Review on pertussis case definitions: a need for reliable disease surveillance

Abstract

Background

Existing clinical case definitions of pertussis are decades old and mainly rely on clinical signs and symptoms in infants and children. In the recent past, an age shift of pertussis towards adolescents and adults has been noted and disease presentation often is different from that in children. Therefore, in 2011 the Global Pertussis Initiative (GPI) proposed an age-stratified case definition, but its uptake has been slow. This prompted members of the GPI steering committee to critically review the case definition. In preparation for this, we performed a review to learn which case definitions have been used worldwide.

Methods

We performed a narrative literature review to collect publications from January 1, 1975, to September 1, 2025, which include pertussis case definitions. This was complimented by a survey amongst GPI members to gather case definitions currently in use for pertussis surveillance in their countries.

Results

The literature review identified 117 relevant publications. The two most often used case definitions were those proposed by CDC and WHO, followed by individual case definitions developed by the respective investigators for the purpose of their studies. Additionally, GPI members provided 16 country-specific surveillance case definitions. Cough and typical pertussis signs paroxysms, whooping and post-tussive vomiting are most commonly used clinical criteria. With regards to laboratory confirmation of B. pertussis infection, all case definitions require at least one criterion, most often a positive culture and/or PCR, followed by specific serology. Most case definitions do not use age-specific criteria.

Discussion

Many different case definitions are in use all over the world. Most of them are focusing on the typical presentation of pertussis, i.e. disregarding less typical disease presentations and do not use age-specific criteria. This hampers a reliable and comparable disease surveillance. Therefore, a harmonized case definition that could be used globally would be highly welcome.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-026-13509-x.

Introduction

Despite the availability of effective vaccines for many decades, pertussis, also known as whooping cough, remains a global health concern with over 940’000 reported cases worldwide in 2024 [1]. Pertussis is a highly infectious respiratory disease caused by Bordetella pertussis. Previously considered to be a typical childhood disease, a shift in age distribution of reported cases towards adolescents and adults has been noted in the past decades; however, the major burden of disease remains in young infants [2–4]. Disease surveillance is a cornerstone of disease prevention and control and is explicitly recommended by the World Health Organization (WHO) [5]. With altering clinical presentation and many different case definitions in use, adequate surveillance is challenging. In 1991, WHO held a meeting to find consensus on a case definition of pertussis primarily for use in vaccine trials, but also for surveillance purposes. With a few alterations, i.e. adding apnea as a typical feature of the disease in infants, the definition derived from that meeting is still broadly used today [6].

In 2001, the Global Pertussis Initiative (GPI), a scientific forum with multidisciplinary experts from all over the world, was founded to examine the rationale for vaccination beyond childhood and to evaluate specific strategies, make recommendations for their implementation, and identify research needs to support their introduction [7]. In 2011 GPI had noted that existing clinical case definitions of pertussis were decades old and mainly relied on clinical signs and symptoms in infants and children, whereas adolescents and adults may demonstrate different patterns of pertussis. These were not necessarily covered by the existing case definitions. Therefore, GPI proposed an age-stratified case definition with the goal to increase diagnostic specificity without decreasing sensitivity [8]. This GPI case definition was tested clinically by various groups. The definition was acknowledged for its age-stratified algorithm, but also criticized for its relatively low sensitivity [9, 10].

This prompted us to perform a narrative literature review to learn which other case definitions are currently in use globally besides the GPI pertussis case definition and compare their characteristics with each other. As a supplement to the literature review, we surveyed GPI members to learn which case definitions are currently used in their countries for pertussis surveillance.

Methods

First, we performed a literature review in PubMed with the following search strategy pertussis OR whooping cough AND case definition published from January 1, 1975, to September 1, 2025. One reviewer (JZ) screened titles and abstracts to identify potentially relevant publications, instructed and supervised by the senior author (UH). In a next step, texts of these publications in English, French, Spanish or German language were evaluated if the abstract seemed relevant or was not informative enough. In case of uncertainties in this selection process, the second reviewer (UH) independently evaluated the respective publications. Publications in languages other than the ones mentioned above and publications, in which no case definition was used, were excluded. Finally, we included all publications which used and specified any kind of case definition of pertussis. Date of publication, used case definition, age of the study population and country were recorded in a database. Publications which used a specific case definition but did not mention a source for the case definition were classified as “Investigators’ own”.

As this is a narrative review conducted to give an overview on what case definitions have been in use in the last decades, the quality of the included publications was not assessed. Due to different requirements regarding sensitivity and specificity of the case definition depending on the clinical situation, we divided the publications into three categories: surveillance, outbreak settings, and vaccine efficacy trials. All publications, which declared that an outbreak was investigated, were classified as “outbreak setting”. We classified origin of publications as high-income countries (HIC) and low- and middle-income countries (LMIC), respectively, based on the world bank country classification by income level [11].

Second, we reached out by E-mail to all members of the GPI and asked them to provide information on pertussis case definitions in use in their respective countries for surveillance purposes.

Results

Figure 1 summarizes the numbers of publications retrieved by the literature review (see also PRISMA style flow diagram, Additional File 1) and the GPI members survey. This resulted in a total of 126 case definitions which were analyzed in detail.

Fig. 1.

Flow chart of publications with pertussis case definitions identified and included from literature review and survey. ^a Published in Chinese and Turkish, respectively. ^b 6 case definitions were identified in both data sources; these were country-specific case definitions from Argentina, Australia, Canada, Spain, Thailand and USA

General findings of the literature review

We identified 199 publications. After exclusion of 82, 117 remained for further analysis (Fig. 1 and Additional Files 1 and 2). Of these, 75 (65%) were surveillance studies, 25 (21%) described pertussis outbreaks, and 17 (15%) were vaccine efficacy trials. Most studies (81; 69%) took place in HICs; 54 (46%) covered all age categories, 56 (48%) covered the pediatric age group only (patients < 18 years of age), and 7 (6%) investigated selectively adolescents and adults.

Case definitions identified in the literature review

The two most often used pertussis case definitions overall were those proposed by the Centers for Disease Control and Prevention (CDC), USA [12], and WHO [5], followed by case definitions developed by the respective investigators for the purpose of their studies (Table 1). These investigators’ own case definitions were highly variable in terms of clinical and confirmatory criteria (laboratory and epidemiological links) but often similar to those by the CDC and WHO (Additional File 3). Fifteen (13%) of all 117 studies used more than one case definition, mostly to compare different case definitions. In 12 of these 15 publications the WHO definition was used in combination with another case definition. Other case definitions, developed with the purpose to be used broadly such as the one by ECDC (European Centre for Disease Prevention and Control) or the GPI, were rarely used.

Table 1.

Case definitions used by type of study and country setting

Case Definition	All Publications	Surveillance Study	Outbreak Investigation	Vaccine Efficacy Trial	High Income Country Setting (HIC)	Low and Middle Income Country Setting (LMIC)	Mixed High, Low and Middle Income Setting
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
CDC a	38 (32)	24 (32)	12 (48)	2 (12)	29 (36)	10 (38)	0 (0)
WHOb	21 (18)	16 (21)	3 (12)	2 (12)	11 (14)	4 (15)	6 (60)
Australia	2 (2)	2 (3)	0 (0)	0 (0)	2 (2)	0 (0)	0 (0)
Canada	5 (4)	1 (1)	2 (8)	2 (12)	5 (6)	0 (0)	0 (0)
ECDCc	2 (2)	2 (3)	0 (0)	0 (0)	2 (2)	0 (0)	0 (0)
GPId	1 (1)	1 (1)	0 (0)	0 (0)	0 (0)	1 (4)	0 (0)
Spain	3 (3)	2 (3)	1 (4)	0 (0)	2 (3)	0 (0)	0 (0)
TJCDCe	1 (1)	0 (0)	1 (4)	0 (0)	0 (0)	1 (4)	0 (0)
Argentina	1 (1)	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (10)
Swiss Sentinel	1 (1)	1 (1)	0 (0)	0 (0)	1 (1)	0 (0)	0 (0)
Investigators’ own	27 (23)	16 (21)	5 (20)	6 (35)	22 (27)	4 (15)	1 (10)
> 1 case definition used	15 (13)	9 (12)	1 (4)	5 (29)	7 (9)	6 (23)	2 (20)
Total	117 (100)	75 (100)	25 (100)	17 (100)	81 (100)	26 (100)	10 (100)

a) Centers for Disease Control and Prevention, U.S.A

b) World Health Organization

c) European Centre for Disease Prevention and Control

d) Global Pertussis Initiative

e) Tianjin Centers for Disease Control and Prevention, China

Survey

Of 260 GPI members from 64 countries, 20 (from 16 countries) responded and provided case definitions used for disease surveillance in their respective countries (Table 2, Additional File 4). Six of these case definitions had also been identified by our literature review, including the CDC case definition used in the United States and the WHO case definition, which is being used in Thailand and most other southeast Asian countries [13].

Clinical and diagnostic features

Table 3 combines the clinical and diagnostic features of all 51 case definitions identified from the literature review and the survey. Besides cough, which is part of every case definition, the hallmarks of so-called typical pertussis, i.e. paroxysms, whooping and post-tussive vomiting, are the most commonly used clinical signs. Several case definitions also contain complications of pertussis such as apnea and cyanosis, often restricted to infants. Most case definitions, and especially those most commonly used (i.e., WHO and CDC) do combine cough of variable minimal duration with at least one other symptom (Additional File 5), but do not require a combination of more than two symptoms (e.g. a cluster of symptoms). Cough duration per se was part of all case definition but varied in terms of minimal duration required between ≥ 5 and ≥ 21 days with ≥ 14 days most often used in surveillance and outbreak publications. In contrast, minimal duration of cough was more variable in case definitions for vaccine efficacy trials.

Table 3.

Clinical and laboratory characteristics of 51 pertussis case definitions ^a

	All Case Definitions	Case Definitions used in Surveillance Studies	Case Definitions used in Outbreak Studies	Case Definitions used in Vaccine Efficacy Studies
	N = 51 (100%)	N = 35 (100%)	N = 10 (100%)	N = 13 (100%)
Clinical characteristics used
Cough	51 (100)	35 (100)	10 (100)	13 (100)
Cough duration
≥ 5 days	1 (2)	0 (0)	0 (0)	1 (8)
≥ 7 days	9 (18)	3 (9)	1 (10)	5 (38)
≥ 14 days	29 (57)	24 (69)	8 (80)	4 (31)
≥ 21 days	4 (8)	1 (3)	0 (0)	3 (23)
Any duration	8 (16)	7 (20)	1 (10)	0 (0)
Paroxysms	35 (69)	28 (80)	9 (90)	5 (38)
Whooping	33 (65)	28 (80)	6 (60)	6 (46)
Post-tussive vomiting	34 (67)	28 (80)	9 (90)	4 (31)
Apneab (total/infants only)	19 (37) / 9 (18)	17 (49) / 8 (23)	6 (60) / 3 (30)	3 (23) / 1 (8)
Cyanosisb (total/infants only)	8 (16) / 3 (6)	7 (20) / 3 (9)	1 (10) / 0 (0)	0 (0)
Seizures	2 (4)	2 (6)	0 (0)	0 (0)
Coryza	2 (4)	2 (6)	0 (0)	0 (0)
Sleeping difficulties / Worsening at night	3 (6)	2 (6)	1 (10)	0 (0)
Subconjunctival hemorrhage	1 (2)	1 (3)	0 (0)	0 (0)
Sweating episodes at night	1 (2)	1 (3)	0 (0)	0 (0)
Fever	2 (4)	2 (6)	0 (0)	0 (0)
Physician diagnosis	9 (18)	8 (23)	2 (20)	2 (15)
Diagnostic Characteristics
Polymerase chain reaction (PCR)	35 (69)	29 (83)	6 (60)	7 (54)
Culture	42 (82)	29 (83)	7 (70)	13 (100)
Serology	27 (53)	15 (43)	6 (60)	9 (69)
No laboratory confirmation	3 (6)	2 (6)	1 (10)	0 (0)
White blood count	2 (4)	2 (6)	0 (0)	0 (0)
Epidemiological link	27 (53)	21 (60)	7 (70)	6 (46)

^a Obtained from literature review and survey. In case definitions with age dependent criteria (15 of 51), criteria of the oldest age group are shown. Of the 51 case definitions, 3 were used in all three study settings and 1 was used in surveillance and outbreak studies

^b Apnea and cyanosis were part of the clinical case definition only in infants in 9 and 3 studies, respectively

With regards to laboratory confirmation of B. pertussis infection, all but 3 case definitions required at least one criterion, most often a positive culture and/or Polymerase Chain Reaction (PCR), followed by serology. Finally, an epidemiological link to a diagnosed case of pertussis was also part of most case definitions (53%, Table 3).

Twelve of the 16 case definitions obtained from our survey amongst GPI members use age specific criteria, of which 10 defined two age categories, mostly infants (i.e., < 1 year of age) or young infants (i.e., < 6 months of age) versus all others (Table 2). This is also true for the WHO case definition, which uses cough of any duration and apnea as case criteria specifically for infants. In contrast, the CDC case definition includes apnea as a clinical criterion independent of patient age (Additional File 5). Three age categories are used for the case definitions in Argentina (< 6 months, 6 months – 11 years and > 11 years of age) and El Salvador (< 4 months, 4 months – 9 years, > 9 years of age). These age categories are similar to (Argentina) or identical with (El Salvador) the GPI case definition, the only case definition which stratifies by three age categories (Additional File 6).

Table 2.

Case definitions obtained from survey amongst Global Pertussis Initiative (GPI) members and their principal elements

Country	Clinical case definition	Laboratory Confirmation	Age-specific criteria (age groups)d
Argentina	Yes	Yes	• < 6mo • 6mo-11y • > 11y
Australia	Yes	Yes	No
Brazil	Yes	Yes	• < 6mo • ≥ 6mo
Canada	Yes	Yes	No
Denmark	Yesa	Yes	• < 6y • ≥ 6y
El Salvador	Yes	Yes	• < 4mo • 4mo-9y • ≥ 10y
Ethiopia	Yes	Yes	• 1y • ≥ 1y
Indonesia	Yes	No	• < 1y • ≥ 1y
Mexico	Yes	Yes	• < 6mo • ≥ 6mo
Paraguay	Yes	Yes	• < 1y • ≥ 1y
Philippines	Yes	Yes	• < 1y • ≥ 1y
Spain	Yes	Yes	• < 6mo • ≥ 6mo
Thailandb	Yes	Yes	• < 1y • ≥ 1y
Turkey	Yes	Yes	No
United States of Americac	Yes	Yes	No
Uruguay	Yes	Yes	• < 1y • ≥ 1y

^a In children < 6 years of age

^b World Health Organization (WHO) case definition

^c Centers for Disease Control and Prevention (CDC) case definition

^d for details see Additional File 6

The heterogeneity of case definitions stratified by study setting, i.e. surveillance, outbreak or vaccine efficacy trial, is summarized in Table 3. It is obvious that the magnitude of heterogeneity of clinical criteria included in the case definitions is similar within each and between all three settings. Moreover, the only clear pattern is that signs of typical pertussis, i.e. paroxysms, whoop and post-tussive vomiting, are more often used in surveillance and outbreak settings than in vaccine efficacy trials.

Discussion

We set out to identify pertussis case definitions which have been and are currently in use worldwide. The two most common ones are those proposed by the CDC and WHO. They were primarily developed for outbreak and surveillance purposes (CDC) and vaccine efficacy trials (WHO). In fact, the CDC case definition was identified as the preferentially used one in outbreak and surveillance studies in our review (Table 1). In contrast, the WHO case definition is rarely used in these settings. This may be explained by the fact that the clinical criteria of the WHO case definition have a relatively low sensitivity and specificity in school-age children [14, 15] and adults [15]. Even though the CDC and the WHO case definitions apparently are the ones most often used, the high proportion of “Investigators’ own” case definition indicates that they are not broadly accepted.

Limitations of pertussis case definitions in use

Of note, most case definitions of pertussis are designed to detect typical cases of disease, characterized by a cough duration of 14 days or longer plus the presence of one or more characteristic signs such as paroxysms, whooping and post-tussive vomiting. However, typical pertussis is much more common in unimmunized children than in older age groups. Cornia et al. performed a literature review on the accuracy of the typical clinical signs of pertussis in adolescents and adults in non-outbreak settings [16]. Based on three studies they found them to be of limited value and quite variable from study to study. While paroxysmal cough was common (86–100%), its specificity was low (12–35%). In contrast, post-tussive vomiting (33–70%) and whoop (26–67%) were less frequent but both had greater specificity for confirmed pertussis (61–68% and 72–85%, respectively). In a similar approach, Moore et al. identified 53 publications which reported signs and symptoms of pertussis in all age groups. They basically confirmed Cornia et al.’s findings with paroxysmal cough (and absence of fever) to have a high sensitivity (93.2% and 81.8%, respectively) but low specificity (20.6% and 18.8%, respectively) and post-tussive vomiting and whoop to have low sensitivity (32.5% and 29.8%, respectively) but high specificity (77.7% and 79.5%, respectively) in adults. In children, only results for post-tussive vomiting were reported and found to be of moderate sensitivity (60.0%) and specificity (66.0%) [17]. Of note, none of the publications included in these two systematic reviews examined the usefulness of combined typical signs, probably because all case definitions in use do not differentiate whether one or more of the three typical signs are present in a patient [16, 17]. There are two publications to our knowledge which have addressed this issue. Ghanaie et al., investigating pertussis in 6–14-year-old children in Tehran, Iran, found a combination of ≥ 14 days cough and two of the three further WHO case definition’s clinical criteria (paroxysmal cough, inspiratory whoop, or post-tussive vomiting) to have a sensitivity of 81.0% and a specificity of 60.3%. With all three additional criteria combined, sensitivity decreased to 9.5% and specificity increased to 91.2% [14].

Age stratification in pertussis case definitions

In a prospective study in Novi Sad, Serbia, from October 1, 2013, to September 30, 2014, Ristic et al. investigated 103 patients with laboratory confirmed pertussis stratified by age 0–3 months (N = 5), 4 months-9 years (N = 34), and ≥ 10 years (N = 64). These stratifications were based on the GPI case definition of pertussis. Moreover, they stratified patients by clinical care as in- or out-patients. Not surprisingly, the usefulness of clinical signs and symptoms associated with a diagnosis of pertussis depended on age and severity of disease (i.e., in- versus out-patients) [9]. This indicates that age stratification, the fundamental difference of the GPI case definition (and several other investigator created case definitions following this model) when compared to those by CDC, WHO and ECDC, appears well justified. Remarkably, CDC had integrated “apnea (with or without cyanosis) for infants” in their case definition in 2014 but removed this age specification in the updated version of 2020 “to achieve consistency across age groups” [18].

Only very few case definitions used age-dependent criteria. However, an age-dependent definition would be helpful to better address the often different presentation of pertussis in infants and the often mitigated disease manifestations in older children, adolescents and adults. In this regard, unrecognized pertussis in adolescents and adults is a major source of infection for the ones most at risk, e.g. infants, and therefore adequate surveillance of adolescents and adults is equally important to take appropriate measures in prevention.

Clinical criteria used in pertussis case definitions

Apnea is a typical complication of pertussis, especially in young infants [19], but can also occur in older age groups [9, 20, 21]. Accordingly, 37% of case definitions contain apnea as a clinical criterion for pertussis, often restricted to infants. However, apnea is not pathognomonic for pertussis and therefore its use in combination with other signs and symptoms indicative of pertussis is important [9].

The minimal duration of cough required in different case definitions varies. Obviously, a short duration of cough is associated with comparatively high sensitivity and low specificity, because acute cough for a short period of time is a common symptom of many other respiratory tract infections. Vice-versa, a long duration of cough increases specificity at costs of a lower sensitivity. Therefore, most case definitions use a duration of at least 14 days of cough as a compromise.

Laboratory criteria and epidemiologic link used in pertussis case definitions

All case definitions identified in this review require some sort of laboratory confirmation of B. pertussis (or B. parapertussis) infection in addition to clinical signs and symptoms. Today, in most HIC PCR has become the gold standard for laboratory confirmation of pertussis due to its higher sensitivity when compared to culture [22]. Yet, both PCR and culture are included in most pertussis case definitions identified in this review. This can be explained by the fact that many included studies were published before PCR was established as a diagnostic tool and that PCR technology for diagnosing B. pertussis infections is comparatively expensive and therefore not widely available, especially not in LMIC. Specific serology can also be used for establishing a laboratory confirmed diagnosis of pertussis, especially during the late stages of disease [23]. Still, many case definitions do not accept serology as a method of laboratory confirmation, possibly due to the complexity of its interpretation with regards to variability and quality of available assays, patient age, immunization status, and variable background seroprevalence in the different general populations [23, 24].

Finally, many case definitions do not include an epidemiological link to a confirmed case of pertussis as a confirmatory criterion. However, we believe that it can be of added value as it supports a presumptive diagnosis of pertussis, especially during the early course of the disease or when laboratory results are unavailable.

Limitations

Our study has strengths and limitations. As a strength, it included not only a literature search but with the additional survey among GPI members we were able to also identify case definitions currently in use from various countries all over the world. However, the low response rate in our survey is a limitation as this may reflect a response bias. Countries with limited interest in and awareness for pertussis are probably under-represented in the survey as well as in publications identified in the literature review. As this is a narrative review and we only used one database (PubMed), which is a further limitation, we aimed to reduce the risk of selection bias by including all publications which used any kind of case definition. To reduce the risk of language bias, we included all publications identified by our search strategy irrespective of language first and only then had to exclude two of them due to language barriers. Therefore, we believe that this did not have a serious negative impact on our results. Finally, no formal quality assessment or validation of the case definitions or risk of bias evaluation was performed.

Conclusion

This review shows that many different case definitions of pertussis are used today around the world. Most of them still focus on typical presentation of pertussis, although it has been recognized that atypical presentations of pertussis are much more common than typical ones. Further, most of them do not use age-dependent criteria. This hampers comparability of data obtained from different study settings. Therefore, a harmonized case definition that could be used globally would be highly welcome. The case definition proposed by the GPI is meant to fulfill this expectation but may need to be revised and improved for better acceptance especially in disease surveillance studies. Mainly, its sensitivity should be increased by adding different levels of diagnostic certainty to the case definition so that atypical cases of pertussis don’t get missed.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

JZ performed the review of literature, analyzed the results, wrote draft versions of the manuscript, and approved the final revised manuscript.UH conceptualized the study, initiated the survey, supervised the analysis of review of literature and survey, reviewed and edited draft manuscripts and finalized the revised manuscript.

Funding

None.

Data availability

Available from corresponding authors on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

UH is a member of the “Global Pertussis Initiative” which receives unrestricted educational grants from Sanofi. He has received product independent lecture fees from GSK and Sanofi, manufacturers of pertussis vaccines. JZ: no conflicts.