benefits [66]. Families must also be educated on infection control measures, including frequent handwashing, covering the mouth and nose when coughing or sneezing, and avoiding close contact with others, particularly unvaccinated infants, until the contagious period has passed.
Recognition of Warning Signs and Emergency Indicators
Caregivers must be vigilant for signs of clinical deterioration that necessitate immediate medical evaluation. These warning signs include respiratory distress, such as rapid or labored breathing; episodes of apnea, which may be the only manifestation in young infants; cyanosis of the lips, face, or extremities during coughing fits; inability to retain fluids or maintain hydration; excessive somnolence, intense irritability, or difficulty arousing the child; and seizures [79]. The presence of any of these symptoms warrants urgent medical attention, as they may indicate the development of severe complications requiring hospitalization and intensive supportive care [67].
Prophylaxis and Public Health Measures
To prevent secondary cases, especially among high-risk contacts, post-exposure prophylaxis with macrolide antibiotics is recommended for all close contacts of a confirmed pertussis case, regardless of age or vaccination status [81]. This includes household members, caregivers, and healthcare workers. In addition to pharmacological prophylaxis, public health strategies such as the "cocooning" approach—vaccinating all individuals in close contact with a newborn—are crucial for protecting infants too young to be fully immunized [82]. This strategy, combined with maternal vaccination during pregnancy, forms a comprehensive defense against pertussis in the most vulnerable population.
Complications and Risk Factors
Pertussis poses significant health risks, particularly in vulnerable populations, with complications ranging from respiratory failure to neurological damage. The severity of the disease is closely tied to age, vaccination status, and underlying health conditions. Infants under six months, especially those unvaccinated or partially immunized, face the highest risk of life-threatening complications due to their immature immune systems and lack of protective IgG antibodies [83]. The pathogenic mechanisms of Bordetella pertussis, including the action of toxina pertussis and tracheal cytotoxin, contribute to tissue damage and immune evasion, exacerbating clinical outcomes [14].
Severe Complications in Infants and Young Children
Infants are disproportionately affected by severe complications of pertussis. The most critical include:
- Apnea: A life-threatening condition characterized by pauses in breathing, often the first or only sign of infection in neonates. Apnea can lead to bradycardia and even cardiorespiratory arrest, requiring immediate medical intervention [37].
- Pneumonia: The most common serious complication, which may be caused directly by B. pertussis or secondary bacterial infections. It significantly increases the risk of hospitalization and mortality, particularly in newborns [82].
- Encephalopathy: A rare but devastating neurological complication associated with severe hypoxia during coughing paroxysms or systemic inflammation. It can result in seizures, permanent brain damage, or death [87].
- Respiratory and cardiac failure: Severe cases may progress to acute respiratory failure requiring mechanical ventilation. pulmonary hypertension is a critical factor linked to increased mortality, while myocardial involvement can lead to heart failure [88].
Additional complications include dehydration and malnutrition due to frequent vomiting post-coughing, and in extreme cases, rib fractures from violent coughing fits [89].
Risk Factors for Severe Disease
Several clinical and demographic factors are strongly associated with poor outcomes in pertussis:
- Young age: Infants under six months, particularly those younger than three months, are at the greatest risk of severe disease and death. Neonates under six weeks are especially vulnerable [90].
- Severe leukocytosis: A white blood cell count exceeding 70 × 10⁹/L is an independent predictor of mortality. This condition may necessitate interventions such as exchange transfusion to improve survival [70].
- Pulmonary hypertension: The presence of elevated pulmonary artery pressure is a key indicator of critical illness and is strongly correlated with fatal outcomes [92].
- Co-infections and comorbidities: Concurrent pneumonia or sepsis significantly increases the risk of complications and death. Pre-existing health conditions further elevate risk [72].
- Vaccination status: Incomplete or absent vaccination schedules leave children unprotected. Unvaccinated infants are at substantially higher risk of hospitalization and death [94].
Other contributing factors include elevated heart rate (over 170 bpm), increased inflammatory markers such as C-reactive protein, and lack of maternal immunization during pregnancy [92].
Long-Term and Systemic Impacts
Beyond acute complications, pertussis can have lasting effects on child development. Prolonged hypoxia during apneic episodes or severe coughing may result in long-term neurological deficits. The economic and social burden is also significant, with extended hospital stays and intensive care requirements placing strain on families and healthcare systems [69].
In adolescents and adults, while complications are less frequent, chronic cough lasting weeks or months—earning pertussis the nickname "the 100-day cough"—can lead to sleep disruption, urinary incontinence, and reduced quality of life [2]. However, these individuals play a crucial role as silent transmitters, often going undiagnosed due to atypical presentations, thereby posing a major risk to unvaccinated infants [98].
Vulnerability in Low-Vaccination Communities
Geographic and socioeconomic disparities in vaccine coverage contribute to clusters of severe disease. Countries and regions with low DTP3 vaccination rates—such as parts of Latin America and the Caribbean—have seen sharp increases in cases and deaths, with Honduras reporting multiple fatalities among infants in 2026 [99]. The World Health Organization (WHO) estimates that globally, pertussis causes approximately 300,000 deaths annually, predominantly in children under five in low-income settings [100]. These disparities underscore the importance of equitable access to the DTaP vaccine and the implementation of maternal immunization programs using the Tdap vaccine [101].
Prevention and Vaccination Strategies
Vaccination is the cornerstone of preventing pertussis, a highly contagious respiratory disease caused by Bordetella pertussis. Despite widespread immunization programs, pertussis has re-emerged globally due to waning immunity, antigen-deficient strains, and gaps in vaccine coverage [7]. Effective prevention relies on a multi-layered strategy that includes routine childhood immunization, booster doses in adolescents and adults, maternal vaccination during pregnancy, and targeted protection of vulnerable populations through cocooning strategies.
Childhood and Adolescent Immunization
The primary defense against pertussis begins in early childhood with the administration of the DTaP vaccine, which protects against diphtheria, tetanus, and acellular pertussis. The recommended schedule includes doses at 2, 4, 6, and 18 months of age, followed by a booster between 4 and 6 years [75]. This regimen provides strong initial protection, with vaccine efficacy estimated between 80% and 90% in the first few years after vaccination [104]. However, immunity from the acellular vaccine declines over time, a phenomenon known as waning immunity, which leaves adolescents and adults susceptible to infection and capable of transmitting the bacteria to unvaccinated infants [42].
To address this, a booster dose of the Tdap vaccine is recommended for adolescents, typically between 11 and 12 years of age [106]. This booster is critical for maintaining community immunity and reducing the reservoir of infection in older populations. The shift from whole-cell (wP) to acellular (aP) vaccines, while improving safety by reducing reactogenicity, has contributed to shorter-lived immunity, as aP vaccines induce a predominantly Th2-type immune response rather than the more durable Th1/Th17 responses seen with natural infection or wP vaccines [107].
Maternal Vaccination and Neonatal Protection
One of the most effective strategies for protecting newborns, who are too young to be vaccinated and at highest risk for severe complications such as apnea and death, is maternal immunization during pregnancy. The Tdap vaccine is recommended for all pregnant women between weeks 27 and 36 of gestation, ideally before week 36, to maximize the transfer of protective IgG antibodies across the placenta [108]. This passive immunity provides critical protection during the first months of life when infants are most vulnerable.
Studies have shown that maternal Tdap vaccination is highly effective, reducing the risk of pertussis in infants under two months of age by over 90% and decreasing hospitalizations and emergency department visits by 70–89% [109]. The safety profile of Tdap in pregnancy is well-established, with no significant association with adverse outcomes such as preterm birth or low birth weight [110]. Despite its proven benefits, implementation of maternal vaccination programs remains uneven, particularly in low- and middle-income countries [111].
Cocooning and Community Protection
In addition to maternal vaccination, the "cocooning" strategy involves vaccinating all close contacts of a newborn—such as parents, siblings, grandparents, and caregivers—to create a protective barrier around the infant [82]. This approach can reduce the risk of infant infection by up to 70% and is especially important in households where vaccine coverage is incomplete [82]. Cocooning complements maternal immunization by reducing the likelihood that an infected household member will transmit the bacteria to the newborn.
Challenges and Limitations of Current Vaccines
Despite high vaccination coverage in many countries, pertussis continues to circulate due to several factors. Waning immunity from acellular vaccines allows for subclinical or mild infections in vaccinated individuals, who can still transmit the pathogen [98]. Furthermore, the widespread use of aP vaccines has exerted selective pressure on Bordetella pertussis, leading to the emergence of strains deficient in key vaccine antigens such as pertactin (PRN) [7]. These PRN-negative strains may have a fitness advantage in highly vaccinated populations, potentially reducing vaccine effectiveness over time [116].
The limited ability of current vaccines to induce mucosal immunity and prevent nasopharyngeal colonization also contributes to ongoing transmission. Unlike natural infection or whole-cell vaccines, acellular vaccines do not generate robust local immune responses in the respiratory tract, allowing vaccinated individuals to become asymptomatic carriers [117].
Emerging Vaccination Strategies and Future Directions
To overcome these limitations, researchers are exploring next-generation vaccines that can provide longer-lasting and more comprehensive protection. Promising approaches include live attenuated intranasal vaccines, such as BPZE1, which can colonize the respiratory tract without causing disease and stimulate strong mucosal immunity [118]. Another strategy involves using outer membrane vesicles (OMVs) from B. pertussis, which present multiple antigens and have shown efficacy against PRN-negative strains in preclinical models [119].
Mixed vaccination schedules—using whole-cell vaccines for primary immunization followed by acellular boosters—are also being evaluated. These regimens may combine the durable cellular immunity of wP vaccines with the improved safety of aP boosters [120]. Additionally, systems biology approaches are being used to identify correlates of protection and guide the development of more effective formulations [117].
Public Health Recommendations and Vaccine Hesitancy
Public health authorities such as the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) emphasize the importance of maintaining high vaccination coverage across all age groups [42]. This includes not only routine childhood immunization but also Tdap boosters every 10 years for adults, particularly those in close contact with infants [123]. The disruption of vaccination programs during the COVID-19 pandemic has created cohorts of under-immunized children, increasing the risk of outbreaks [124].
Addressing vaccine hesitancy is crucial for sustaining high coverage. Misinformation about vaccine safety, particularly regarding maternal immunization, can undermine public confidence. However, extensive surveillance data support the safety of Tdap in pregnancy, and education campaigns are essential to promote vaccine acceptance [125]. Ensuring equitable access to vaccines, especially in underserved communities, is also key to achieving herd immunity and preventing the resurgence of pertussis [126].
Epidemiology and Global Trends
Pertussis remains a significant global public health challenge despite the widespread availability of vaccines. The disease exhibits cyclical patterns of transmission and has experienced a notable resurgence in recent decades, even in countries with high vaccination coverage. This resurgence reflects a complex interplay of immunological, microbial, and sociological factors that undermine long-term control. Global surveillance data from organizations such as the World Health Organization (WHO) and the Pan American Health Organization (PAHO) indicate a marked increase in reported cases, with approximately 941,565 cases documented worldwide in 2024 alone, representing the highest levels in over 35 years in some regions [127][128].
Resurgence and Cyclical Patterns
The epidemiology of pertussis has shifted significantly since the introduction of mass immunization programs, which drastically reduced incidence, hospitalizations, and mortality, particularly among infants [129]. However, since the 1990s, many high-income countries have observed a biphasic age distribution of cases, with peaks among unvaccinated or incompletely vaccinated infants and among adolescents and adults with waning immunity [130]. This shift is largely attributed to the transition from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines, which, while safer and less reactogenic, induce a shorter duration of protection. The phenomenon of "waning immunity" leads to a gradual decline in vaccine effectiveness—estimated to decrease by 2% to 10% annually—leaving older children and adults susceptible to infection and capable of transmitting the pathogen to vulnerable infants [131][132].
The disease follows a natural epidemic cycle, with outbreaks occurring every 3 to 5 years, a pattern that persists even in highly vaccinated populations [133]. The cyclical nature is influenced by the accumulation of susceptible individuals over time, particularly due to waning immunity and gaps in vaccination coverage. In 2024, Europe experienced an 85% increase in cases compared to 2023, with over 32,000 cases reported in the first months of the year, highlighting the ongoing vulnerability of even advanced health systems [134].
Global and Regional Incidence Patterns
The burden of pertussis varies significantly across regions, closely tied to vaccination coverage and health infrastructure. In the Americas, PAHO has issued multiple epidemiological alerts due to a sustained rise in cases, linking the trend directly to declining immunization rates [135][136]. In 2025, over 14,000 cases and 93 deaths were reported across the region, with outbreaks in Argentina, Mexico, and Honduras, where five deaths were recorded in 2026, primarily among infants under one year [137][99]. In Spain, cases surged from 47 in 2023 to over 2,500 in early 2024, a more than 5,000% increase, underscoring the potential for rapid spread [125].
In the European Union and European Economic Area (EU/EEA), 26,033 cases were reported in 2023, with Croatia and Denmark accounting for over 40% of the total [140]. Australia has also faced record-high case numbers, described as a "potentially catastrophic resurgence," despite high nominal vaccination coverage, further illustrating the limitations of current aP vaccines in providing long-term herd immunity [141]. In Asia, countries like South Korea have documented significant resurgences, particularly among adolescents and young adults, indicating a failure of long-lasting immunity [142].
Impact of Vaccination and Contributing Factors to Outbreaks
While national immunization programs using the DTaP vaccine and Tdap vaccine have been instrumental in reducing severe disease, their effectiveness is constrained by several factors. The most significant is the limited durability of immunity conferred by aP vaccines, which do not prevent asymptomatic or paucisymptomatic infection and transmission as effectively as natural infection or wP vaccines [98]. This allows vaccinated individuals to act as silent reservoirs, particularly dangerous for neonates who lack protective immunity.
Another critical factor is the microbial evolution of Bordetella pertussis under selective pressure from vaccination. There has been a documented increase in the circulation of pertactin-deficient (PRN-negative) strains, which lack a key antigen included in aP vaccines. These strains appear to have a fitness advantage in vaccinated populations, potentially evading vaccine-induced immunity and contributing to the re-emergence of the disease [7][145]. Additionally, disruptions to routine immunization services during the COVID-19 pandemic created cohorts of under-vaccinated children, increasing population susceptibility [124].
Low vaccination coverage remains a primary driver of outbreaks in many regions. The WHO estimates that pertussis causes 30 to 50 million cases and approximately 300,000 deaths annually, with the majority occurring in children under five in low-income countries where access to the DTP (diphtheria, tetanus, pertussis) vaccine is limited [100]. The third dose of the DTP vaccine (DTP3) is a key indicator of immunization program performance, and its decline below 80% in several countries correlates strongly with increased case numbers and fatalities [136].
Role of Maternal Vaccination and Public Health Response
The implementation of maternal immunization with the Tdap vaccine during the third trimester of pregnancy has proven to be a highly effective strategy for protecting newborns during their most vulnerable period. This practice transfers protective IgG antibodies transplacentally, providing passive immunity until the infant can begin their own vaccination series at two months. Studies show this intervention can reduce pertussis incidence in infants under two months by over 90% and hospitalizations by 70-89% [109][6]. Countries like Spain and Colombia have observed significant reductions in neonatal pertussis following the introduction of maternal vaccination programs [151][152].
To combat the resurgence, public health authorities emphasize a multifaceted response. This includes strengthening epidemiological surveillance, enhancing diagnostic capacity through widespread use of polymerase chain reaction (PCR), and promoting timely booster doses for adolescents and adults. Strategies such as "cocooning"—vaccinating close contacts of newborns—further reduce the risk of infant exposure [82]. The integration of digital tools, like the Iboca platform in Bogotá, Colombia, enables real-time monitoring of respiratory infections and rapid outbreak response [154]. Ultimately, controlling pertussis requires sustained high vaccination coverage, adaptation of immunization schedules to address waning immunity, and continued research into next-generation vaccines that can induce more durable and transmission-blocking immunity [126].
Public Health Response and Outbreak Control
Effective public health response and outbreak control are critical in mitigating the spread of pertussis, a highly contagious respiratory disease caused by Bordetella pertussis. Despite widespread vaccination programs, pertussis continues to re-emerge globally due to waning immunity, antigen-deficient strains, and gaps in vaccine coverage [7]. A coordinated, multi-pronged approach involving surveillance, vaccination strategies, case management, and community engagement is essential to protect vulnerable populations and prevent large-scale outbreaks.
Surveillance and Early Detection Systems
Robust epidemiological surveillance is the cornerstone of pertussis outbreak control. Timely detection of cases enables rapid intervention and containment. Many countries have strengthened their surveillance systems in response to the global resurgence of pertussis, with over 941,565 cases reported worldwide in 2024 [127]. The Organización Panamericana de la Salud (OPS) has issued epidemiological alerts for the Americas, urging member states to enhance monitoring and reporting [158].
Digital tools have improved early detection in high-density urban areas. For example, Bogotá, Colombia, implemented the digital platform Iboca, which monitors respiratory infections in real time, enabling rapid identification of pertussis clusters and targeted public health responses [154]. Similarly, Mexico’s Ministry of Health uses a national surveillance system to detect and respond to outbreaks, particularly in densely populated regions [160]. These systems allow for prompt activation of outbreak protocols, including contact tracing and prophylaxis.
Outbreak Response and Rapid Intervention
Rapid intervention is crucial to contain pertussis outbreaks, especially in communities with high population density where transmission is efficient. The effectiveness of response measures depends on early case confirmation and immediate implementation of control strategies. In Valencia, Spain, a 2015 outbreak among adolescents with complete vaccination was successfully controlled through timely administration of booster vaccinations and antibiotic treatment, demonstrating the importance of swift action [161].
Key components of an effective outbreak response include:
- Case confirmation using sensitive diagnostic methods such as polymerase chain reaction (PCR), which is most reliable during the catarrhal phase [162].
- Immediate isolation of confirmed cases to reduce transmission, particularly during the first 5 days of antibiotic treatment [67].
- Coordination between health authorities, clinics, and communities to ensure consistent messaging and implementation of control measures within 24–48 hours of case identification [164].
Contact Tracing and Antibiotic Prophylaxis
Contact tracing is a vital strategy in interrupting pertussis transmission. Close contacts—especially household members, caregivers, and healthcare workers—are at high risk of infection and can serve as silent reservoirs, transmitting the disease to vulnerable infants [165]. A prospective study in Spain (2012–2013) showed that identifying and treating symptomatic contacts in households significantly reduced secondary transmission [166].
Antibiotic prophylaxis with macrolide antibiotics such as azithromycin or clarithromycin is recommended for close contacts, particularly those who interact with infants under six months [81]. This approach is especially important because adults and adolescents often present with mild or atypical symptoms and may unknowingly spread the infection [130].
Mass Vaccination Campaigns
Mass vaccination is a proven strategy for controlling pertussis outbreaks, particularly in areas with low vaccine coverage or high transmission rates. In Peru, following 10 deaths from pertussis, the Ministry of Health launched a door-to-door vaccination campaign in Lima Este, prioritizing children and pregnant women [169]. Similarly, Mexico resumed vaccination campaigns after a surge of 288 cases linked to incomplete immunization schedules [170].
Vaccination with DTaP vaccine in children and Tdap vaccine in adolescents and adults helps maintain herd immunity and protect those who cannot be vaccinated. The Centros para el Control y la Prevención de Enfermedades (CDC) recommends Tdap boosters every 10 years to sustain protection [123]. Vaccination during pregnancy, ideally between weeks 27 and 36, has been shown to reduce infant hospitalizations by 70–89% through transplacental transfer of IgG antibodies [6].
Public Education and Community Engagement
Public awareness plays a critical role in outbreak control. Misinformation and vaccine hesitancy have contributed to stagnating immunization rates in some regions, increasing population susceptibility [173]. Public health campaigns must emphasize the safety and effectiveness of pertussis vaccines, particularly for pregnant women and caregivers of infants.
The "cocooning" strategy—vaccinating all close contacts of newborns—can reduce transmission risk by up to 70% [82]. Educating families on hygiene practices such as handwashing, respiratory etiquette, and avoiding contact with symptomatic individuals further supports outbreak control. In-home care guidance should include recognizing danger signs like apnea, cyanosis, or difficulty breathing, which require immediate medical attention [79].
Global and Regional Coordination
International collaboration is essential for managing pertussis as a re-emerging global threat. The Organización Mundial de la Salud (OMS) and the Grupo Asesor Estratégico de Expertos en Inmunización (SAGE) continuously evaluate vaccine effectiveness and recommend optimal immunization strategies [176]. The OPS has organized national workshops across Latin America to strengthen surveillance, diagnosis, and treatment protocols [177].
Despite high national vaccination coverage in some countries, localized pockets of low immunization create vulnerabilities. The resurgence of pertussis in nations with advanced healthcare systems underscores the need for sustained vigilance, equitable vaccine access, and adaptive strategies that address evolving bacterial strains such as pertactin-negative Bordetella pertussis [7]. A comprehensive public health response—integrating surveillance, rapid intervention, vaccination, and education—remains the most effective way to protect communities and prevent future outbreaks.