Pertussis Across the Globe

REVIEW ARTICLE Pertussis Across the Globe Recent Epidemiologic Trends From 2000 to 2013 Tina Tan, MD,* Tine Dalby, PhD,† Kevin Forsyth, MD,‡ Scott A. Halperin, MD,§ Ulrich Heininger, MD,¶ Daniela Hozbor, MD,║ Stanley Plotkin, MD,** Rolando Ulloa-Gutierrez, MD,†† and Carl Heinz Wirsing von König, MD,‡‡ Abstract: Pertussis has reemerged as a problem across the world. To better understand the nature of the resurgence, we reviewed recent epidemiologic data and we report disease trends from across the world. Published epidemiologic data from January 2000 to July 2013 were obtained via PubMed searches and open-access websites. Data on vaccine coverage and reported pertussis cases from 2000 through 2012 from the 6 World Health Organization regions were also reviewed. Findings are confounded not only by the lack of systematic and comparable observations in many areas of the world but also by the cyclic nature of pertussis with peaks occurring every 3–5 years. It appears that pertussis incidence has increased in school-age children in North America and western Europe, where acellular pertussis vaccines are used, but an increase has also occurred in some countries that use whole-cell vaccines. Worldwide, pertussis remains a serious health concern, especially for infants, who bear the greatest disease burden. Factors that may contribute to the resurgence include lack of booster immunizations, low vaccine coverage, improved diagnostic methods, and genetic changes in the organism. To better understand the epidemiology of pertussis and optimize disease control, it is important to Accepted for publication June 8, 2015. *Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL; †Department of Immunology, Microbiology, and Molecular Biology, Statens Serum Institut, Copenhagen, Denmark; ‡Department of Pediatrics, Flinders University, Adelaide, Australia; §Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; ¶Department of Pediatrics, University Children’s Hospital (UKBB), University of Basel, Basel, Switzerland; ║Department of Pediatrics, Laboratorio VacSal, Instituto de Biotecnología y Biología Molecular (IBBM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, CCT-CONICET La Plata, Argentina; **Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; ††Department of Pediatrics, Hospital Nacional de Niños de Costa Rica “Dr. Carlos Sáenz Herrera,” San José, Costa Rica; and ‡‡Labor:Medizin Krefeld MVZ, Krefeld, Germany. T.T. has received grants from Merck & Co. and Sanofi Pasteur, personal fees from GlaxoSmithKline Biologicals and Sanofi Pasteur, and fees for participating in data safety monitoring boards from Pfizer Wyeth and Biota. S.A.H. has received grants, speaker honoraria, and personal fees for conducting clinical trials and participating in advisory boards from Sanofi Pasteur Inc, GlaxoSmithKline Biologicals, Merck & Co., Novartis Vaccines and Diagnostics, and Pfizer Canada Inc. R.U.G. has received honorary fees for attending pertussis-related conferences and advisory boards from Sanofi Pasteur and GlaxoSmithKline. S.P. is a paid consultant to Sanofi Pasteur, Merck & Co, and GlaxoSmithKline Biologicals. C.H.W.v.K. has received honoraria for attending meetings sponsored by Sanofi Pasteur, GlaxoSmithKline Biologicals SA, and Novartis Vaccines. K.F. has received grants from Sanofi Pasteur. T.D. and D.H. have nothing to disclose. U.H. has received personal fees from both Sanofi Pasteur and GlaxoSmithKline Biologicals SA. Medical writing support was funded by Sanofi Pasteur. The Global Pertussis Initiative is supported by Sanofi Pasteur SA and was established in 2001 to evaluate the on-going problem of pertussis worldwide and to recommend appropriate pertussis control strategies. Sanofi Pasteur continues to fund this important initiative to provide a forum for scientific and policy-based discussions. The views and opinions expressed in this publication, which could include use of Sanofi Pasteur products that is inconsistent with current labeling or licensed indication, are solely those of the authors and do not reflect the position of Sanofi Pasteur SA. Address for correspondence: Tina Tan, MD, Ann & Robert H. Lurie Children’s Hospital, 225 E. Chicago Ave, Box 20, Chicago, IL 60611. E-mail: ttan@ northwestern.edu. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3409-e222 DOI: 10.1097/INF.0000000000000795 e222 | www.pidj.com improve surveillance worldwide, irrespective of pertussis vaccine types and schedules used in each country. Key Words: pertussis, epidemiology, acellular vaccines, whole-cell vaccine (Pediatr Infect Dis J 2015;34:e222–e232) P ertussis is vaccine-preventable, and 2 types of vaccines exist: whole-cell pertussis (wP), containing the entire inactivated Bordetella pertussis organism, and acellular pertussis (aP). The aP vaccines were developed because of concerns about adverse reactions associated with wP vaccines. Since the 1980s, aP vaccines have replaced wP vaccines in many industrialized countries; however, in developing countries wP vaccines are still used for primary vaccination doses, mainly because of their lower cost. Despite routine and widespread vaccination, pertussis remains a significant public health issue. Moreover, in some countries with high vaccination coverage, a resurgence in pertussis has occurred.1,2 Many hypotheses for the resurgence are postulated, including improved surveillance, diagnostic methods and disease awareness, but also incomplete vaccination, waning vaccineinduced or natural infection-induced immunity and the adaptability of the bacteria to immunity conferred by the vaccines.1–8 Worldwide, infants bear the greatest disease burden and mortality, so preventing pertussis is an important public health goal.9 Because optimal vaccination recommendations are predicated on accurate epidemiologic data, and in light of the recent resurgence, our goals in this article are to (1) review published epidemiologic data from January 2000 to July 2013 and report disease trends across the world, and (2) present data on vaccine coverage and reported pertussis cases between 2000 and 2012 from the 6 World Health Organization (WHO) defined regions (Africa, the Americas, the eastern Mediterranean, Europe, southeast Asia and the western Pacific). SEARCH STRATEGY AND COLLECTION CRITERIA Data were identified from PubMed searches and openaccess websites. The predefined PubMed search criteria were employed not only to assure that the articles would be generated in an objective manner but also to guarantee that a manageable number of relevant articles would be identified. The PubMed search used the keywords in the following format: (pertussis[Title] AND prevalence[Title]) OR (pertussis[Title] AND incidence[Title]) OR (pertussis[Title] AND epidemiology[Title]) AND (“2000/01/01”[PDat]: “2013/06/17”[PDat]) NOT Review. Only articles published between January 1, 2000, and July 13, 2013, containing data from 2000 onward were included. Articles were excluded if the data contained within were published before 2000, or if the content was not directly related to epidemiology. After the search, a lack of data from certain countries was noted and subsequent country-specific searches were conducted; in addition, country-specific sources were added from the authors. The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 RESULTS Although pertussis is a mandatory notifiable disease in most countries, there is significant under-reporting, especially in adolescents and adults.10 Studies actively seeking cases found that passive surveillance statistics underestimate the true incidence by 10- to 1000-fold, depending on the quality of the surveillance system.11–13 Under-reporting in some countries may be exacerbated by weak health care infrastructure, a lack of diagnostic tools that hinders case detection and the challenges that arise from poverty.14,15 Although both the WHO and the US Centers for Disease Control and Prevention (CDC) established pertussis case definitions,16,17 these are difficult to apply to all age groups because of the frequently atypical clinical characteristics of pertussis and variable severity of symptoms in different age groups.10,18 Worldwide per the WHO, the percentage of infants receiving 3 doses of the diphtheria, tetanus and pertussis vaccine (DTP3) increased between 2000 and 2012 (Fig. 1)19 Similar data for booster coverage are not available. Although the overall number of cases reported to the WHO was stable from 2000 to 201219 (Fig. 1), many regions experienced a resurgence. The stable number of reported cases may represent under-reporting because of poor surveillance systems in some regions.20 Regional Trends in the WHO-defined Regions Africa Percent coverage 75 84 91 82 84 92 83 91 83 91 83 91 73 250,000 200,000 150,000 50 100,000 25 0 50,000 2000 2008 DTP3 coverage 2010 2009 Year DTP1 coverage 2011 2012 0 Number of reported cases Surveillance and Epidemiological Trends. Few publications were identified from Africa and most did not contain data from surveillance systems. Obstacles to measuring pertussis in Africa include a lack of adequate diagnostic laboratories and surveillance systems along with the political and societal situations present in many countries.21,22 On the basis of WHO data, the number of reported pertussis cases decreased from 2000 to 2010, except in 2011 when an increase occurred (Figs 2 and 3).23 In 2008, the WHO/United Nations Children's Fund (UNICEF) Child Health Epidemiology Reference Group estimated that 2% of child (0–59 months) deaths in Africa were because of pertussis; the same analysis in 2010 found the estimated number had dropped to <1%.9,24 Most recent reporting comes from Nigeria and South Africa, where pertussis is a notifiable disease. Nigeria had a No. cases FIGURE 1. Worldwide DTP3 coverage in infants and overall number of reported pertussis cases.19 WHO data presented include 2000 and 2008–2012.19 Numeral indicates number of doses of DTP vaccine. © 2015 Wolters Kluwer Health, Inc. All rights reserved. 60,000 50,000 40,000 30,000 20,000 10,000 0 2000 2008 2009 2010 2011 2012 Year Africa Americas Eastern Mediterranean Europe Southeast Asia Western Pacific FIGURE 2. Number of reported pertussis cases across the 6 WHO regions in 2000 and 2008–2012.23,25–29 Number of reported cases Worldwide Epidemiology Trends Number of reported cases 70,000 A total of 109 sources were included in this review. Eighty articles were generated by the PubMed search, of which 37 articles were retained. The country-specific searches yielded 16 additional articles. From open-access websites, 28 sources were identified. Finally, the authors contributed 28 articles. 100 Pertussis Worldwide 60,000 2011 56,941 2012 52,089 50,000 45,847 34,432 28,019 30,000 23,489 20,000 10,000 43,213 38,995 40,000 16,839 14,540 8514 5816 0 a ric Af s ca eri an ne Am i ra ter ed s ea h ut r ste cif tA So nM ic sia pe ro Eu a nP ter es W Ea Region FIGURE 3. Number of reported pertussis cases across the 6 WHO regions from 2011 to 2012.23,25–29 peak in pertussis activity in 2009, reporting the second highest number of cases worldwide, but by contrast a decrease was reported in all of Africa combined.22 In Nigeria, few laboratories can culture the organism, so diagnosis is primarily clinical.22 The Integrated Disease Surveillance and Response system, which links epidemiological and laboratory data,30,31 was created by the Member States of the WHO Regional Office for Africa in Africa to improve surveillance; however, data from this system are currently limited. In South Africa, there is evidence of underreporting to the WHO. For example, in 2008, WHO surveillance centers reported that there were no pertussis cases; however, for this year many laboratory-confirmed cases were reported to the National Health Laboratory Service.32 Positive polymerase chain reaction (PCR) is available in the public health sector via the National Health Laboratory Service laboratories, but is significantly underused. Vaccine Coverage. Most countries employ wP vaccines in public vaccination programs (Tables 1 and 2),33 and coverage is lower compared with other regions.23 In some countries, coverage is very low, as was measured in 2011 in Chad (22%), Equatorial Guinea (33%), Gabon (45%), Nigeria (47%), Liberia (49%), Ethiopia (51%), Central African Republic (54%), Guinea (59%), Ivory Coast (62%) and Cameroon (68%).34 In South Africa, vaccinations are free for www.pidj.com | Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e223 The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 Tan et al TABLE 1. DTP3 (Infant Series) Antigen Composition Use by Region and Country (as Reported to WHO)33 Region Africa Vaccine Antigen DTwPHib DTwPHibHepB DTwPHibHep The Americas DTaPHib DTaPHibIPV DTwP DTwPHibHep Eastern Mediterranean DTaPHibHepIPV DTaPHibIPV DTwPHibHepIPV DTwPHibHepB DTaP DTaPHepBIPV DTwPHibHep DTwPHibHepB European region DTaPHibHepIPV DTwPHep DTwP DTaPHibIPV DTaPHib DTwPHib/4 mo DTwPHibHepB DTaPHibHepIPV DTaPHibIPV DTwPHibHep DTwP Southeast Asia Western Pacific DTaPIPV DTwPHibIPV DTaP DTaPHepIPV DTwPHib DTwPHibHepB/6, 10, 14 wk DTwPHep DTwPHibHepB DTwP DTaPHibHep DTwPHibHepB DTaP DTaPHibHepB DTaPIPV DTaPHibIPV DTaPHepIPV DTaPHibHepIPV Infant Schedule: Country 3, 4, 5 mo: Algeria 2, 4, 6 mo: Angola, Cape Verde; 6, 10, 14 wk: Benin, Burundi, Cameroon, Chad, United Republic of Tanzania; 2, 3, 4 mo: Botswana, Gambia; 8, 12, 16 wk: Burkina Faso 4, 10, 14 wk: Nigeria; 6, 10, 14 wk: Comoros, Ivory Coast, Democratic Republic of the Congo, Eritrea, Ethiopia, Gabon, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mozambique, Namibia, Niger, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Swaziland, Togo, Uganda, Zambia, Zimbabwe; 8, 12, 16 wk: Congo; 3, 4, 5 mo: Seychelles 6, 10, 14 wk: Mauritius 6, 10, 14 wk: South Africa 6, 10, 14 wk: Equatorial Guinea, South Sudan 6, 10, 14 wk: Haiti; 2, 4, 6 mo: Antigua and Barbuda, Argentina, Barbados, Belize, Bolivia, Brazil, Cuba, Dominica, Ecuador, El Salvador, Guatemala, Guyana, Honduras, Nicaragua, Panama, Paraguay, Saint Kitts and Nevis Saint Vincent and the Grenadines, Suriname, Uruguay, Venezuela; 6–8, 16–20, 24–28 wk: Grenada; 6 wk, 3, 5–6 mo: Jamaica; 3, 5, 7 mo: Saint Lucia Premature babies <1500 g: Argentina; 2, 4, 6 mo: Canada; Mexico 2, 4, 6 mo: The Bahamas, Canada, Costa Rica, US 2, 4, 6 mo: The Bahamas 2, 4, 6 mo: Chile, Colombia, Dominican Republic, Peru 2, 4, 6 mo: US 2, 4, 6 mo: US 6, 10, 14 wk: Afghanistan 4, 6 mo: Bahrain; 6, 10, 14 mo: Djibouti, Pakistan, the Sudan, Yemen; 2, 4, 6, mo: Kuwait, Lebanon, Libya, Oman, Saudi Arabia; 2, 3, 4 mo: Morocco; 2, 6 mo: Syrian Arab Republic; 2, 3, 6 mo: Tunisia; 6, 10, 14 wk (from January 2014): South Sudan 2 mo: Bahrain, Qatar 2, 4, 6 mo: Egypt 2, 4, 6, mo: Iran, Iraq; 6, 10, 14 wk: Somalia 3, 4, 5 mo: Jordan 15 mo: Qatar Syrian Arab Republic; 2, 4, 6 mo: United Arab Emirates 2, 4, 6 mo: Albania; 2, 3, 4 mo: Azerbaijan, Georgia, Turkmenistan, Uzbekistan; 2, 4 mo: Kazakhstan; 2, 3.5, 5 mo: Kyrgyzstan 2, 6 mo: Andorra, Austria; 8, 12, 16 wk: Belgium; 2, 4, 6 mo: Cyprus, Ireland, Latvia, Spain; 9, 13, 17 wk: Czech Republic; 2, 4 mo: France; 2, 4, 11 mo: Germany; 2, 3, 4, 11–14 mo: Italy; 2, 3 mo: Luxembourg; 4 mo, 16–18 mo: Monaco; 2, 6 mo: Romania; 3, 6, 12 mo: San Marino; 2, 4, 10 mo: Slovakia; 3, 5, 12 mo: Sweden 4 mo: Andorra; 3, 4, 5 mo: Belarus; 2, 3, 4 mo: Bulgaria, Germany, Hungary, Iceland, Netherlands; 2, 4, 6 mo: Croatia, Cyprus, Israel, Portugal, Romania, Switzerland, Turkey; 3, 5, 12 mo: Denmark, Norway, Finland, Sweden; 3, 4.5, 6 mo: Estonia, Slovenia;; 3 mo: France, Monaco; 9, 17, 23 wk: Montenegro; 2, 3, 4 mo: United Kingdom 6, 12, 18 wk: Armenia; 2, 3, 4 mo: Tajikistan 3, 4, 5 mo: Belarus, Ukraine; 7–8 wk, 3–4 mo, 5–6 mo: Poland; 3, 4.5, 6, mo: Russian Federation; 8, 14, 20 wk: Serbia; 2, 3, 5, mo: The former Yugoslav Republic of Macedonia; 2, 3, 4 mo: Uzbekistan 3, 4, 5 mo: Belarus; 2, 4, 6 mo: Bosnia and Herzegovina, Cyprus 3, 4, 5 mo: Bosnia and Herzegovina 2, 3, 4 mo: Germany; 2, 4, 6 mo: Greece, Israel 3, 5–6, 11–13 mo: Italy 3 mo: Kazakhstan; 3, 4 mo: Ukraine 6, 10, 14 wk: Bangladesh, Democratic People’s Republic of Korea, Bhutan, Nepal, Timor-Leste 6, 10, 14 wk Democratic People’s Republic of Korea, Timor-Leste; 2, 3, 4, mo: Indonesia; 2, 4, 6 mo: Thailand 6, 10, 14 wk: India; 2, 3, 4 mo: Indonesia; 2, 4, 6 mo: Maldives, Myanmar, Sri Lanka 6, 10, 14 wk: India, Maldives, Myanmar 2, 4, 6 mo: Australia, Brunei Darussalam; 6, 10, 14 wk: Samoa, Tonga 6, 10, 14 wk: Cambodia, Fiji, Kiribati, Lao People’s Democratic Republic, Nauru, Philippines, Solomon Islands, Tuvalu, Vanuatu; 2, 3, 4 mo: Mongolia, Vietnam; 1, 2, 3, mo: Papua New Guinea 3, 4, 5 mo: China, Singapore; 2, 4, 6 mo: Marshall Islands; 2, 4, 6 mo: Republic of Korea 6 wk, 3, 5 mo: Cook Island 3, 4.5, 6 mo: Japan; 2, 4, 6 mo: Republic of Korea 2, 3, 5 mo: Malaysia 2, 6 mo (from May 2013): Micronesia; 6 wk; 4, 6 mo: Palau 6 wk; 3, 5 mo: New Zealand, Niue aP vaccines are shaded gray. In countries where the wP vaccines are part of the national health program, aP vaccines are available in private settings. children <6 years of age,35 but there are substantial differences in coverage rates, with poorer areas having lower coverage.36,37 The Americas Surveillance. The literature search identified many articles, primarily from Canada and the US. Canada has 2 surveillance e224 | www.pidj.com networks (passive and active) and pertussis is notifiable.38 The Canadian Immunization Monitoring Program (IMPACT) is the active system, based in 12 pediatric tertiary-care hospitals.38 Collected data are limited, as transmission source and suspected cases are not included. Confirmation by culture is rare and diagnosis is © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 Pertussis Worldwide TABLE 2. Antigen Composition of Early Childhood Booster Doses Used by Region and Country (as Reported to WHO)33 Region Vaccine Antigen Africa The Americas DTwPHib DTwP DTaPHib DTaPHibIPV DTwP Eastern Mediterranean DTwPHib DTaPHibIPV DTaPIPV DTwPHibHepB DTaPHibHepIPV DTaP DTwPHibHep DtaP/5 yr DTwP European region DTwPHib DTwPHibIPV DTwP DTaPHibIPV DTaP DTaPHibHepIPV DTaPIPV Southeast Asia Western Pacific DTwPHib DTwP DTaPIPV DTaP DTaPHibIPV DTwP Country (Infant Schedule) Algeria (18 mo) Gambia (1 yr after third dose), Seychelles (18 mo), Equatorial Guinea (15 mo) Mauritius (18 mo) South Africa (18 mo) Antigua and Barbuda (18 mo), Argentina (6 yr), Barbados (18 mo, 4.5 yr), Belize (4–5 yr), Bolivia (18 mo, 4 yr), Brazil (15 mo; 4 yr), Colombia (18 mo; 5 yr), Cuba (18 mo), Dominica (18 mo; 3 yr), the Dominican Republic (18 mo; 5 yr), Ecuador (12–23 mo), El Salvador (18 mo; 3 yr), Grenada (18 mo), Guatemala (18 mo; 4 yr), Honduras (18 mo; 4 yr), Jamaica (18 mo; 4–6 yr), Mexico (4 yr), Nicaragua (18 mo; 6 yr), Panama (4 yr), Paraguay (18 mo; 4 yr), Peru (18 mo; 4 yr), Saint Kitts and Nevis (18 mo; 4–5 yr), Saint Lucia (18 mo), Saint Vincent and the Grenadines (18, 60 mo), Suriname (18 mo; 4 yr), Uruguay (5 yr), Venezuela (5 yr) Argentina (18 mo), The Bahamas (15 mo), Panama (18 mo) Canada (18 mo), Costa Rica (15 mo), US (15–18 mo) Canada (4–6 yr), Costa Rica (4 yr), US [4–6 yr (2×)] Chile (18 mo) Mexico (18 mo) US (15–18 mo; 4–6 yr) Uruguay (15 mo), Venezuela (15 mo) Bahrain (5 yr) Djibouti (15 mo), Egypt (18 mo), Iran (18 mo; 6 yr), Iraq (4–6 yr), Jordan (18 mo), Kuwait (3.6 yr), Lebanon (4–5 yr), Libya (18 mo), Morocco (18 mo; 5 yr), Oman (18 mo), Saudi Arabia (6 yr) Lebanon (18 mo), Saudi Arabia (18 mo), Syrian Arab Republic (18 mo) United Arab Emirates (18 mo) Albania (2 yr), Azerbaijan (18 mo), Belarus (18 mo), Turkmenistan (18 mo), Kyrgyzstan (2 yr), Republic of Moldova (22 mo), Russian Federation (18 mo), Serbia (18 mo), Tajikistan (16–23 mo), The former Yugoslav Republic of Macedonia (18 mo; 4 yr), Ukraine (18 mo), Uzbekistan (18 mo) Andorra (18 mo), Croatia (1 yr), Cyprus (15–18 mo), Estonia (2 yr), Hungary (18 mo), Iceland (18 mo), Israel (18 mo), Lithuania (18 mo), Malta (18 mo), Romania (12 mo), Slovenia (18 mo), Spain (15–18 mo), Switzerland (15–24 mo), Turkey (18 mo) Andorra (5 yr), Armenia (18 mo), Croatia (3 yr), Germany (11–14 mo), Greece (15–18 mo; 4–6 yr), Israel (12 mo), Poland (6 yr), Romania (4 yr), San Marino (5–6 yr), Spain (4–6 yr) Austria (1–2 yr), Belgium (15 mo), Czech Republic (18 mo), Germany (11–14 mo), Latvia (12–15 mo), Luxembourg (13 mo) Belgium (6 yr), Bosnia and Herzegovina (5 yr), Bulgaria (6 yr), Cyprus (15–18 mo; 4–6 yr), Denmark (5 yr), Estonia (6–7 yr), Finland (4 yr), Ireland (4–5 yr), Luxembourg (5–6 yr), the Netherlands (4 yr), Portugal (5–6 yr), San Marino (5–6 yr), Slovakia (5 yr), Sweden (5–6 yr), Switzerland (4–7 yr), Turkey (6 yr), United Kingdom (3 yr; 4 mo) Kazakhstan (18 mo), Portugal (18 mo) India (16–24 yr; 5 yr), Sri Lanka (18 mo), Thailand (1.5, 4 yr) Brunei Darussalam (5 yr), Japan (18 mo), New Zealand (4 yr) China, Singapore (18 mo), Marshall Islands (12 mo; 4–6 yr), Micronesia (12 mo; 4 yr), Palau (15 mo; 4–5 yr); Republic of Korea (15–18 mo; 4–6 yr), Tonga (18 mo; 6 yr) Malaysia (18 mo) Cook Island (4 yr), Tuvalu (5–6 yr), Vietnam (18 mo) aP vaccines are shaded gray. In countries where the wP vaccines are part of the national health program, aP vaccines are available in private settings. primarily based on PCR. The Canadian case definition is similar to the US definition (Halperin S, personal communication, 2014). In the US, pertussis is nationally notifiable and cases are reported by health care workers (HCWs) and laboratories to local and state health departments and then to the CDC via the National Notifiable Diseases Surveillance System (NNDSS).39 CDC clinical case definitions and laboratory criteria are used. Both probable and confirmed cases are reported. Diagnosis is based on isolation of the pertussis organism in culture, a positive PCR result, or by serology.16 It is recognized that there is under-reporting of disease, especially in adults, because of lack of recognition. In Latin America, pertussis is a notifiable disease and surveillance in most countries is based on CDC and WHO recommendations (Ulloa-Gutierrez R, personal communication).40 The laboratory diagnostic criteria are mainly based on isolation of B. pertussis from clinical specimens and/or PCR. Some countries integrate laboratory criteria into their surveillance program, which increases accuracy (Argentina, Brazil, Costa Rica, Chile, Colombia and Mexico), whereas in Central America, only Costa Rica and Panama have reference laboratories that use PCR. To strengthen surveillance, the Latin American Pertussis Project, a collaborative © 2015 Wolters Kluwer Health, Inc. All rights reserved. effort between the Sabin Vaccine Institute, the Pan American Health Organization, the CDC and the Latin American Ministries of Health, was implemented in 2009. Preliminary data from 3 countries demonstrate an improvement in the establishment of real-time PCR testing for case confirmation. Epidemiologic Trends. In the Americas, since 2000, the number of reported cases has fluctuated (Figs 2 and 3).25 Although surveillance is more accurate here compared with other regions, under-reporting still occurs; in 2012, the WHO reported 23,489 cases in the Americas, but in the same year, the CDC reported almost 49,000 cases in the US alone.25,41 In North America, since 2010, large outbreaks occurred that were associated with a shift in peak incidence across age cohorts. In Canada, a 2010 outbreak in Saskatchewan affected infants primarily.42 By contrast, during a 2012 outbreak in New Brunswick, the peak incidence occurred in children 7–10 years old.42 Similarly, in the US, a peak incidence in school-aged children was observed during 2010 (California) and 2012 (Washington, Minnesota and Wisconsin) outbreaks.42 The increase in incidence in school-aged children contrasts with data from 2007 and earlier, when adolescents were found to have high rates of www.pidj.com | Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e225 The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 Tan et al pertussis.16,43–46 Consistent with this in 2012, CDC NNDSS data revealed that the greatest number of reported pertussis cases occurred in individuals 7–10 years of age, representing a shift from 2004 when the peak occurred in adolescents aged 11–19 years.41 It is hypothesized that the outbreaks may be related to not only waning vaccine immunity but also under or no vaccination in some children.47,48 African American and Hispanic infants and those who were unvaccinated or incompletely vaccinated were found to be at the greatest risk for disease.38,39,46,49,50 There are also data that suggest the resurgence, in part, may reflect increased pertussis testing and improved test sensitivity.1 In some Latin American countries, over the past decades an increasing number of cases have been also detected. Most of these cases occurred in patients younger than 6 months old who received fewer than 3 doses of vaccine. However, an increase in cases in adolescents and adults has also been detected.40 Vaccine Coverage. Outside of Canada, Mexico and the US, most countries employ wP vaccines (Tables 1 and 2).33 Regardless of which vaccine is employed, coverage is high compared with other regions (Fig. 4).25 In response to the pertussis resurgence, some countries now recommend a booster for adolescents and adults, pregnant women and HCW. In Canada, since 2000, a booster is recommended for individuals aged 11–54 years.50 In the US, since 2006, a booster is recommended for all adolescents51 and since 2012, vaccination during each pregnancy is recommended.52 Following these US guidelines, coverage increased in adolescents (84.6%)53 but remains low in adults (14.2%),54 with variability across the adult cohorts: ≥65 years (8%),54 HCW (20.3%),55 close contacts of infants (25.9%)54 and pregnant women.54,56,57 Data suggest that the adolescent booster doses are effective, as Canadian and US studies found a reduction in pertussis in the target population.50,56 In Latin America, countries recommending booster doses include Argentina (2010), Panama (2010) and Uruguay (2012), but only for children ages 11–12 years (Ulloa-Gutierrez R, personal communication). In Chile, high-risk populations are targeted. To protect infants the following strategies are used: Argentina and Panama (2010) implemented immunization of HCWs who care for infants, and in Argentina, Colombia, Mexico (2012) and Costa Rica (2013), women are now vaccinated during pregnancy (Ulloa-Gutierrez R, personal communication). Eastern Mediterranean Region Epidemiological Trends. Data are limited, owing to surveillance systems and diagnostic laboratories in this region not being well established, and to political and societal factors.58 Since 2000, the number of cases reported to the WHO increased (Figs 2 and 3).26 In 2008, 2% of all child deaths in the region were because Percent coverage 100 80 60 40 20 0 2000 2008 2009 2010 2011 2012 Year Africa Americas Eastern Mediterranean Europe Southeast Asia Western Pacific FIGURE 4. DTP3 coverage in infants across the 6 WHO regions.23,25–29 Data presented include 2000 and 2008–2012. e226 | www.pidj.com of pertussis, which decreased to <1% in 2010.9,24 An outbreak occurred in Pakistan from 2004 to 2006, and isolates were identified in vaccinated children using the cough plate method.59 Outbreaks also occurred in Afghanistan between 2007 and 2008; when vaccination coverage was found to be <50%.60 Vaccine Coverage. Most countries use the wP vaccine (Tables 1 and 2)33 and coverage is low compared with other regions (Fig. 4).26 In 2011, countries with low coverage included Somalia (60%) and South Sudan (46%), the poorest countries in the region.61 Infants bear the greatest disease burden, which is exacerbated when coverage is low. In Tunisia, data from infants hospitalized with pertussis found low coverage, and family members were found to be the primary source of transmission.58 Similarly, low coverage was seen in Pakistani immunization clinics; factors associated with full coverage included higher income and short distance between home and clinic.62 European Region Surveillance. The review identified many publications from this region. Pertussis is a notifiable disease in most countries of the European region, except in France and until 2013, Germany. Most countries have surveillance systems; although differences exist that can impact interpretation of incidence trends.63 Longstanding systems with laboratory capabilities exist, that is, in the Netherlands, Sweden and the United Kingdom; passive surveillance systems are often used in central and eastern Europe64 and diagnosis is either clinical or laboratory-confirmed. In Bulgaria, a passive system is used and diagnosis is primarily clinical. In the Czech Republic, reporting pertussis is mandatory and diagnosis is made either clinically or based on laboratory data. In Croatia, a passive system is used and pertussis is reported by general practitioners and hospitals. Switzerland has a sentinel system that monitors pertussis continuously, whereas hospitalization of children because of pertussis is periodically monitored via the Pediatric Surveillance Unit,65 however, reporting is not mandatory. Most reported cases in Switzerland (75%) are diagnosed based on clinical data; the remainder includes PCR diagnosis, which is free for physicians in the sentinel network, but underused (Heininger U, personal communication).65 In Denmark, reporting of laboratory-confirmed pertussis is mandatory for practitioners in patients <2 years old, however, it is also mandatory for laboratories to report all confirmed cases to the national level. An electronic system monitoring all laboratory data ensures 100% surveillance coverage.66 Most cases are confirmed by PCR, but the use of serology is increasing, in particular for diagnosis of adults (Dalby T, personal communication). In addition, member states of the European Union (EU) and the European Economic Area (EEA) countries report their pertussis data into the European Surveillance System.67,68 Epidemiological Trends. In Europe, the number of cases reported to the WHO fluctuated greatly, with a notable increase in 2012 (Figs 2 and 3).27 An increase was observed in Austria using a national surveillance system and confirmed by laboratory tests,69 in the Czech Republic using archives and a national surveillance system,70 in Germany using a regional surveillance system confirmed by laboratory tests,71 in Israel using a passive surveillance system,72 in the Netherlands,73 Poland,74 Spain75,76 and Denmark77 using notifiable surveillance data, and in Switzerland using national surveillance systems supplemented by laboratory tests.65,78 By contrast, a decrease was observed in Greece using hospital cases, although epidemic cycles were observed every 3–5 years.79 In 2011, increases in case rates were reported by Finland, Ireland, Malta, the Netherlands, Norway and Spain.11 Norway reported the highest confirmed case rate, with 89.5 cases per 100,000 population. Estonia and the Netherlands followed with 35.7 and 32.7 cases per 100,000, respectively. The Netherlands reported the highest total number of © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 cases (n=5450), representing 28.1% of the total EU/EEA reported number of cases, followed by Norway (n=4405, 22.7%). These 2 countries accounted for an estimated 47% of the total number of pertussis cases since 2007. In the United Kingdom, an increase from 1053 confirmed cases in 2011 to 9367 in 2012 occurred, which decreased to 4623 in 2013.80 In 2011, the age group most affected in countries with higher case rates was school-aged children (5–14 years, with 15 cases per 100,000 population); however, when taking into account all countries, children aged 0–4 years have the highest incidence.11 Although case rates are lower, an increase in pertussis was observed in adolescents and adults across many countries, including Austria,69 the Czech Republic,70 France,81 Germany,71,82 Greece,83 Israel,84 Poland,74 Spain,75,76 Denmark (Dalby T, personal communication), Switzerland,65 Turkey85,86 and the United Kingdom.87 In Denmark, there was a shift in the peak age after the introduction of a preschool booster in 2003, from children aged 5–7 years to adolescents aged 13–14 years. The percentage of confirmed cases in adults aged >19 years increased from 14% in 1995 to 38% in 2012, but improved diagnostic methods and awareness possibly contributed to a portion of the increase (Dalby T, personal communication). During an outbreak in the United Kingdom, the number of cases was highest in adolescents and adults, including HCWs, although the incidence was highest in infants <3 months of age.88,89 Vaccine Coverage. Countries in western Europe (Tables 1 and 2)33 primarily use aP vaccines, whereas eastern European countries tend to use wP vaccines, and coverage is high with both (Fig. 4).27 In 2011, only the Ukraine had low (50%) DTP3 coverage.90 In central and eastern European countries, despite high coverage, pertussis infections persist, and the age distribution has shifted toward older children.91 In Sweden, using data from the national surveillance system, a dose– response reduction in incidence after vaccination was found, highlighting the importance of completing the infant series on schedule. Booster doses are critical for controlling pertussis in older cohorts. The inclusion of a school entry booster in several countries was associated with a decrease of disease in young children in Austria,69 the Czech Republic,70 Denmark,92 Israel,72 the Netherlands,73 Poland74 and Sweden.93 In adolescents and adults, booster coverage rates are low, and only a few countries have recommendations for their use.69,71,94–96 Southeast Asia Region Surveillance and Epidemiological Trends. Few papers were identified and the majority of data were not from surveillance systems. Similar to other regions comprising primarily developing countries, surveillance is impacted by lack of diagnostic laboratories and weak health care infrastructure. South Korea has a national passive surveillance system that receives clinically diagnosed cases from medical practitioners.97 This system was updated in 2010 to collect data using standardized WHO clinical and laboratory case definitions and includes transmission source and disease severity. Since the early 2000s, the number of reported pertussis cases has increased, especially in adolescents aged ≥15 years and adults, now accounting for 29% of the cases. This represents a shift in pertussis incidence to an older age group, which is attributed to waning of vaccine or natural immunity.97 In the region, the number of reported cases remained relatively stable since 2000, except in 2009 when there was an increase (Figs 2 and 3).28 By contrast, fluctuations have been observed in child mortality, as in 2008 the WHO/UNICEF estimated that 4% of child (0–59 months of age) deaths in Southeast Asia were because of pertussis, but in 2010 the estimated number decreased to <1%.9,24 An outbreak was detected in India in 2007, and among affected children ≤5 years of age, none were vaccinated.98 In Thailand, a © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pertussis Worldwide country that primarily uses the wP vaccine, no evidence of a resurgence in pertussis was observed in an analysis of incidence data using a likelihood-based statistical inference method.99 Vaccine Coverage. The wP vaccine is primarily used (Tables 1 and 2),33 and coverage is lower than in other regions (Fig. 4). In 2013, the Indian Academy of Pediatrics recommended administration of the Tdap to pregnant women and booster doses for young children, adolescents and adults.100 In 2012, the Korean Advisory Committee on Immunization Practices introduced Tdap vaccine into the National Immunization Program for adolescents and adults who have frequent contact with infants <1 year of age.101 Western Pacific Region Surveillance and Epidemiological Trends. The review yielded few papers, with most from Australia. In Australia, a confirmed case requires either laboratory-definitive evidence or laboratorysuggestive evidence, and clinical evidence, or clinical evidence and epidemiologic evidence (Forsyth K, personal communication). A probable case requires clinical evidence only. Serologic data are often not obtained and data show that the proportion of cases diagnosed by different methods (eg, culture, PCR and serology) varies with age. There is no national reference laboratory; however, reimbursement for laboratory diagnostics occurs through Commonwealth funding. Australia has a national surveillance system that implements active surveillance, and pertussis is a notifiable disease. Data collected include hospitalizations and mortality, but not vaccination status or transmission source. In China, pertussis is a reportable disease and surveillance is passive and variable, however, diagnosis is almost exclusively clinical; laboratory methods such as culture, PCR and serologic analysis are rarely used and there is significant under-reporting of the disease.102 In Japan, pertussis clinical cases are reported weekly by 3000 sentinel pediatric sites under the National Epidemiological Surveillance of Infectious Diseases; there is no established reporting system for cases in adolescents and adults or for fatal cases.103 Laboratory diagnosis of pertussis is available in Japan through use of bacterial isolation, serologic testing and PCR.103 In this region, the number of reported cases has increased from 2000 to 2012 (Figs 2 and 3).29 In Australia since 1991, the notification rate increased from 4.4 per 100,000 in January 1991 to 161.6 per 100,000 in January 2012 (Forsyth K, personal communication). Also, the overall rates in 2013 were approximately 150–160 per 100,000, whereas in infants the rate was 200–400 in 2010, 300–500 in 2011 and 200–300 in 2012. In Japan, the incidence of disease has increased since 2008 corresponding to an outbreak that lasted until 2011.104 During this outbreak, adolescent and adult cases accounted for 40%–52% of the reported cases, however, an increased amount of disease was also seen in primary and junior high school children.103 In infants, a delay in the vaccine schedule has been associated with pertussis.105 Despite high coverage, a resurgence was observed in adolescents and adults in Australia,106,107 New Zealand,108,109 China110 and Taiwan.111 In Australia, an outbreak occurred in 2008 and lasted until 2011.107,112–114 In New Zealand, an outbreak began in 2011 that persisted until 2013.115 Although the use of PCR has increased and may contribute to the increased incidence, there is evidence that the outbreaks are a real phenomenon.113 In Australia, it is suggested that the outbreaks were, in part, because of the elimination of the booster dose in 2 year olds in 2003, which was replaced with a booster in adolescents to address increasing incidence in the older age group.42,116 Vaccine Coverage. Both aP and wP vaccines are used, and coverage is high (Fig. 4; Tables 1 and 2).29,33 An aP vaccine with reduced antigen content was introduced for children at 12–17 years of age in school-based programs in 2004 in New South Wales and Western Australia. www.pidj.com | Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e227 The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 Tan et al DISCUSSION Pertussis incidence data are known to be incomplete and subject to country-specific variations in the quality of surveillance and reporting. Thus, a comparison from year-to-year within and between countries is difficult, because pertussis is a cyclical disease with natural peaks occurring every 3–5 years. Accordingly, cyclical fluctuations were seen in the WHO/UNICEF data analysis of child mortality because of pertussis. In 2008, the estimated number of pertussis child deaths was ≥1% in all WHO regions, but in 2010 it was <1% in all regions.9,24 Strengthening surveillance and laboratory confirmation in coming years will be critical components in further defining the problem. Table 3 summarizes some variables that can be relevant for pertussis as a notifiable disease, and their possible influence on notification rates of pertussis. Most variables will decrease the notification rate, consistent with under-reporting observed worldwide. Seroepidemiologic studies may provide data about the circulation of the bacteria mainly in nonvaccinated and vaccinated adolescents and adults, independent of the quality of routine surveillance.117 Although heterogeneous, the collected data point to some major features of the current epidemiological situation of the disease. First, despite routine and worldwide vaccination efforts, pertussis remains a serious health concern, especially for infants.9,38 Another key finding is that in many regions, there has been an increase in cases in school-aged children and adolescents.11,41 WHO data from 2011 to 2012 show an increase in reported cases in Africa, Europe, Southeast Asia and the eastern Mediterranean.23,26–28 Although it is not surprising to see an increase in regions with inadequate DTP3 coverage, the increase in Europe, which in general has high DTP3 coverage, suggests that other factors contribute to the increase. Similarly, the US, which also has high coverage, experienced several large outbreaks in 2005, 2010 and 2012.117 There is an ongoing debate on the possible factors that could contribute to the current pertussis epidemiological situation. Improvements in disease awareness, surveillance and diagnostics would be expected to increase the number of reported cases, especially in age groups typically not tested for pertussis. The introduction of non–culture-based methods of diagnosis (eg, PCR and serology) would also impact notifications. This review revealed that surveillance and diagnostic techniques were improved in some countries, which may in part underlie observed increases.113 Interpretation of epidemiological data from different countries will also be impacted by vaccine coverage and the vaccine type used. Low vaccination coverage and the use of ineffective vaccines are expected to adversely affect the pertussis epidemiological situation. Concerning the type of vaccine used, it seems straightforward to distinguish between countries vaccinating either with wP vaccines or with aP vaccines, which assumes that vaccines in TABLE 3. Variables That Can Be Relevant for Pertussis as a Notifiable Disease, and Their Possible Influence on Notification Rates of Pertussis Type Clinical Public health General public/media Laboratory Scientific community e228 Parameter True for Pertussis? Vaccine preventable disease Yes Childhood disease Partly Typical symptomatology Partly Typical symptoms induced only by one or few agents Re-infection possible No Symptoms similar in all age groups Many/almost all cases hospitalized No Universally accepted clinical/ laboratory case definition Effective surveillance system easily established High case fatality ratio New infectious disease Cyclicity of disease No High interest in disease No Novel infectious disease Single laboratory test No No Direct detection very sensitive Indirect detection very specific No No Laboratory tests universally available New problem in infectious diseases Abrupt increase in interest No | www.pidj.com Yes No No No No Yes No Yes Comments Vaccine preventable diseases are perceived as eradicated Diagnosis of disease not entertained in older age group Influence on Notification Lowers perception of disease Lowers perception of disease in older children adolescents, adults Textbook symptoms may apply mainly to unvac- Lowers perception of disease cinated children Various microorganisms produce symptoms Lowers quality of diagnosis similar to pertussis and notification Symptoms of re-infection may differ from Lowers perception of disease primary infection ie, infants may present with apnea as the only Lowers perception of diseases symptoms Hospitalization rate low beyond infancy, disease Lowers notification of disease rates in infants may better reflect epidemiology Various case definitions in various countries Low comparability of data reduce comparability among jurisdictions Difficult to establish, not a high priority Limited reliable surveillance data Known Lowers interest in disease Media pressure is focused on “novel” diseases Lowers interest in disease Public health attention may be negatively Over- or underestimation of skewed during trough years, as well as posidisease burden tively during peak years Many lay people regard vaccine-preventable Lowers interest in disease diseases as eradicated No hype about “standard” infectious diseases Lowers interest in disease Depending on age, vaccination status and duration of symptoms, culture, PCR or serology may be needed Culture and PCR have varying sensitivity Lowers diagnosis of disease Immune response after infection and vaccinaIncrease in non-specific notition cannot be distinguished fications Tests may be expensive, and because of low interest in disease, not available Difficult funding of scientific studies Few recent epidemiological data In or after peak years, studies may be initiated Over- or underestimation of that are then done in trough years disease burden © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 34, Number 9, September 2015 each class are equally efficacious. However, the vaccine trials in the 1990s showed that differences in efficacy of licensed wP vaccines varied between 40% and 90%, and may go unnoticed outside of vaccine studies.118,119 Thus, it cannot be assumed that all wP vaccines are equally effective. Similarly, aP vaccines contain 1–5 antigens, and therefore, comparison is difficult. The switch from wP to aP vaccines for the primary series in some regions is another factor proposed to underlie the resurgence in pertussis. A recent study using a nonhuman primate model found that while the aP vaccine protects the individual from disease symptoms, the vaccine does not prevent colonization and transmission of pertussis, whereas the wP vaccine prevents both.120 In humans, a US study found that adolescents who received 4 doses of an infant wP vaccine were less likely to contract pertussis as teenagers compared with those who were vaccinated with an aP vaccine.121 Similarly, another study found the risk of pertussis was increased in schoolchildren and adolescents whose infant schedule was composed exclusively of aP doses compared with subjects who received ≥1 wP dose.122 Moreover, in a large case-control study conducted during the 2010 US epidemic in California, receipt of 5 doses of aP was 98% protective among children aged 4–10 years within the first year after receipt of the fifth dose, but protection waned to <90% after 3 years and 71% by ≥5 years.48 In contrast, in 2 Canadian studies, the use of aP vaccines was associated with a decrease in pertussis incidence,38,50 although this was in the face of a change from a relatively low efficacy wP vaccine. Despite this, pertussis incidence has remained lower than it was before the use of aP vaccine. Since 1997, Denmark has used a monocomponent aP vaccine containing hydrogen peroxide–inactivated B. pertussis toxoid as the only pertussis antigen for the primary infant series, and coverage is high at 87%–91%. In 2003, a booster dose for preschool-age children (5 years of age) was introduced using the same monocomponent aP vaccine, but with reduced antigen content (aP). Despite use of the single pertussis antigen vaccine, there has been no evidence of increased vaccine failure in Denmark. Pertussis epidemics have, however, occurred in countries with high vaccine coverage where wP vaccine was used until recent switches to aP vaccine (Finland, Portugal and Singapore), probably because of the cyclical nature of pertussis.123,124 The resurgence may also be impacted by changes in the bacterial genome such as pertussis toxin promoters and alleles and increased occurrence of pertactin-negative strains against which some vaccines may be less protective.125 Recently, it was also reported that among isolates from the 2012 UK pertussis outbreak, acellular vaccine antigen encoding genes were evolving at higher rates than other surface protein encoding genes.126 Although already found before pertussis vaccines were used, it has become more pronounced because the introduction of the current acellular vaccines. Further studies are needed to determine more clearly the effect that antigenic and genotypic changes in circulating B. pertussis organisms are having on pertussis epidemiology.8,114,127–129 In conclusion, it is difficult to draw a clear picture of the worldwide epidemiology of pertussis. Whereas, it is evident that young infants bear the greatest burden of disease, the poor reporting and dubious statistics from many countries confound attempts to discern disease patterns. Although it appears that recently pertussis is more prevalent, and although it is clear that waning immunity is a problem in countries using aP vaccines, the situation in countries still using wP vaccines is uncertain. On the basis of old data, it is clear that both types of vaccines give impermanent immunity. There are many potential ways of alleviating that problem, © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pertussis Worldwide including the development of better vaccines, but more immediate solutions include immunization during pregnancy and “cocooning” (ie, immunization of close contact persons) to protect newborns. More systematic epidemiologic studies of pertussis throughout the world are critically needed to elucidate the true extent of the problem and develop solutions. ACKNOWLEDGMENTS Medical writing support was provided by Mary Burder, PhD, and Matthew Booth, PhD, of PAREXEL and funded by Sanofi Pasteur. Authors’ contributions: All authors equally participated in the design of the review, gathering and analyzing the data and writing the paper. REFERENCES 1. Fisman DN, Tang P, Hauck T, et al. Pertussis resurgence in Toronto, Canada: a population-based study including test-incidence feedback modeling. BMC Public Health. 2011;11:694. 2. Riolo MA, King AA, Rohani P. Can vaccine legacy explain the British pertussis resurgence? Vaccine. 2013;31:5903–5908. 3. 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