Resurgence of pertussis: whopping the ‘100-day cough’

Abstract

Purpose of review

Against the WHO's report of 84% diphtheria–pertussis–tetanus (DPT) primary vaccination coverage globally, the resurgence of pertussis (whooping cough), contributing factors and measures to control it are described.

Recent findings

USA and China, with 94–97% primary DPT immunization uptake, reported a 6-fold and 65-fold increase in pertussis between two time periods in 2023 and 2024. The global post-COVID-19 pertussis epidemic is trending towards a shift from infants towards older persons. Macrolide resistance is prevalent in 98% of Bordetella pertussis strains in China and is now reported from other countries. Pertactin-deficient mutant acellular pertussis vaccine-evasive strains are now transmitted in older children and adults. Pertactin-producing B. pertussis is causing fulminant pertussis in newborns whose mothers were not immunized in pregnancy and in under-immunized infants. Circulating epidemic strains of B. pertussis were discordant to those contained in whole-cell (Bp137) pertussis vaccine. The pertussis resurgence maybe explained by increased case ascertainment and reporting, mutant B. pertussis strains with immune escape from acellular and whole cell vaccines, and/or macrolides, waning natural, or vaccine-induced immunity and COVID-19 pandemic factors.

Summary

Pertussis maybe curtailed with public education, active clinical and microbiological surveillance, appropriate antimicrobial treatment and prophylaxis, public health reporting, infection control and optimized immunizations to reduce attributable morbidity and mortality.

INTRODUCTION

Pertussis (whooping cough, the ‘100-day cough’) is a highly contagious respiratory disease affecting all age groups. It is caused primarily by Bordetella pertussis. A peak of 260 000 pertussis cases was reported in 1934 and  9000 attributable childhood deaths occurred in 1923 in the United States of America in the prevaccine era when pertussis was endemic [1]. Pertussis incidence was trending at 157 per 100000 population in the early 1940's. Whole cell pertussis vaccines were introduced in the USA in 1949, and their use controlled the disease, with a nadir of 1010 cases and seven deaths reported by 1976 [1]. Pertussis surges in 3- to 4-year cycles; these have been increasing since the 1980s, with a peak of 48 277 reported cases (15.36 per 100,000 population) and 18 deaths in 2012 [2^▪]. It was recommended that whole-cell pertussis vaccines be changed (primarily because of their reactogenicity) to acellular vaccines in the USA, beginning with the fourth and fifth doses and then the primary series, in 1992 and in 1997, respectively [3,4]. Currently, everyone aged older than 7 years, including pregnant women, is recommended to receive tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine boosters [5–7]. 

Box 1.

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PERTUSSIS RESURGENCE IN 2024 AND MOLECULAR IMMUNOLOGY

The WHO reported a global resurgence of pertussis, although 84% received three doses of diphtheria–pertussis–tetanus (DPT) vaccine [8^▪▪,9^▪▪]. The WHO's recommended vaccination target for populations is > 95% for the primary DPT series. USA, China, Canada, Australia, Brazil, Korea, several European countries, and other highly vaccinated populations have reported a resurgence in pertussis in 2024. On a background of 94% DPT vaccine coverage with the primary series, the USA's surveillance revealed a pertussis incidence of 10.63 per 100 000 population with 35 435 total pertussis cases provisionally reported through epidemiological week 52 of 2024, with a more than six-fold increase over reports for the same period in 2023 [2^▪,10^▪▪].  China, with 97% DPT primary immunization coverage of its target population, reported a 23-fold increase in pertussis cases for the first 2 months of 2024, over 2023 [9^▪▪]. China later reported a 65-fold increased trend in pertussis cases, from 1512 in June 2023 to 97 669 in May 2024, with increased attributable mortality (Fig. 1) [11^▪▪]. Furthermore, these exceeded the reported pertussis cases in the COVID-19 prepandemic period [2^▪,9^▪▪,10^▪▪,11^▪▪]. The ‘pandemic immunity gap’ likely contributed to the intervening lull of pertussis cases [9^▪▪,12]. Nonpharmaceutical interventions, school or day care closures, and lockdowns likely created a pool of susceptible persons who avoided infection during the pandemic [12]. Therefore, surges of infections occurred with the relaxation of mitigation strategies when the children returned to school [2^▪,12]. The reasons for this pertussis resurgence include improved and changing physician and laboratory diagnostic practices, improved pertussis case surveillance and reporting, genetic mutations of B. pertussis with immune escape from acellular and whole cell vaccines, or macrolide antibiotics, waning acellular pertussis vaccine efficacy over time, vaccine hesitancy and COVID-19 pandemic factors [2^▪,9^▪▪–11^▪▪,12–16,17^▪▪,18–24,25^▪▪,26,27^▪▪–29^▪▪,30^▪▪,31^▪▪–33^▪▪,34–39].

FIGURE 1.

(a) Annual number of nationally reported pertussis cases and associated deaths, 2010–2023 in China; (b) Monthly number of reported pertussis cases and associated deaths, January 2019–May 2024. Data from Yahong et al. [11^▪▪]. Copyright: © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd. is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The molecular pathogenesis of B. pertussis changes with the immune escape of mutant acellular vaccine-induced strains, which are different from strains that were circulating when pertussis was endemic and whole cell vaccines were in widespread use [14–16]. Newer epidemic B. pertussis strains are selecting ‘vaccine escape mutants’, which have changes in vaccine-expressing genes, which may contribute to the virulence of this pathogen [14–16,17^▪▪,18–24,25^▪▪,26,27^▪▪]. Globally, there has been a significant increase in the rate of evolution of acellular vaccine antigen-encoding genes, including pertussis toxin, pertactin, filamentous hemagglutinin, and fimbriae, as compared to the genes that encode surface antigens that are not included in the vaccine [14,15]. Japan, Australia, Sweden, Italy, the USA, and other countries have also reported pertactin-deficient B. pertussis strains [19–21,24]. These immune evasive strains may be relevant to inform acellular pertussis vaccine effectiveness.

Molecular typing showed that the B. pertussis strains that were circulating during the recent epidemic were discordant with the strains used for immunizations with whole cell vaccines in midwestern Brazil [27^▪▪]. The prevalent genotypes observed among epidemic B. pertussis isolates were fim3-24/ptxP-3 (68%), fim3-1/ptxP-3 (15%) and fim3-3/ptxP-3 (17%)[27^▪▪]. However, the fim3-1/ptxP-2 genotype, which was found in the whole cell (wP) vaccine (Bp137), was absent [27^▪▪]. Serotype changes and biofilm production of B. pertussis have been reported after the introduction of the acellular pertussis vaccine in Finland [28^▪▪]. The Pasteur Institute reported an increase in less virulent B. pertussis strains that did not express pertactin because of widespread vaccination with acellular vaccines in France [25^▪▪]. These immune-evasive mutant strains in acellular pertussis vaccine recipients are transmitted more effectively than the original strains that express pertactin [25^▪▪]. However, pertactin-producing strains cause fulminant pertussis in newborns, characterized by a leukocyte count greater than 40 × 10⁹/l and at least one of the following criteria: respiratory failure, pulmonary hypertension, shock or multiple organ failure[25^▪▪]. Furthermore, young age, preterm birth and absence of whooping cough vaccination were independent risk factors for fulminant pertussis in France [25^▪▪]. Therefore, maternal immunization reduces attributable mortality in newborns and infants [25^▪▪]. Epidemic pertussis in newborns and incompletely immunised infants in 11 pediatric hospitals was similarly reported with an 800% increased hospitalisation rate in Italy [29^▪▪]. Macrolide-resistant B. pertussis isolates have been identified in China, France and Finland [11^▪▪,17^▪▪30^▪▪–33^▪▪]. Resistance rates of B. pertussis to the macrolide antibiotics approach 70–100% in China [30^▪▪]. The ptxP3-allele, macrolide-resistant B. pertussis clone MR-MT28 was the dominant circulating strain in 2023 in Shanghai, China [17^▪▪,30^▪▪,33^▪▪]. This ptxP3 strain produces more pertussis toxin than the ptxP1 strain, with the potential of increasing the virulence of this pathogen [30^▪▪].

PERTUSSIS THE DISEASE AND RECENT TRENDS

Pertussis is currently defined clinically, in the absence of a more plausible diagnosis, as a coughing illness that lasts for at least 2 weeks, with paroxysms, or inspiratory whoop, posttussive vomiting, apnea with, or without cyanosis, with laboratory evidence of B. pertussis [13]. In the past, laboratory diagnostics included a nasopharyngeal swab that was positive for B. pertussis by direct fluorescent antibody, or culture, while today many laboratories rely on confirmatory PCR testing, if available [13]. Contact with a laboratory-confirmed pertussis case and epidemiological linkage to a confirmed case were also included [13]. Recurrent infections occur due to waning protective antibodies that provide natural immunity (for 4–20 years) and vaccine-induced immunity (for 4–12 years) [34–38]. Reported cases represent the ‘tip of the iceberg’, as evidenced by serological surveys in 23 countries, which prove that pertussis is largely under-diagnosed, and that asymptomatic transmission` occurs [39]. Despite reported inter-observer bias, studies suggest an incidence of 370–500 per 100 000 population, or about 800 000 to one million pertussis cases are identified in the USA each year; however, these studies were performed in adults and adolescents who have coughing illnesses [22,23].

Pertussis is a respiratory illness that occurs primarily in humans. It is transmitted via large respiratory droplets through coughing and sneezing. The illness can be mild or severe. Clinically, pertussis is characterized by three phases. The ‘catarrhal’ phase is indistinguishable from a ‘flu-like’ upper respiratory illness and lasts up to 10 days. The ‘paroxysmal’ phase follows with severe coughing spells, characterized by a loud inspiratory whoop, followed by bouts of staccato coughing on expiration, concluding with vomiting. Newborns and infants may present with apnea, bradycardia and cyanosis [40]. This phase may last for up to 6 weeks [40]. The ‘convalescent’ phase then follows, as the coughing illness resolves over a period of weeks to months. The entire illness may be mild, presenting with bronchitis and prolonged cough, especially in older, previously immunized persons, or it may manifest as the characteristic ‘100-day cough’, especially in newborns, infants and persons without natural, or vaccine-induced immunity [40–43]. The groups at the highest risk for complications were newborns, under-immunized infants aged less than 6  months and preschool-aged children [1,2^▪,40–43]. Serious complications include pneumonia, seizures, dehydration, malnutrition and hemorrhage – which may be intracranial, with severe acute and long-term consequences [40–43].

European surveillance now reports that 70% of pertussis cases occur in adolescents older than 14 years and 6% in infants [44^▪,45^▪]. Although infants have the highest pertussis incidence and attributable deaths, a similar trend has been observed in China [9^▪▪]. Pertussis surveillance reports in 2024 showed a shift in the age of pertussis cases from young infants, whose mothers were not immunized, to older persons in Europe [29^▪▪,44^▪–47^▪]. Pertussis also surges in the 5–14-year age group in Korea [46^▪]. In the current post COVID-19 pandemic, attributable morbidity and mortality have been the highest in young infants, especially in those whose mothers were unimmunized during pregnancy, in the USA, Italy, Denmark and France [2^▪,29^▪▪,45^▪,47^▪]. Adults with comorbidities, especially chronic obstructive pulmonary disease, are now reportedly at risk for severe pertussis disease [48^▪▪,49^▪].

Macrolide antibiotics, or trimethoprim/sulfamethoxazole are traditionally recommended for treatment in the catarrhal phase and for prophylaxis of exposed persons [43]. In China, where there is now widespread resistance to the macrolide antibiotics, trimethoprim/sulfamethoxazole and certain B lactam antibiotics are being evaluated for the management of pertussis in children [11^▪▪].

CASE STUDY: EPIDEMIC PERTUSSIS IN A HIGHLY VACCINATED POPULATION (DESCRIPTION AND CONTROL)

Christie and colleagues, from the Cincinnati Children's Hospital Medical Center, Cincinnati Health Department, the USA's Centers for Disease Control and Prevention and Massachusetts Public Health Biologic Laboratories described epidemic pertussis in the highly vaccinated childhood population of Greater Cincinnati from many diverse perspectives [50–56]. These included the clinical epidemiology of the epidemic cases in children and adults, the interventions and effectiveness of pertussis control in the population, the regional children's hospital and in schools and day care centers, the molecular epidemiology of B. pertussis strains and a clinical trial of acellular pertussis vaccine in hospital employees [50–56].

Given the recent resurgence began circa 1993, this case study, and its multi-pronged holistic interventions especially, maybe relevant to other communities and/or countries both now and in the future.

In the context of active microbiological surveillance of pertussis for 15 years, a spike in pertussis cases triggered the declaration of a community-wide epidemic in the Greater Cincinnati tristate areas of Ohio, Kentucky and Indiana when the 14-year baseline incidence of 0.4–5.8 cases per 100 000 population, increased to 20.7 per 100 000 in the epidemic year [50]. The 1.7 million geographic areas were served by a single 361-bed pediatric hospital. There, 352 pertussis cases were identified within 1 year, a 259% increase over the previous year, with 255 of these pertussis cases diagnosed within the 3 months of summer, representing 195 excess cases over the maximal baseline rate of 20 per month for the preceding 14 years [50]. These cases had nasopharyngeal swabs that were positive by culture for B. pertussis (63%), by direct fluorescent antibody testing (18%), or were clinically diagnosed only, in hospitalized children (19%) [50]. This epidemic was unique in that there was a dramatic shift from pertussis cases occurring in younger children and infants to older children, adolescents, and adults, compared to previous cases. Hospitalized children experienced paroxysmal cough (97%), posttussive emesis (78%), cyanosis (63%), apnea (42%) and whoop (22%) [50]. Of significance, epidemic cases were age-appropriately highly immunized – 74% (75 of 101) of those aged 19 months to 12 years had received four or five DPTs, whereas 82% (103 of 126) aged 7–71 months received three doses of DPT vaccine [50]. Verified immunization records showed that the whole-cell DPT vaccines used were from two major manufacturers (Connaught, 72%; Lederle, 28%) [50]. The epidemic was halted within 7 weeks by multiple interventions, including community education, active microbiological surveillance, accelerated immunization schedules (at 1, 2 and 3 months of age), infection control and erythromycin for cases and contacts [50]. In conclusion: ‘Since the 1993 pertussis epidemic in Cincinnati occurred primarily among children who had been appropriately immunized, it is clear that the whole cell pertussis vaccine failed to give full protection against the disease’ [50].

With the Children's Hospital diagnosing and treating the burden of pertussis cases from the community-wide epidemic, a 14-point plan was implemented to prevent nosocomial transmission [53]. The employees were educated about pertussis. Symptomatic employees with respiratory illnesses were evaluated clinically and with laboratory testing for B. pertussis. Employees with pertussis were treated with erythromycin, or trimethoprim/sulfamethoxazole. Symptomatic employees with pertussis were sent on 5-day furloughs. Contacts received antibiotic prophylaxis. Suspected cases were triaged and admitted in respiratory isolation or placed in ‘coughing respiratory cohorts’. Respiratory masks were required for all persons visiting the ‘Test Referral Center’, where nasopharyngeal swabs for microbiological tests were performed. Visitor restrictions were enforced hospital-wide. Only the parents and guardians were permitted to enter the neonatal ICU. A childcare center managed inpatient sibling visitors. Symptomatic children at Employee Childcare Center were excluded. These comprehensive interventions were effective in identifying pertussis in employees (87; 2%), with a delay in commencing respiratory isolation in 9 of the 102 hospitalized children with pertussis, with only one child who developed nosocomial disease.

With the high burden of pertussis in hospital employees, to curtail the employee epidemic, an emergency-randomized, double-blind, controlled trial of an acellular pertussis vaccine containing 25.25 g of pertussis toxoid and 3.25 g of filamentous haemagglutinin in 199 hospital employees using the meningococcal vaccine as a control was administered in a 1 : 1 ratio [54]. The vaccine was well tolerated, with similar local and systemic reactions observed among acellular pertussis and meningococcal vaccine recipients [54]. The acellular pertussis vaccine was immunogenic with two-fold and four-fold increases in IgG antipertussis toxoid antibody in 85 and 73% of participants, respectively, and 92 and 63% similar increases in antifilamentous hemagglutinin antibody [54]. Although there was no serological evidence of symptomatic or asymptomatic pertussis identified during 6 months of follow-up, there was considerable serological evidence of recent B. pertussis infection acquired before the study, suggesting a ‘burnt out’ epidemic even in these adults [54].

With the summer ending and children needing to return to school, a comprehensive eight-point plan was developed to identify, prevent and treat pertussis transmission in schools and day care centers in Greater Cincinnati [55]. Recommendations were sent by facsimile and ‘pony express’ to public schools (82), Catholic Schools (85), day care centers (100), neighborhood health centers (100), and were also promulgated through the news media and to community pediatricians [55]. The implementation of the guidelines was tested by identifying laboratory-confirmed cases from The Children's Hospital laboratory records, case report forms from the Cincinnati Health Department, and patient follow-up. Surveillance for pertussis from 2097 nasopharyngeal cultures yielded 66 B. pertussis culture-positive cases in September [55]. The eight guidelines were as follows: confirmed cases barred from school until more than 5 days of antibiotics [55]. Others with coughing illnesses were barred, pending physician evaluations [55]. Asymptomatic siblings completed 5 days of erythromycin (EES) [55]. Classroom exposures over 3 h required no special actions, if DPT vaccines were ‘up to date’ [55]. Classroom exposures lasting for more than 3 h, if their DPT was not up to date, were to be barred from school pending physician evaluation [55]. Asymptomatic exposed persons who have delayed DTP were to stay in school, obtain EES, and update their DTP status [55]. Symptomatic patients exposed to delayed DTP were excluded if they completed 5 days of EES [55]. One-third of the 66 B. pertussis cases identified in September were of school age. Guidelines were received by 19 of their corresponding schools/day care centers and implemented [55]. This novel experience confirmed the importance of prompt community dissemination of guidelines, surveillance, and evaluation in controlling pertussis outbreaks in childhood educational institutions [55].

In querying the initial cause of the community-wide Greater Cincinnati pertussis epidemic, the Centers for Disease Control and Prevention and others evaluated the clinical and molecular epidemiology of stored B. pertussis strains at the Cincinnati Children's Hospital that were circulating 4 years before the epidemic, during the epidemic year, and for the 3 years after the epidemic using pulsed field gel electrophoresis (PFGE) for molecular typing [56]. A total of 496 B. pertussis strains yielded 30 unique PFGE profiles. Thirty-two percent were CYXX1-010, which predominated annually [56]. There was no association between any PFGE type and seasonality, age, hospitalization or pneumonia in infants [56]. This epidemic was, therefore, associated with an increased prevalence of PFGE profiles that were circulating before and after the epidemic, concluding that there were other reasons for the resurgence of pertussis other than the emergence of a novel B. pertussis strain [56].

Randomized double-blind controlled clinical trials of newer acellular pertussis vaccines were compared to the whole-cell pertussis vaccine among thousands of children by Greco et al. in Italy and Gustaffson et al. in Sweden [57,58]. The whole cell vaccine was selected as the comparator vaccine, as they were withdrawn from 1979 in Sweden and were being changed to the less reactogenic acellular vaccines in Italy, as compared to the USA where the whole-cell vaccine was previously in widespread long-term use, including in Greater Cincinnati. Surprisingly, both scientific clinical trials, which were performed similarly by different investigators in different European countries, independently confirmed low pertussis vaccine efficacy rates of 36% and 48% for Connaught's whole-cell DPT pertussis vaccine – which was also used by 72% of the children in the Cincinnati epidemic [50,57,58]. This compared to significantly higher vaccine efficacy rates for the acellular DPT pertussis vaccines of 84% each, for the Smith Kline Beecham and the Chiron Biocine vaccines and 85% for Connaught's five-component acellular pertussis vaccine [57,58]. USA's pertussis national vaccination policy changed from the whole cell to acellular DPT pertussis vaccines.

In summary, a large community-wide epidemic of pertussis in highly immunized children and also in adults occurred in the tristate Greater Cincinnati region during a nationwide resurgence, the most reported in the USA in the preceding 26 years [50–56]. A multipronged collaborative interventional approach successfully controlled the epidemic within seven weeks. This included community-wide education, active clinical and microbiological surveillance, public health reporting, prompt antimicrobial treatment for cases and prophylaxis for contacts, accelerated immunization schedules and infection control. This epidemic was caused by whole-cell pertussis vaccine failure and not from the emergence of a novel B. pertussis strain [50,56–58]. These multipronged intensive interventions are still relevant to curtail today's pertussis epidemics. Improved clinical and laboratory pertussis diagnosis should be pursued, including PCR testing, where accessible; efficacious acellular vaccines can now be offered to everyone older than 7 years, although this might be hampered by post pandemic ‘vaccine hesitancy’ and the newer antimicrobials should be administered for treatment and prophylaxis, where resistant strains are identified.

CONCLUSION

Pertussis has been surging globally. It is caused by a complex bacterium and is difficult to fully control, given the waning vaccine-induced and natural immunity, COVID-19 pandemic factors, changing molecular characteristics of B. pertussis strains, improving case ascertainment and reporting, which still identifies only a subset of cases. Despite the ongoing threat of present and future pertussis epidemics, a multipronged approach, can still be utilized to prevent, treat, and control pertussis outbreaks to reduce attributable morbidity and mortality. Whopping pertussis, the ‘100-day cough’, will require adherence to optimized immunization strategies with effective pertussis vaccines, especially to infants, children, adolescents, adults and pregnant women to protect those vulnerable newborns and infants, who are too young to be immunized, or are incompletely immunized. Periodic re-evaluation of the current vaccines should be continued. The development and use of newer vaccines that are matched to mutant evasive B. pertussis strains should be pursued. Therefore, active clinical and microbiological community surveillance should continue to monitor and evaluate these trends. As in the Cincinnati epidemic, community education should continue outlining measures to contain communitywide pertussis epidemics, especially in hospitals, schools and daycare centers, where children with pertussis may present and other places where children are likely to congregate. Restriction of household visits to unimmunized newborns and under-immunized infants should be encouraged. The use of appropriate antimicrobials to which B. pertussis is proven to be susceptible to treat pertussis and to block transmission to susceptible exposed populations should be explored. Evaluation of the molecular epidemiology of circulating B. pertussis strains should be ongoing, especially during epidemics. Pertussis is a globally reportable disease; therefore, all healthcare providers and diagnostic laboratories are required to report all individuals with suspected or confirmed pertussis to their health departments, including use of the newer PCR testing methodology, in countries where this may be available. Contact tracing, especially in households, hospitals, schools and daycare centers, should be continued. Artificial intelligence (AI) and machine learning (ML) could be applied to improve clinical and laboratory diagnosis of pertussis to guide inpatient management, reduce complications and disease transmission, and assist public health management [59^▪▪–61^▪▪]. AI and deep ML could also be explored to improve the development of vaccines and immuno-therapeutic agents [62^▪▪]. Although epidemic pertussis will occur continually, careful implementation and adherence to these strategies may control this re-emerging disease and reduce attributable morbidity and mortality, thereby ‘whopping the 100-day cough, towards a whoopla for all our children’.

Acknowledgements

I acknowledge use of the figure (a) Annual number of nationally reported pertussis cases and associated deaths, 2010–2023 in China; (b) Monthly number of reported pertussis cases and associated deaths, January 2019–May 2024. Data from Yahong et al. [11^▪▪]. Copyright: © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd. is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

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• ▪▪ of outstanding interest