TRAM, TRAN TAN MD; THINH, LE QUOC MD; NGA, TRAN TUYET MD; VY, NGUYEN NGOC TUONG MD; PEDERSEN, FREDDY KARUP MD; SCHLUMBERGER, M. MD
From the Pediatric Hospital No. 1, Ho Chi Minh City, Vietnam (TTT, LQT, TTN, NNTV); the University Clinic of Pediatrics II, Rigshospitalet, Copenhagen, Denmark (FKP); and Pasteur Mérieux Connaught and AMP, Marnes-la-Coquette, France (MS).
Address for reprints: Association pour l'Aide à la Médicine Préventive, 3 avenue Pasteur, 92430 Marnes-la-Coquette, France.
Background. To date no studies on the incidence of Haemophilus influenzae type b (Hib) disease, Hib carrier rates in infants and children or the proportion of bacterial meningitis cases caused by Hib in Vietnam have been performed. The availability of safe and highly effective Hib vaccines makes such information important.
Methods. The bacterial etiology of a sample of infants and children with pneumonia and meningitis seen at Pediatric Hospital No. 1 in Ho Chi Minh City was studied by culture and latex agglutination of blood, cerebrospinal fluid, urine and pleural fluid. The carriage rate of pneumococci and Hib was studied in a sample of outpatient children.
Results. Hib caused 53% of 34 culture-proven bacterial meningitis cases and pneumococci caused 18%. Of 31 meningitis cases diagnosed by latex agglutination, 39% were caused by Hib and 55% by pneumococci. Ninety percent of cases of Hib meningitis occurred in children <1 year of age. Fifty percent of meningitis cases were associated with acute respiratory infection. In 213 bacteremic pneumonia cases 92.5% of blood cultures grew Streptococcus pneumoniae and only 1% grew Hib. The carrier rate of Hib in outpatients <5 years of age with upper respiratory tract infection increased from 2% to 7.6% between 1993 and 1996.
Conclusion. Hib is the most frequent cause of meningitis in infants and children admitted to hospitals in South Vietnam. Ninety percent of Hib meningitis cases occur in patients <1 year of age. Bacteremic Hib pneumonia in Vietnam is rare. The results suggest that Hib is the major cause of meningitis in Vietnam but do not permit conclusions regarding its true incidence. The carrier rate of Hib in children <5 years of age in Vietnam has increased to ∼7% since 1993.
The epidemiology of disease in children caused by Haemophilus influenzae type b (Hib) in Vietnam is not known. There have been no studies to date in Vietnam on the incidence of Hib disease, Hib carrier rates in infants and children or the proportion of purulent or bacterial meningitis cases caused by Hib. The availability of a vaccine against Hib, which in Europe and North America has proved safe and highly effective in infants and children against invasive Hib disease, makes such information important so that rational decisions about vaccination strategies can be made.
For many years Pediatric Hospital No. 1 in Ho Chi Minh City has cooperated with the University Clinic of Pediatrics II at Rigshospitalet in Copenhagen, Denmark, with the support of the Danish Vietnamese Association and the Danish National Aid Agency. As a result of this cooperation on training and study of acute respiratory infections [acute respiratory infection (ARI)] in Vietnam, the capabilities of the clinical microbiology laboratory have been improved and strengthened. Based on this laboratory facility and the research experience accumulated in the acute respiratory infection (ARI) study group, a study of the etiology of pneumonia and meningitis was carried out with financial support provided by Pasteur Mérieux Connaught, Marnes-la-Coquette, France. Previously a small study of carriage rates of H. influenzae and pneumococci in outpatient children was performed as part of the ARI study.
MATERIALS AND METHODS
Case recruitment. Infants and children between 30 days and 5 years of age admitted to Pediatric Hospital No. 1 in Ho Chi Minh City between May 1, 1995, and November 30, 1996, were studied.
Patients with pneumonia were included if they fulfilled the World Health Organization ARI criteria for pneumonia.1 Patients with meningitis were included if they had cloudy cerebrospinal fluid (CSF) or polymorphonuclear neutrophils above 50/μl and albumin concentration in CSF above 45 g/l. Concomitant respiratory manifestations in meningitis patients were defined as either acute upper respiratory infections (AURI) or acute lower respiratory infection (ALRI). AURI was defined by the Board on Science and Technology for International Development (BOSTID)2 as the presence of one of the following signs: purulent nasal discharge; injected throat; earache; or purulent discharge from the ears. ALRI was defined by BOSTID2 as the presence of one of the following signs: inspiratory stridor; wheezing; crepitation on auscultation; respiratory rate >50 per minute; chest wall retractions; or cyanosis.
Laboratory studies. In pneumonia patients the following studies were performed: blood culture; and latex agglutination in serum, urine and pleural fluid (when appropriate).
In meningitis patients the following studies were performed: cell counts; differential count, albumin concentration; microscopy (Gram stain); culture and latex agglutination of CSF.
From 1 to 2 ml of blood were inoculated into 20 ml of brain-heart infusion broth in reusable bottles with rubber stoppers, which were incubated at 35°C and examined daily for turbidity and hemolysis for 7 days. Terminal subculture was done. Identification was performed on Müller-Hinton agar (MHA; Oxoid), 5% sheep blood MHA plates for pneumococci and chocolate agar prepared from MHA with 5% sheep blood supplemented with 5 μg/ml nicotinamide adenine dinucleotide (Factor V) for H. influenzae.
Latex agglutination was used to test for Hib, pneumococci, meningococci type B and Staphylococcus aureus.
Case definition. Pneumonia was classified as definitely bacterial if blood culture was positive and as suspected bacterial if latex agglutination in serum, urine or pleural fluid was positive.
Meningitis was classified as definitely bacterial if culture or Gram-stained smear of CSF was positive and as suspected bacterial if latex agglutination of CSF was positive. Bacteremia was considered present if either blood culture or latex agglutination in either serum or urine was positive.
Carriage studies. For determination of the carrier rate of pneumococci and H. influenzae, nasopharyngeal culture was obtained from 208 children from 6 months to 5 years of age who were seen in the outpatient department with AURI in 1993 and again from 51 children from October to December, 1996.
Of 300 pneumonia cases 213 (71%) had bacteremic pneumonia. Streptococcus pneumoniae grew in 197 (92.5%) of the blood cultures, 2 (1%) grew Hib and 14 (6.6%) grew other organisms.
Of the 86 meningitis cases 34 (39.5%) were definitely bacterial as defined by positive CSF culture, 31 (36%) were suspected bacterial as defined by latex agglutination, whereas the remaining 21 (24%) had pleocytosis and elevated albumin concentration but no evidence of bacterial etiology by culture or latex agglutination of the CSF. Of the 34 definite bacterial meningitis cases 18 (53%) were caused by Hib, 6 (18%) by pneumococci and 10 (29%) by other organisms. Of the 31 suspected cases 12 (39%) were caused by Hib, 17 (55%) by pneumococci and 2 (6%) by other organisms.
Of the 86 meningitis cases 60 (70%) were blood culture-positive. Of those 60 cases 30 (50%) were caused by Hib, 24 (40%) were caused by pneumococci and 6 (10%) were caused by other organisms (meningococci and S. aureus). Figure 1 shows the age distribution of cases of Hib meningitis, and Figure 2 shows the age distribution of pneumococcal meningitis and pneumococcal pneumonia.
Of the 86 meningitis cases 43 (50%) were associated with ARI manifestations, including 14 of 30 caused by Hib, 18 of 23 caused by pneumococci and 11 of 33 caused by other organisms. Details of associated ARI are shown in Figure 3.
Table 1 shows results of the study of bacterial carriage among infants and children with AURI seen at the outpatient department. Thirty-four percent of the nasopharyngeal cultures in 1993 grew pneumococci and 33% grew H. influenzae, but only 2% of all cultures grew Hib. In contrast, in 1996, 27% of the cultures grew pneumococci and 57% grew H. influenzae, with 8% of all cultures showing Hib.
The most frequently encountered pneumococcal serotypes in the carrier study were 6A, 6B, 14, 19F and 23F, in that order of frequency. Serotyping was not performed on pneumococcal isolates from blood and CSF.
This study clearly demonstrates that Hib is the most frequent cause of meningitis in infants and children admitted to Pediatric Hospital No. 1 in Ho Chi Minh City. Because most of the cases are from the hospital's catchment area covering approximately one-half of the population of 4 million of Ho Chi Minh City, this is likely to be representative of at least urban, if not rural, South Vietnam. Because children with meningitis also are admitted to other hospitals in the catchment area, the figures found do not permit conclusions regarding the incidence of Hib meningitis in the area. It is noteworthy that 90% of the Hib meningitis cases occurred in patients <1 year of age. This figure is higher than that found in most meningitis studies from other countries3 and may be the result of the high population concentration and crowding, as well as reflecting the high carrier rate. The carrier studies performed in 1993 and 1996 showed an increase in the Hib carriage rate from 2 to 8%, the latter high rate being from the months immediately after the year of the meningitis study.
In contrast to the situation with meningitis the proportion of bacteremic cases of pneumonia caused by Hib was as low as 1%, whereas pneumococci caused 56% of bacteremic pneumonia cases in Ho Chi Minh City. Whether this was because of a higher tendency to bacteremia in pneumococcal pneumonia than in Hib pneumonia; to a lower degree of bacteremia (below 105 colony-forming units/ml) in Hib pneumonia,4 thus requiring higher blood volumes for detection; to other factors, such as the influence of previous antibiotic treatment; or whether it truly reflects a very low incidence of Hib pneumonia is not known. The very low proportion of Hib-positive blood cultures in pneumonia, as compared with the number positive for pneumococci, would indicate the latter. A possible cross-reactivity between pneumococcal serotypes 6A or 6B and Hib could contribute to a low apparent Hib incidence in situations where these pneumococcal serotypes occur frequently.5
Fifty percent of the cases of meningitis were associated with ARI, including 47% of Hib meningitis cases. These figures may indicate that Hib pneumonia occurs more frequently than suggested by the blood culture results in pneumonia patients.
In 1994 WHO suggested that there would be a high impact from vaccination against pneumococci and a medium impact from Hib vaccination.6 Indeed the association between ARI and meningitis found in this study, the importance of both Hib and pneumococci in the etiology of meningitis, the substantial importance of pneumococci in pneumonia and the suggested contribution of Hib to the etiology of pneumonia point to the importance of considering possibilities for the prevention of both pneumococcal disease and Hib disease by vaccination in infants and children in Vietnam in the future, when conjugate pneumococcal vaccines may become available.
Pediatric Hospital No. 1 is indebted to the following agencies for their substantial support to this study: Pasteur Mérieux Connaught (France), Danish Vietnamese Association and Danish International Development Assistance, Danish Ministry of Foreign Affairs, Denmark.
1. World Health Organization. Technical basis for the WHO recommendations on the management of pneumonia in children at first-level health facilities (WHO/ARI/91.20). Geneva: WHO, 1991.
2. Selwyn J, on behalf of the Coordinated Data Group of BOSTID Researchers. The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries. Rev Infect Dis 1990;12(Suppl.): S870-88.
3. Clements DA. Cost of treatment and prevention of Haemophilus influenzae
type b disease. Pharmaco-Economics 1994;6:442-52.
4. Funkhouser A, Steinhoff MC, Ward J. Haemophilus influenzae
disease and immunization in developing countries. Rev Infect Dis 1991;13(Suppl 6):S542-54.
5. Montgomery JM, Lehmann D, Smith T, et al. Bacterial colonization of the upper respiratory tract and its association with acute lower respiratory tract infections in highland children of Papua New Guinea. Rev Infect Dis 1990;12(Suppl 8):S1006-15.
6. World Health Organization. ARI programme for control of acute respiratory infections: sixth programme report, 1992-93 (WHO/ARI/94.33). Geneva: WHO, 1994.
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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