Epidemiology of the Disease

A global modeling study estimated that there were 24.1 million pertussis cases and 160,700 deaths from pertussis in children < 5 years in 2014, with the largest proportion in Africa. Global and regional epidemiologic data for pertussis have been summarized in Table 1. Globally, 21% of the estimated cases and 53% of the estimated deaths were in infants < 1 year old [5]. Between 2008 and 2016, substantial pertussis outbreaks were reported in many countries including the USA, Canada, Australia, Japan, UK, Sweden, Poland, Malaysia, Argentina, Brazil, Colombia, and Mexico [6,7,8,9]. Although no extensive outbreaks have been reported since 2016, several smaller local outbreaks have been reported. In 2019, a pertussis outbreak was announced in an early-years school in England among 7–11-year-old students who had their last booster dose at the age of 40 months. Vaccination coverage was found to be lower than the national average in this school and considered to be the main reason for the high transmission [10].

Table 1 Number of reported pertussis cases in different regions [17, 37]

Since December 2019, a pandemic caused by novel coronavirus SARS-CoV-2 disrupted routine childhood immunization by reducing the use of healthcare facilities and increasing the risk of vaccine-preventable diseases including pertussis [11]. In 2021, 25.0 million children had not completed the three-dose DTP series worldwide, of whom 18.2 million (73%) had received no doses, and 6.8 million (27%) were incompletely vaccinated with DTP. This is almost 50% higher compared to the numbers in 2019. According to the World Health Organization (WHO) and UNICEF reports, global DTP1 coverage reduced from 90% in 2019 to 87% in 2020 and 86% in 2021, which is the lowest rate since 2005. The highest fall in first (DTP1) and third dose DTP (DTP3) coverage between 2019 and 2021 was in the Southeast Asia Region (from 94 to 86% for DTP1 and from 91 to 82% for DTP3) [12].

US and Canada

While approximately 4000 pertussis cases were reported annually in the US in the 1980s, reported cases increased to 25,827, 27,500, and 48,277 cases in 2004, 2010, and 2012, respectively [13]. From 2000 to 2016, 339,420 pertussis cases were reported in the USA. Throughout all age groups, almost 10% were hospitalized, and the mortality rate was 0.1%. Infants had the highest incidence of mortality (75.3/100,000 population), accounting for almost 90% of deaths. Incidence gradually rose, and this increase were observed for all groups except the age groups 0–12 months and 19–64 years [14]. Another study from the USA revealed that 11,378 pertussis cases were identified from 2006 to 2015. Adjusted pertussis incidence was 15.55 cases per 100,000 person-years. Although infants and children were the most affected population, around 60% of total cases were adolescents or adults [15].

A total of 33,481 pertussis cases were reported in Canada between 2005 and 2019 with an average annual incidence rate of 6.4 cases per 100,000 population. The highest average age-specific incidence rate was among infants < 1 year of age (n = 68.7 cases per 100,000 population). Hospitalization rates were almost eightfold higher in infants under the age of 3 months compared to those between 4 to 11 months of age [16]. However, there was a significant decrease in the incidence of pertussis during the pandemic. In British Columbia, one of the largest provinces of Canada, annual incidence of pertussis was found to be the lowest since 1990 in 2020 and 2021 (3/100,000 in 2020 and < 1/100,000 in 2021) [17].

European Countries

Surveillance data from Europe have shown that 35,627 cases of pertussis were reported in 30 European Union/European Economic Area (EU/EEA) countries in 2018; 72% of total European cases were reported from five countries including Germany, The Netherlands, Norway, Spain, and UK. Consistent with the previous years, 8.2 cases were reported per 100,000 population in 2018 whereas 62% of total cases were ≥ 15 years of age. Infants younger than 12 months were the most affected age group, with the highest rate 44.4 per 100,000 population (and three deaths reported), followed by the children between 10 to 14 years old [18]. A study funded by European Centre for Disease Prevention and Control evaluated the pertussis seroprevalence among adults of reproductive age (20–39 years) in 14 European countries. There was a noteworthy diversity in the ratio of samples with anti-PT IgG ≥ 100 IU/ml, illustrating a recent infection varying from 0.2% in Hungary to 5.7% in Portugal. However, the countries with the top reported incidences did not have the greatest degree of seroprevalence. In Portugal, the seroprevalence rate was 5.7%, whereas the incidence was only 0.1–2.2 per 100,000 people. Thus, many cases may have been underdiagnosed [19]. The pertussis incidence and hospitalization rate have been increasing in Spain with the highest rate in children under 12 months of age. However, vaccination has remarkably decreased hospital admissions; following the vaccination of pregnant women hospitalization rates showed a 20% reduction [20].

The number of pertussis cases remarkably reduced during the COVID-19 pandemic; a national Swedish cohort study showed that the average number of infant cases declined from 21 to 1 per quarter of a year during the pandemic [21]. Similarly, pertussis incidence decreased in England in all age groups, especially in infants younger than 12 months of age during the pandemic (0.50/100,000 during July 2020 to June 2021 compared to 24.49/100,000 from July 2014 to June 2019) [22].

Asia-Pacific Region

The WHO estimated that among children younger than 60 months of age, pertussis was the fourth most common vaccine-preventable disease after measles, diphtheria, and mumps, and the most prevalent one in the Asia-Pacific region [7]. The highest number of pertussis cases in the past 5 years in the Asia-Pacific region was reported in 2019 (63,483), whereas the lowest number of reported cases occurred in 2017 (27,624) [7]. Although surveillance systems are poor in some Asian countries, it has been reported that the burden of pertussis in children remains high in many Asian countries [25]. A recent surveillance study in Asian children and teenagers aged 10–18 years from China, India, Japan, South Korea, Sri Lanka, Taiwan, and Thailand (N = 1802) from July 2013 to June 2016 revealed that 4.8% had anti-PT IgG levels ≥ 62.5 IU/ml, which was interpreted as B. pertussis infection within the previous 12 months. Among the seropositive ones, 83.9% had minimum three doses of DTP vaccination before the age of 6 years [9, 23].

Middle East

While the surveillance data are insufficient in the Middle East, there was an alteration in reported pertussis cases in 2019 including nine in the United Arab Emirates, 78 in Lebanon, 242 in Iran, and 302 in Syria [24]. Data from the Middle East region suggest that pertussis is an extensive concern and that it might be affecting older age groups [24]. A few countries in the Middle East region administer a Tdap booster for adolescents. Israel was the only country with population health data that delivers Tdap, and the results showed that the utilization of the adolescent booster dose led to a remarkable drop in pertussis among children between 5 and 14 years of age [25].

Türkiye

In Türkiye, diphtheria and pertussis immunization was initiated in 1937; routine childhood pertussis immunization with wP (DTP) was started in 1968, and aP (DTaP-IPV/Hib) has been given since 2008 [26]. The pertussis vaccine has been administered in the 2nd, 4th, and 6th months of age, and in combination with a booster dose administered in the 18th month, in accordance with the childhood vaccination schedule. Since 2010, a single-dose diphtheria, tetanus toxoid, acellular pertussis, and inactivated polio vaccine (DTaP-IPV) has also been applied to children at 7 years of age (Supplementary Fig. 1) [27]. After 2020, the DTaP-IPV dose was moved to the age of 48 months (Supplementary Table 1). In 2005, pertussis incidence decreased (0.38 per 100,000) compared to 1986 (2.03 per 100,000). However, the proportion of the patients ≥ 15 years of age increased from 6.5 to 16.9% within that period [28]. According to the data from national authorities, pertussis incidence decreased 99.5% with the vaccination from 1980 to 2014 [29]. In 2010, the number of pertussis cases was 48, the incidence of pertussis was 0.07 per 100,000 population, and no deaths due to pertussis were reported in Türkiye [30]. In a study conducted by Oksuz et al. in Istanbul, the largest city in Türkiye, in a sample of 410 nasopharyngeal aspirates taken from children who exhibited symptoms of whooping cough from 2010 to 2014, the Bordetella polymerase chain reaction (PCR) positivity rates were 36% in 2010 and gradually decreased as 29% in 2011, 15% in both 2012 and 2013. Since the initiation of DTaP-IPV vaccination at age 7 in 2010, pertussis has not been detected in the 5–9-year-old age group [31]. In another study from Türkiye, 214 adolescents and adults who had a cough lasting > 2 weeks were investigated for the presence of B. pertussis. Three (1.4%) patients were B. pertussis culture-positive; 15 (7%) were B. pertussis PCR-positive (including the culture-positive patients), and 11 (5.1%) were Bordetella spp. PCR-positive [32]. In another study, nasopharyngeal specimens were collected from 101 children between the age of 7–18 years with prolonged cough, and 19.8% were PCR positive for B. pertussis. Children who had their last vaccine dose > 5 years ago had a 6.13-fold higher risk of PCR-confirmed pertussis than those who were vaccinated within 5 years. Paroxysmal cough, whooping, and post-tussive vomiting were observed in approximately 30%, 15%, and 25% of the PCR-positive children, respectively [33]. Although pertussis is known to present generally with prolonged cough, prevalence of pertussis was found to be 3.5% among 115 adult patients with acute cough in a recent study from Türkiye [34].

In a seroprevalence study from Türkiye, high levels of anti-pertussis IgG (anti-PT IgG) (≥ 100 EU/ml) were detected in 9.7% (52/538) of the patients between 18 and 87 years who had a prolonged cough. Among cases with high antibody levels, age, gender, education level, vaccination, and smoking history or average daily cigarette consumption did not significantly differ [35]. Among a convenience sample of 228 adults who were admitted to the emergency departments without any respiratory problems, 40% were anti-PT IgG positive, 60% were negative. Anti-PT IgG positivity was increasing by age, as 26% at both 19–35 years and 36–50 years and 48% in the 51–65-year group, which may be illustrating a recent history for a typical or atypical pertussis infection [36].

In 2019, both DTP1 and DTP3 coverages were significantly high with a 99% rate in Türkiye [37]. A cross-sectional online survey study from Türkiye revealed that vaccination rates in Ankara, the capital city, fell 2–5% during the pandemic, with the highest drop in the vaccines administered after 18 months of age [38]. The pandemic has led to concern about other global health areas being neglected, including the delivery of vaccination and immunization programs particularly in low-income countries and among vulnerable populations.

Burden of Disease

Infants under 12 months of age, particularly those between 0 and 6 months, have the highest burden of pertussis disease [39]. According to Swiss National Surveillance Data, hospitalization rates were significantly higher (38.8 per 100,000 population) than the rate in patients < 16 years (2.6 per 100,000) [40]. During the 2010 outbreak in the US, although pertussis was detected in all age groups, the greatest incidence and hospitalization were seen in infants < 6 months old [41]. From 2010 to 2017, pertussis was reported in 27,370 infants aged < 12 months; 9199 cases (33.6%) occurred among infants aged < 2 months. Among the 7731 infant pertussis hospitalizations within that 8-year period, a total of 3928 (50.8%) were among infants aged < 2 months. Meanwhile, 69% of pertussis deaths were recorded in infants < 2 months old [42]. Similarly, during the pertussis resurgence in the UK in 2012, the highest incidence of pertussis was seen in infants < 3 months old whereas a remarkable rise was also reported in the age cohort of > 15 years [43]. In Spain, infants < 3 months of age accounted for almost 60% of hospitalizations due to pertussis, and > 90% of hospitalized patients were infants < 1 year of age [44]. Mortality rates in infants < 3 months old were the highest in all these epidemics [45]. In addition, the most recent data show that pertussis remains an important cause for deaths in infants and young children [20, 44]. Thus, when implementing elimination plans for pertussis, it is essential to develop routes that stop pertussis dissemination among both newborns and young infants.

Main symptoms of pertussis are cough with or without paroxysms, cyanosis, apnea, tachypnea, and difficulty in breathing. Pertussis can also cause important complications, particularly in infants who are too young to be vaccinated. In a study from Türkiye, pertussis was found in 44 (25.6%) of the 172 infants diagnosed with acute bronchiolitis and as a co-infection with respiratory viruses in 27 (61.4%) infants. Of those 44 pertussis-positive infants, only 17 (38.6%) had a paroxysmal cough, 13 (29.5%) experienced whooping, and 15 (34.1%) had post-tussive vomiting [46].

Pertussis can cause especially severe disease in newborns and unvaccinated infants [44]. A study conducted in Türkiye reviewed 18 patients in a pediatric intensive care unit with a diagnosis of pertussis, all of whom were unvaccinated. The median age was 40 (38–47.5) days. All patients had respiratory distress, 14 patients had cough (77.7%), 4 patients had fever (22.2%), and 3 patients had seizures (16.6%). Seven patients required mechanical ventilation. Three patients died because of multi-organ failure and cardiogenic shock despite extracorporeal life support [47]. A retrospective study from Singapore between 2007 and 2016 revealed that key risk factors for intensive care unit (ICU) admission included age < 3 months, positive contact history, underlying comorbidity, prematurity, and being unvaccinated [48].

Although pertussis is often considered a childhood disease, approximately 32% of all notified pertussis cases in England in 2019 were in people aged ≥ 45 years [49]. While adolescent and adult infections remain underrecognized and undiagnosed, they can be a source of transmission to higher risk groups, including as neonates and the patients with chronic diseases [24]. Although 1.4–7.5% of individuals 10–19 years of age and 3.5–5.7% of individuals ≥ 20 years of age required hospitalization, older individuals may require longer hospitalization. While death from pertussis occurs in ∼ 0.1% of cases among patients > 10 years old, complications of pertussis are not rare in adults and adolescents [50]. As the general population ages, the disease burden is therefore predicted to rise [51, 52].

Patients with respiratory and other systemic comorbidities—including chronic obstructive pulmonary disease (COPD) and asthma—may have an elevated chance of experiencing severe pertussis infections [53, 54]. Both human immunodeficiency virus (HIV) infection and exposure were also associated with greater pertussis incidences and rates of hospitalization and mortality [55].

In a study from the Philippines, the most frequent complications from pertussis disease were pneumonia requiring intubation (64%), acute respiratory distress syndrome (ARDS) (28%), seizures (21%), nosocomial pneumonia (11%), and myocarditis (11%) [56]. While the most common are pulmonary complications including both interstitial and alveolar pneumonia and, in serious cases, respiratory failure, neurologic and nutritional complications have also been observed. Cough paroxysms and related hypoxia may cause acute encephalopathy and/or cerebral hemorrhage, which may result in epilepsy or permanent brain damage [57]. Other pertussis-related complications include urinary incontinence, headache, sleep disturbances, rib fractures, fainting, sinusitis, and otitis media [24].

Obstacles in Pertussis Prevention

The primary goal of pertussis vaccination is to decrease the possibility of serious disease in infants and young children. Despite the success of widespread mass vaccination schemes, pertussis causes a noteworthy health burden in various countries. Furthermore, actual pertussis incidence is estimated to be considerably higher than the reported incidence [3]. The resurgence of pertussis reporting in the recent years may be partially attributable to improved recognition, reporting, and diagnosis of pertussis. Although the culture has 100% specificity, the sensitivity is very poor, and it is difficult because of the fastidious nature of the organism [58]. As the nasopharyngeal cultures should be collected in the first 15 days, diagnosis of pertussis may be missed because of its non-specific symptoms. Moreover, isolation of the bacterium can be affected by the antibiotic usage. Molecular techniques, including real time-polymerase chain reaction (rt-PCR), are currently extensively accessible allowing rapid diagnosis of pertussis with a higher sensitivity (70–99%) in the early stages of infection [59, 60]. Moreover, to verify the infection after this stage, serologic methods detecting anti-PT IgG in serum and saliva have been established [3]. Both PCR and serologic test applications may cause a relative increase in pertussis recognition. In Canada, clinical application of a sensitive PCR assay was related to an accompanying fivefold rise in the detection of pertussis-positive cases [61]. A comparison of diagnostic tests for pertussis is shown in Table 2.

Table 2 Comparison of the diagnostic tests for pertussis [58,59,60,61]

Waning immunity is an important concern regarding pertussis prevention. Neither natural infection nor immunization with wP and aP vaccines gives life-long immunity [52]. A 10-year study of pertussis immunity in the UK showed that the protection afforded by vaccination remained effective in 85% of children during the first 4 years post-vaccination but declined to 50% within 3 years. A meta-analysis of 11 studies showed that during each year following administration of DTaP, the risk of pertussis rose 1.33-fold; consequently, 8.5 years after their last aP dose, only 10% of children were still immune against pertussis [62]. A comparison study of adolescent booster doses revealed that upon completion the absolute effectiveness of the full six-dose aPV series was estimated to be 85% but declined by 11.7% each year thereafter. At 18 years of age, protection was reduced to 28.2% of immunized patients [63]. This rapidly declining effectiveness indicates that additional booster doses are necessary to ensure continuing protection.

After the introduction of wP and aP vaccines, genetic mutations have been widely observed in the circulating strains of B. pertussis. The deletion of pertactin (PRN), over-expression of PT, as well as, in a few cases, deletion of PT or filamentous hemagglutinin have been documented [64]. PRN-deficient strains have become prevalent in Australia, Israel, and the USA [65,66,67]. From 2008 to 2012, during an important outbreak of pertussis in Australia, 30% (96/320) of B. pertussis isolates did not have PRN [65]. The pertussis flare-up in Israel was also related to the increased prevalence of PRN-negative strains [66]. Such mutant strains may evade a vaccine-induced immune response but not necessarily cause more disease or reduced vaccine efficacy.

Regional differences in the vaccination coverage, due to the varying national immunization schedules and vaccine hesitancy, may also foster pertussis resurgence. Although mean global DTP3 coverage was 81% in 2021, regional coverage levels vary extensively, ranging from 71 to 94%, depending on the country [12].

Strategies for Effective Pertussis Prevention

As pertussis remains an important global concern, to address the potential barriers for pertussis control and provide better prevention, several immunization strategies have been developed. These are maternal immunization during pregnancy, immunization of family and close contacts of newborns (cocooning), universal immunization of adolescents and adults, and immunization of healthcare workers. These should be carried out together with the application of a fourth or fifth booster dose for all pre-school children (4–6 years of age) and advancement of current infant and children immunization plans.

Maternal Immunization

Pertussis is a remarkable cause of morbidity and mortality in children, particularly in infants < 6 months of age via transmission from a relative in close contact [20, 44]. Generally, the initial pertussis vaccine is given at the age of 6 or 8 weeks but can be delayed up to 3 months in several countries [1]. Although the initial dose provides partial protection against severe disease, higher rates of immunity (80–90%) can be produced after the third dose [1, 3, 52]. The approaches to further decrease infant mortality from pertussis have therefore focused on supportive action plans such as maternal immunization during pregnancy and cocooning.

In the UK, pertussis-including vaccines have been delivered in infancy since 1957, at 2, 3, and 4 months of age since 1990, a preschool booster at 40 months of age, and aP vaccine since 2004. Although good disease control was achieved, a national rise in pertussis was recorded in late 2011, first limited to adolescents and adults, and then spread through younger children in 2012 [43]. As a response to this, in 2012 a five-component acellular-pertussis-containing vaccine was offered to all women between 28 and 38 weeks of pregnancy. There was a 78% fall in the number of confirmed cases and 68% drop in hospital admissions in infants < 3 months old. Vaccine effectiveness was 90% when the analysis was narrowed to cases < 2 months of age [43]. Pertussis vaccination in pregnancy was available in all regions of Spain in early 2016. While the national mean of death from pertussis was 5.1 per year between 2007 and 2015, annual mortality rate fell to 2.5 per year between 2016 and 2019 [44].

Since the introduction of maternal immunization in the US in 2012, the incidence of pertussis in infants < 6 months of age reduced from 169.0 per 100,000 population in 2014 to 57.2 per 100,000 in 2018. The number of deaths in infants < 12 months was 16 in