Epidemiology of Haemophilus influenzae type b disease in France

Epidemiology of Haemophilus influenzae type b disease in France P. Reinert*, A. Liwartowski, H. Dabernat, C. Guyot, J. B o u c h e r and C. Carrere t

Results are reported of an epidemiological study which ,spanned ten years and was carried out in two French departments. A total o.['277 cases oJ'Hib disease occurring in children < 5 years oht are reported and, in this age group, the incidence is evaluated at 21/100 000. Meningitis accounted Jor 64% qf infections and epiglottitis Jor 7%. While the overall mortali O' rate was 3.3%, death was secondary to meningitis in 7/8 eases. Sequelae, which were all related to meningitis, were major in 1.2% oJ" cases, severe in 9% of cases, and involved some hearing loss in 3.3% qf cases. The monitoring networks set up in the two departments were characterized by sensitivities q f 87 and 94%, respectively. They should prove useful in assessing the impact o f vaccination, when large-scale implementation 01 vaccination has spread to both departments. Keywords: Haemophih~s iplltuenzae b; epidemiology: meningitis: epiglottitis

INTRODUCTION

Haemophilus inJtuenzae type b (Hib) infections rank as one of the most c o m m o n causes of severe disease in children under three years of age. Incidence varies worldwide from one area to the next, and the age relationship and the relative attack rates of meningitis and epiglottitis are not uniform in all countries. A number of epidemiological studies have been conducted, both in the USA and in Europe. The present survey is the first one to have been carried out in France with the intention of determining the incidence of meningitis and other systemic disease (OSD), as well as the frequency of sequelae and the mortality rate. Hopefully, this study will permit the introduction of some preventive measures in the form of vaccination, and should provide helpful epidemiological data towards setting up national recommendations to that effect.

MATERIAL AND METHODS The study spanned 10 years (from 1 January 1980 to 31 December 1989) and encompassed the two French departments of Val-de-Marne and Haute Garonne, with a total population of 2 165 642 (in 1982), including 131 786 children, i.e. 6% with ages ranging from 0 to 4 years. The child population 0 4 years old that was followed up during the study period represented 3.8% of this age

University Department of Public Health, Faculty of Medicine of University of Creteil, Paris 12, France. tHaemophilusStudy Centre, GEEP, CHU Purpan, Toulouse, France. * To whom correspondence should be addressed at Paediatric Department, Centre Hopitalier Intercommunal, 94000, Creteil, France 0264-410X/93/110S38-05 @ 1993 Butterworth-Heinemann Ltd

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group. The mean population was calculated from data derived from the 1982 census. Since 1980, a permanent epidemiological screening network has been operating in each department. In Valde-Marne, this control system investigates all cases of bacterial meningitis. The department of Haute Garonne harbours the National Haemophilus Record Centre, which lists all Haemophilus infections detected by bacteriologists. The screening network in Val-de-Marne operates in the following manner. Twice a week, a physician in the department in charge of dealing with all epidemics telephones the correspondent bacteriologist at each hospital; this part of the operation is called active data collection. On other days, the bacteriology correspondents telephone the physician responsible for epidemiological record-keeping; this constitutes the passive data collection. The screening network in Haute Garonne functions solely in the active mode, i.e. the physician in charge of the network checks regularly with the hospital bacteriologists. In addition to the above-mentioned control systems, our sources comprised bacteriological laboratory registers and patients' files compiled from 16 hospitals known to admit children originating from the two departments of interest, so that we could detect any case which may have escaped the screening network's attention. The record files of all the hospitals participating in this monitoring system, as well as those issued by other remote hospitals not included in the programme, were reviewed by two epidemiologists. Examination of registers covering the period 1980 1986 took place in 1987, while those covering the years 1987 and 1988 were reviewed in 1989. Children enrolled in the survey were aged 4 years and resided in one of the two departments. Severe Hib infec-

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7% Figure 1 Distribution of Hib infections in 277 cases. I~, Meningitis; ~, epiglottitis; D, pneumonia; D, arthritis; 3 , septicaemia; I~I, cellulitis; [], other

tion was diagnosed on the basis of one of the following criteria: positive cultures from cerebrospinal, joint, pleural or pericardial fluid or blood specimens; clinical and biological picture compatible with severe Hib disease with the presence of specific soluble antigens identifiable by countercurrent immunoelectrophoresis or agglutination of latex particles to which antibody is adsorbed. RESULTS In Val-de-Marne, 177 cases of meningitis were reported, 90 of which appeared in the screening network listing. All cases detected by the network were Haemophiluscaused meningitis. Sensitivity was 87% and specificity 100%. A total of 59 OSD cases appeared in the reference listings used in the paediatric and bacteriological services. In Haute Garonne, 84 cases were reported including 57 meningitis, all of which were caused by Haemophilus. Sensitivity was 94% and specificity 100%. A total of 277 cases of Haemophilus influenzae disease were detected among children aged 1 to 59 months, residents of one of the two departments. The serotype of the isolates was determined for 196 specimens and type b strains were identified for 100%. The 50 cases which were not serotyped were not excluded from the series. Meningitis was the most common form of severe Hib disease affecting 177 children (65%); next in importance were epiglottitis (20 cases; 7%), pneumonia (17 cases; 7 %), a rth ri ti s ( 16 cases, 7 % ), septicaemia ( 15 cases; 6 % ), cellulitis (11 cases; 4%) and other infections (9 cases; 4%) (Figure 1). Yearly incidence assessed for all Hib infections was 21/ 100 000; it was 15/100 000 and 17/100 000 for meningitis and OSD cases, respectively. Among the OSD group, the epiglottitis incidence rate was 2/100 000, with only 18 occurrences in 9 years. Over the ten-year study period, the number of

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observed cases was stable (Figure 2). The cumulated monthly rate of meningitis showed a biphasic seasonal distribution pattern, with peak occurrences during the months of March and October. The month of lowest incidence was August, with three cases only. As regards ODSs, although there was a peak incidence during October, this did not happen in March (Figure 3). Boys were more affected than girls and the sex ratio (male/ female) was 1.3. The mean age of meningitis was 17 months. Epiglottitis tended to occur later in life, at the mean age of 30 months. As far as the occurrence of meningitis in the 0-5 year age group was concerned, 6% of cases were observed before 6 months, 42% before 12 months, 68% before 18 months and 78% before two years. In these subgroups OSDs showed overall incidence rates of 9, 38, 61 and 68%, respectively (Figure 4). Overall mortality in this series was 3% with eight deaths occurring, seven of which were meningitis-related and one followed septicaemia. Permanent sequelae were noted in 27 cases (15%). Meningitis-related cases were most frequently reported, with 27 cases out of 177 (15%). Amongst these, we recorded two cases of major neurological deficit causing sufficient disability to warrant long-term institutionalization (retarded growth, hemiplegia, disturbances of equilibrium, shunted hydrocephalus). There were nine cases of isolated hearing loss, four of which were bilateral. OSDassociated sequelae involved the occurrence of febrile convulsions requiring long-term antiepileptic therapy, plus radiological sequelae in one child presenting with knee arthritis.

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Epidemiology of Hib disease in France: P. Reinert et al.

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Age distribution for different forms of Hib disease. I~, Meningitis; r j, epiglottitis; _J, other systemic disease excluding epiglottitis

Bacteriological criteria were applicable as follows. The microorganism was isolated from cerebrospinal fluid (CSF) cultures in 168 cases of meningitis (96%) versus 129 cases (80%), where it could be visualized by direct examination. In one case of positive clinical and biological diagnosis, CSF culture was negative and blood culture was positive. In five cases for which cultures could be obtained neither from CSF nor blood, diagnosis was arrived at because of the presence of soluble antigens in the blood, CSF, or urine. Blood cultures were positive in 74 cases, and the microorganism was identified in 62 cases from patients with OSD (74%). The agent was detected in other specimens collected from 21 patients; in three cases the disease was known to be Hib-caused due to the presence of specific Hib soluble antigens. The microorganism was biotyped in 149 cases which, for meningitis yielded the following data: type ! (139 cases; 93%), type II (6 cases; 5%), type IIl (2 cases) and type IV (2 cases). The biotype of the OSD-causing microorganisms was determined for 50 cases, yielding the following results: type I (39 cases; 78%), type II (six cases, 12%), type III (three cases; 6%) and type IV (two cases; 4%). Resistance of the bacteria to antibiotics via production of [3-1actamase was investigated in 253 cases. Such resistance was demonstrated for 73 strains, i.e. 29% of cases. In 1980, only 4% of the strains were resistant to [~-lactam antibiotics. The rate of resistant strains reached 55% by 1989. Figure 5 depicts the evolution of the frequency of resistant strains. Chloramphenicol-resistant strains were checked for in 205 cases and were detected in eight (4%). Seven chloramphenicol-resistant strains were also found to be resistant to the J3-1actams.

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DISCUSSION The measured incidence rate of severe Hib disease was 21/100 000. The real incidence was probably higher for the following reasons. Certain infections may have escaped detection despite investigators' efforts to the contrary. Bacteriological criteria were needed for positive diagnosis and certain infections may have been thwarted by blind antibiotic treatments. Children living in the department of interest may have been hospitalized elsewhere, particularly during the summer. During the same period, the network monitoring meningitis cases in Val-de-Marne recorded 26 cases of presumably aborted bacterial meningitis, one-third of which might have been accounted for by Hib infections (onethird would have been due to meningococcal infections and another third caused by other organisms). We also assume that 5% of cases have escaped the attention of the investigators because some children would have been

Epidemiology of Hib disease in France: P. Reinert et al.

hospitalized far from their homes. The real incidence of meningitis would then exceed that which was observed by 10%. If the same holds true for OSD, the true incidence of severe Hib-related disease would be 25/100 000. The incidence observable for meningitis is less than recorded in the USA. On the other hand, this incidence rate is comparable to that quoted for other European countries, 18/100 000 ~, and 23.6/100 0002 in the UK; 22/ 100 000 in The Netherlands3; 27/100 000 in Sweden 4 and 30/100 000 in Switzerland 5. The incidence of OSD (8/100 000) is lower than in other countries. In the USA, figures range from 22 to 60/ 100 000. In Europe, studies have mostly focused on epiglottitis, yielding figures varying from 4/100 0002 or 9/100 000 ~in the UK to 11.3/100 0006 and 28/100 0007 in Finland and Sweden, respectively. Compared to our own observations (2/100 000), it would seem that the incidence in France is lower. In our study, we were able to observe that the mean age of occurrence of both meningitis and OSD (exclusive ofepiglottitis) was the same, i.e. 17 months. On the other hand, epiglottitis occurs later in life (30 months); moreover, it appears that the mean age of occurrence of Hib infections bears some impact on the distribution of these diseases. Among populations of very high incidence rates (Inuits, Navajo and Apache Indians), all meningitis cases occur before the age of 24 months and children are never found to have epiglottitis ~-~°. In Northern Europe, meningitis occurs at a later period in life than in France; thus, before the age of 2 years, the incidence rate is 52, 53.6 or 54% TM ~. In these countries, the incidence of epiglottitis is comparable to that of meningitis, i.e. 28/100 000, respectively, in Sweden 4-7. In the USA, 71% of meningitis cases occur before 18 months ~2, and the frequency of epiglottitis in relation to Haemophilus infections as a whole varies from 4 to 17%9.~L~3 w. In our study, 68% of meningitis occurred before the age of 18 months, and the frequency of epiglottitis occurrence in proportion to all Haemophilusrelated diseases was 7%. Therefore, it appears that French and North American epidemiological data are comparable with respect to age relationship and localization, although the overall incidence in the USA is threetimes greater. As was noted in many studies, there is a slightly greater incidence in boys s,~s. Furthermore, there is a peak incidence rate of meningitis in October ~2, which is also in keeping with observations made in most other studies. The meningitis-caused mortality rate (4.4%) is comparable with that quoted in all recent publicationsl,4.6.8,gAl.16 22,23in all of which it is below 5%. The comparison between the different rates of occurrence of sequelae raises a problem of definition. Major sequelae requiring long-term care in special institutions are usually adequately listed 23. Our findings included 2/ 160 cases (1.2%). This is similar to such rates in all other publications, i.e. varying from 0 to 1.6%c4,22.'-3. Other neurological sequelae (14/160, i.e. 9%) need be compared to observations made by the authors of seven other studies, who found rates ranging from 7.5% to 20%

the children have had an audiogram done systematically following meningitis 25. Whenever hearing disturbances are checked for systematically, their incidence may be evaluated at 7.5-14.6% j,4,'-1,2426. Ampicillin-resistance associated with the production of [3-1actamase has been noted in many countries and the prevalence of such resistant strains has shown variable growth patterns depending upon the country, the type of infection, the encapsulated or non-encapsulated character of the isolate, and the testing method used. This figure is higher than that which was reported in 1987 by the French governmental Haemophilus Study Centre, i.e. 22% of resistant organisms isolated from cerebrospinal fluid. However, the Centre-tested strains were derived from the whole country, whereas our study was limited to a highly medicalized region, which may provide an explanation for the high rate observed 26. On the basis of the results obtained in two departments, our findings may be extrapolated to the entire country of France. All Hib-related infections are evaluated at 960 cases annually, including 620 meningitis, nearly 100 permanent sequelae and 20 deaths, i.e. onethird of the meningitis-caused deaths, occurring in the 0 to 5 years age group. This study confirms the important contribution of Hib to severe childhood infections. Some differences with other countries may be stressed. Although the age of occurrence is comparable to that noted in North America, the affected child population in Northern Europe (Scandinavia) is younger. The incidence rates observed for meningitis are comparable to those common to all European countries, but the rate of occurrence of epiglottitis is much lower in France than in the rest of the Continent. The frequency of epiglottitis in proportion to all other Hib infections is comparable in France and in the USA. Many authors have implicated the similar age of occurrence of Hib disease in these two areas of the world, and we support this point of view. CONCLUSION We confirm the important role of Hib as a causative agent of childhood infections. Accurate epidemiological data collected by us should provide a basis for discussing possible initiation of a preventive strategy by effective vaccination at the age of six months. Epidemiological monitoring networks are validated tools, which will make it possible to assess the evolution of the incidence of meningitis, as well as to evaluate the efficacy of the vaccine through controlled trials. REFERENCES 1 2

3

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1,4,9,19,24 26

However, we agree with many authors that owing to the occurrence of 6/160 cases of secondary hearing loss (3.3%), this type of sequela is under-rated. Only 20% of

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