Prospective pertussis surveillance in Switzerland, 1991–2006

Vaccine 29 (2011) 2058–2065

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Prospective pertussis surveillance in Switzerland, 1991–2006 Monica N. Wymann a , Jean-Luc Richard a , Beatriz Vidondo a , Ulrich Heininger b,∗ a b

Federal Office of Public Health, Berne, Switzerland University Children’s Hospital, Basel, Switzerland

a r t i c l e

i n f o

Article history: Received 12 November 2010 Received in revised form 5 January 2011 Accepted 7 January 2011 Available online 18 January 2011 Keywords: Pertussis Sentinel surveillance system Age distribution Vaccination status Switzerland

a b s t r a c t Pertussis has been monitored in Switzerland since 1991 by the nationwide Swiss Sentinel Surveillance Network (SSSN), consisting of approximately 200 general practitioners, internists and pediatricians representing about 3% of the total primary care physicians of these specialities. SSSN members report patients with cough ≥14 days plus either an epidemiological link or characteristic symptoms (paroxysms, whoop, post-tussive vomiting) on a weekly basis to the Federal Office of Public Health. Confirmatory PCR from nasopharyngeal specimens is offered for free. A total of 4992 cases have been reported until 2006. Yearly incidence has dropped from 70 cases per 100,000 inhabitants in 1992 to 40 in 2006, with a single epidemic in 1994–1995 with 280–370 cases/100,000. On average 80% of reported cases were tested by PCR, 24% of these were confirmed as Bordetella pertussis infections. For 2.6% of patients complications were reported, most commonly pneumonia, asthma bronchiale, otitis media, bronchitis and rib fractures. On average, 1.5% of patients were hospitalized. Disease in vaccinated patients was mitigated with less frequent complications (unvaccinated: 5.1%; 3 doses: 3.0%; ≥4 doses: 1.7%), hospitalizations (unvaccinated: 3.6%; ≥1 dose: 1.1%) and various clinical symptoms compared to unvaccinated patients. Comparing the periods 1991–1996, 1997–2001 and 2002–2006, a shift of pertussis from age group 1–9 years to 10–19 and ≥40 years was observed among patients cared for by general practitioners and internists. The benefits of further booster doses in adolescents and/or adults need to be considered. © 2011 Elsevier Ltd. All rights reserved.

1. Introduction Pertussis, caused by the gram-negative bacterium Bordetella pertussis, occurs endemically worldwide. According to the current Swiss vaccination schedule primary vaccination with acellular pertussis component vaccines is recommended at age 2, 4 and 6 months followed by two booster doses at age 15–24 months and 4–7 years [1]. This highly communicable disease had been mandatory reportable in Switzerland from 1943 to 1973. After nearly 20 years of interruption in reporting, it has been monitored again from June 1991 onwards by the Swiss Sentinel Surveillance Network (SSSN). Here, after 15 years of surveillance by the SSSN, we report trends in pertussis incidence, age distribution, and vaccination status. 2. Methods 2.1. Swiss Sentinel Surveillance Network (SSSN) The SSSN consists of approximately 200 (range: 146–242 for the 1991–2006 period) primary care physicians (general practi-

∗ Corresponding author at: University Children’s Hospital (UKBB), P.O. Box CH4031, Basel, Switzerland. Tel.: +41 61 704 2909; fax: +41 61 704 1213. E-mail address: [email protected] (U. Heininger). 0264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.01.017

tioners, internists and pediatricians), who account for about 3% of the total physicians of these specialties in Switzerland. The average proportion of pediatricians for the whole period was 12.2% (range: 7.7–16.3%). These physicians cover about 3.5% of the annual number of all physician consultations in private practice. Participation in the SSSN is voluntary and each year a part of participants is replaced by new physicians [2]. The Federal Office of Public Health (FOPH) aims at selecting representative participants for the SSSN with regards to region of practice, primary care specialty as mentioned above, and sex. However, out-patient departments of hospitals are not included. The SSSN members report the number of first consultations for a selected number of conditions, including pertussis, weekly to the FOPH. 2.2. Case definition The case definition used by the SSSN for pertussis is a cough lasting for ≥14 days with either (1) an anamnestic epidemiological link to another clinical case or laboratory confirmed pertussis case (epidemic case) or (2) at least one of the following symptoms: paroxysmal cough, wheezing inspiration (whoop) or post-tussive vomiting (sporadic case). All cases corresponding to the epidemic or the sporadic case definition are to be reported. In addition, physicians may report cases of pertussis based on their clinical judgment, even if duration of cough is <14 days, in agreement with the per-

2305 (46.2)

1084 (21.7)

48 (41.0)

36 (30.8)

66 (42.3)

38 (24.4)

2.3. Laboratory diagnosis Since 1994, the FOPH has offered a PCR (polymerase chain reaction) test based on nasopharyngeal specimens free of charge to SSSN members to confirm the clinical diagnosis [4]. PCR tests have been performed in the same laboratory (University Children’s Hospital Basel) for the whole study period. Oligonucleotide primers pTp1 and pTp2, which amplify a 191 bp sized DNA fragment from the pertussis toxin operon were used for demonstration of B. pertussis infection [5] and specific primers for insertion sequence 1001 were used for demonstration of Bordetella parapertussis infection.

59 (34.3) 45 (21.7)

2.4. Data analyses

SSSN surveillance for pertussis started in June 1991. a

29 (19.9) 15 (20.0)

17 (12.0)

167 (19.0)

146 (22.4)

97 (25.5)

74 (15.5)

110 (26.1)

86 (19.5)

62 (18.2)

65 (27.7)

65 (37.8) 162 (47.5) 106 (45.1) 97 (46.9) 214 (48.4) 179 (42.5) 255 (53.6) 157 (41.3) 279 (42.9) 438 (49.8) 69 (47.3) 69 (48.6) 37 (49.3)

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tussis clinical case definition recommended by WHO [3]. For each reported case, the reporting physician receives a complementary anonymous questionnaire to fill in information about the patient’s pertussis vaccination history, specific symptoms, occurrence of complications, the possible source of infection and demographics.

38 (25.2)

1251 (25.1) 22 (18.8) 41 (26.3) 35 (20.3) 42 (20.3) 47 (32.2) 13 (17.3)

47 (33.1)

229 (26.1)

185 (28.4)

95 (25.0)

119 (25.0)

100 (23.8)

106 (24.0)

85 (24.9)

52 (22.1)

64 (42.4)

351 (7.0) 11 (9.4) 11 (7.1) 13 (7.6) 23 (11.1) 1 (0.7) 10 (13.3)

9 (6.3)

45(5.1)

41 (6.3)

31 (8.2)

28 (5.9)

32 (7.6)

36 (10.6)

32 (9.4)

12 (5.1)

33 (21.9)

126 40 57 53 71 370 70 70

70

280

165

185

180

155

105

80

75

16 (10.6)

144,800 3000 3900 5200 26,000 5000 5000

5000

20,000

11,500

13,000

13,000

11,000

7500

6000

5500

4200

Total

4’992

2006 2005 2004

151

2003

172

2002

207 235

2001 2000

342 442

1999 1998

421 476

1997 1996

380 651 879 146

1995 1994 1993

142

1992 1991a

75

N clinical cases reported Estimated total annual number of clinical cases in Switzerland Estimated annual incidence (rate per 100,000) N with age <1 year (%) N with age 1–4 years (%) N with age 5–19 years (%) N with age ≥20 years (%)

Table 1 Cases of pertussis reported in the Swiss Sentinel Surveillance Network, 1991–2006.

156

117

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Only cases from physicians with consistent reporting (at least during 39 weeks/year, i.e. ≥75% of the yearly reporting period) were used for analysis.The annual age specific incidence of pertussis was extrapolated from SSSN data by multiplying the number of reported cases by the proportion of SSSN consultations among the nationwide total of consultations conducted by primary care physicians. These calculations were stratified by region and physician specialty. The number of consultations by region and physician specialty was provided weekly by SSSN, while the corresponding data for the whole of Switzerland were supplied by santésuisse, the association of the Swiss health insurance companies. The effect of pertussis vaccination status (unvaccinated, vaccinated with ≥1 dose, vaccinated with other dose cut-offs) on occurrence of complications, hospitalizations, and the occurrence of clinical symptoms was analyzed using Fisher’s exact Chi-square tests. Frequencies of symptoms were compared between hospitalized and ambulatory cases using Fisher’s exact Chi-square tests. Fisher’s exact Chi-square tests were also used to test for a difference in the PCR confirmation rate between sporadic and epidemic pertussis cases and between cases occurring during an epidemic or an inter/post-epidemic period. The influence of different factors on results of pertussis PCR tests were analyzed using multiple logistic regression models. The variables considered were clinical symptoms (presence/absence of a cough ≥14 days duration, paroxysms of coughing, post-tussive vomiting, wheezing inspiration, whooping cough, cyanosis, dyspnea, fever and rhinitis), contact to a pertussis case (yes/no), age category (<1 year, 1–5 years, 6–19 years, ≥20 years), sex (male/female), region (West, Central West, North, Center, North East, and South East of Switzerland), number of doses of a pertussis component vaccine and epidemic year for pertussis (1994–1995 versus 1996–2006). 3. Results From June 1991 to December 2006, a total of 4992 cases of pertussis were reported via the SSSN. Of these, 2383 (47.7%) fulfilled the sporadic case definition; 879 (17.6%) the epidemic case definition; 1730 (34.7%) fulfilled neither. Of these, 917 (53.0%) cases had a cough lasting <14 days at time of consultation, of which 376 (41.0%) had nevertheless an epidemiological link to another pertussis case, 774 (44.7%) cases had an unknown length of the cough, and 39 (2.3%) had a cough lasting ≥14 days but without any other symptoms or contact with another case. The estimated incidence of all reported pertussis cases in Switzerland decreased from 70 cases/100,000 inhabitants in 1992

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2.50

250 PCR negative cases PCR positive cases Clinical cases of pertussis per 1000 consultations and month

200

1.50

150

1.00

100

0.50

50

0.00 1991

Number of PCR

Cases per 1000 consultations

2.00

0 1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

Year Fig. 1. Monthly reports of pertussis cases and results of PCR tests, SSSN 1991–2006.

to 40/100,000 in 2006, interrupted by a single epidemic in 1994–1995 with 280–370 cases/100,000 inhabitants (Table 1 and Fig. 1). Although the lack of appropriate denominators does not allow the calculation of age dependent disease incidences, with approximately a third of all cases occurring in children up to 4 years of age it is obvious that incidence must be highest among infants and young children. Since 1994, nasopharyngeal specimens from 3721 (80.4%) of 4629 reported cases have been tested for B. pertussis and B. parapertussis by PCR and 904 (24.3%) of these were positive for B. pertussis by PCR (Table 2 and Fig. 1). For 4225 (84.6%) of 4992 cases pertussis vaccination status was known (Table 3). A history of pertussis immunization was reported in 3362 (79.6%) of them, of which the number of vaccine doses was known in 2619 (77.9%) and most of these had received 3 doses (72.0%). Among patients aged between 3 months and 19 years with a known vaccination status including the number of doses administered, only 702 (23.3%) were fully vaccinated for their age according to the current Swiss vaccination plan. With only 14.9% this proportion was particularly low for those older than 24 months, for which 4 or 5 doses of a pertussis component vaccine are recommended depending on age. The proportion of PCR tested cases that were positive was more than twice as high for cases fulfilling the epidemic case definition than for cases fulfilling the sporadic case definition (276 of 685, 40.3% versus 378 of 2038, 18.5%; p < 0.001). Even for tested cases fulfilling neither the epidemic nor the sporadic case definition due to a cough lasting less than 14 days, the proportion of PCR positive cases was higher in cases with a reported contact compared to those without a contact (118 of 312, 37.8% versus 92 of 452, 20.4%; p < 0.001). The proportion of PCR positive cases among tested cases is comparable for cases corresponding to the sporadic or the epidemic case definitions, and for cases fulfilling neither case definitions (654 of 2723, 24.0% versus 250 of 998, 25.1%; p = 0.5). Moreover, PCR was more often positive for cases with a cough lasting less than 14 days than for cases with a cough lasting ≥14 days (224 of 796, 28.1% versus 656 of 3555, 24.8%; p = 0.013) at the time of specimen collection. Finally, the proportion of PCR confirmed cases among tested cases was higher during the epidemic in 1994–1995 than during the post/inter-epidemic years 1996–2006 (350 of 1265, 27.7% versus 554 of 2456, 22.6%; p = 0.001). This was

observed for cases fulfilling the epidemic case definition (134 of 288, 46.5% versus 142 of 397, 35.8%; p = 0.006) but not for cases fulfilling the sporadic case definition (132 of 634, 20.8% versus 246 of 1404, 17.5%; p = 0.085). Overall, cases cared for by pediatricians were more likely to be PCR positive than cases cared for by general practitioners or internists (571 of 1851 = 30.8% versus 287 of 1419 = 20.2%, p < 0.001). A positive PCR test was associated with pertussis vaccination status: when tested, after logistic regression, PCR on specimens of patients vaccinated with ≥3 doses was significantly less often positive compared with specimens of unvaccinated patients (OR = 0.4 for 3 doses, 95% CI 0.3–0.6; p < 0.001; OR = 0.3 for 4 doses, 95% CI 0.2–0.4; p < 0.001; OR = 0.3 for ≥5 doses, 95% CI 0.1–0.7; p = 0.004). The trend was the same for 1 and 2 doses, but not statistically significant. Contact to a pertussis case was also associated with a positive PCR test (OR = 2.1, 95% CI 1.7–2.6; p < 0.001). Compared with <1 year-old patients, PCR was more likely to be positive in patients 1–4 years of age (OR = 1.7, 95% CI 1.1–2.7; p = 0.025) or 5–19 years of age (OR = 2.3, 95% CI 1.5–3.7; p < 0.001). When we used <6 month-old patients as the reference, the OR for a positive PCR was 0.5 (p = 0.08) for those 6–11 months old, 1.3 (p = 0.5) for those 1–4 years old, 1.7 (p = 0.07) for those 5–19 years old and 0.6 (p = 0.09) for those ≥20 years of age. Further, PCR was more likely to be positive for patients living in the north eastern (OR = 1.4, 95% CI 1.0–1.9; p = 0.039) and south eastern (OR = 2.0, 95% CI 1.3–3.1; p = 0.001) parts of Switzerland, compared with the western part. In contrast tests were less likely to be positive for patients living in the northern part of the country (OR = 0.5, 95% CI 0.4–0.8; p = 0.002). Some signs and symptoms typical for pertussis were significantly associated with a positive PCR test: wheezing inspiration (OR = 2.1, 95% CI 1.6–2.6; p < 0.001), cyanosis (OR = 1.5, 95% CI 1.0–2.2; p = 0.046), and rhinitis (OR = 0.6, 95% CI 0.5–0.8; p < 0.001), whereas paroxysmal cough (OR = 1.9, 95% CI 0.9–3.8; p = 0.072) and post-tussive vomiting (OR = 1.2, 95% CI 0.9–1.5; p = 0.076) were less strongly associated with a positive PCR. During the study period, a shift towards older age of patients with pertussis cared for by general practitioners or internists (N = 2487) was observed (Fig. 2). Median age of cases was 11, 12,

4629 3721 (80.4) 904 (24.3) 25,400 27 117 95 (81.2) 23 (24.2) 600 8 Identification of Bordetella pertussis in naso-pharyngeal specimens by PCR. Rate per 100,000. a

Estimated total PCR confirmed cases Estimated annual incidence of PCR confirmed casesb

N (%) with positive PCR

b

2006

151 131 (86.8) 41 (31.3) 1100 14 172 151 (87.8) 32 (21.2) 1000 13

2005 2004 2003

207 175 (84.5) 38 (21.7) 1000 14

2002 2001

235 185 (78.7) 55 (29.7) 1400 19 342 280 (81.9) 63 (22.5) 1400 19

2000 1999

442 330 (74.7) 73 (22.1) 1800 25 421 328 (77.9) 65 (19.8) 2000 28

1998

Fig. 2. Age distribution of pertussis patients reported by general practitioners and internists during the time periods 1991–1996, 1997–2001 and 2002–2006, SSSN (N = 4991).

476 351 (73.7) 76 (21.7) 2100 29

1997 1996

380 294 (77.4) 58 (19.7) 1800 25 651 546 (83.9) 105 (19.2) 3200 46

1995 1994

879 719 (81.8) 245 (34.1) 7200 103 N clinical cases reported N (%) with PCR result availablea

Table 2 Cases of PCR confirmed pertussis reported in the Swiss Sentinel Surveillance Network, 1994–2006.

2061

156 136 (87.2) 30 (22.1) 800 11

Total

M.N. Wymann et al. / Vaccine 29 (2011) 2058–2065

and 23 years for the time periods 1991–1996, 1997–2001 and 2002–2006, respectively, with a significant decrease in the proportion of cases in age groups 1–4 and 5–9 years and a significant increase in age groups 10–19 and ≥40 years between the last two periods. No such age shift was found for patients treated by pediatricians (N = 2504, median age 63, 63 and 58 months, respectively for the three time periods). Signs and symptoms of pertussis by age groups and pertussis immunization status are presented in Table 4. Almost all patients presented with paroxysmal cough while other typical signs or symptoms for pertussis were less frequent in all age groups. Of note, frequencies of paroxysms, sleeping difficulties and fever were independent of patient age, whereas dyspnea and cyanosis were more frequently present in infants compared to older children and adolescents and, for cyanosis, also when compared to adults. A history of immunization with ≥1 dose of pertussis component vaccine was associated with reduced severity of disease, mainly due to lower rates of cyanosis, whooping, and wheezing inspirations in infants and children. In 128 (2.6%) of 4992 patients complications were reported and these were specified in 65 cases: pneumonia (n = 21), asthma bronchiale (n = 11), otitis media (n = 8), bronchitis (n = 8), rib fracture (n = 6), thorax pain (n = 4), apnea (n = 2), extensive vomiting (n = 2), sinusitis (n = 1), respiratory insufficiency (n = 1), and conjunctival bleeding (n = 1). Vaccination history was known for 117 of the 128 patients with reported complications. Overall, unvaccinated patients had a higher risk of developing complications than vaccinated patients: 40 (5.1%) of 777 versus 77 (2.8%) of 2706; p = 0.002. This was also observed as a trend in all age categories but without statistical significance (data not shown). Further, the risk of complications decreased with increasing number of pertussis component vaccine doses from 5.1% in unvaccinated patients to 3.0% and 1.7% in individuals with 3 (48 of 1606; p = 0.009) and ≥4 doses (8 of 481; p = 0.02), respectively. No effect of 1 or 2 doses in reducing complications could be shown (10 of 177, 5.6%; p = 0.8). Of the 4992 reported cases, 74 (1.5%) patients were hospitalized. The annual proportion of hospitalized patients ranged from 0% to 2.7%. For 69 (93%) of the hospitalized patients pertussis vaccination status was known. The proportion of hospitalization was lower in vaccinated patients (≥1 dose) than in unvaccinated patients (38 of 3362, 1.1% versus 31 of 863, 3.6%; p < 0.001). The following signs and symptoms were more frequent in hospitalized versus ambulatory cases: wheezing inspiration (43% versus 27%; p = 0.005), cyanosis

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Table 3 Pertussis vaccination status by age category, 1991–2006, Swiss Sentinel Surveillance Network. Age

N cases per age categorya

Vaccination status

N vaccinated cases with known number of vaccine doses

N unknown

N not vaccinated

N vaccinated (≥1 dose)

Number of vaccine doses 1

2

69

9

51 85.0%

9 15.0%

7

6 85.7%

1 14.3%

3

4

≥5

3–4 months

94

6

20 22.7%

68 77.3%

62

46 74.2%

16 25.8%

0 0.0%

0 0.0%

0 0.0%

1 or 2 doses 77.3%

5–6 months

66

5

14 23.0%

47 77.0%

40

9 22.5%

18 45.0%

13 32.5%

0 0.0%

0 0.0%

2 or 3 doses 57.4%

7–24 months

407

29

88 23.3%

290 76.7%

246

7 2.8%

13 5.3%

199 80.9%

27 11.0%

0 0.0%

3 or 4 doses 67.7%

25–47 months

637

51

116 19.8%

470 80.2%

394

6 1.5%

12 3.01%

236 59.9%

140 35.5%

4–7 years

1325

81

176 14.1%

1068 85.9%

907

11 1.2%

26 2.9%

673 74.2%

176 19.4%

21 2.37%

4 or 5 doses 18.2%

8–19 years

1309

104

114 9.5%

1091 90.5%

831

21 2.5%

18 2.2%

658 79.2%

94 11.3%

40 4.8%

5 doses 4.2%

≥20 years

1084

481

284 47.1%

319 52.9%

132

1 0.8%

3 2.3%

107 81.1%

17 12.9%

4 3.0%

Total

Not applicable

4991

766

863 20.4%

3362 79.6%

2619

107 4.1%

107 4.1%

1886 72.0%

454 17.3%

65 2.5%

702 23.3%

4 doses 27.5%

Of 4992 cases reported, age was unknown in one patient. Primary vaccination at age 2, 4 and 6 months, booster doses at age 15–24 months and 4–7 years. The second booster dose was introduced in 1996 without a catch-up vaccination program. Patients with unknown vaccination status or number of doses were not included in percent calculations. b

M.N. Wymann et al. / Vaccine 29 (2011) 2058–2065

≥1 0–2 months

a

Percentage of patients <20 years fulfilling the Swiss vaccination planb

M.N. Wymann et al. / Vaccine 29 (2011) 2058–2065

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Table 4 Signs and symptoms of pertussis cases by age groups and pertussis immunization status, 1991–2006, Swiss Sentinel Surveillance Network (N = 4991). Signs or symptoms

Present

Absent

N

%c

N

%c

Unknowna

Present in vaccinated (≥1 dose) cases

Present in unvaccinated cases

N

%

%

P Valueb

Paroxysmal cough

<1 year 1–4 years 5–19 years ≥20 years Total

291 1014 1897 900 4102

95.7 97.1 97.5 97.0 97.2

13 30 49 28 120

4.3 2.9 2.5 3.0 2.8

47 207 359 156 769

96.3 97.5 97.6 98.2 97.5

94.4 96.4 96.4 97.2 96.4

0.56 0.35 0.28 0.58 0.07

Sleeping difficulties

<1 year 1–4 years 5-19 years ≥20 years Total

264 929 1701 803 3697

88.9 90.8 89.1 88.0 89.3

33 94 209 109 445

11.1 9.2 10.9 12.0 10.7

54 228 395 172 849

88.7 90.7 89.7 87.8 87.8

88.5 91.2 86.0 90.3 90.3

1.00 0.89 0.10 0.41 0.61

Whooping

<1 year 1–4 years 5–19 years ≥20 years Total

181 735 1414 513 2843

62.0 72.3 74.1 57.1 69.1

111 282 494 386 1273

38.0 27.7 25.9 42.9 30.9

59 234 397 185 875

56.3 67.6 72.7 51.1 68.2

70.9 88.9 84.2 62.4 76.6

0.02 ≤0.001 ≤0.001 0.01 ≤0.001

Rhinitis

<1 year 1–4 years 5–19 years ≥20 years Total

243 746 1242 565 2796

83.2 73.4 65.6 62.8 68.2

49 270 652 334 1305

16.8 26.6 34.4 37.2 31.8

59 235 411 185 890

80.2 70.3 65.3 66.0 67.7

88.5 83.7 66.8 65.2 73.3

0.10 ≤0.001 0.66 0.86 0.02

Post-tussive vomiting

<1 year 1–4 years 5–19 years ≥20 years Total

167 656 1154 408 2385

57.6 64.1 60.4 45.0 57.7

123 367 757 499 1746

42.4 35.9 39.6 55.0 42.3

61 228 394 177 860

59.3 62.9 60.9 46.1 60.0

54.5 67.0 57.1 41.0 54.1

0.45 0.30 0.26 0.26 0.03

Fever

<1 year 1–4 years 5–19 years ≥20 years Total

122 432 726 387 1667

43.7 45.4 42.1 45.8 43.8

157 520 1000 458 2135

56.3 54.6 57.9 54.2 56.2

72 299 579 239 1189

45.1 45.1 42.1 43.3 43.3

40.8 45.5 38.3 48.1 43.8

0.53 0.94 0.30 0.29 0.80

Wheezing inspiration

<1 year 1–4 years 5–19 years ≥20 years Total

100 345 558 123 1126

34.2 34.1 29.4 13.8 27.5

192 667 1337 769 2965

65.8 65.9 70.6 86.2 72.5

59 239 410 192 900

30.6 28.5 27.5 13.9 26.7

41.7 53.5 43.8 17.5 37.5

0.07 ≤0.001 ≤0.001 0.29 ≤0.001

Dyspnea

<1 year 1–4 years 5–19 years ≥20 years Total

97 201 376 262 936

33.6 20.1 19.9 29.4 23.0

192 799 1517 630 3138

66.4 79.9 80.1 70.6 77.0

62 251 412 192 917

31.9 19.7 19.7 25.9 21.1

39.0 21.4 19.4 35.4 27.6

0.30 0.62 1.00 0.02 ≤0.001

Cyanosis

<1 year 1–4 years 5–19 years ≥20 years Total

62 87 122 32 303

21.5 8.6 6.5 3.6 7.4

227 926 1767 854 3774

78.5 91.4 93.5 96.4 92.6

62 238 416 198 914

17.5 7.4 5.6 2.3 6.6

30.0 13.3 11.3 4.8 12.0

0.02 0.01 0.002 0.16 ≤0.001

a b c

Clinical details were not requested for the 363 cases reported between 1991 and 1993 and missing in variable numbers of cases reported between 1994 and 2006. Comparing presence in vaccinated and unvaccinated cases (Fisher’s exact Chi-square test). Proportions of cases with known absence or presence of respective signs and symptoms.

(48% versus 7%; p ≤ 0.001), catarrhal symptoms (85% versus 68%; p = 0.003) and dyspnea (65% versus 22%; p ≤ 0.001). The majority of hospitalized patients were children and their median age was 5 months compared to 90 months for all cases. In infants (age <12 months), proportions of hospitalizations decreased by increasing age: 23.7% (0–1 month), 22.6% (2–3 months), 16.2% (4–5 months), and 2.6% (6–11 months). In the Swiss mortality statistics, period 1995–2006, three infant deaths have been attributed to pertussis but none of them had occurred in a sentinel case. Based on incidence rates calculated in this study, the estimated total number of pertussis cases in Switzerland between 1995 and 2006 was 104,600 cases, resulting in an overall fatality rate of 0.003%.

4. Discussion Here we report results from 16 ongoing years of prospective pertussis surveillance in Switzerland by use of a sentinel physician network. Although the overall annual estimated incidence decreased by almost 50% during the study period, it is still considerably higher [6–8] than or close to [9] figures reported from other European national surveillance systems in recent years. This heterogeneity can be explained by multiple factors including variability in pertussis immunization schedules and coverage rates as well as data collection systems and case verification (surveillance of the general population, sentinel surveillance, serology based surveillance, case defi-

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nitions and/or laboratory tests, voluntary versus mandatory notifications) [10,11]. In the absence of immunization programs, pertussis occurred in epidemic cycles every 2–5 years [12]. This pattern was also found in Switzerland during the period 1943–1977 when pertussis was part of the mandatory reporting system [13]. Since restarting surveillance in 1991, a single epidemic has been recorded during 1994–1995. Since then, a steadily decreasing number of pertussis cases and 15 years without a new epidemic wave have been observed until today. Although increases in incidences of pertussis have been reported from other European countries, continuation of pre-immunization era epidemic cycles has not been observed [9,14]. Because of the gap in surveillance between 1977 and 1991, the precise development of epidemic pertussis cycles in Switzerland is difficult to assess. However, the time-span of 15 years since the last epidemic is certainly longer than the expected cycle rhythm. The documented recent decrease in the number of reported pertussis cases is a success that can be attributed to the high pertussis vaccination coverage in children achieved in Switzerland. During 2005–2007, 93.9% of toddlers aged 24–35 months were vaccinated with ≥3 doses and 89.5% of children aged 8 years with 4 doses of pertussis component vaccine [15]. However, the achieved reduction of pertussis incidence should not deflect from the fact that current pertussis vaccination coverage in children and adolescents in Switzerland is still suboptimal, especially with regards to booster doses and timely administration of recommended doses. In this respect it is noteworthy that the median age of cases treated by general practitioners and internists increased from 11 to 23 years when comparing the time periods 1991–1996 and 2002–2006. Possibly, increased awareness among these physician groups that pertussis is not an exclusive childhood disease may explain this observation. Based on the basic reproductive rate of pertussis, to achieve full protection through herd immunity, 92–95% of the population need to be immune [16]. This can hardly be achieved by vaccination of children only because pertussis vaccine efficacy is approximately 90%. The concept of herd immunity is further complicated in the case of pertussis by the fact that both naturally acquired and vaccine induced immunity decrease over time. Duration of immunity after natural B. pertussis infection is estimated to last 7–20 years and that acquired through vaccination is estimated to last for 4–12 years [17]. A 4th (at 15–24 months of age) and 5th dose (at 4–7 years) have been introduced in the Swiss vaccination schedule in 1996. Currently, vaccination coverage for the 5th dose (70.6% in children aged 8 years) is still far away from the target [15]. Furthermore, even if a high coverage was reached in children, herd immunity would not be gained without booster doses in the adult population [18]. The aim of the Swiss immunization program is therefore not eradication of pertussis but to control the disease (and thereby protect the most vulnerable parts of the population) and to reduce severity of disease in vaccinated individuals. Our analysis has confirmed that breakthrough disease in vaccinated individuals is mitigated, i.e. less frequent occurrence of typical signs and symptoms and a lower rate of complications [19]. As a consequence, hospitalizations due to pertussis occur also less frequently in vaccinated than in unvaccinated individuals. In addition, since initiation of the Swiss national pertussis immunization program, deaths due to pertussis have become very rare. Before introduction of pertussis vaccination, an annual average of 91 deaths had been registered between 1931 and 1950 (among 4.1–4.7 million inhabitants). After the introduction of vaccination, the number dropped to 14 deaths in the period 1951 to 1970 (4.7–6.3 million), 6 deaths in the period 1971–1990 (all cases aged <12 months; 6.2–6.8 million inhabitants) and in recent years three deaths have occurred in infants, all aged 1–2 months (1997/1998/2001; 7.0–7.5 million inhabitants) [13]. However, fur-

ther deaths due to unrecognized pertussis may have occurred. With consequent application of available diagnostic tools not limited to PCR but including sensitive serological assays in infants suffering from fatal respiratory tract disease and in cases of sudden infant death, deaths caused by pertussis can be revealed which would otherwise remain undetected [20–23]. Confirmation of pertussis by PCR is an important feature of surveillance systems as the pure clinical case definition recommended by WHO has been shown to be of limited specificity [24]. As expected, the proportion of positive PCR was higher for cases with an epidemiological link (epidemic cases) compared to sporadic cases and it was also higher during the epidemic of 1994–1995 (but not significantly according to the logistic regression). Not surprisingly, the probability of being PCR positive tends to decrease with the increasing number of doses received suggesting a vaccine effectiveness increasing with the number of pertussis doses. The presence of most typical symptoms of pertussis was also associated with a positive PCR, except for a cough lasting ≥14 days. Maybe such indicator is not predictive of a laboratory confirmation because it does not always reflect the final length of cough. The majority of cases are indeed reported after the first consultation, sometimes before a two weeks course of the illness. Further, there were differences in the probability of being PCR positive by age groups and region for which we have no ready explanation. One may speculate on regional differences in pertussis incidence, possibly linked with regional differences in vaccination coverage, or the use of PCR may vary according to patient characteristics other than those controlled for in the logistic regression analysis. Most cases of severe pertussis occur in small infants and mortality in hospitalized infants can be as high as 2% [25,26]. In our study, about 25% of all infants aged less than 6 months with pertussis were hospitalized. Pertussis is commonly considered a typical childhood disease. However, the important role of pertussis in adolescents and adults has been rediscovered [19]. In our study, 21.7% of the reported cases occurred in adults ≥20 years. The true proportion could even be much higher, because adolescents and adults with B. pertussis infection often have cough without other characteristic symptoms [19,27]. Specifically, 13–20% of long lasting cough illnesses in adults are caused by B. pertussis infection [18]. The untypical disease pattern can leave adults unaware of their potential role as a source of infection for infants. As a consequence, expecting parents or parents with young infants as well as caretakers of infants should be informed about this risk and should be encouraged to seek a medical examination if they are bothered by a long-lasting insistent cough. This recommendation may gain in importance as a shift in the age of patients occurs. The proportion (but not the number) of pertussis cases among adolescents and adults has increased over the time period of our study while the proportion of cases among toddlers and mainly 1–9 year-old children decreased. The introduction of a 5th dose of pertussis component vaccine for children aged 4–7 years in 1996 and the progressive increase of coverage for this dose may further increase the average age of pertussis patients in the future and this may ultimately lead to an increase of cases in young, unprotected exposed infants. In England and Wales for example, an increase in proportion and number of pertussis cases in over 15 year old patients was accompanied by an increase of cases in infants aged less than 6 months [28]. In this context, the benefits of further booster doses in adolescents and adults should seriously be considered [29]. We recognize several limitations in our study. First, not all reported cases of pertussis fulfilled the SSSN reporting criteria the main reason being a cough lasting less than 14 days. Reports are indeed frequently made at the time of clinical diagnosis, i.e. before the end of the cough illness, and follow-up of patients is not part of the SSSN. PCR free of charge was introduced in the SSSN in 1994 to confirm reported cases and to test if differences exist between

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cases according to case definition. No difference in the proportion of cases tested PCR positive between cases fulfilling and not fulfilling either the epidemic or the sporadic case definition were found, and cases lasting less than 14 days were even more often PCR positive than cases with a longer documented cough. This justifies including all reported cases in the analyses. Second, the number of primary care physicians and the proportion of pediatricians in the SSSN as well as the vaccination schedule varied over this 16 year study period which may particularly influence number, age distribution and vaccination status of cases. Third, like for every sentinel surveillance system, the representativeness of physicians in the SSSN over such a long period may be questioned. It is also likely that children followed by SSSN physicians, who are usually very committed to public health, on average have higher vaccination rates than other children. This could underestimate the national incidence for pertussis. On the other side, the reporting of pertussis in the SSSN is very sensitive (some cases were reported even if they do not satisfy the case definition and about three quarters of the cases tested were negative by PCR), which tends to overestimate the incidence of the disease. Fourth, we were unable to calculate the vaccine effectiveness because (1) vaccination schedule and vaccination coverage have strongly changed over the period, (2) detailed corresponding vaccination coverage per year and age was not available, and (3) only few cases were completely unvaccinated. Finally, etiologic diagnosis of pertussis relied solely on PCR whereas serological tests were not performed or collected in a standardized fashion. Therefore, the number of laboratory confirmed cases is limited. In conclusion, we have characterized the epidemiology of pertussis in Switzerland by use of data from a nationwide, prospective sentinel physician network over a period of 15.5 years. Despite an overall trend for a decrease of pertussis incidence over the last decade, there is good evidence for an increase of cases in adolescents and adults. This observation should be considered with regards to potential benefits of introducing further booster doses in adolescents and/or adults in the Swiss immunization schedule. Conflicts of interest All authors declare no conflicts of interest. Acknowledgments Most sincere thanks to all members of the SSSN for their active interest in public health and their steady support of the sentinel surveillance system. We are grateful to Jocelyne Villoz, Maria Schabel, Hans-Peter Zimmermann, Hans Matter, Mirjam Mäusezahl and Virginie Masserey from the Federal Office of Public Health for reviewing and support in data collection. Also, we would like to sincerely thank S. Balogh, E. Dertschnig, C. Möller, R. Hertel, and G. Schmidt-Schläpfer, Microbiological Laboratories University Children’s Hospital Basel, for performing PCR assays throughout the study years. References [1] Bundesamt für Gesundheit, Eidgenössische Kommission für Impffragen (EKIF). Schweizerischer Impfplan 2010. Richtlinien und Empfehlungen. Bern: Bundesamt für Gesundheit, 2010. Available at: http://www.ekif.ch. Accessed 5 January, 2011.

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[2] Matter HC, Cloetta J, Zimmermann H, Sentinella-Arbeitsgemeinschaft. Das Meldesystem Sentinella in der Schweiz am Beispiel des Pertussismonitorings von 1991 bis 1993. Schweiz Rundschau für Medizin (PRAXIS) 1995;84:690–7. [3] WHO-recommended surveillance standard of Pertussis. Available at: http://www.who.int/immunization monitoring/diseases/pertussis surveillance/en/index.html Accessed 5 January, 2011. [4] Schläpfer G, Cherry JD, Heininger U, Überall M, Schmitt-Grohé S, Laussucq S, et al. Polymerase chain reaction identification of Bordetella pertussis infections in vaccinees and family members in a pertussis vaccine efficacy trial in Germany. Pediatr Infect Dis J 1995;14:209–14. [5] Houard S, Hackel C, Herzog A, Bollen A. Specific identification of Bordetella pertussis by the polymerase chain reaction. Res Microbiol 1989;140:477–87. [6] Celentano LP, Massari M, Paramatti D, Salmaso S, Tozzi AE. EUVAC-NET Group. Resurgence of pertussis in Europe. Pediatr Infect Dis J 2005;24:761–5. [7] Carlsson RM, Trollfors B. Control of Pertussis - lessons learnt from a 10-year surveillance programme in Sweden. Vaccine 2009;27:5709–18. [8] Fabiánová K, Benes C, Kríz B. A steady rise in incidence of pertussis since nineties in the Czech Republic. Epidemiol Mikrobiol Imunol 2010;59:25–33. [9] Hellenbrand W, Beier D, Jensen E, Littmann M, Meyer C, Oppermann H, et al. The epidemiology of pertussis in Germany: past and present. BMC Infect Dis 2009;9:22. [10] Tozzi AE, Pandolfi E, Celentano LP, Massari M, Salmaso S, Ciofi degli Atti ML. Comparison of pertussis surveillance systems in Europe. Vaccine 2007;25:291–7. [11] de Greeff SC, de Melker HE, van Gageldonk PG, Schellekens JF, van der Klis FR, Mollema L, et al. Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis. PLoS One 2010;5(12):e14183. [12] Duclos P. Pertussis, parapertussis (whooping cough). In: Heymann DL, editor. Control of communicable diseases manual. 18th ed. Washington: American Public Health Association; 2004. p. 399–404. [13] Matter HC, Schmidt-Schlapfer G, Zimmermann H, SentinellaArbeitsgemeinschaft. Erfassung einer Keuchhustenepidemie 1994/95 in der Schweiz durch das Sentinella-Meldesystem. Schweiz Med Wochenschr 1996;126:1423–31. [14] EUVAC.Net. Available at: http://www.euvac.net/graphics/euvac/trends pertussis.html Accessed 5 January 2011. [15] Bundesamt für Gesundheit. Durchimpfung in der Schweiz 2005–2007. Bull BAG 2010;11:367–77. [16] Anderson RM, May RM. Modern vaccines. Immunisation and herd immunity. The Lancet 1990;335:641–5. [17] Wendelboe AM, van Rie A, Salmaso S, Englund JA. Duration of immunity against pertussis after natural infection or vaccination. Pediatr Infect Dis J 2005;24:58–61. [18] Cherry JD. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics 2005;115:1422–7. [19] Heininger U. Pertussis: an old disease that is still with us. Curr Opin Infect Dis 2001;14:329–35. [20] Heininger U, Stehr K, Cherry JD. Serious pertussis overlooked in infants. Eur J Pediatr 1992;151:342–3. [21] Crowcroft NS, Andrews N, Rooney C, Brisson M, Miller E. Deaths from pertussis are underestimated in England. Arch Dis Child 2002;86:336–8. [22] Heininger U, Stehr K, Schmidt-Schläpfer G, Penning R, Vock R, Kleemann WJ, et al. Bordetella pertussis infections and sudden unexpected deaths in children. Eur J Pediatr 1996;155:551–3. [23] Lindgren C, Milerad J, Lagercrantz H. Sudden infant death and prevalence of whooping cough in the Swedish and Norwegian communities. Eur J Pediatr 1997;156:405–9. [24] Ghanaie RM, Karimi A, Sadeghi H, Esteghamti A, Falah F, Armin S, et al. Sensitivity and specificity of the World Health Organization pertussis clinical case definition. Int J Infect Dis 2010;14:e1072–5. [25] Centers for Diseases Control and Prevention. Pertussis. In: Atkinson W, Wolfe S, Hamborsky J, McIntyre L, editors. Epidemiology and prevention of vaccinepreventable diseases. 11th ed. Washington, DC: Public Health Foundation; 2009. p. 199–216. [26] Bonmarin I, Levy-Bruhl D, Baron S, Guiso N, Njamkepo E, Caro V. Pertussis surveillance in French hospitals: results from a 10 year period. Eurosurveillance 2007;12:1–8. [27] Centers for Diseases Control Prevention. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. MMWR 2006;55(RR03):1–34. [28] Van Buynder PG, Owen D, Vurdien JE, Andrews NJ, Matthews RC, Miller E. Bordetella pertussis surveillance in England and Wales: 1995–1997. Epidemiol Infect 1999;123:403–11. [29] Heininger U, Cherry JD. Pertussis immunisation in adolescents and adults – Bordetella pertussis epidemiology should guide vaccination recommendations. Expert Opin Biol Ther 2006;6:685–97.