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Pediatric Infectious Disease Journal:
Haemophilus Influenzae Type B Disease And Vaccination: Asia

Haemophilus influenzae type b infections in Hong Kong

LAU, YU LUNG MD; YUNG, RAYMOND MBBS; LOW, LOUIS FRCP; SUNG, RITA FRCP; LEUNG, CHI WAI MBBS; LEE, WAI HONG FRCP

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From the Department of Pediatrics, Queen Mary Hospital, The University of Hong Kong (YLL, LL), Department of Microbiology, Pamela Youde Nethersole Eastern Hospital (RY), Department of Pediatrics, Prince of Wales Hospital, Chinese University of Hong Kong (RS), Department of Pediatrics, Princess Margaret Hospital (CWL), and Department of Pediatrics, Queen Elizabeth Hospital (WHL), Hong Kong.

Address for reprints: Association pour l'Aide à la Médicine Préventive, 3 avenue Pasteur, 92430 Marnes-la-Coquette, France.

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Abstract

A 5-year territory-wide retrospective survey of invasive Haemophilus influenzae type b (Hib) diseases in Hong Kong established that the annual incidence for children <5 years old was 2.7 per 100 000 [95% confidence interval (CI), 2.0 to 3.5]. However, the corresponding annual incidence in Vietnamese refugees in Hong Kong was 42.7 per 100 000 (95% CI 17.2 to 87.9), giving a relative risk of 18.5 (95% CI 8.3 to 41.0). The nasopharyngeal carriage rate of Hib was zero in 621 healthy Chinese children and 1.3% (95% CI 0.04 to 2.63%) in 300 healthy Vietnamese refugees 2 months to 5 years old in Hong Kong. The corresponding carriage rate of nontypable H. influenzae was 5.8% (95% CI 1.4 to 7.6%) in Chinese and 65.4% (95% CI 58.9 to 69.8) in Vietnamese. In a larger study of 1812 healthy Chinese children between 6 months and 5 years of age investigated by throat swabs, again no Hib was isolated but 141 children (7.8%) were found to be carriers of non-type b H. influenzae. In a study of 596 healthy Chinese children and adults, 25% had the protective level of anti-Hib antibody of >0.15 μg/ml by 1 year and 90% had reached >0.15 μg/ml by 6 years of age. There was some evidence that these "natural" antibodies against Hib in Hong Kong Chinese were cross-reacting antibodies against antigens on other encapsulated bacteria.

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INTRODUCTION

Before the introduction of universal vaccination against Haemophilus influenzae type b (Hib), Hib was a major cause of morbidity and mortality among children <5 years of age in Europe and North America.1-4 The annual incidence of invasive Hib disease was estimated to be between 22 and 109 per 100 000 children <5 years of age in these regions,1-4 and universal vaccination was extremely successful and cost-effective in nearly wiping out invasive Hib diseases. It follows naturally that the question is being asked whether universal Hib vaccination should be introduced in other less developed countries and regions.

There are several issues that need to be addressed by the public health bodies of these various countries or regions before a universal Hib vaccination could be introduced. The first issue is the documentation of the absolute disease burden caused by Hib in these regions. The second issue is the relative disease burden in the broader context of both total disease burden and the total resources committed by the government for health issues. We shall review in this paper only the existing data regarding the first issue in Hong Kong and not the health economic issue, which involves a multitude of variables and considerations.

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EPIDEMIOLOGY OF INVASIVE HIB INFECTIONS

Studies outside Europe and North America, such as those from Chile and Israel,5-7 have suggested a similar incidence of invasive Hib infections (between 21 and 60 per 100 000) in children <5 years of age. However, there are very few published studies on the epidemiology of Hib diseases in Asia. Studies from Singapore8 and Malaysia9 on pyogenic meningitis in children showed that 13 and 50% of cases, respectively, were caused by H. influenzae. In Beijing, China, a hospital-based study showed that 29% of bacterial meningitis in children were caused by Hib.10,11 A recent prospective study in Hefei City, China, established that Hib accounted for 52% of childhood bacterial meningitis and that the incidence of Hib meningitis was 10.4 per 100 000 children <5 years of age.12

In Hong Kong a 5-year, territory-wide retrospective survey of invasive Hib disease was conducted in two teaching hospitals, five regional hospitals, one military hospital and five private hospitals.13 These hospitals together provided inpatient care for all children in Hong Kong during the study period from January 1, 1986, to December 31, 1990. All patients <12 years of age admitted to these hospitals and with positive Hib culture were included. All cultures were carried out according to standard techniques. Capsular typing of cerebrospinal fluid (CSF) and blood isolates was performed by counterimmunoelectrophoresis, utilizing Hib antisera prepared by Burroughs Wellcome Company (UK). Latex slide agglutination tests (Wellcogen; Burroughs Wellcome) were performed on freshly obtained CSF.

Fifty-seven cases (28 male) of invasive Hib disease were recorded in children <12 years of age between 1986 and 1990; 46, 77 and 91% of cases occurred before 1, 3 and 5 years of age, respectively (Fig. 1). The primary diagnosis was meningitis in 37 (65%), septicemia in 9 (16%) and bacteremic pneumonia in 11 cases (19%). Of the 37 cases of meningitis 22 had positive culture in both CSF and blood, 13 in CSF only and 2 had no positive culture in CSF or blood but had a positive Hib antigen test and pleocytosis in CSF. There were no cases of epiglottitis. Seasonal distribution is shown in Figure 1, with most cases in the autumn and winter months of Hong Kong.

Fig. 1
Fig. 1
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The yearly incidences of invasive Hib diseases are shown in Table 1. The average annual incidences were 2.67 per 100 000 [95% confidence interval (CI), 2.0 to 3.5] and 7.10 per 100 000 (95% CI 4.6 to 10.4) for children <5 years and 1 year, respectively. The average annual incidence <5 years was 42.7 per 100 000 for Vietnamese refugees and 2.3 per 100 000 for Hong Kong residents, giving a relative risk for Vietnamese refugees of 18.5 (95% CI 8.3 to 41.0). Moreover Chinese patients (68% of cases) were underrepresented, because Chinese accounted for at least 95% of the total population. Furthermore 14 of the 39 Chinese patients had preexisting medical problems (Table 2), compared with only 1 of the 18 non-Chinese patients (P = 0.022).

Table 1
Table 1
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Table 2
Table 2
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The discrepancy in incidence of Hib disease between local Hong Kong Chinese and the Vietnamese refugees could be the result of environmental, genetic or other unknown factors. The high incidence rate of Hib disease in the Vietnamese refugees suggests that the low incidence rate in the local Chinese cannot be attributed to inadequate laboratory facilities for isolation and serotyping, because both groups of children were served by the same hospitals. However, the medical care of the Vietnamese refugees was tightly controlled, whereas the local Chinese had ample opportunities to obtain antibiotics over the counter or through private practitioners before presenting to hospitals. This indiscriminate use of antibiotics among the local Chinese might interfere with culture of the bacterial agent responsible for infection.14 In contrast the Vietnamese refugees might have little or no pretreatment with antibiotics before admission to hospital. This possibility is supported by the observation that 48% of the 129 children with postneonatal bacterial meningitis admitted to a teaching hospital in Hong Kong between 1981 and 1988 had no growth in the CSF.13 The three most common organisms obtained in culture were Salmonella species (n = 16), H. influenzae (n = 14) and Streptococcus pneumoniae (n = 14).13 Similarly in Thailand up to 60% of cases of bacterial meningitis in young children were of unknown etiology.15 Antibiotic abuse is still a common problem in Asia14, 15 and might partially explain the "low" incidence of Hib disease in this part of the world.

Overcrowding in the Vietnamese refugee camps might be another factor for their high incidence of Hib diseases. Their living area per person was 1.71 m2, compared with 10.20 m2 for the local Chinese.16 These are extremely crowded urban conditions when compared with those in the developed world.

The observation that 14 of the 39 Chinese patients and only 1 of the 18 non-Chinese patients had preexisting medical problems (P = 0.022) suggests that extra risks must be present in Chinese for Hib disease to occur, e.g. prolonged hospital care for underlying medical problems. The coexisting medical problems also explain the high fatality rate of the Chinese patients (12.8%) compared with that of the non-Chinese patients (5%).

The apparently low incidence of Hib diseases among the local Chinese could be the result of unreported cases or culture-negative cases. Even ascribing all the culture-negative cases to Hib, the incidence would have been increased by only 4- to 5-fold, i.e. 10.8 to 13.5 per 100 000 children <5 years of age. This incidence rate is still lower than that reported in the West before the introduction of universal Hib vaccination, but quite comparable with that reported in a recent prospective study done in Hefei City, China.12 There may be genuine and significant differences in incidence of Hib disease between Chinese and Caucasians, but further studies are mandatory to resolve this issue.

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CARRIAGE OF HIB

Attempting to explain the apparently low incidence of Hib diseases in Hong Kong, 2 studies investigating the carriage rate of Hib were performed.16, 17 In a study of 621 healthy Chinese children and 300 healthy Vietnamese refugees ages 2 months to 5 years in Hong Kong, the nasopharyngeal carriage rate of Hib was found to be zero in Chinese and 1.3% (95% CI 0.04% to 2.63%) in Vietnamese refugees.16 The carriage rate of nontypable H. influenzae was 5.8% (95% CI 1.4% to 7.6%) in Chinese and 65.4% (95% CI 58.9% to 69.8%) in Vietnamese.16 The carriage rates of both type b and nontypable H. influenzae in Vietnamese refugee children were similar to those reported from other parts of the world,18-20 whereas the rates in local Chinese children were extremely low, with Hib being absent from 802 swabs from 621 children.16 The possibility of sampling or laboratory errors was considered unlikely to explain the low rate among the Chinese children because a much higher carriage rate was found in the Vietnamese refugees and the same staff and techniques were used for both groups of children. Ethnic group was the only significant predictor for the carriage of Hib (P = 0.0013). For the carriage of non-type B H. influenzae, three factors were significantly associated with higher carriage rates: Vietnamese race (odds ratio, 27); age >3 months vs. <3 months (odds ratio, 3.4); and having >2 siblings (odds ratio, 3.7).

It has been argued that nasopharyngeal swabs might underestimate the carriage rate of Hib when compared with throat swabs. However, in a larger study of Hib and non-type b H. influenzae carriage rates among 1812 healthy Chinese children ages 6 months to 5 years investigated by throat swabs, again no Hib was isolated but 141 children (7.8%) were found to be carriers of non-type b H. influenzae.17 The low carriage rate could be the result of sampling error because this was only a cross-sectional study rather than a longitudinal study. Nevertheless the 2 carriage rate studies corroborated each other,16-17 and the findings reflected the discrepancy in the incidences of invasive Hib disease between the local Hong Kong Chinese children and Vietnamese refugee children.13

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NATURALLY ACQUIRED ANTIBODIES AGAINST HIB

In a study of age-related natural anti-Hib antibody among 596 healthy Chinese children and adults in Hong Kong, the antibody profile was found to be similar to that in Finland; i.e. only 25% had the protective level of >0.15 μg/ml by 1 year but 90% had reached >0.15 μg/ml by 6 years of age.17 This finding would suggest exposure to the Hib capsular polysac-charide in Hong Kong Chinese similar to that in the Finns. However, the extremely low carriage rate of Hib among Hong Kong Chinese would suggest otherwise. Indeed there was some evidence that these "natural" antibodies against Hib in the Hong Kong Chinese were cross-reacting antibodies against antigens on other encapsulated bacteria.21

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CONCLUSION

The documentation of disease burden caused by Hib in Hong Kong is still far from satisfactory. The limited number of published studies thus far could underestimate the magnitude of Hib diseases because of widespread antibiotic abuse, study design or some other unknown factors. It is essential to refine the documentation of the disease burden in various Asian countries, perhaps using a common protocol prospectively. Thus far the evidence suggests that Hib disease occurs at a lower absolute level in Hong Kong than in the West. Nevertheless the relative importance of Hib in causing childhood bacterial meningitis has been well-documented in Hong Kong and several other Asian countries. This single observation should be powerful enough to urge public health authorities to put universal Hib vaccination on their agenda for urgent discussion.

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ACKNOWLEDGMENTS

We thank all of the members of the Hong Kong Hib Study Group: Drs. A. K. H. Chan (Caritas Medical Centre); G. Chan and W. H. Lee (Queen Elizabeth Hospital); C. B. Chow and C. W. Leung (Princess Margaret Hospital); A. Ho, S. J. Oppenheimer and R. Sung (Prince of Wales Hospital); P. Ip (United Christian Hospital); E. Kwan, Y. L. Lau, L. Low and R. Yung (Queen Mary Hospital); K. W. Ng (Department of Statistics, University of Hong Kong); and R. Yuen (Kwong Wah Hospital).

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REFERENCES

1. Murphy TV, Osterholm MT, Peirson LM, et al. Prospective surveillance of Haemophilus influenzae type b disease in Dallas County, Texas, and in Minnesota. Pediatrics 1987;79:173-80.

2. Tudor-Williams G, Frankland J, Isaacs D, et al. Haemophilus influenzae type b disease in the Oxford region. Arch Dis Child 1989;64:517-9.

3. Gilbert GL, Clements DA, Broughton SJ. Haemophilus influenzae type b infections in Victoria, Australia, 1985 to 1987. Pediatr Infect Dis J 1990;9:252-7.

4. Black SB, Shinefield HR, The Kaiser Permanente Pediatric Vaccine Study Group. Immunization with oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine on a large health maintenance organization population: extended follow-up and impact on Haemophilus influenzae disease epidemiology. Pediatr Infect Dis J 1992;11:610-3.

5. Ferreccio C, Ortiz E, Astroza L, Rivera C, Clemens J, Levine MM. A population-based retrospective assessment of the disease burden resulting from invasive Haemophilus influenzae in infants and young children in Santiago, Chile. Pediatr Infect Dis J 1990;9:488-94.

6. Halfon-Yaniv I, Dagan R. Epidemiology of invasive Haemophilus influenzae type b infections in Bedouins and Jews in Southern Israel. Pediatr Infect Dis J 1990;9:321-6.

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9. Choo KE, Ariffin WA, Ahmad T, Lim WL, Gururaj AK. Pyogenic meningitis in hospitalized children in Kelantan, Malaysia. Ann Trop Paediatr 1990;10:89-98.

10. Zhang GR, Yang YH, Shen XZ, et al. Evaluation of CIE for detecting bacterial antigen. Chin J Med Lab Technol 1992;15:18-9.

11. Shen XZ, Yang YH, Zhang GR, et al. Significance of antigen detection by CIE applied to etiologic diagnosis of bacterial meningitis. Chung-hua Erh Ko Tsa Chih [Chin J Pediatr] 1990;28:210-2.

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16. Sung RYT, Ling JM, Fung SM, et al. Carriage of Haemophilus influenzae and Streptococcus pneumoniae in healthy Chinese and Vietnamese children in Hong Kong. Acta Paediatr 1995;84:1262-7.

17. Lau YL, Yung R, Lam B, Karlberg J, Shen SM, Low L. Natural antibody against and pharyngeal carriage of Haemophilus influenzae type b (Hib) among Chinese children in Hong Kong [Abstract 184]. Presented at the Sixth International Congress for Infectious Diseases, Prague, Czech Republic, April 26 to 30, 1994.

18. Michaels RH, Poziviak CS, Stonebraker FE, et al. Factors affecting pharyngeal Haemophilus influenzae type b colonization rates in children. J Clin Microbiol 1976;4:413-7.

19. Lerman SJ, Kucera JC, Brunken JM. Nasopharyngeal carriage of antibiotic-resistant Haemophilus influenzae in healthy children. Pediatrics 1979;64:287-91.

20. Murphy TV, Granoff D, Chrane DF, et al. Pharyngeal colonization with Haemophilus influenzae type b in children in a day care center without invasive disease. J Pediatr 1985;106:712-6.

21. Ulanova M, Hann-Zoric M, Lau YL, Lucas A, Hanson LA. Expression of Haemophilus influenzae type b idiotype 1 on naturally acquired antibodies. Clin Exp Immunol 1996;105:422-8.

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Section Description

FIRST INTERNATIONAL CONFERENCE ON HAEMOPHILUS INFLUENZAE TYPE b INFECTION IN ASIA

The Editors thank the Association pur l'Aide à la Médicine Préventive, the Foundation Mérieux, and the World Health Organization for supporting publication of these proceedsings, and Jennifer Wells for her editorial assistance.

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Keywords:

Haemophilus influenzae; Haemophilus influenzae type b; Hong Kong; meningitis

© Williams & Wilkins 1998. All Rights Reserved.

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