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Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014
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Original article
Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014 Incidence de la coqueluche chez les 50 ans et plus en France en 2013–2014 N. Guiso a,∗ , J.-L. Gallais b , G. Gavazzi c , D. Pinquier d , J. Gaillat e a
Institut Pasteur, unité de prévention et thérapies moléculaires des maladies humaines, 25-28, rue du Docteur-Roux, 75724 Paris cedex 15, France b Société fran¸ caise de médecine générale (SFMG), 141, avenue de Verdun, 92130 Issy-les-Moulineaux, France c Clinique universitaire de médecine gériatrique, université Grenoble-Alpes, GREPI AGIM, CHU de Grenoble, boulevard de La Chantourne, 38700 La Tronche, France d Service de pédiatrie néonatale et réanimation, hôpital Charles-Nicolle, pavillon Mère-et-Enfant, 1, rue de Germont, 76031 Rouen cedex, France e Service des maladies infectieuses et médecine interne, centre hospitalier d’Annecy Genevois, 1, avenue de l’Hôpital, Metz-Tessy, BP 90074, 74374 Pringy cedex, France Received 13 October 2016; received in revised form 3 February 2017; accepted 1st September 2017
Abstract Objective. – To assess the incidence of pertussis (whooping cough) in subjects aged 50 years and older in France. ® Methods. – Participating family physicians (FPs) using the patient record management software AxiSanté included patients aged 50 years and older, who had signed an informed consent form, presenting with persistent cough for 7 to 21 days. Bordetella genetic material was detected by polymerase chain reaction (PCR) on nasopharyngeal samples collected at the FP’s discretion. Results. – A total of 42 FPs included 129 patients from June 2013 to August 2014 (large cities: 38; medium-sized cities: 57; rural areas: 34); 106 samples were analyzed. Overall, 30 pertussis cases were diagnosed: 10 cases confirmed by PCR, 18 purely clinical cases, and two direct epidemiological cases. The crude incidence rate per 100,000 patients aged ≥ 50 years was 103.6 (95% CI: 69.9–47.9): 77.1 in large cities, 103.1 in medium-sized cities, and 143.9 in rural areas. The extrapolated incidence rate per 100,000 persons aged ≥ 50 years was 187.1 (95% CI: 126.2–67.1): 131.1 in large cities, 256.1 in medium-sized cities, and 242.2 in rural areas. Conclusion. – The population aged 50 years and older can serve as a reservoir. Its role in Bordetella pertussis circulation should be taken into account for pertussis booster vaccination programs. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Adult; France; Whooping cough
Résumé Objectif. – Déterminer l’incidence de la coqueluche chez les adultes âgés de 50 ans et plus en France. ® Méthodes. – Les médecins volontaires utilisant le logiciel Axisanté devaient inclure les patients, ayant signé un consentement, de 50 ans et plus présentant une toux persistante depuis 7 à 21 jours. Une recherche de matériel génétique des espèces bactériennes du genre Bordetella était réalisée par réaction de polymérisation en chaîne (PCR) sur un échantillon nasopharyngé prélevé à la discrétion du médecin. Résultats. – De juin 2013 à août 2014, 42 médecins ont inclus 129 patients (grandes agglomérations : 38 ; moyennes agglomérations : 57 ; zones rurales : 34) ; 106 prélèvements ont été analysés. Au total, 30 cas de coqueluche ont été diagnostiqués : 10 cas confirmés par PCR, 18 cas purement cliniques, et deux cas épidémiologiques directs. Le taux d’incidence brut calculé pour 100 000 patients ≥ 50 ans était de 103,6 (IC 95 % : 69,9–147,9) : 77,1 en grandes agglomérations ; 103,1 en moyennes agglomérations ; 143,9 en zones rurales. Le taux d’incidence extrapolé calculé pour 100 000 habitants ≥ 50 ans était de 187,1 (IC 95 % : 126,2–267,1) : 131,1 en grandes agglomérations ; 256,1 en moyennes agglomérations ; 242,2 en zones rurales. ∗
Corresponding author. E-mail address: [email protected] (N. Guiso).
http://dx.doi.org/10.1016/j.medmal.2017.09.002 0399-077X/© 2017 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Guiso N, et al. Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.09.002
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Conclusion. – La population âgée de 50 ans et plus peut servir de réservoir. Son rôle dans la circulation de Bordetella pertussis devrait être pris en compte dans les programmes de vaccinations de rappel coquelucheuses. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Adulte ; Coqueluche ; France
1. Introduction The reservoir of Bordetella pertussis (B. pertussis), the agent of pertussis or whooping cough, has shifted from children to adults [1] due to the intensive vaccination of young children. The incidence in this latter population has indeed fallen sharply. In highly vaccinated regions, such as France, the main contaminators of < 6-month-old infants are now adults, and particularly the parents [2]. Adult vaccination, following the “cocooning” strategy, has therefore been advocated; it is aimed at young and future parents and at people who may be in close and sustained contact with the future baby during their first six months of life, such as the grandparents. In addition to this vaccination strategy, the most recent guidelines issued by the French Ministry of Health recommend the following for young adults: “Except for young adults who have been vaccinated against pertussis in the previous five years, a pertussis booster using DTaP-polio quadrivalent vaccine should be included in the diphtheria–tetanus–poliomyelitis booster given at the age of 25 years. Individuals aged over 25 years who have not received this booster may receive DTaP-polio vaccination up to the age of 39 inclusive” [3]. As the duration of protection afforded by the natural agent is limited and that conferred by the acellular vaccine presently used does not exceed 10 years [4,5], a pertussis booster may also be necessary in older subjects. In the Paris region of France (Île-de-France), the adult annual incidence of pertussis was estimated at 884/100,000 in 1999–2000 (18 to 88 years) [6] and at 145/100,000 in 2008–2009 (14 to 89 years) [7]. The incidence remains high, although lower. It has never been specifically measured in adults aged ≥ 50 years. Better knowledge of the incidence in this population could improve the vaccination schedule for adults outside the particular cocooning context. Apart from protecting infants, adult vaccination could also protect the adults themselves against a potentially serious infection, especially the elderly. Nursing homes for dependent elderly persons are regularly confronted with pertussis epidemics [8]. We performed an exploratory observational study (EPICOQSEN) to measure the incidence of pertussis in adults aged ≥ 50 years consulting their family physician (FP) for persistent cough. We distinguished three survey areas that differ by population-density: large cities, medium-sized cities, and rural areas. 2. Material and methods EPICOQSEN was an observational epidemiological study. Patients were included in this nationwide French multicenter prospective study from June 2013 to August 2014. The National
Health Research Data Processing Committee (French acronym CCTIRS) and data protection authority (French acronym CNIL) gave prior approval (respectively, December 21, 2011 [no 12.086] and March 30, 2012 [DR-2012-146]), in line with regulations for non-interventional studies. All volunteer patients signed an informed consent form ahead of inclusion. Data was rendered anonymous. Only FPs using the patient record management software ® AxiSanté (version 4 or 5; CompuGroup Medical Solution, formerly Axilog) were recruited. Each FP was asked to include all patients aged ≥ 50 years spontaneously consulting for a 7to-21-day history of persistent cough or chronic cough. Patients with recent cough of known etiology, including drug-induced side effects or persistent cough following flu infection during an influenza epidemic were excluded. A register of eligible patients was regularly updated. At consultation, FPs prescribed a nasopharyngeal swab for Bordetella screening at their discretion. Patients had the swab taken in the laboratory of their choice, which then sent it preferably to the CERBA laboratory for real-time polymerase chain reaction (PCR) analysis specific to the Bordetella genus. Positive samples (PCR+) were then sent to the Institut Pasteur for further PCR analysis to determine the species: B. pertussis, B. parapertussis, B. bronchiseptica, or B. holmesii [9,10]. Samples sent elsewhere than to the CERBA laboratory were followed up to ensure PCR+ samples were sent to the Institut Pasteur. The following definitions were used for study purposes. A biologically confirmed case patient was defined as a patient with a positive PCR for Bordetella. An epidemiologically confirmed case patient was defined as a patient without biological confirmation, presenting with coughing attacks for at least eight days and having been, during the three weeks preceding onset, in contact with a case patient confirmed biologically in a laboratory (direct epidemiological case patient). A clinical case patient was defined as a patient without biological or epidemiological confirmation but with minimum a 14-day history of nocturnal cough disturbing sleep, without fever and without known etiology, presenting with at least one of the following symptoms: suggestive cough attacks, paroxysms, whooping cough, cyanosis or apnea, post-cough vomiting, and/or hyperlymphocytosis for at least eight days. Biologically confirmed case patients, epidemiologically confirmed case patients, and clinical case patients were considered positive cases for statistical analysis. ® Statistical analysis was performed using SAS System 9.3 software (SAS Institute, NC, USA) for Windows XP. Missing data was not replaced. Qualitative variables were described by number and percentage, and quantitative data by number, mean, standard deviation (SD), median, range,
Please cite this article in press as: Guiso N, et al. Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.09.002
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and Q1–Q3 interquartile range; 95% confidence intervals (CI) were estimated parametrically (Poisson law for number of positive case patients or incidence). Qualitative or discrete variables were compared using Chi2 test or Fisher’s exact test, and quantitative variables using two-sample Student’s t-test after checking equality of variance (Fisher’s test) and normality (Shapiro–Wilk test); Wilcoxon, Mann–Whitney or Kruskal–Wallis tests or analysis of variance were used if equality of variance and normality were not confirmed. All tests were two-tailed, with the significance threshold set at 5%. The crude incidence per area was determined as the ratio of the total number of pertussis cases of FPs in a given area to the number of ≥ 50-year-old patients in the FPs’ patient registry. The extrapolated incidence per area was determined as: {[sum of positive cases for FPs in the area × (12 months/duration of the FP’s practice in months) × (number of FPs in the area/number of participating FPs in the area)]/[French population aged ≥ 50 years in the area according to the French National Institute for Statistics and Economic Studies (French acronym INSEE)]}. Given the expected rate of positive diagnoses (20%), the expected frequency of pertussis in ≥ 50 year-old (0.5 case patients per FP, according to previous studies [6,7]) and the rate per age group according to the IMS Health Disease Analyzer patient database, 95 FPs recruiting 237 patients with nasopharyngeal swab (i.e., about 80 per population-density area) were required to ensure 47 expected positive cases of pertussis. As not all recruited FPs are practicing FPs, the number of FPs was increased to 119 (attrition rate of 20%), i.e., 40 FPs per survey area. The required number of eligible patients aged 50 years and older was then estimated at 774. 3. Results Out of the 4371 FPs contacted, 123 (respectively 42, 49, and 32 in large cities, medium-sized cities, and rural areas) agreed to participate and fulfilled the corresponding administrative requirements. Of these 123 FPs, 32 (including five practicing FPs) dropped out of the study, mainly for lack of time, and 63 did not actively respond; 14 of the FPs who dropped out of the study were from rural areas. The 60 practicing FPs mainly practiced in medium (n = 26) or large cities (n = 22), and more rarely in rural areas (n = 12). Only 42 of the 60 practicing FPs recruited patients with nasopharyngeal swabs: 22 from medium-sized cities, 11 from large cities, and nine from rural areas. The 60 practicing FPs were mainly male (63.3%), with a mean age of 47.0 years (SD, 10.0); 81.6% reported “often or always” vaccinating prospective fathers against pertussis in case of pregnancy. This practice was significantly (P = 0.045) more common in large (prospective fathers always or often vaccinated: 36.4% and 50.0%, respectively) and in medium-sized cities (23.1% and 61.5%, respectively) than in rural areas (0.0% and 66.7%, respectively); 16.7% of practicing FPs from rural areas reported “never vaccinating” prospective fathers. Practicing FPs managed between 134 and 917 patients aged ≥ 50 years during the study period (mean ± SD, 526.5 ± 186.0).
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Overall, 255 patients seen by the FPs were recorded in the register of eligible patients. Of these 255 registered patients, 138 were eligible for the study, 133 signed an informed consent form, and 129 with a complete inclusion questionnaire filled out by their FP were included in the study. Of these 129 patients, 38 lived in large cities, 57 in medium-sized cities, and 34 in rural areas. Overall, 23 patients left the study: six lost to follow-up and 17 without nasopharyngeal swab. Table 1 details the characteristics of the 129 included patients and the 23 patients who prematurely withdrew from the study. Patients who prematurely withdrew from the study mainly lived in large cities, and were older than the included population as a whole. The 129 included patients presented on average 1.7 distinct clinical signs of cough, mainly (n = 89) cough attacks leading to difficult breathing. Clinical characteristics and mean duration of cough to consultation (14.0 ± 4.0 days) did not differ between included and withdrawn patients, except for cough with cyanosis or apnea, which was less frequent in those who prematurely withdrew from the study (P = 0.008). At end of consultation, FPs diagnosed suspected pertussis in 59.7% of included patients, but only 26.1% of withdrawn patients (P = 0.006) (Table 2). Out of the 129 included patients, 106 (respectively, 26, 50, and 30 from large cities, medium-sized cities, and rural areas) had biological data. Nasopharyngeal swabs were analyzed between 0 and 21 days after consultation (mean ± SD, 1.9 ± 3.25 days) and between 7 and 35 days after onset (mean ± SD, 16.0 ± 5.16 days); no statistical difference was observed between population-density areas (Table 3). Overall, we identified 10 cases confirmed by PCR, 21 clinical cases, and two direct epidemiological cases of pertussis. Of the 10 patients presenting with pertussis confirmed by biological analysis (PCR+), six had consulted in a large city (Table 4). None had been vaccinated against pertussis since 2004 and none reported a history of pertussis, whereas 11 (11.5%) of the 96 PCR– patients had been vaccinated against pertussis since 2004 and 20 (20.8%) reported a history of pertussis. B. pertussis was detected by the Institut Pasteur in 5 of the 10 PCR+ samples. The other five PCR+ samples were classified as Bordetella infection; B. pertussis could not be identified, either for lack of genetic material (n = 2) or when samples were not sent to the Institut Pasteur (n = 3). No other Bordetella species (parapertussis, bronchiseptica, holmesii) were detected. Tables 1 and 2 present demographic and clinical characteristics of cough and FPs’ diagnosis of suspected pertussis according to biological diagnosis. PCR+ patients more often lived in large cities, almost systematically presented with coughing attacks leading to difficult breathing, and statistically significantly more often presented with cough and cyanosis or apnea. Suspected pertussis was diagnosed by FPs more often in PCR+ patients than PCR– patients or prematurely withdrawn patients (respectively, 90.0%, 64.6%, and 26.1%; P = 0.006). PCR+ nasopharyngeal samples in which B. pertussis was detected were analyzed at a mean 14.0 ± 8.3 days after onset, compared with 20.8 ± 8.3 days for PCR+ Bordetella samples in which B. pertussis was not detected and 15.8 ± 4.9 days for PCR– samples (Table 3). Out of the 21 clinical cases of pertussis, three had PCR+ nasopharyngeal samples classified as Bordetella, leading to a
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Table 1 Demographic characteristics of included patients according to biological diagnosis (France, 2013–2014). Caractéristiques démographiques des patients inclus selon leur diagnostic biologique (France, 2013–2014).
Geographic area Large cities, n (%) Medium-sized cities, n (%) Rural areas, n (%) Male gender, n (%) Age (years), mean (SD) Working patients, n (%)
Included patients (n = 129)
B. pertussis (n = 5)
Bordetella (ind.) (n = 5)
PCR– patients (n = 96)
Discontinued the study (n = 23)
38 (29.5) 57 (44.2) 34 (26.4) 43 (33.3) 64.6 (9.8) 37 (28.7)
4 (80.0) 0 (0.0) 1 (20.0) 2 (40.0) 67.2 (8.3) 0 (0.0)
2 (40.0) 2 (40.0) 1 (20.0) 3 (60.0) 58.8 (5.6) 3 (60.0)
20 (20.8) 48 (50.0) 28 (29.2) 31 (32.3) 63.6 (9.6) 29 (30.2)
12 (52.2) 7 (30.4) 4 (17.4) 7 (30.4) 69.1 (10.7) 5 (21.7)
P* 0.013
0.608 0.048 0.167
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05.
total of 18 purely clinical cases of pertussis (PCR–). Of these 18 patients with purely clinical diagnosis, five had a history of pertussis, only one reported being vaccinated since 2004, and six did not know their vaccinal status. The two PCR– patients who were counted as direct epidemiological case patients had had at least one case patient of documented pertussis in their close environment. They had neither been vaccinated since 2004 nor reported a history of pertussis. Thus, a total of 30 pertussis case patients were diagnosed (Table 4).
The practicing FPs who did not subsequently drop out of the study had a total of 28,960 ≥ 50-year-old patients: 10,374 in large cities, 11,638 in medium-sized cities, and 6948 in rural areas. The crude incidence rate per 100,000 ≥ 50-year-old patients was thus 103.6 (95% CI: 69.9–147.9): 77.1 (33.3–151.9) in large cities, 103.1 (53.3–180.1) in medium-sized cities, and 143.9 (69.0–264.7) in rural areas (Fig. 1). The incidence rate extrapolated to the French population aged ≥ 50 years was 187.1/100,000 (95% CI: 126.2–267.1): 131.1 (56.6–258.3) in large cities, 256.1 (132.3–447.3) in medium-sized cities, and 242.2 (116.2–445.5) in rural areas (Fig. 2).
Table 2 Clinical characteristics of cough of included patients according to biological diagnosis (France, 2013–2014). Caractéristiques cliniques de la toux chez les patients inclus selon leur diagnostic biologique (France, 2013–2014). Included patients (n = 129) Number of distinct cough symptoms per patient (0 to 6), mean (SD) Predominantly nocturnal cough, n (%) Duration of cough (days): mean (SD) Cough with cough attacks leading to difficult breathing, n (%) Whooping cough, n (%) Cough with cyanosis or apnea, n (%) Cough with post-cough vomiting, n (%) Cough associated with hyperlymphocytosis for > 8 days: n (%)a Aggravation of chronic cough, n (%) Pertussis suspected by FPb
1.7 (1.1)
63 (48.8) 14.0 (4.0)
B. pertussis (n = 5) 1.8 (1.1)
2 (40.0) 14.2 (5.7)
Bordetella (ind.) (n = 5) 2.8 (0.4)
4 (80.0) 16.0 (3.7)
PCR– patients (n = 96) 1.7 (1.2)
48 (50.0) 14.0 (4.0)
Discontinuation of study (n = 23) 1.3 (1.0)
9 (39.1) 13.5 (4.0)
P* 0.054
0.389 0.670
89 (69.0)
4 (80.0)
5 (100.0)
67 (69.8)
13 (56.5)
0.238
30 (23.3) 19 (14.7)
0 (0.0) 3 (60.0)
2 (40.0) 2 (40.0)
23 (24.0) 12 (12.5)
5 (21.7) 2 (8.7)
0.502 0.008
15 (11.6)
0 (0.0)
1 (20.0)
13 (13.5)
1 (4.3)
0.470
1 (0.8)
0 (0.0)
0 (0.0)
1 (1.0)
0 (0.0)
0.928
18 (14.0)
1 (20.0)
2 (40.0)
12 (12.5)
3 (13.0)
0.367
77 (59.7)
5 (100.0)
4 (80.0)
62 (64.6)
6 (26.1)
0.006
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); FP: family physician; PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05. a Missing data for 111 of the 129 included patients. b Missing data for 20 patients.
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Table 3 Time to PCR from inclusion and cough onset (France, 2013–2014). Délais de réalisation de la PCR par rapport à la date d’inclusion et au début de la toux (France, 2013–2014).
Inclusion-to-PCR interval (days) Mean (SD) [Range] Onset-to-PCR interval (days) Mean (SD) [Range]
Inclusion-to-PCR interval (days) Mean (SD) [Range] Onset-to-PCR interval (days) Mean (SD) [Range]
Patients analyzed (n = 106)
Large cities (n = 26)
Medium-sized cities (n = 50)
Rural areas (n = 30)
1.9 (3.3) [0.0–21.0]
2.1 (2.3) [0.0–9.0]
2.1 (4.3) [0.0–21.0]
1.5 (1.6) [0.0–5.0]
16.0 (5.2) [7.0–35.0]
16.4 (5.2) [8.0–27.0]
16.7 (5.4) [8.0–35.0]
14.5 (4.6) [7.0–24.0]
P* 0.670
0.173
Included patients (n = 129)
B. pertussis (n = 5)
Bordetella (ind.) (n = 5)
PCR– patients (n = 96)
1.9 (3.2) [0.0–21.0]
0.8 (0.5) [0.0–1.0]
4.8 (8.0) [0.0–9.0]
1.8 (2.9) [0.0–21.0]
16.0 (5.2) [7.0–35.0]
14.0 (6.1) [8.0–22.0]
20.8 (8.3) [13.0–34.0]
15.8 (4.9) [7.0 - 35.0]
P* 0.105
0.080
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05. Data for three patients with outlying inclusion dates has been excluded.
Table 4 Number of patients presenting with bordetellosis by geographic area (France, 2013–2014). Nombre de cas de bordetelloses identifiés en fonction de la zone géographique (France, 2013–2014).
Biological case patient, n (%) Direct epidemiological case patient, n (%) Clinical case patient, n (%) Total, n (%)
Patients analyzed (n = 106)
Large cities (n = 26)
Medium-sized cities (n = 50)
Rural areas (n = 30)
P
10 (9.4) 2 (1.9) 18 (17.0) 30 (28.3)
6 (23.1) 0 (0.0) 2 (7.7) 8 (30.8)
2 (4.0) 1 (2.0) 9 (18.0) 12 (24.0)
2 (6.7) 1 (3.3) 7 (23.3) 10 (33.3)
0.022* NS NS NS
NS: non-significant. * Significant difference by population-density areas, P ≤ 0.05.
Fig. 1. Crude incidence rate of pertussis in patients aged ≥ 50 years by geographic area (France, 2013–2014). CI: confidence interval. Taux d’incidence brut de la coqueluche chez les patients de 50 ans et plus en France selon les zones géographiques en 2013–2014.
Fig. 2. Extrapolated incidence rate of pertussis in people aged ≥ 50 years by geographic area (France, 2013–2014). CI: confidence interval. Taux d’incidence de la coqueluche extrapolé aux habitants de 50 ans et plus en France selon les zones géographiques en 2013–2014.
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4. Discussion Results of the EPICOQSEN study revealed that pertussis was present and diagnosed in patients aged ≥ 50 years consulting their FP for a 7-to-21-day history of cough; the crude incidence per 100,000 patients aged ≥ 50 years was 103.1 (95% CI: 69.9–147.9) and the extrapolated incidence per 100,000 persons aged ≥ 50 years in France was 187.1 (95% CI: 126.2–267.1). It was about two-fold higher in medium-sized cities and rural areas than in large cities. The present global incidence of pertussis is similar to that of 2008–2009 reported in a study of patients aged 14–89 years in the Paris region [7], and to that of a 2006–2008 American study of adults ≥ 50 years, but lower than in the same study data for 2009–2010 where it was 292.0/100,000 patients aged 50–64 years and 463.8/100,000 patients ≥ 65 years in 2010 [11]. None of the 10 PCR+ patients for B. pertussis or Bordetella genus and neither of the two epidemiologically confirmed patients had been vaccinated against pertussis in the 10 years preceding the study, and none reported a history of pertussis. Eleven of the 96 PCR– patients (11.5%, including one clinical case patient) reported being vaccinated since 2004 and 20 (20.8%, including five clinical case patients) reported a history of pertussis. Vaccination and natural disease thus exerted a protective effect, even if not absolute. The date of natural infection was not recorded in this study, but protection was shown to be limited in time. Although exploratory, the present study has strengths: its prospective design, the pre-established definition of case patients, and the use of a specific biological diagnostic method. Moreover, defining the observation period as a complete year took into account possible seasonal variation, and the fact that the inclusion period began more or less simultaneously for all study FPs meant that the same period of the year was covered in the three population-density areas, thus strengthening ® our results. Finally, the systematic use of the AxiSanté software package ensured homogeneity and exhaustiveness of data collection; there was also very little missing data. The study also has limitations. Fewer FPs were recruited than expected; the number of included patients was thus also lower than expected. This is perhaps due to the requirement of using ® the AxiSanté patient record management software, intended to allow easy access to the study protocol, to minimize redundant data input, and above all to have effective inclusion with the possibility of sending messages. Data input was efficient and few patients were lost to follow-up. Nevertheless, further results obtained in a larger study are required to support these results. With a mean age of 47.0 years, the study FPs were younger than the mean age of the 25,202 FPs in the three study areas as a whole (mean age: 55.1 years; data not shown). This might suggest a recruitment bias. The number of patients discontinuing the study or for whom no swab was taken was small but not exactly negligible (n = 23; 17.8% of included patients). Comparing this subgroup with the group of patients analyzed was thus important. The demographic characteristics of included patients revealed that patients prematurely withdrawn mainly lived in large cities and were relatively older, which may represent an attrition bias.
Cough characteristics were, however, comparable to those of analyzed patients, although they less frequently led to suspicion of pertussis. Finally, the number of pertussis case patients was lower than in previous years [12]; pertussis is a cyclical disease and, despite the lower rate observed during the study period, case patients were observed in all three population-density areas. The number of PCR+ patients was lower than expected, which is a further study limitation. PCR shows high sensitivity, but diminishing over time: beyond 21 days, PCR results for Bordetella are negative [13]. In the present study, the maximum interval between cough onset and nasopharyngeal swab analysis in patients presenting with B. pertussis infection confirmed by PCR was 22 days, compared with 34 days for Bordetella-indeterminate patients (i.e., genetic material of Bordetella genus detected but species not identified [n = 2] or PCR+ samples not sent to the Institut Pasteur [n = 3]) and 35 days for PCR– patients (i.e., genetic material of Bordetella genus not detected by PCR). This delay probably accounts for some PCR– results. B. pertussis failed to be identified in two samples due to lack of genetic material despite highly suggestive clinical findings. Patients presenting with persisting cough for > 21 days or aggravated chronic cough for > 21 days were not eligible; even so, several included patients had delayed nasopharyngeal swab, which may have led to underestimate the incidence of pertussis. It is important to note that FPs suspected pertussis in all patients in whom PCR confirmed B. pertussis and 80% of those in whom Bordetella was confirmed: i.e., 90.0% of PCR+ patients versus 64.6% of PCR– patients and 26.1% of those who discontinued the study. 5. Conclusion Pertussis is a frequent cause of persistent cough in adults aged 50 years or older. This may be due to the limited protection time afforded by vaccination and also by the natural infection. Patients aged over 50 years may constitute a reservoir for B. pertussis circulation and should be taken into account for booster vaccination programs, like healthcare professionals who have to be vaccinated every 20 years (at the age of 25, 45, and 65 years) as part of the diphtheria–tetanus–polio (DTpolio) booster. Prior peer-reviewed presentation at a professional/scientific conference Presented at the Journées Nationales d’Infectiologie June 2017. Funding The study was co-funded by Sanofi Pasteur-MSD (AnneCarole Jacquard) and GSK (Céline Pribil). The sponsors were not involved in the content of the present article. Contribution of authors Study design and data analysis and interpretation was performed by all authors. N.G. wrote the article and all authors reviewed it. All authors read and approved the article.
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Disclosure of interest J.G.: remuneration as member of the scientific committee for EPICOQSEN study for GSK and Sanofi Pasteur-MSD. J.-L. G. declares that he has no competing interest. G.G.: remuneration as speaker at conferences on “vaccination in the elderly” for Sanofi Pasteur-MSD. D.P.: remuneration as member of the scientific committee for EPICOQSEN study for GSK and Sanofi Pasteur-MSD; invitation as a speaker or an auditor at scientific conferences on vaccination for GSK and Sanofi Pasteur-MSD. N.G. declares that he has no competing interest before April 2015. As of April 2015, remuneration as participant in a “master class” for Sanofi Pasteur-MSD and in expert boards for GSK and Bionet Asia. Acknowledgments The authors would like to thank the family physicians who took part in the study, IMS Health (for the study), and Abelia Science (for the article). They would also like to thank Sandra Corre for performing PCR analyses at the Institut Pasteur, and the French Infectious Diseases Society (French acronym SPILF) for their support. References [1] Tubiana S, Belchior E, Guillot S, Guiso N, Lévy-Bruhl D, Renacoq Participants. Monitoring the impact of vaccination on pertussis in infants using an active hospital-based Pediatric Surveillance Network: results from 17 years’ experience, 1996–2012, France. J Pediatr Infect Dis 2015;34(8):814–20. [2] Wiley KE, Zuo Y, Macartney KK, McIntyre PB. Sources of pertussis infection in young infants: a review of key evidence informing targeting of the cocoon strategy. Vaccine 2013;31:618–25.
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[3] Anonyme. Calendrier des vaccinations et recommandations vaccinales. Ministère des Affaires Sociales et de la Santé; 2016 http://social-sante.gouv. fr/IMG/pdf/calendrier vaccinal 2016.pdf (Accessed October 10, 2016). [4] Baron S, Njamkepo E, Grimprel E, Begue P, Desenclos JC, Drucker J, et al. Epidemiology of pertussis in French hospitals in 1993 and 1994: thirty years after a routine use of vaccination. J Pediatr Infect Dis 1998;17:412–8. [5] Guiso N, Njamkepo E, Vie Le Sage F, Zepp F, Meyer Cu, Abitbol V, et al. Long-term humoral and cell-mediated immunity after acellular pertussis vaccination compares favourably with whole-cell vaccines 6 years after booster vaccination in the second year of life. Vaccine 2007;25(8): 1390–7. [6] Gilberg S, Njamkepo E, Du Châtelet IP, Partouche H, Gueirard P, Ghasarossian C, et al. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J Infect Dis 2002;186(3):415–8. [7] Lasserre A, Laurent E, Tuberlin C, Hanslik T, Blanchon T, Guiso N. Pertussis incidence among adolescents and adults surveyed in general practices in the Paris area, France May 2008 to March 2009. Euro Surveill 2011;16(5) [pii:19783]. [8] Succo T, Braunstein D, Desmons S, Sampol P, Belchior E, Guiso N, et al. Épidémie de coqueluche dans un établissement d’hébergement pour personnes âgées dépendantes Bouches-du-Rhône, août 2013. Bull Epidemiol Hebd 2015;5:83–8. [9] Njamkepo E, Bonacorsi S, Debruyne M, Gibaud SA, Guillot S, Guiso N. Significant finding of Bordetella holmesii DNA in nasopharyngeal samples from French patients with suspected pertussis. J Clin Microbiol 2011;49(12):4347–8. [10] Tizolova A, Brun D, Guiso N, Guillot S. Development of real-time PCR assay for differential detection of Bordetella bronchiseptica and Bordetella parapertussis. Diagn Microbiol Infect Dis 2014;78(4):347–51. [11] Masseria C, Krishnarajah G. The estimated incidence of pertussis in people aged 50 years old or older in the United States, 2006–2010. BMC Infect Dis 2015;15:534. [12] Anonyme. Rapport annuel d’activité Année d’exercice 2014. Centre national de référence de la coqueluche et autres bordetelloses; 2015 https://www.pasteur.fr/sites/www.pasteur.fr/files/rapport cnrcoqr-exercice 2014.pdf (Accessed October 10, 2016). [13] Riffelmann M, Wirsing von König CH, Caro V, Guiso N, Pertussis PCR, Consesus Group. Nucleic acid amplification tests for diagnosis of Bordetella infections. J Clin Microbiol 2005;43(10):4925–9.
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Original article
Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014 Incidence de la coqueluche chez les 50 ans et plus en France en 2013–2014 N. Guiso a,∗ , J.-L. Gallais b , G. Gavazzi c , D. Pinquier d , J. Gaillat e a
Institut Pasteur, unité de prévention et thérapies moléculaires des maladies humaines, 25-28, rue du Docteur-Roux, 75724 Paris cedex 15, France b Société fran¸ caise de médecine générale (SFMG), 141, avenue de Verdun, 92130 Issy-les-Moulineaux, France c Clinique universitaire de médecine gériatrique, université Grenoble-Alpes, GREPI AGIM, CHU de Grenoble, boulevard de La Chantourne, 38700 La Tronche, France d Service de pédiatrie néonatale et réanimation, hôpital Charles-Nicolle, pavillon Mère-et-Enfant, 1, rue de Germont, 76031 Rouen cedex, France e Service des maladies infectieuses et médecine interne, centre hospitalier d’Annecy Genevois, 1, avenue de l’Hôpital, Metz-Tessy, BP 90074, 74374 Pringy cedex, France Received 13 October 2016; received in revised form 3 February 2017; accepted 1st September 2017
Abstract Objective. – To assess the incidence of pertussis (whooping cough) in subjects aged 50 years and older in France. ® Methods. – Participating family physicians (FPs) using the patient record management software AxiSanté included patients aged 50 years and older, who had signed an informed consent form, presenting with persistent cough for 7 to 21 days. Bordetella genetic material was detected by polymerase chain reaction (PCR) on nasopharyngeal samples collected at the FP’s discretion. Results. – A total of 42 FPs included 129 patients from June 2013 to August 2014 (large cities: 38; medium-sized cities: 57; rural areas: 34); 106 samples were analyzed. Overall, 30 pertussis cases were diagnosed: 10 cases confirmed by PCR, 18 purely clinical cases, and two direct epidemiological cases. The crude incidence rate per 100,000 patients aged ≥ 50 years was 103.6 (95% CI: 69.9–47.9): 77.1 in large cities, 103.1 in medium-sized cities, and 143.9 in rural areas. The extrapolated incidence rate per 100,000 persons aged ≥ 50 years was 187.1 (95% CI: 126.2–67.1): 131.1 in large cities, 256.1 in medium-sized cities, and 242.2 in rural areas. Conclusion. – The population aged 50 years and older can serve as a reservoir. Its role in Bordetella pertussis circulation should be taken into account for pertussis booster vaccination programs. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Adult; France; Whooping cough
Résumé Objectif. – Déterminer l’incidence de la coqueluche chez les adultes âgés de 50 ans et plus en France. ® Méthodes. – Les médecins volontaires utilisant le logiciel Axisanté devaient inclure les patients, ayant signé un consentement, de 50 ans et plus présentant une toux persistante depuis 7 à 21 jours. Une recherche de matériel génétique des espèces bactériennes du genre Bordetella était réalisée par réaction de polymérisation en chaîne (PCR) sur un échantillon nasopharyngé prélevé à la discrétion du médecin. Résultats. – De juin 2013 à août 2014, 42 médecins ont inclus 129 patients (grandes agglomérations : 38 ; moyennes agglomérations : 57 ; zones rurales : 34) ; 106 prélèvements ont été analysés. Au total, 30 cas de coqueluche ont été diagnostiqués : 10 cas confirmés par PCR, 18 cas purement cliniques, et deux cas épidémiologiques directs. Le taux d’incidence brut calculé pour 100 000 patients ≥ 50 ans était de 103,6 (IC 95 % : 69,9–147,9) : 77,1 en grandes agglomérations ; 103,1 en moyennes agglomérations ; 143,9 en zones rurales. Le taux d’incidence extrapolé calculé pour 100 000 habitants ≥ 50 ans était de 187,1 (IC 95 % : 126,2–267,1) : 131,1 en grandes agglomérations ; 256,1 en moyennes agglomérations ; 242,2 en zones rurales. ∗
Corresponding author. E-mail address: [email protected] (N. Guiso).
http://dx.doi.org/10.1016/j.medmal.2017.09.002 0399-077X/© 2017 Elsevier Masson SAS. All rights reserved.
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Conclusion. – La population âgée de 50 ans et plus peut servir de réservoir. Son rôle dans la circulation de Bordetella pertussis devrait être pris en compte dans les programmes de vaccinations de rappel coquelucheuses. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Adulte ; Coqueluche ; France
1. Introduction The reservoir of Bordetella pertussis (B. pertussis), the agent of pertussis or whooping cough, has shifted from children to adults [1] due to the intensive vaccination of young children. The incidence in this latter population has indeed fallen sharply. In highly vaccinated regions, such as France, the main contaminators of < 6-month-old infants are now adults, and particularly the parents [2]. Adult vaccination, following the “cocooning” strategy, has therefore been advocated; it is aimed at young and future parents and at people who may be in close and sustained contact with the future baby during their first six months of life, such as the grandparents. In addition to this vaccination strategy, the most recent guidelines issued by the French Ministry of Health recommend the following for young adults: “Except for young adults who have been vaccinated against pertussis in the previous five years, a pertussis booster using DTaP-polio quadrivalent vaccine should be included in the diphtheria–tetanus–poliomyelitis booster given at the age of 25 years. Individuals aged over 25 years who have not received this booster may receive DTaP-polio vaccination up to the age of 39 inclusive” [3]. As the duration of protection afforded by the natural agent is limited and that conferred by the acellular vaccine presently used does not exceed 10 years [4,5], a pertussis booster may also be necessary in older subjects. In the Paris region of France (Île-de-France), the adult annual incidence of pertussis was estimated at 884/100,000 in 1999–2000 (18 to 88 years) [6] and at 145/100,000 in 2008–2009 (14 to 89 years) [7]. The incidence remains high, although lower. It has never been specifically measured in adults aged ≥ 50 years. Better knowledge of the incidence in this population could improve the vaccination schedule for adults outside the particular cocooning context. Apart from protecting infants, adult vaccination could also protect the adults themselves against a potentially serious infection, especially the elderly. Nursing homes for dependent elderly persons are regularly confronted with pertussis epidemics [8]. We performed an exploratory observational study (EPICOQSEN) to measure the incidence of pertussis in adults aged ≥ 50 years consulting their family physician (FP) for persistent cough. We distinguished three survey areas that differ by population-density: large cities, medium-sized cities, and rural areas. 2. Material and methods EPICOQSEN was an observational epidemiological study. Patients were included in this nationwide French multicenter prospective study from June 2013 to August 2014. The National
Health Research Data Processing Committee (French acronym CCTIRS) and data protection authority (French acronym CNIL) gave prior approval (respectively, December 21, 2011 [no 12.086] and March 30, 2012 [DR-2012-146]), in line with regulations for non-interventional studies. All volunteer patients signed an informed consent form ahead of inclusion. Data was rendered anonymous. Only FPs using the patient record management software ® AxiSanté (version 4 or 5; CompuGroup Medical Solution, formerly Axilog) were recruited. Each FP was asked to include all patients aged ≥ 50 years spontaneously consulting for a 7to-21-day history of persistent cough or chronic cough. Patients with recent cough of known etiology, including drug-induced side effects or persistent cough following flu infection during an influenza epidemic were excluded. A register of eligible patients was regularly updated. At consultation, FPs prescribed a nasopharyngeal swab for Bordetella screening at their discretion. Patients had the swab taken in the laboratory of their choice, which then sent it preferably to the CERBA laboratory for real-time polymerase chain reaction (PCR) analysis specific to the Bordetella genus. Positive samples (PCR+) were then sent to the Institut Pasteur for further PCR analysis to determine the species: B. pertussis, B. parapertussis, B. bronchiseptica, or B. holmesii [9,10]. Samples sent elsewhere than to the CERBA laboratory were followed up to ensure PCR+ samples were sent to the Institut Pasteur. The following definitions were used for study purposes. A biologically confirmed case patient was defined as a patient with a positive PCR for Bordetella. An epidemiologically confirmed case patient was defined as a patient without biological confirmation, presenting with coughing attacks for at least eight days and having been, during the three weeks preceding onset, in contact with a case patient confirmed biologically in a laboratory (direct epidemiological case patient). A clinical case patient was defined as a patient without biological or epidemiological confirmation but with minimum a 14-day history of nocturnal cough disturbing sleep, without fever and without known etiology, presenting with at least one of the following symptoms: suggestive cough attacks, paroxysms, whooping cough, cyanosis or apnea, post-cough vomiting, and/or hyperlymphocytosis for at least eight days. Biologically confirmed case patients, epidemiologically confirmed case patients, and clinical case patients were considered positive cases for statistical analysis. ® Statistical analysis was performed using SAS System 9.3 software (SAS Institute, NC, USA) for Windows XP. Missing data was not replaced. Qualitative variables were described by number and percentage, and quantitative data by number, mean, standard deviation (SD), median, range,
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and Q1–Q3 interquartile range; 95% confidence intervals (CI) were estimated parametrically (Poisson law for number of positive case patients or incidence). Qualitative or discrete variables were compared using Chi2 test or Fisher’s exact test, and quantitative variables using two-sample Student’s t-test after checking equality of variance (Fisher’s test) and normality (Shapiro–Wilk test); Wilcoxon, Mann–Whitney or Kruskal–Wallis tests or analysis of variance were used if equality of variance and normality were not confirmed. All tests were two-tailed, with the significance threshold set at 5%. The crude incidence per area was determined as the ratio of the total number of pertussis cases of FPs in a given area to the number of ≥ 50-year-old patients in the FPs’ patient registry. The extrapolated incidence per area was determined as: {[sum of positive cases for FPs in the area × (12 months/duration of the FP’s practice in months) × (number of FPs in the area/number of participating FPs in the area)]/[French population aged ≥ 50 years in the area according to the French National Institute for Statistics and Economic Studies (French acronym INSEE)]}. Given the expected rate of positive diagnoses (20%), the expected frequency of pertussis in ≥ 50 year-old (0.5 case patients per FP, according to previous studies [6,7]) and the rate per age group according to the IMS Health Disease Analyzer patient database, 95 FPs recruiting 237 patients with nasopharyngeal swab (i.e., about 80 per population-density area) were required to ensure 47 expected positive cases of pertussis. As not all recruited FPs are practicing FPs, the number of FPs was increased to 119 (attrition rate of 20%), i.e., 40 FPs per survey area. The required number of eligible patients aged 50 years and older was then estimated at 774. 3. Results Out of the 4371 FPs contacted, 123 (respectively 42, 49, and 32 in large cities, medium-sized cities, and rural areas) agreed to participate and fulfilled the corresponding administrative requirements. Of these 123 FPs, 32 (including five practicing FPs) dropped out of the study, mainly for lack of time, and 63 did not actively respond; 14 of the FPs who dropped out of the study were from rural areas. The 60 practicing FPs mainly practiced in medium (n = 26) or large cities (n = 22), and more rarely in rural areas (n = 12). Only 42 of the 60 practicing FPs recruited patients with nasopharyngeal swabs: 22 from medium-sized cities, 11 from large cities, and nine from rural areas. The 60 practicing FPs were mainly male (63.3%), with a mean age of 47.0 years (SD, 10.0); 81.6% reported “often or always” vaccinating prospective fathers against pertussis in case of pregnancy. This practice was significantly (P = 0.045) more common in large (prospective fathers always or often vaccinated: 36.4% and 50.0%, respectively) and in medium-sized cities (23.1% and 61.5%, respectively) than in rural areas (0.0% and 66.7%, respectively); 16.7% of practicing FPs from rural areas reported “never vaccinating” prospective fathers. Practicing FPs managed between 134 and 917 patients aged ≥ 50 years during the study period (mean ± SD, 526.5 ± 186.0).
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Overall, 255 patients seen by the FPs were recorded in the register of eligible patients. Of these 255 registered patients, 138 were eligible for the study, 133 signed an informed consent form, and 129 with a complete inclusion questionnaire filled out by their FP were included in the study. Of these 129 patients, 38 lived in large cities, 57 in medium-sized cities, and 34 in rural areas. Overall, 23 patients left the study: six lost to follow-up and 17 without nasopharyngeal swab. Table 1 details the characteristics of the 129 included patients and the 23 patients who prematurely withdrew from the study. Patients who prematurely withdrew from the study mainly lived in large cities, and were older than the included population as a whole. The 129 included patients presented on average 1.7 distinct clinical signs of cough, mainly (n = 89) cough attacks leading to difficult breathing. Clinical characteristics and mean duration of cough to consultation (14.0 ± 4.0 days) did not differ between included and withdrawn patients, except for cough with cyanosis or apnea, which was less frequent in those who prematurely withdrew from the study (P = 0.008). At end of consultation, FPs diagnosed suspected pertussis in 59.7% of included patients, but only 26.1% of withdrawn patients (P = 0.006) (Table 2). Out of the 129 included patients, 106 (respectively, 26, 50, and 30 from large cities, medium-sized cities, and rural areas) had biological data. Nasopharyngeal swabs were analyzed between 0 and 21 days after consultation (mean ± SD, 1.9 ± 3.25 days) and between 7 and 35 days after onset (mean ± SD, 16.0 ± 5.16 days); no statistical difference was observed between population-density areas (Table 3). Overall, we identified 10 cases confirmed by PCR, 21 clinical cases, and two direct epidemiological cases of pertussis. Of the 10 patients presenting with pertussis confirmed by biological analysis (PCR+), six had consulted in a large city (Table 4). None had been vaccinated against pertussis since 2004 and none reported a history of pertussis, whereas 11 (11.5%) of the 96 PCR– patients had been vaccinated against pertussis since 2004 and 20 (20.8%) reported a history of pertussis. B. pertussis was detected by the Institut Pasteur in 5 of the 10 PCR+ samples. The other five PCR+ samples were classified as Bordetella infection; B. pertussis could not be identified, either for lack of genetic material (n = 2) or when samples were not sent to the Institut Pasteur (n = 3). No other Bordetella species (parapertussis, bronchiseptica, holmesii) were detected. Tables 1 and 2 present demographic and clinical characteristics of cough and FPs’ diagnosis of suspected pertussis according to biological diagnosis. PCR+ patients more often lived in large cities, almost systematically presented with coughing attacks leading to difficult breathing, and statistically significantly more often presented with cough and cyanosis or apnea. Suspected pertussis was diagnosed by FPs more often in PCR+ patients than PCR– patients or prematurely withdrawn patients (respectively, 90.0%, 64.6%, and 26.1%; P = 0.006). PCR+ nasopharyngeal samples in which B. pertussis was detected were analyzed at a mean 14.0 ± 8.3 days after onset, compared with 20.8 ± 8.3 days for PCR+ Bordetella samples in which B. pertussis was not detected and 15.8 ± 4.9 days for PCR– samples (Table 3). Out of the 21 clinical cases of pertussis, three had PCR+ nasopharyngeal samples classified as Bordetella, leading to a
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Table 1 Demographic characteristics of included patients according to biological diagnosis (France, 2013–2014). Caractéristiques démographiques des patients inclus selon leur diagnostic biologique (France, 2013–2014).
Geographic area Large cities, n (%) Medium-sized cities, n (%) Rural areas, n (%) Male gender, n (%) Age (years), mean (SD) Working patients, n (%)
Included patients (n = 129)
B. pertussis (n = 5)
Bordetella (ind.) (n = 5)
PCR– patients (n = 96)
Discontinued the study (n = 23)
38 (29.5) 57 (44.2) 34 (26.4) 43 (33.3) 64.6 (9.8) 37 (28.7)
4 (80.0) 0 (0.0) 1 (20.0) 2 (40.0) 67.2 (8.3) 0 (0.0)
2 (40.0) 2 (40.0) 1 (20.0) 3 (60.0) 58.8 (5.6) 3 (60.0)
20 (20.8) 48 (50.0) 28 (29.2) 31 (32.3) 63.6 (9.6) 29 (30.2)
12 (52.2) 7 (30.4) 4 (17.4) 7 (30.4) 69.1 (10.7) 5 (21.7)
P* 0.013
0.608 0.048 0.167
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05.
total of 18 purely clinical cases of pertussis (PCR–). Of these 18 patients with purely clinical diagnosis, five had a history of pertussis, only one reported being vaccinated since 2004, and six did not know their vaccinal status. The two PCR– patients who were counted as direct epidemiological case patients had had at least one case patient of documented pertussis in their close environment. They had neither been vaccinated since 2004 nor reported a history of pertussis. Thus, a total of 30 pertussis case patients were diagnosed (Table 4).
The practicing FPs who did not subsequently drop out of the study had a total of 28,960 ≥ 50-year-old patients: 10,374 in large cities, 11,638 in medium-sized cities, and 6948 in rural areas. The crude incidence rate per 100,000 ≥ 50-year-old patients was thus 103.6 (95% CI: 69.9–147.9): 77.1 (33.3–151.9) in large cities, 103.1 (53.3–180.1) in medium-sized cities, and 143.9 (69.0–264.7) in rural areas (Fig. 1). The incidence rate extrapolated to the French population aged ≥ 50 years was 187.1/100,000 (95% CI: 126.2–267.1): 131.1 (56.6–258.3) in large cities, 256.1 (132.3–447.3) in medium-sized cities, and 242.2 (116.2–445.5) in rural areas (Fig. 2).
Table 2 Clinical characteristics of cough of included patients according to biological diagnosis (France, 2013–2014). Caractéristiques cliniques de la toux chez les patients inclus selon leur diagnostic biologique (France, 2013–2014). Included patients (n = 129) Number of distinct cough symptoms per patient (0 to 6), mean (SD) Predominantly nocturnal cough, n (%) Duration of cough (days): mean (SD) Cough with cough attacks leading to difficult breathing, n (%) Whooping cough, n (%) Cough with cyanosis or apnea, n (%) Cough with post-cough vomiting, n (%) Cough associated with hyperlymphocytosis for > 8 days: n (%)a Aggravation of chronic cough, n (%) Pertussis suspected by FPb
1.7 (1.1)
63 (48.8) 14.0 (4.0)
B. pertussis (n = 5) 1.8 (1.1)
2 (40.0) 14.2 (5.7)
Bordetella (ind.) (n = 5) 2.8 (0.4)
4 (80.0) 16.0 (3.7)
PCR– patients (n = 96) 1.7 (1.2)
48 (50.0) 14.0 (4.0)
Discontinuation of study (n = 23) 1.3 (1.0)
9 (39.1) 13.5 (4.0)
P* 0.054
0.389 0.670
89 (69.0)
4 (80.0)
5 (100.0)
67 (69.8)
13 (56.5)
0.238
30 (23.3) 19 (14.7)
0 (0.0) 3 (60.0)
2 (40.0) 2 (40.0)
23 (24.0) 12 (12.5)
5 (21.7) 2 (8.7)
0.502 0.008
15 (11.6)
0 (0.0)
1 (20.0)
13 (13.5)
1 (4.3)
0.470
1 (0.8)
0 (0.0)
0 (0.0)
1 (1.0)
0 (0.0)
0.928
18 (14.0)
1 (20.0)
2 (40.0)
12 (12.5)
3 (13.0)
0.367
77 (59.7)
5 (100.0)
4 (80.0)
62 (64.6)
6 (26.1)
0.006
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); FP: family physician; PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05. a Missing data for 111 of the 129 included patients. b Missing data for 20 patients.
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Table 3 Time to PCR from inclusion and cough onset (France, 2013–2014). Délais de réalisation de la PCR par rapport à la date d’inclusion et au début de la toux (France, 2013–2014).
Inclusion-to-PCR interval (days) Mean (SD) [Range] Onset-to-PCR interval (days) Mean (SD) [Range]
Inclusion-to-PCR interval (days) Mean (SD) [Range] Onset-to-PCR interval (days) Mean (SD) [Range]
Patients analyzed (n = 106)
Large cities (n = 26)
Medium-sized cities (n = 50)
Rural areas (n = 30)
1.9 (3.3) [0.0–21.0]
2.1 (2.3) [0.0–9.0]
2.1 (4.3) [0.0–21.0]
1.5 (1.6) [0.0–5.0]
16.0 (5.2) [7.0–35.0]
16.4 (5.2) [8.0–27.0]
16.7 (5.4) [8.0–35.0]
14.5 (4.6) [7.0–24.0]
P* 0.670
0.173
Included patients (n = 129)
B. pertussis (n = 5)
Bordetella (ind.) (n = 5)
PCR– patients (n = 96)
1.9 (3.2) [0.0–21.0]
0.8 (0.5) [0.0–1.0]
4.8 (8.0) [0.0–9.0]
1.8 (2.9) [0.0–21.0]
16.0 (5.2) [7.0–35.0]
14.0 (6.1) [8.0–22.0]
20.8 (8.3) [13.0–34.0]
15.8 (4.9) [7.0 - 35.0]
P* 0.105
0.080
Bordetella (ind.): indeterminate, i.e., genetic material of Bordetella genus detected but species not identified (n = 2) or PCR+ samples not sent to the Institut Pasteur (n = 3); PCR: polymerase chain reaction; PCR–: genetic material of Bordetella genus not detected by PCR in the nasopharyngeal sample; SD: standard deviation. * Significant difference, P ≤ 0.05. Data for three patients with outlying inclusion dates has been excluded.
Table 4 Number of patients presenting with bordetellosis by geographic area (France, 2013–2014). Nombre de cas de bordetelloses identifiés en fonction de la zone géographique (France, 2013–2014).
Biological case patient, n (%) Direct epidemiological case patient, n (%) Clinical case patient, n (%) Total, n (%)
Patients analyzed (n = 106)
Large cities (n = 26)
Medium-sized cities (n = 50)
Rural areas (n = 30)
P
10 (9.4) 2 (1.9) 18 (17.0) 30 (28.3)
6 (23.1) 0 (0.0) 2 (7.7) 8 (30.8)
2 (4.0) 1 (2.0) 9 (18.0) 12 (24.0)
2 (6.7) 1 (3.3) 7 (23.3) 10 (33.3)
0.022* NS NS NS
NS: non-significant. * Significant difference by population-density areas, P ≤ 0.05.
Fig. 1. Crude incidence rate of pertussis in patients aged ≥ 50 years by geographic area (France, 2013–2014). CI: confidence interval. Taux d’incidence brut de la coqueluche chez les patients de 50 ans et plus en France selon les zones géographiques en 2013–2014.
Fig. 2. Extrapolated incidence rate of pertussis in people aged ≥ 50 years by geographic area (France, 2013–2014). CI: confidence interval. Taux d’incidence de la coqueluche extrapolé aux habitants de 50 ans et plus en France selon les zones géographiques en 2013–2014.
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4. Discussion Results of the EPICOQSEN study revealed that pertussis was present and diagnosed in patients aged ≥ 50 years consulting their FP for a 7-to-21-day history of cough; the crude incidence per 100,000 patients aged ≥ 50 years was 103.1 (95% CI: 69.9–147.9) and the extrapolated incidence per 100,000 persons aged ≥ 50 years in France was 187.1 (95% CI: 126.2–267.1). It was about two-fold higher in medium-sized cities and rural areas than in large cities. The present global incidence of pertussis is similar to that of 2008–2009 reported in a study of patients aged 14–89 years in the Paris region [7], and to that of a 2006–2008 American study of adults ≥ 50 years, but lower than in the same study data for 2009–2010 where it was 292.0/100,000 patients aged 50–64 years and 463.8/100,000 patients ≥ 65 years in 2010 [11]. None of the 10 PCR+ patients for B. pertussis or Bordetella genus and neither of the two epidemiologically confirmed patients had been vaccinated against pertussis in the 10 years preceding the study, and none reported a history of pertussis. Eleven of the 96 PCR– patients (11.5%, including one clinical case patient) reported being vaccinated since 2004 and 20 (20.8%, including five clinical case patients) reported a history of pertussis. Vaccination and natural disease thus exerted a protective effect, even if not absolute. The date of natural infection was not recorded in this study, but protection was shown to be limited in time. Although exploratory, the present study has strengths: its prospective design, the pre-established definition of case patients, and the use of a specific biological diagnostic method. Moreover, defining the observation period as a complete year took into account possible seasonal variation, and the fact that the inclusion period began more or less simultaneously for all study FPs meant that the same period of the year was covered in the three population-density areas, thus strengthening ® our results. Finally, the systematic use of the AxiSanté software package ensured homogeneity and exhaustiveness of data collection; there was also very little missing data. The study also has limitations. Fewer FPs were recruited than expected; the number of included patients was thus also lower than expected. This is perhaps due to the requirement of using ® the AxiSanté patient record management software, intended to allow easy access to the study protocol, to minimize redundant data input, and above all to have effective inclusion with the possibility of sending messages. Data input was efficient and few patients were lost to follow-up. Nevertheless, further results obtained in a larger study are required to support these results. With a mean age of 47.0 years, the study FPs were younger than the mean age of the 25,202 FPs in the three study areas as a whole (mean age: 55.1 years; data not shown). This might suggest a recruitment bias. The number of patients discontinuing the study or for whom no swab was taken was small but not exactly negligible (n = 23; 17.8% of included patients). Comparing this subgroup with the group of patients analyzed was thus important. The demographic characteristics of included patients revealed that patients prematurely withdrawn mainly lived in large cities and were relatively older, which may represent an attrition bias.
Cough characteristics were, however, comparable to those of analyzed patients, although they less frequently led to suspicion of pertussis. Finally, the number of pertussis case patients was lower than in previous years [12]; pertussis is a cyclical disease and, despite the lower rate observed during the study period, case patients were observed in all three population-density areas. The number of PCR+ patients was lower than expected, which is a further study limitation. PCR shows high sensitivity, but diminishing over time: beyond 21 days, PCR results for Bordetella are negative [13]. In the present study, the maximum interval between cough onset and nasopharyngeal swab analysis in patients presenting with B. pertussis infection confirmed by PCR was 22 days, compared with 34 days for Bordetella-indeterminate patients (i.e., genetic material of Bordetella genus detected but species not identified [n = 2] or PCR+ samples not sent to the Institut Pasteur [n = 3]) and 35 days for PCR– patients (i.e., genetic material of Bordetella genus not detected by PCR). This delay probably accounts for some PCR– results. B. pertussis failed to be identified in two samples due to lack of genetic material despite highly suggestive clinical findings. Patients presenting with persisting cough for > 21 days or aggravated chronic cough for > 21 days were not eligible; even so, several included patients had delayed nasopharyngeal swab, which may have led to underestimate the incidence of pertussis. It is important to note that FPs suspected pertussis in all patients in whom PCR confirmed B. pertussis and 80% of those in whom Bordetella was confirmed: i.e., 90.0% of PCR+ patients versus 64.6% of PCR– patients and 26.1% of those who discontinued the study. 5. Conclusion Pertussis is a frequent cause of persistent cough in adults aged 50 years or older. This may be due to the limited protection time afforded by vaccination and also by the natural infection. Patients aged over 50 years may constitute a reservoir for B. pertussis circulation and should be taken into account for booster vaccination programs, like healthcare professionals who have to be vaccinated every 20 years (at the age of 25, 45, and 65 years) as part of the diphtheria–tetanus–polio (DTpolio) booster. Prior peer-reviewed presentation at a professional/scientific conference Presented at the Journées Nationales d’Infectiologie June 2017. Funding The study was co-funded by Sanofi Pasteur-MSD (AnneCarole Jacquard) and GSK (Céline Pribil). The sponsors were not involved in the content of the present article. Contribution of authors Study design and data analysis and interpretation was performed by all authors. N.G. wrote the article and all authors reviewed it. All authors read and approved the article.
Please cite this article in press as: Guiso N, et al. Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.09.002
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Disclosure of interest J.G.: remuneration as member of the scientific committee for EPICOQSEN study for GSK and Sanofi Pasteur-MSD. J.-L. G. declares that he has no competing interest. G.G.: remuneration as speaker at conferences on “vaccination in the elderly” for Sanofi Pasteur-MSD. D.P.: remuneration as member of the scientific committee for EPICOQSEN study for GSK and Sanofi Pasteur-MSD; invitation as a speaker or an auditor at scientific conferences on vaccination for GSK and Sanofi Pasteur-MSD. N.G. declares that he has no competing interest before April 2015. As of April 2015, remuneration as participant in a “master class” for Sanofi Pasteur-MSD and in expert boards for GSK and Bionet Asia. Acknowledgments The authors would like to thank the family physicians who took part in the study, IMS Health (for the study), and Abelia Science (for the article). They would also like to thank Sandra Corre for performing PCR analyses at the Institut Pasteur, and the French Infectious Diseases Society (French acronym SPILF) for their support. References [1] Tubiana S, Belchior E, Guillot S, Guiso N, Lévy-Bruhl D, Renacoq Participants. Monitoring the impact of vaccination on pertussis in infants using an active hospital-based Pediatric Surveillance Network: results from 17 years’ experience, 1996–2012, France. J Pediatr Infect Dis 2015;34(8):814–20. [2] Wiley KE, Zuo Y, Macartney KK, McIntyre PB. Sources of pertussis infection in young infants: a review of key evidence informing targeting of the cocoon strategy. Vaccine 2013;31:618–25.
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[3] Anonyme. Calendrier des vaccinations et recommandations vaccinales. Ministère des Affaires Sociales et de la Santé; 2016 http://social-sante.gouv. fr/IMG/pdf/calendrier vaccinal 2016.pdf (Accessed October 10, 2016). [4] Baron S, Njamkepo E, Grimprel E, Begue P, Desenclos JC, Drucker J, et al. Epidemiology of pertussis in French hospitals in 1993 and 1994: thirty years after a routine use of vaccination. J Pediatr Infect Dis 1998;17:412–8. [5] Guiso N, Njamkepo E, Vie Le Sage F, Zepp F, Meyer Cu, Abitbol V, et al. Long-term humoral and cell-mediated immunity after acellular pertussis vaccination compares favourably with whole-cell vaccines 6 years after booster vaccination in the second year of life. Vaccine 2007;25(8): 1390–7. [6] Gilberg S, Njamkepo E, Du Châtelet IP, Partouche H, Gueirard P, Ghasarossian C, et al. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J Infect Dis 2002;186(3):415–8. [7] Lasserre A, Laurent E, Tuberlin C, Hanslik T, Blanchon T, Guiso N. Pertussis incidence among adolescents and adults surveyed in general practices in the Paris area, France May 2008 to March 2009. Euro Surveill 2011;16(5) [pii:19783]. [8] Succo T, Braunstein D, Desmons S, Sampol P, Belchior E, Guiso N, et al. Épidémie de coqueluche dans un établissement d’hébergement pour personnes âgées dépendantes Bouches-du-Rhône, août 2013. Bull Epidemiol Hebd 2015;5:83–8. [9] Njamkepo E, Bonacorsi S, Debruyne M, Gibaud SA, Guillot S, Guiso N. Significant finding of Bordetella holmesii DNA in nasopharyngeal samples from French patients with suspected pertussis. J Clin Microbiol 2011;49(12):4347–8. [10] Tizolova A, Brun D, Guiso N, Guillot S. Development of real-time PCR assay for differential detection of Bordetella bronchiseptica and Bordetella parapertussis. Diagn Microbiol Infect Dis 2014;78(4):347–51. [11] Masseria C, Krishnarajah G. The estimated incidence of pertussis in people aged 50 years old or older in the United States, 2006–2010. BMC Infect Dis 2015;15:534. [12] Anonyme. Rapport annuel d’activité Année d’exercice 2014. Centre national de référence de la coqueluche et autres bordetelloses; 2015 https://www.pasteur.fr/sites/www.pasteur.fr/files/rapport cnrcoqr-exercice 2014.pdf (Accessed October 10, 2016). [13] Riffelmann M, Wirsing von König CH, Caro V, Guiso N, Pertussis PCR, Consesus Group. Nucleic acid amplification tests for diagnosis of Bordetella infections. J Clin Microbiol 2005;43(10):4925–9.
Please cite this article in press as: Guiso N, et al. Incidence of pertussis in subjects aged 50 years and older in France in 2013–2014. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.09.002