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Study of the risk factors for severe childhood pertussis based on hospital surveillance data
Vaccine 25 (2007) 7224–7232
Study of the risk factors for severe childhood pertussis based on hospital surveillance data Val´erie Briand ∗ , Isabelle Bonmarin, Daniel L´evy-Bruhl National Institute for Public Health Surveillance, Department of Infectious Diseases, 12 rue du Val d’Osne, 94415 Saint-Maurice Cedex, France Received 11 August 2006; received in revised form 6 July 2007; accepted 15 July 2007 Available online 2 August 2007
Abstract We used data collected through the French national hospital-based pertussis surveillance network to investigate the risk factors for severe childhood pertussis and more specifically the impact of the vaccination status. For infants, factors associated with a decreased risk of severe disease (defined as hospitalization in intensive care unit, assisted ventilation or death) were having received the first dose of vaccine, being seen late in the course of the disease and in a local hospital. Data also suggested that protection may increase with the number of doses administered. For older children, factors associated with a decreased risk of severity, measured by the hospitalization, were having received a recent booster injection and identification of the contaminator in the close environment. This study reinforces the need for an early start of the primary course in infants and the administration of booster injections in older children. © 2007 Elsevier Ltd. All rights reserved. Keywords: Pertussis; Vaccination; Children
1. Introduction Pertussis is a bacterial respiratory disease. Its clinical expression depends on the age and the specific anti-pertussis immune status of the subject. The severity of the disease is greatest in the youngest children, and pertussis may even be fatal in very young infants. In France, whole cell vaccination has been routinely used from 1966. Thanks to extensive vaccination coverage and the high effectiveness of the vaccine, a rapid decline in pertussis morbidity and mortality was then observed. The disease did not disappear and particularly persisted in infants in the first few months of life, too young to be protected by vaccination [1]. In early 1990s a resurgence of pertussis, with a change in epidemiologic pattern, was observed in France [2] as in other countries [3]. While the disease affected primarily young children before the introduction of vaccination, adolescents and young adults then ∗
Corresponding author. Tel.: +33 1 41 79 6741; fax: +33 1 41 79 6872. E-mail address: [email protected] (V. Briand).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.07.020
became the principal source of contamination of very young infants [1–4]. In a context of low circulation of the bacterium, and because the immunity induced by vaccination or acquired by infection lasts less than 10 years [5–7], adolescents and young adults were receptive to infection again. In France, this observation was based on a multicenter hospital study carried out in 1993–1994, in the context of a resurgence in pertussis in infants observed by hospital pediatricians [2]. The participants in this study agreed to take part in a sustained network for the surveillance of pertussis cases seen in hospital. This network, Renacoq, has been operational since 1996 and allow to monitor the epidemiology of the disease and the impact of the recommended vaccination schedule. The data collected for each case of pertussis identified by the pediatricians or bacteriologists of the Renacoq network, include clinical, epidemiological and sociodemographic information as well as vaccination status data. The aim of this study was to investigate the risks factors for severe childhood pertussis, based on the data from the Renacoq network.
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2. Materials and methods Until 2000, the Renacoq network consisted of 44 participating hospitals in 21 regions of mainland France: 17 general hospitals and 27 regional or university hospitals. This network is coordinated by the Institut de Veille Sanitaire (InVS), in collaboration with the National Reference Center for Bordetella (CNRB) at the Pasteur Institute, which provides microbiological expertise. Based on the national hospital admissions database, it was estimated that this network covers 29% of pediatric hospitalizations in France. Information is collected from bacteriologists and pediatricians at the participating hospitals. The information collected pertains to all children under-21 years old with suspected pertussis admitted to hospital or attending out-patients clinics at the hospital. The bacteriologists are asked to send a list of the biological examinations performed for pertussis and their results to the InVS. The pediatricians are asked to send completed clinical forms for each child meeting the case definition for pertussis. The information collected includes the age, sex and residence of the child, vaccination status, symptoms, biological investigations carried out and the likely contaminator assessed through family interview. 2.1. Case definition The diagnosis of pertussis is confirmed for every child with a paroxysmal cough lasting more than 8 days who fulfils one of the 3 following case definitions: - Laboratory confirmed case: isolation of Bordetella pertussis by culture or detection of Bordetella by polymerase chain reaction (PCR) from nasopharyngeal aspirates, or an increase or decrease in anti-pertussis toxin antibodies (anti-PTX) in two serum samples taken 1 month apart in the absence of recent vaccination (≤6 months). The detection of anti-PTX antibodies in serum was performed with purified PT antigen and Western blot. Results were semiquantitative and graded from 0 to 3. Serologic confirmation was determined by an increase (0 to >0, 1 to >1, 2 to >2) or a decrease in detection of antibodies between paired sera. - Clinical case: cough lasting at least 21 days, with paroxysms evocating pertussis (consisting in difficulty breathing in, whooping, apnea, bouts of cyanosis, vomiting after paroxysms or hyperlymphocytosis). - Epidemiological case: contact with a laboratory-confirmed case. 2.2. Statistical analysis All cases of pertussis confirmed between April 1996 and December 2000 occurring in subjects under the age of 21 years were considered for analyses. The severity of pertussis was defined differently according to the age of the child (less than 1 year versus 1 year and over). In children aged less than 1 year, the disease was
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considered severe if at least one of the following criteria was met: hospitalization in intensive care, assisted ventilation or death. In children aged 1 year and over, in whom these criteria were rare, the disease was considered severe if the child was hospitalized in a pediatrics ward. The risk factors for severe pertussis were studied separately in children under the age of 2 months, as they could not have been vaccinated, children aged 2–11 months and children aged 1 year and over. Vaccination status was mainly (≥80%) determined from the patient-kept medical booklet. Otherwise, it was determined by interviewing the family. Children were considered correctly vaccinated according to age when: aged 3 months they had received at least one dose, aged 4 months at least two doses, aged 5–18 months at least three doses and aged more than 19 months four doses (or five doses when aged over 14 years in 1998 and subsequent years). Acellular vaccines became available in France in 1998. From 1998 to 2000, it was recommended to use preferentially the whole-cell vaccine for the primary vaccination, either type of vaccine for the first booster, and exclusively acellular vaccines for the second booster. In addition to the vaccination status, we assessed the effect of the following factors on the severity of the disease: age of the child at onset of symptoms, sex, region of residence, case definition, time to diagnosis (<14, ≥15 days)—corresponding to the time between the onset of symptoms and the date of sampling or clinical diagnosis, type of hospital declaring the case (general versus university or regional hospital) and possible source of contamination (inside versus outside the household). For 81 children (4%), the date on which the symptoms began was unknown. It was estimated by the median time interval between onset of symptoms and diagnosis, calculated for children of a similar age for whom both dates were known. For case definition, we considered separately cases confirmed by culture (whatever the result of PCR and/or serology), cases only confirmed by PCR and/or serology (no culture done or culture-negative) as they were more likely to correspond to milder cases or cases seen later in the course of the disease, and clinical or epidemiological cases (biological tests done but negative). Finally, when information about the source of contamination was not available (20% of cases) we assumed that there were no cases of pertussis in the household and close social environment. For each of the three age groups, logistic regression was performed for univariate and multivariate analysis using severity of pertussis as the dependant variable. In analyses, categorical variables were considered as dummy variables. For the multivariate analysis, all variables with p ≤ 0.20 in univariate analysis were initially introduced into the model, and those with higher p-values were removed following a backwards-stepwise selection procedure, leaving only variables with p < 0.05 in the final model. For children aged 2–11 months, age was forced into the final model. The fit of the models to the data were evaluated by means of the Hosmer–Lemeshow test.
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All statistical analyses were carried out with STATA version 8.0 (Stata statistical software, Stata Corporation, College Station, TX, USA).
3. Results 3.1. Description of the study population Between April 1996 and December 2000, the Renacoq network notified 1943 confirmed cases of pertussis to InVS. Confirmation was biological in 72% of these cases (12% by culture alone, 53% by PCR alone, 10% by serological testing alone and 25% by several biological tests), clinical in 24% of cases and epidemiological in 4% of cases. More than 60% of the children were less than 6 months at onset of the symptoms – 26% were less than 2 months – and 8% were 10 years and more (mean age: 2 years 4 months, median age: 4 months) (Table 1). There were 51% of girls and 49% of boys. The clinical symptoms most frequently reported were paroxysmal cough and coughing for more than 21 days (Fig. 1). Problems with inspiration after paroxysms, cyanosis, apnea and hyperlymphocytosis were more frequent in children under the age of 1 year whereas persistent coughs, vomiting and whooping were more frequent in children aged at least 1 year. In our study population, hospitalization and admission to intensive care units (ICUs) were required in 76 and 15% of cases, respectively. The proportion of hospitalized cases, admissions in ICUs and children requiring an assisted ventilation decreased with age. In total, 20 children (1%) died. All of them were less than 5 months of age at
the onset of symptoms (one child was less than 15 days, 3 were between 15 and 30 days, 9 were in their second month and 7 were more than 2 months old). Death occurred in 11 boys and 9 girls. Most of them (n = 17) were laboratory confirmed. Only one child, aged 3 months with a positive PCR, had received a first dose of vaccine, 1 month before the onset of symptoms. Based on the aged specific severity criteria, 28% (143/508), 10% (72/739) and 34% (206/611) of the children aged less than 2 months, 2–11 months and 1 year and over had severe pertussis, respectively (Table 1). Of note, 90% of the children aged 2–11 months and 2% of the children aged 1 year and over had severe pertussis according to the criteria used for the other age group. Finally, only 25% were correctly vaccinated according to age and more than 50% had never been vaccinated. We found, in children aged 1 year and over for whom the information was available (n = 236), that they received the first booster around 2 years of age (data not shown). So, we considered that the booster was administered more than 6 years ago in children aged 8 years and over. Only 16 children received a second booster injection. 3.2. Factors associated with severe pertussis—children aged less than 2 months Age was the only factor significantly associated with the severity of the disease in univariate analysis (OR = 0.53 [0.22–1.28] and OR = 0.38 [0.17–0.89] for children aged 15–30 days and children aged 1 month and over compared to children aged 1–14 days, respectively). As the other associations were found with a p-value more than 0.20, we did not perform a multivariate analysis.
Fig. 1. Distribution of clinical and biological signs suggestive of pertussis and management of the child, according to age at onset of symptoms. For all symptoms, except fit of coughing, frequencies were significantly different in children aged less than 1 year compared to children aged 1 year and over. Renacoq data 1996–2000.
Table 1 Characteristics of the children of the study
V. Briand et al. / Vaccine 25 (2007) 7224–7232 Renacoq data 1996–2000. a The national age specific hospitalisation rates were calculated from the number of cases observed in the network (representing 29% of paediatric admissions) and the age specific population size from 1996 to 2000. b Proportions of admissions in intensive care units (ICU) and use of an assisted ventilation in hospitalized children. c In children aged 2–11 months, pertussis was considered severe in case of hospitalization in intensive care, assisted ventilation or death. In children aged 1 year and over, pertussis was considered severe in case of hospitalization. d Children were considered correctly vaccinated according to age when: aged 3 months they had received at least one dose, aged 4 months at least two doses, aged 5–18 months at least three doses and aged more than 19 months four doses (or five doses when aged over 14 years in 1998 and subsequent years). None of the children less than 2 months were vaccinated, except one who received the first dose of vaccine at 1 month.
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3.3. Factors associated with severe pertussis—children aged 2–11 months
the nature of the contaminating contact (global tests, p = 0.19 and p = 0.08, respectively).
3.3.1. Univariate analysis The proportion of severe cases decreased significantly with increasing age of the child (Table 2). We found a protective effect of the vaccination starting from the first dose, and the protection seemed increased with the number of doses received. Severe pertussis was less frequent in the following situations: cases confirmed clinically or epidemiologically, diagnosis made more than 15 days after the onset of symptoms and hospitalization in a general hospital. Severity was significantly associated with the region of residence of the child (global test, p = 0.05). No significant association was found between disease severity and the sex of the child or
3.3.2. Multivariate analysis All the variables were included in the multivariate model. After a backwards-stepwise selection procedure, sex, nature of the contaminator and case definition were removed from the final model. Using odds ratio values as an estimate of relative risks, we found that the risk for the unvaccinated children of having a severe pertussis was multiplied, respectively, by 3 and by 8 compared to the children who had received one dose of vaccine and two or three doses of vaccine (Table 2). We found a marginally significant association between the risk of having a severe disease and the age of the child. Late diagnosis appeared to be significantly associated with milder
Table 2 Factors associated with severe pertussis in children aged 2–11 months Univariate analysis
Multivariate analysisa
ORb
CIb
ORb
CIb
Age at onset of symptoms (months) 2–3 4–5 6–11
1 0.50 0.38
– 0.26–0.98 0.16–0.91
1 0.70 0.37
– 0.30–1.64 0.12–1.11
Number of doses of vaccine 0 1 2 or 3
1 0.45 0.08
– 0.23–0.85 0.01–0.59
1 0.42 0.13
– 0.19–0.91 0.02–0.98
Time to diagnosis (days) 0–14 ≥15
1 0.26
– 0.13–0.52
1 0.18
– 0.08–0.41
Type of hospital General University or regional
1 0.50
– 0.25–1.00
1 0.31
– 0.14–0.73
Region of residence of the case Ile de France North-West North-East South-East South-West
1 1.06 1.85 0.61 0.50
– 0.52–2.18 0.91–3.77 0.22–1.65 0.14–1.82
1 1.37 1.80 0.28 0.36
– 0.61–3.10 0.76–4.25 0.07–1.04 0.07–1.71
Case definitionc Positive culture Positive PCR and/or serology Clinical or epidemiological
1 1.23 0.43
– 0.70–2.15 0.19–0.98
–
–
Type of contamination No case among family & friends Household contamination (parents or siblings) Extra-familial contamination (school, day-care centers or others)
1 0.62 0.39
– 0.35–1.08 0.14–1.12
–
–
Sex ratio Girls Boys
1 0.72
– 0.44–1.18
–
–
Renacoq 1996–2000. a n = 574; after a backwards-stepwise selection procedure, type of contamination, sex and case definition were removed from the final model; age was forced into the final model. R2 = 0.16; Hosmer–Lemeshow test p = 0.43. b OR, Odds ratio; CI, 95% confidence interval. c Case definition: “positive culture”, case confirmed by culture (+/− positive PCR and/or serology); “PCR and/or serology”, case confirmed by PCR and/or serology (no culture done or negative culture); “clinical or epidemiological”, case not confirmed by a biological test.
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Table 3 Factors associated with pertussis requiring hospitalization in children aged 1 year and over Univariate analysis ORb
CIb
Age at onset of symptoms (years) 1–2 3–4 5–7 ≥8 years
1 0.51 0.36 0.32
– 0.29–0.89 0.22–0.60 0.21–0.51
Number of doses 0 1, 2 or 3 ≥4
1 0.94 0.54
– 0.59–1.49 0.35–0.83
Multivariate analysisa
Dose effect by age 1–2 years 0 dose 1, 2 or 3 ≥4 3–4 years 0 dose 1, 2 or 3 ≥4 5–7 years 0 dose 1, 2 or 3 ≥4 ≥8 years 0 dose 1, 2 or 3 ≥4
ORb
CIb
1 0.75 0.17
– 0.29–1.93 0.05–0.60
1 1.20 0.38
– 0.30–4.73 0.10–1.48
1 0.28 0.23
– 0.07–1.12 0.07–0.69
1 0.63 1.18
– 0.22–1.80 0.52–2.70
Region of residence of the case Ile de France North-West North-East South-East South-West
1 3.80 1.64 1.15 4.31
– 2.21–6.49 0.93–2.89 0.62–2.13 1.98–9.37
1 4.39 1.50 1.23 3.31
– 2.28–8.46 0.75–3.00 0.58–2.62 1.32–8.31
Type of contamination No case among family & friends Household contamination (parents or siblings) Extra-familial contamination (school, day-care centers or others)
1 0.59 0.37
– 0.39–0.91 0.21–0.65
1 0.47 0.32
– 0.28–0.81 0.16–0.64
Case definitionc Positive culture Positive PCR and/or serology Clinical or epidemiological
1 1.00 1.03
– 0.61–1.63 0.62–1.70
–
–
Time to diagnosis (days) 0–14 ≥15
1 0.76
– 0.51–1.13
–
–
Type of hospital General University or regional
1 1.45
– 1.00–2.08
–
–
Sex ratio Girls Boys
1 1.25
– 0.88–1.77
–
–
Renacoq 1996–2000. a n = 418; time to diagnosis and case definition were not selected for the multivariate analysis. After a backwards-stepwise selection procedure, center and sex were removed from the final model. R2 = 0.15; Hosmer–Lemeshow test p = 0.31. b OR, Odds ratio; CI, 95% confidence interval. c Case definition: “positive culture”, case confirmed by culture (+/− positive PCR and/or serology); “PCR and/or serology”, case confirmed by PCR and/or serology (no culture done or negative culture); “clinical or epidemiological”, case not confirmed by a biological test.
forms, as did management at a general hospital, and living in the South-East of France. 3.4. Factors associated with severe pertussis—children aged 1 year and over 3.4.1. Univariate analysis We found that the proportion of cases requiring hospitalization decreased with increasing age of the child and that it
was significantly lower in children having received the first booster injection (Table 3). Hospitalization appeared to be less frequent in cases in which a source of contamination was identified, particularly if the contamination was extrafamilial (p < 10−3 ). When excluding children for whom this item was not documented (see Section 2), the relationship remained significant (data not shown). Children treated at general hospitals and living in the North-West or the South-West of France were less frequently hospitalized than other children.
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No significant association was found between hospitalization and time to diagnosis or case definition (p > 0.20). 3.4.2. Multivariate analysis Time to diagnosis and case definition were not selected for the multivariate analysis. After a backwards-stepwise selection procedure, center and sex were removed from the final model (Table 3). The protective effect of vaccination depended on the age of the child (corresponding to an interaction between age and vaccination status; p = 0.03). In children under the age of 8 years, the risk of hospitalization was lower for children having received the first booster. This protective effect was observed primarily in children aged 1–2 years or 5–7 years (OR = 0.17 [0.05–0.60] and OR = 0.23 [0.07–0.69], respectively). Conversely, for children over the age of 8 years, no association was found between the risk of hospitalization and vaccination status. Finally, living in the North-West or the South-West of France and the absence of an identified source of contamination among family and close social environment were identified as risk factors for severe cases.
4. Discussion This study confirmed the importance of vaccination status as a protective factor for severe pertussis. According to our criteria, there were a relatively high number of children (17% of children less than 1 year and 34% of children 1 year and over) who had a severe disease. We found a higher case fatality rate (2% for the under-one) than what is generally observed (e.g. 6.3/1000 in infants youngest than 1 year [3]), as we worked with hospital data and not data collected through general population surveillance. For the same reason, we found high rates of hospitalization. During the 1993–1994 period, the estimated hospitalization rates for children less than 6 and 3 months were 196/100,000 and 231/100,000, respectively [2]. These rates are slightly higher than those we found during the 1996–2000 period (216/100,000 and 279/100,000, respectively) probably because of the peaks that occurred in 1997 and 2000. Our data showed also that cases are not timely vaccinated as only 25% of them were correctly vaccinated according to age, even if at 24 months of age more than 95% of children have received three doses of vaccine [8]. This study confirmed that vaccination is protective against severe forms in infants, starting with the administration of the first dose. Sixty-four percent of the severe cases that occurred in children less than 1 year and who were not vaccinated could have been avoided if those children had received at least one dose of vaccine. In children aged 1 year and over, the risk of hospitalization was lower in children having received the first booster injection, particularly when the booster had been administered recently. These results are consistent with estimates of the duration of protection conferred by four doses of whole-cell vaccine administered during the first 2 years of
life of about 6 years [5–7]. In children aged 3–4 years, this protective effect was not statistically significant, probably due to the small sample size. Our results are consistent with those of other studies carried out in children and focusing on the effect of age [3,9–15] and vaccination status on the severity of pertussis [3,9,12,13,15–18]. In these studies, children were mainly compared according to their vaccine status (correct versus not correct according to age). To our knowledge, only few studies have addressed the effectiveness of partial pertussis vaccination in reducing the occurrence of severe cases [3,9,12,16]. The originality of our study is based upon the assessment of the protective effect of the first dose of vaccine, after adjustment for factors that influence the severity of the disease such as the age of the child. Similar analyses were performed in only two studies. Celentano et al. showed that infants who received one dose of vaccine were one and a half less at risk of being hospitalized compared to unvaccinated children [3]. Juretzko et al. also showed the protective role of vaccination (acellular vaccines) on hospitalization starting from the first dose, after adjustment for the child’s age [16]. We are quite confident in the determination of the vaccination status. In more than 80% of cases, the information was obtained through medical booklets, and whatever the source of data (medical booklet or interview) it was collected by pediatricians. Finally, adjusting the analyses for the source of data (booklet or interview) did not change our results (data not shown). We did not adjust for the type of vaccine administered (whole-cell or acellular), as the information was rarely available. However, during the study period the vast majority of the children received whole-cell vaccines. Indeed, acellular vaccines have been available in France from 1998, and available data show that up to 2000 less than 5% of the infants were vaccinated with acellular pertussis containing vaccines (Source IMS-Health) [19]. In children over the age of 1 year, we found that hospitalization was less frequent if a source of contamination had been identified among family and close social environment. Diagnosis may have been easier in these children and hospitalization, particularly for investigation purposes, may therefore have proved unnecessary. If household cases were identified first, it is also possible that some children had a less severe disease as they received an antibiotic prophylaxis (data not collected). However, it is much likely that the diagnosis of pertussis in the household environment has been, in the vast majority of cases, made retrospectively, based on the child’s diagnosis. There is no obvious explanation to the higher risk to be hospitalised in the North-West and SouthWest of France for children aged 1 year and over. There is not a higher risk of severity for younger children in these areas, which would be expected if a virulent strain had circulated. Moreover isolates are very stable according to CNRB. It could be linked to different hospitalisation policies according to age between regions and hospitals, or could reflect confounding factors which have not been identified yet.
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Whatever the age of the child, we did not show any effect of sex on the severity of the disease. Recent studies found contradictory results on the association between sex and severity of pertusssis [9,10,18]. Socioeconomic level, term and birth weight of the child have been suggested to have an effect on the severity of the disease [10–15]. These factors were not considered in our study. However, as they have smaller individual effects than age and vaccination, they would probably not have modified our results. In infants, the criteria we used to define severe cases were objective and available for almost all children. This was not the case for the variables “cyanosis”, “apnea” and “seizures”, not enough properly collected to be considered as a criteria for severity in our study. In children over the age of 1 year, we considered that hospitalization was a criteria of severity. These hospitalizations may have not been justified solely by the clinical condition of the child (severe pertussis in the strict sense of the term, investigation of a protracted cough), but also by considerations of the social context in which the child was living (preventing the sick child from remaining at home, for example) or were dictated by the hospital or department policy. In this case, the association between severity and age and vaccine status has been underestimated. Finally, non hospitalized children served as the control group for analyses. We could not assess their representativity as there is no surveillance of pertussis conducted in general population in France. This is one of the limitations of our study. The Renacoq network is currently the main tool for the epidemiological and microbiological surveillance of pertussis in France. Our work is entirely based on the data produced by this network and depends on the sustained participation of hospital pediatricians and bacteriologists since 1996. The maintenance of this network is essential to continue to follow the epidemiological features of the disease and, particularly, to evaluate the impact of the second booster injection on pertussis in infants. In conclusion, despite a vaccination coverage of more than 95% [8] and the proven effectiveness of anti-pertussis vaccines, the disease persists in France, notably among very young infants who have not yet been vaccinated. These children, due to their young age, are also more likely to develop severe forms. This study has reaffirmed the need to vaccinate children as early as possible—starting at 2 months, as recommended by the current French vaccination schedule. It confirms the protective effect of the vaccine against severe forms and shows that this effect exists from the first dose administered. It also highlights the need for older children to receive the first booster injection. We should not forget that the protection of infants also requires control of the disease in the infant’s contacts, based upon rapid use of antibiotics for cases and their contacts at risk, on a second booster at the age of 11–13 years and since 2004 on the cocoon strategy consisting in vaccinating household members. Finally, considering the high rate of severe pertussis in children less than
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2 months, further researches should be encouraged for the development of vaccines that could be administered before 2 months of life.
Acknowledgements We would like to thank all the participating laboratories and pediatric services of the network: Centre hospitalier de Dunkerque, Centre hospitalier r´egional de Lille, hˆopital Calmette, Centre hospitalier r´egional d’Amiens, hˆopital Nord, Centre hospitalier de Compi`egne, Centre hospitalier de F´ecamp, Centre hospitalier r´egional de Rouen, hˆopital C. Nicolle, Centre hospitalier de Lisieux, Centre hospitalier r´egional de Caen, Centre hospitalier de Saint-Brieuc, Centre hospitalier r´egional de Brest, hˆopital Morvan, Centre hospitalier r´egional de Nantes, hˆopital M`eres-Enfants, Centre hospitalier r´egional d’Angers, Centre hospitalier de Cholet, Centre hospitalier du Mans, Centre hospitalier r´egional d’Orl´eans, Centre hospitalier r´egional de Tours, hˆopital Clocheville, Centre hospitalier de La Rochelle, Centre hospitalier r´egional de Bordeaux, hˆopital Pellegrin, Centre hospitalier de Pau, Centre hospitalier de Cahors, hˆopital Purpan, Centre hospitalier r´egional de Montpellier, hˆopital A. de Villeneuve, Centre hospitalier r´egional de Marseille, hˆopital Nord, Centre hospitalier d’Avignon, Centre hospitalier g´en´eral d’Aix-en-Provence, Centre hospitalier r´egional de Clermont-Ferrand, hˆopital Hˆotel-Dieu, Centre hospitalier r´egional de Limoges, hˆopital Dupuytren, Centre hospitalier r´egional de Lyon, hˆopital E. Herriot, Centre hospitalier r´egional de Grenoble, Centre hospitalier de Nevers, Centre hospitalier r´egional de Dijon, Centre hospitalier r´egional de Besanc¸on, Hˆopitaux civils de Colmar, Clinique m´edico-chirurgicale Le Parc, Centre hospitalier r´egional de Strasbourg, hˆopital Hautepierre, Centre hospitalier de Neufchateau, Centre hospitalier r´egional de Nancy, Centre hospitalier de Charleville-M´ezi`eres, Hˆopital Intercommunal de Cr´eteil, Assistance publique-Hˆopitaux de Paris: hˆopital R. Debr´e, hˆopital A. Trousseau, hˆopital Necker-Enfant Malades, hˆopital St. Vincent de Paul, hˆopital Jean Verdier a` Bondy, hˆopital Louis Mourier a` Colombes.
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V. Briand et al. / Vaccine 25 (2007) 7224–7232 with very high whole-cell vaccine coverage. J Infect Dis 2002;186: 415–8. Grimprel E, Begue P, Anjak I, Njamkepo E, Francois P, Guiso N. Long-term human serum antibody responses after immunization with whole-cell pertussis vaccine in France. Clin Diagn Lab Immunol 1996;3(1):93–7. He Q, Viljanen MK, Nikkari S, Lyytikainen R, Mertsola J. Outcomes of Bordetella pertussis infection in different age groups of an immunized population. J Infect Dis 1994;170:873–7. Gustafsson L, Hessel L, Storsaeter J, Olin P. Long-term follow-up of Swedish children vaccinated with acellular pertussis vaccines at 3, 5 and 12 months of age indicates the need for a booster dose at 5–7 years of age. Pediatrics 2006;118:978–84. Antona D, Bussiere E, Guignon N, Badeyan G, Levy-Bruhl D. Vaccine coverage of pre-school age children in France in 2000. Euro Surveill 2003;8(6):139–44. 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. Nielsen NM, Hedegaard K, Aaby P. Intensity of exposure and severity of pertussis. J Infect 2001;43:177–81. Langkamp DL, Davis JP. Increased risk of reported pertussis and hospitalization associated with pertussis in low birth weight children. J Pediatr 1996;128(5):654–9. Stojanov S, Liese J, Belohradsky BH. Hospitalization and complications in children under 2 years of age with Bordetella pertussis infection. Infection 2000;28:106–10.
[13] Farizo KM, Cochi SL, Zell ER, Brink EW, Wassilak LG, Patriarca PA. Epidemiological features of pertussis in the United States, 1980–1989. Clin Infect Dis 1992;14:708–19. [14] Halperin SA, Wang EEL, Law B, Mills E, Morris R, Dery P, et al. Epidemiological features of pertussis in hospitalized patients in Canada, 1991–1997: report of the Immunization Monitoring Program—Active (IMPACT). Clin Infect Dis 1999;28:1238–43. [15] Gordon M, Davies HD, Gold R. Clinical and microbiologic features of children presenting with pertussis to a Canadian pediatric hospital during an 11-year period. Pediatr Infect Dis J 1994;13: 617–22. [16] Juretzko R, von Kries R, Hermann M, Wirsing von Konig CH, Weil J, Giani G. Effectiveness of acellular pertussis vaccine assessed by hospital-based active surveillance in Germany. Clin Infect Dis 2002;35:162–7. [17] Grant CC, Roberts M, Scragg R, Stewart J, Lennon D, Kivell D, et al. Delayed immunisation and risk of pertussis in infants: unmatched case–control study. BMJ 2003;326:852–3. [18] Preziosi MP, Halloran ME. Effects of pertussis vaccination on disease: vaccine effectiveness in reducing clinical severity. Clin Infect Dis 2003;37(6):772–9. [19] Bonmarin I, Laurent E, Guiso N, Gueirard P, Njamkepo E. Renacoq: surveillance de la coqueluche a` l’hˆopital en 2000. In: Desenclos JC, Vaillant V, Bonmarin I. Surveillance nationale des maladies infectieuses, 1998–2000. Paris, Institut de Veille Sanitaire, 2002:81–4. Available from http://www.invs.sante.fr/publications/2003/snmi/SNMI-Fp079-122.pdf.
Study of the risk factors for severe childhood pertussis based on hospital surveillance data Val´erie Briand ∗ , Isabelle Bonmarin, Daniel L´evy-Bruhl National Institute for Public Health Surveillance, Department of Infectious Diseases, 12 rue du Val d’Osne, 94415 Saint-Maurice Cedex, France Received 11 August 2006; received in revised form 6 July 2007; accepted 15 July 2007 Available online 2 August 2007
Abstract We used data collected through the French national hospital-based pertussis surveillance network to investigate the risk factors for severe childhood pertussis and more specifically the impact of the vaccination status. For infants, factors associated with a decreased risk of severe disease (defined as hospitalization in intensive care unit, assisted ventilation or death) were having received the first dose of vaccine, being seen late in the course of the disease and in a local hospital. Data also suggested that protection may increase with the number of doses administered. For older children, factors associated with a decreased risk of severity, measured by the hospitalization, were having received a recent booster injection and identification of the contaminator in the close environment. This study reinforces the need for an early start of the primary course in infants and the administration of booster injections in older children. © 2007 Elsevier Ltd. All rights reserved. Keywords: Pertussis; Vaccination; Children
1. Introduction Pertussis is a bacterial respiratory disease. Its clinical expression depends on the age and the specific anti-pertussis immune status of the subject. The severity of the disease is greatest in the youngest children, and pertussis may even be fatal in very young infants. In France, whole cell vaccination has been routinely used from 1966. Thanks to extensive vaccination coverage and the high effectiveness of the vaccine, a rapid decline in pertussis morbidity and mortality was then observed. The disease did not disappear and particularly persisted in infants in the first few months of life, too young to be protected by vaccination [1]. In early 1990s a resurgence of pertussis, with a change in epidemiologic pattern, was observed in France [2] as in other countries [3]. While the disease affected primarily young children before the introduction of vaccination, adolescents and young adults then ∗
Corresponding author. Tel.: +33 1 41 79 6741; fax: +33 1 41 79 6872. E-mail address: [email protected] (V. Briand).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.07.020
became the principal source of contamination of very young infants [1–4]. In a context of low circulation of the bacterium, and because the immunity induced by vaccination or acquired by infection lasts less than 10 years [5–7], adolescents and young adults were receptive to infection again. In France, this observation was based on a multicenter hospital study carried out in 1993–1994, in the context of a resurgence in pertussis in infants observed by hospital pediatricians [2]. The participants in this study agreed to take part in a sustained network for the surveillance of pertussis cases seen in hospital. This network, Renacoq, has been operational since 1996 and allow to monitor the epidemiology of the disease and the impact of the recommended vaccination schedule. The data collected for each case of pertussis identified by the pediatricians or bacteriologists of the Renacoq network, include clinical, epidemiological and sociodemographic information as well as vaccination status data. The aim of this study was to investigate the risks factors for severe childhood pertussis, based on the data from the Renacoq network.
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2. Materials and methods Until 2000, the Renacoq network consisted of 44 participating hospitals in 21 regions of mainland France: 17 general hospitals and 27 regional or university hospitals. This network is coordinated by the Institut de Veille Sanitaire (InVS), in collaboration with the National Reference Center for Bordetella (CNRB) at the Pasteur Institute, which provides microbiological expertise. Based on the national hospital admissions database, it was estimated that this network covers 29% of pediatric hospitalizations in France. Information is collected from bacteriologists and pediatricians at the participating hospitals. The information collected pertains to all children under-21 years old with suspected pertussis admitted to hospital or attending out-patients clinics at the hospital. The bacteriologists are asked to send a list of the biological examinations performed for pertussis and their results to the InVS. The pediatricians are asked to send completed clinical forms for each child meeting the case definition for pertussis. The information collected includes the age, sex and residence of the child, vaccination status, symptoms, biological investigations carried out and the likely contaminator assessed through family interview. 2.1. Case definition The diagnosis of pertussis is confirmed for every child with a paroxysmal cough lasting more than 8 days who fulfils one of the 3 following case definitions: - Laboratory confirmed case: isolation of Bordetella pertussis by culture or detection of Bordetella by polymerase chain reaction (PCR) from nasopharyngeal aspirates, or an increase or decrease in anti-pertussis toxin antibodies (anti-PTX) in two serum samples taken 1 month apart in the absence of recent vaccination (≤6 months). The detection of anti-PTX antibodies in serum was performed with purified PT antigen and Western blot. Results were semiquantitative and graded from 0 to 3. Serologic confirmation was determined by an increase (0 to >0, 1 to >1, 2 to >2) or a decrease in detection of antibodies between paired sera. - Clinical case: cough lasting at least 21 days, with paroxysms evocating pertussis (consisting in difficulty breathing in, whooping, apnea, bouts of cyanosis, vomiting after paroxysms or hyperlymphocytosis). - Epidemiological case: contact with a laboratory-confirmed case. 2.2. Statistical analysis All cases of pertussis confirmed between April 1996 and December 2000 occurring in subjects under the age of 21 years were considered for analyses. The severity of pertussis was defined differently according to the age of the child (less than 1 year versus 1 year and over). In children aged less than 1 year, the disease was
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considered severe if at least one of the following criteria was met: hospitalization in intensive care, assisted ventilation or death. In children aged 1 year and over, in whom these criteria were rare, the disease was considered severe if the child was hospitalized in a pediatrics ward. The risk factors for severe pertussis were studied separately in children under the age of 2 months, as they could not have been vaccinated, children aged 2–11 months and children aged 1 year and over. Vaccination status was mainly (≥80%) determined from the patient-kept medical booklet. Otherwise, it was determined by interviewing the family. Children were considered correctly vaccinated according to age when: aged 3 months they had received at least one dose, aged 4 months at least two doses, aged 5–18 months at least three doses and aged more than 19 months four doses (or five doses when aged over 14 years in 1998 and subsequent years). Acellular vaccines became available in France in 1998. From 1998 to 2000, it was recommended to use preferentially the whole-cell vaccine for the primary vaccination, either type of vaccine for the first booster, and exclusively acellular vaccines for the second booster. In addition to the vaccination status, we assessed the effect of the following factors on the severity of the disease: age of the child at onset of symptoms, sex, region of residence, case definition, time to diagnosis (<14, ≥15 days)—corresponding to the time between the onset of symptoms and the date of sampling or clinical diagnosis, type of hospital declaring the case (general versus university or regional hospital) and possible source of contamination (inside versus outside the household). For 81 children (4%), the date on which the symptoms began was unknown. It was estimated by the median time interval between onset of symptoms and diagnosis, calculated for children of a similar age for whom both dates were known. For case definition, we considered separately cases confirmed by culture (whatever the result of PCR and/or serology), cases only confirmed by PCR and/or serology (no culture done or culture-negative) as they were more likely to correspond to milder cases or cases seen later in the course of the disease, and clinical or epidemiological cases (biological tests done but negative). Finally, when information about the source of contamination was not available (20% of cases) we assumed that there were no cases of pertussis in the household and close social environment. For each of the three age groups, logistic regression was performed for univariate and multivariate analysis using severity of pertussis as the dependant variable. In analyses, categorical variables were considered as dummy variables. For the multivariate analysis, all variables with p ≤ 0.20 in univariate analysis were initially introduced into the model, and those with higher p-values were removed following a backwards-stepwise selection procedure, leaving only variables with p < 0.05 in the final model. For children aged 2–11 months, age was forced into the final model. The fit of the models to the data were evaluated by means of the Hosmer–Lemeshow test.
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All statistical analyses were carried out with STATA version 8.0 (Stata statistical software, Stata Corporation, College Station, TX, USA).
3. Results 3.1. Description of the study population Between April 1996 and December 2000, the Renacoq network notified 1943 confirmed cases of pertussis to InVS. Confirmation was biological in 72% of these cases (12% by culture alone, 53% by PCR alone, 10% by serological testing alone and 25% by several biological tests), clinical in 24% of cases and epidemiological in 4% of cases. More than 60% of the children were less than 6 months at onset of the symptoms – 26% were less than 2 months – and 8% were 10 years and more (mean age: 2 years 4 months, median age: 4 months) (Table 1). There were 51% of girls and 49% of boys. The clinical symptoms most frequently reported were paroxysmal cough and coughing for more than 21 days (Fig. 1). Problems with inspiration after paroxysms, cyanosis, apnea and hyperlymphocytosis were more frequent in children under the age of 1 year whereas persistent coughs, vomiting and whooping were more frequent in children aged at least 1 year. In our study population, hospitalization and admission to intensive care units (ICUs) were required in 76 and 15% of cases, respectively. The proportion of hospitalized cases, admissions in ICUs and children requiring an assisted ventilation decreased with age. In total, 20 children (1%) died. All of them were less than 5 months of age at
the onset of symptoms (one child was less than 15 days, 3 were between 15 and 30 days, 9 were in their second month and 7 were more than 2 months old). Death occurred in 11 boys and 9 girls. Most of them (n = 17) were laboratory confirmed. Only one child, aged 3 months with a positive PCR, had received a first dose of vaccine, 1 month before the onset of symptoms. Based on the aged specific severity criteria, 28% (143/508), 10% (72/739) and 34% (206/611) of the children aged less than 2 months, 2–11 months and 1 year and over had severe pertussis, respectively (Table 1). Of note, 90% of the children aged 2–11 months and 2% of the children aged 1 year and over had severe pertussis according to the criteria used for the other age group. Finally, only 25% were correctly vaccinated according to age and more than 50% had never been vaccinated. We found, in children aged 1 year and over for whom the information was available (n = 236), that they received the first booster around 2 years of age (data not shown). So, we considered that the booster was administered more than 6 years ago in children aged 8 years and over. Only 16 children received a second booster injection. 3.2. Factors associated with severe pertussis—children aged less than 2 months Age was the only factor significantly associated with the severity of the disease in univariate analysis (OR = 0.53 [0.22–1.28] and OR = 0.38 [0.17–0.89] for children aged 15–30 days and children aged 1 month and over compared to children aged 1–14 days, respectively). As the other associations were found with a p-value more than 0.20, we did not perform a multivariate analysis.
Fig. 1. Distribution of clinical and biological signs suggestive of pertussis and management of the child, according to age at onset of symptoms. For all symptoms, except fit of coughing, frequencies were significantly different in children aged less than 1 year compared to children aged 1 year and over. Renacoq data 1996–2000.
Table 1 Characteristics of the children of the study
V. Briand et al. / Vaccine 25 (2007) 7224–7232 Renacoq data 1996–2000. a The national age specific hospitalisation rates were calculated from the number of cases observed in the network (representing 29% of paediatric admissions) and the age specific population size from 1996 to 2000. b Proportions of admissions in intensive care units (ICU) and use of an assisted ventilation in hospitalized children. c In children aged 2–11 months, pertussis was considered severe in case of hospitalization in intensive care, assisted ventilation or death. In children aged 1 year and over, pertussis was considered severe in case of hospitalization. d Children were considered correctly vaccinated according to age when: aged 3 months they had received at least one dose, aged 4 months at least two doses, aged 5–18 months at least three doses and aged more than 19 months four doses (or five doses when aged over 14 years in 1998 and subsequent years). None of the children less than 2 months were vaccinated, except one who received the first dose of vaccine at 1 month.
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3.3. Factors associated with severe pertussis—children aged 2–11 months
the nature of the contaminating contact (global tests, p = 0.19 and p = 0.08, respectively).
3.3.1. Univariate analysis The proportion of severe cases decreased significantly with increasing age of the child (Table 2). We found a protective effect of the vaccination starting from the first dose, and the protection seemed increased with the number of doses received. Severe pertussis was less frequent in the following situations: cases confirmed clinically or epidemiologically, diagnosis made more than 15 days after the onset of symptoms and hospitalization in a general hospital. Severity was significantly associated with the region of residence of the child (global test, p = 0.05). No significant association was found between disease severity and the sex of the child or
3.3.2. Multivariate analysis All the variables were included in the multivariate model. After a backwards-stepwise selection procedure, sex, nature of the contaminator and case definition were removed from the final model. Using odds ratio values as an estimate of relative risks, we found that the risk for the unvaccinated children of having a severe pertussis was multiplied, respectively, by 3 and by 8 compared to the children who had received one dose of vaccine and two or three doses of vaccine (Table 2). We found a marginally significant association between the risk of having a severe disease and the age of the child. Late diagnosis appeared to be significantly associated with milder
Table 2 Factors associated with severe pertussis in children aged 2–11 months Univariate analysis
Multivariate analysisa
ORb
CIb
ORb
CIb
Age at onset of symptoms (months) 2–3 4–5 6–11
1 0.50 0.38
– 0.26–0.98 0.16–0.91
1 0.70 0.37
– 0.30–1.64 0.12–1.11
Number of doses of vaccine 0 1 2 or 3
1 0.45 0.08
– 0.23–0.85 0.01–0.59
1 0.42 0.13
– 0.19–0.91 0.02–0.98
Time to diagnosis (days) 0–14 ≥15
1 0.26
– 0.13–0.52
1 0.18
– 0.08–0.41
Type of hospital General University or regional
1 0.50
– 0.25–1.00
1 0.31
– 0.14–0.73
Region of residence of the case Ile de France North-West North-East South-East South-West
1 1.06 1.85 0.61 0.50
– 0.52–2.18 0.91–3.77 0.22–1.65 0.14–1.82
1 1.37 1.80 0.28 0.36
– 0.61–3.10 0.76–4.25 0.07–1.04 0.07–1.71
Case definitionc Positive culture Positive PCR and/or serology Clinical or epidemiological
1 1.23 0.43
– 0.70–2.15 0.19–0.98
–
–
Type of contamination No case among family & friends Household contamination (parents or siblings) Extra-familial contamination (school, day-care centers or others)
1 0.62 0.39
– 0.35–1.08 0.14–1.12
–
–
Sex ratio Girls Boys
1 0.72
– 0.44–1.18
–
–
Renacoq 1996–2000. a n = 574; after a backwards-stepwise selection procedure, type of contamination, sex and case definition were removed from the final model; age was forced into the final model. R2 = 0.16; Hosmer–Lemeshow test p = 0.43. b OR, Odds ratio; CI, 95% confidence interval. c Case definition: “positive culture”, case confirmed by culture (+/− positive PCR and/or serology); “PCR and/or serology”, case confirmed by PCR and/or serology (no culture done or negative culture); “clinical or epidemiological”, case not confirmed by a biological test.
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Table 3 Factors associated with pertussis requiring hospitalization in children aged 1 year and over Univariate analysis ORb
CIb
Age at onset of symptoms (years) 1–2 3–4 5–7 ≥8 years
1 0.51 0.36 0.32
– 0.29–0.89 0.22–0.60 0.21–0.51
Number of doses 0 1, 2 or 3 ≥4
1 0.94 0.54
– 0.59–1.49 0.35–0.83
Multivariate analysisa
Dose effect by age 1–2 years 0 dose 1, 2 or 3 ≥4 3–4 years 0 dose 1, 2 or 3 ≥4 5–7 years 0 dose 1, 2 or 3 ≥4 ≥8 years 0 dose 1, 2 or 3 ≥4
ORb
CIb
1 0.75 0.17
– 0.29–1.93 0.05–0.60
1 1.20 0.38
– 0.30–4.73 0.10–1.48
1 0.28 0.23
– 0.07–1.12 0.07–0.69
1 0.63 1.18
– 0.22–1.80 0.52–2.70
Region of residence of the case Ile de France North-West North-East South-East South-West
1 3.80 1.64 1.15 4.31
– 2.21–6.49 0.93–2.89 0.62–2.13 1.98–9.37
1 4.39 1.50 1.23 3.31
– 2.28–8.46 0.75–3.00 0.58–2.62 1.32–8.31
Type of contamination No case among family & friends Household contamination (parents or siblings) Extra-familial contamination (school, day-care centers or others)
1 0.59 0.37
– 0.39–0.91 0.21–0.65
1 0.47 0.32
– 0.28–0.81 0.16–0.64
Case definitionc Positive culture Positive PCR and/or serology Clinical or epidemiological
1 1.00 1.03
– 0.61–1.63 0.62–1.70
–
–
Time to diagnosis (days) 0–14 ≥15
1 0.76
– 0.51–1.13
–
–
Type of hospital General University or regional
1 1.45
– 1.00–2.08
–
–
Sex ratio Girls Boys
1 1.25
– 0.88–1.77
–
–
Renacoq 1996–2000. a n = 418; time to diagnosis and case definition were not selected for the multivariate analysis. After a backwards-stepwise selection procedure, center and sex were removed from the final model. R2 = 0.15; Hosmer–Lemeshow test p = 0.31. b OR, Odds ratio; CI, 95% confidence interval. c Case definition: “positive culture”, case confirmed by culture (+/− positive PCR and/or serology); “PCR and/or serology”, case confirmed by PCR and/or serology (no culture done or negative culture); “clinical or epidemiological”, case not confirmed by a biological test.
forms, as did management at a general hospital, and living in the South-East of France. 3.4. Factors associated with severe pertussis—children aged 1 year and over 3.4.1. Univariate analysis We found that the proportion of cases requiring hospitalization decreased with increasing age of the child and that it
was significantly lower in children having received the first booster injection (Table 3). Hospitalization appeared to be less frequent in cases in which a source of contamination was identified, particularly if the contamination was extrafamilial (p < 10−3 ). When excluding children for whom this item was not documented (see Section 2), the relationship remained significant (data not shown). Children treated at general hospitals and living in the North-West or the South-West of France were less frequently hospitalized than other children.
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No significant association was found between hospitalization and time to diagnosis or case definition (p > 0.20). 3.4.2. Multivariate analysis Time to diagnosis and case definition were not selected for the multivariate analysis. After a backwards-stepwise selection procedure, center and sex were removed from the final model (Table 3). The protective effect of vaccination depended on the age of the child (corresponding to an interaction between age and vaccination status; p = 0.03). In children under the age of 8 years, the risk of hospitalization was lower for children having received the first booster. This protective effect was observed primarily in children aged 1–2 years or 5–7 years (OR = 0.17 [0.05–0.60] and OR = 0.23 [0.07–0.69], respectively). Conversely, for children over the age of 8 years, no association was found between the risk of hospitalization and vaccination status. Finally, living in the North-West or the South-West of France and the absence of an identified source of contamination among family and close social environment were identified as risk factors for severe cases.
4. Discussion This study confirmed the importance of vaccination status as a protective factor for severe pertussis. According to our criteria, there were a relatively high number of children (17% of children less than 1 year and 34% of children 1 year and over) who had a severe disease. We found a higher case fatality rate (2% for the under-one) than what is generally observed (e.g. 6.3/1000 in infants youngest than 1 year [3]), as we worked with hospital data and not data collected through general population surveillance. For the same reason, we found high rates of hospitalization. During the 1993–1994 period, the estimated hospitalization rates for children less than 6 and 3 months were 196/100,000 and 231/100,000, respectively [2]. These rates are slightly higher than those we found during the 1996–2000 period (216/100,000 and 279/100,000, respectively) probably because of the peaks that occurred in 1997 and 2000. Our data showed also that cases are not timely vaccinated as only 25% of them were correctly vaccinated according to age, even if at 24 months of age more than 95% of children have received three doses of vaccine [8]. This study confirmed that vaccination is protective against severe forms in infants, starting with the administration of the first dose. Sixty-four percent of the severe cases that occurred in children less than 1 year and who were not vaccinated could have been avoided if those children had received at least one dose of vaccine. In children aged 1 year and over, the risk of hospitalization was lower in children having received the first booster injection, particularly when the booster had been administered recently. These results are consistent with estimates of the duration of protection conferred by four doses of whole-cell vaccine administered during the first 2 years of
life of about 6 years [5–7]. In children aged 3–4 years, this protective effect was not statistically significant, probably due to the small sample size. Our results are consistent with those of other studies carried out in children and focusing on the effect of age [3,9–15] and vaccination status on the severity of pertussis [3,9,12,13,15–18]. In these studies, children were mainly compared according to their vaccine status (correct versus not correct according to age). To our knowledge, only few studies have addressed the effectiveness of partial pertussis vaccination in reducing the occurrence of severe cases [3,9,12,16]. The originality of our study is based upon the assessment of the protective effect of the first dose of vaccine, after adjustment for factors that influence the severity of the disease such as the age of the child. Similar analyses were performed in only two studies. Celentano et al. showed that infants who received one dose of vaccine were one and a half less at risk of being hospitalized compared to unvaccinated children [3]. Juretzko et al. also showed the protective role of vaccination (acellular vaccines) on hospitalization starting from the first dose, after adjustment for the child’s age [16]. We are quite confident in the determination of the vaccination status. In more than 80% of cases, the information was obtained through medical booklets, and whatever the source of data (medical booklet or interview) it was collected by pediatricians. Finally, adjusting the analyses for the source of data (booklet or interview) did not change our results (data not shown). We did not adjust for the type of vaccine administered (whole-cell or acellular), as the information was rarely available. However, during the study period the vast majority of the children received whole-cell vaccines. Indeed, acellular vaccines have been available in France from 1998, and available data show that up to 2000 less than 5% of the infants were vaccinated with acellular pertussis containing vaccines (Source IMS-Health) [19]. In children over the age of 1 year, we found that hospitalization was less frequent if a source of contamination had been identified among family and close social environment. Diagnosis may have been easier in these children and hospitalization, particularly for investigation purposes, may therefore have proved unnecessary. If household cases were identified first, it is also possible that some children had a less severe disease as they received an antibiotic prophylaxis (data not collected). However, it is much likely that the diagnosis of pertussis in the household environment has been, in the vast majority of cases, made retrospectively, based on the child’s diagnosis. There is no obvious explanation to the higher risk to be hospitalised in the North-West and SouthWest of France for children aged 1 year and over. There is not a higher risk of severity for younger children in these areas, which would be expected if a virulent strain had circulated. Moreover isolates are very stable according to CNRB. It could be linked to different hospitalisation policies according to age between regions and hospitals, or could reflect confounding factors which have not been identified yet.
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Whatever the age of the child, we did not show any effect of sex on the severity of the disease. Recent studies found contradictory results on the association between sex and severity of pertusssis [9,10,18]. Socioeconomic level, term and birth weight of the child have been suggested to have an effect on the severity of the disease [10–15]. These factors were not considered in our study. However, as they have smaller individual effects than age and vaccination, they would probably not have modified our results. In infants, the criteria we used to define severe cases were objective and available for almost all children. This was not the case for the variables “cyanosis”, “apnea” and “seizures”, not enough properly collected to be considered as a criteria for severity in our study. In children over the age of 1 year, we considered that hospitalization was a criteria of severity. These hospitalizations may have not been justified solely by the clinical condition of the child (severe pertussis in the strict sense of the term, investigation of a protracted cough), but also by considerations of the social context in which the child was living (preventing the sick child from remaining at home, for example) or were dictated by the hospital or department policy. In this case, the association between severity and age and vaccine status has been underestimated. Finally, non hospitalized children served as the control group for analyses. We could not assess their representativity as there is no surveillance of pertussis conducted in general population in France. This is one of the limitations of our study. The Renacoq network is currently the main tool for the epidemiological and microbiological surveillance of pertussis in France. Our work is entirely based on the data produced by this network and depends on the sustained participation of hospital pediatricians and bacteriologists since 1996. The maintenance of this network is essential to continue to follow the epidemiological features of the disease and, particularly, to evaluate the impact of the second booster injection on pertussis in infants. In conclusion, despite a vaccination coverage of more than 95% [8] and the proven effectiveness of anti-pertussis vaccines, the disease persists in France, notably among very young infants who have not yet been vaccinated. These children, due to their young age, are also more likely to develop severe forms. This study has reaffirmed the need to vaccinate children as early as possible—starting at 2 months, as recommended by the current French vaccination schedule. It confirms the protective effect of the vaccine against severe forms and shows that this effect exists from the first dose administered. It also highlights the need for older children to receive the first booster injection. We should not forget that the protection of infants also requires control of the disease in the infant’s contacts, based upon rapid use of antibiotics for cases and their contacts at risk, on a second booster at the age of 11–13 years and since 2004 on the cocoon strategy consisting in vaccinating household members. Finally, considering the high rate of severe pertussis in children less than
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2 months, further researches should be encouraged for the development of vaccines that could be administered before 2 months of life.
Acknowledgements We would like to thank all the participating laboratories and pediatric services of the network: Centre hospitalier de Dunkerque, Centre hospitalier r´egional de Lille, hˆopital Calmette, Centre hospitalier r´egional d’Amiens, hˆopital Nord, Centre hospitalier de Compi`egne, Centre hospitalier de F´ecamp, Centre hospitalier r´egional de Rouen, hˆopital C. Nicolle, Centre hospitalier de Lisieux, Centre hospitalier r´egional de Caen, Centre hospitalier de Saint-Brieuc, Centre hospitalier r´egional de Brest, hˆopital Morvan, Centre hospitalier r´egional de Nantes, hˆopital M`eres-Enfants, Centre hospitalier r´egional d’Angers, Centre hospitalier de Cholet, Centre hospitalier du Mans, Centre hospitalier r´egional d’Orl´eans, Centre hospitalier r´egional de Tours, hˆopital Clocheville, Centre hospitalier de La Rochelle, Centre hospitalier r´egional de Bordeaux, hˆopital Pellegrin, Centre hospitalier de Pau, Centre hospitalier de Cahors, hˆopital Purpan, Centre hospitalier r´egional de Montpellier, hˆopital A. de Villeneuve, Centre hospitalier r´egional de Marseille, hˆopital Nord, Centre hospitalier d’Avignon, Centre hospitalier g´en´eral d’Aix-en-Provence, Centre hospitalier r´egional de Clermont-Ferrand, hˆopital Hˆotel-Dieu, Centre hospitalier r´egional de Limoges, hˆopital Dupuytren, Centre hospitalier r´egional de Lyon, hˆopital E. Herriot, Centre hospitalier r´egional de Grenoble, Centre hospitalier de Nevers, Centre hospitalier r´egional de Dijon, Centre hospitalier r´egional de Besanc¸on, Hˆopitaux civils de Colmar, Clinique m´edico-chirurgicale Le Parc, Centre hospitalier r´egional de Strasbourg, hˆopital Hautepierre, Centre hospitalier de Neufchateau, Centre hospitalier r´egional de Nancy, Centre hospitalier de Charleville-M´ezi`eres, Hˆopital Intercommunal de Cr´eteil, Assistance publique-Hˆopitaux de Paris: hˆopital R. Debr´e, hˆopital A. Trousseau, hˆopital Necker-Enfant Malades, hˆopital St. Vincent de Paul, hˆopital Jean Verdier a` Bondy, hˆopital Louis Mourier a` Colombes.
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