Cost of illness due to typhoid fever in five Asian countries.

OBJECTIVE: To generate community-based estimates of the public (paid by the government) and private (paid by households) costs of blood culture-confirmed typhoid fever in Hechi, China; North Jakarta, Indonesia; Kolkata, India; Karachi, Pakistan and Hue, Vietnam. METHODS: To measure out-of-pocket costs of illness and lost earnings, families with culture-proven cases were surveyed 7, 14 and 90 days after onset of illness. Public costs of treatment were measured at local health facilities using a micro costing (bottom-up) method. RESULTS: The costs of hospitalized cases ranged from USD 129 in Kolkata to USD 432 in North Jakarta (hospitalization rates varied from 2% in Kolkata to 40% in Hechi) and the costs of non-hospitalized cases ranged from USD 13 in Kolkata to USD 67 in Hechi. Where costs were highest (Hechi, North Jakarta and Karachi), the bulk of the costs of hospitalized cases was borne by families, comprising up to 15% of annual household income. CONCLUSION: Although these estimates may understate true costs due to the fact that higher quality treatment may have been provided earlier-than-usual, this multi-country community-based study contributes to evidence on the public and private costs of typhoid fever in developing countries. These cost estimates were used in a cost-effectiveness analysis of typhoid vaccines and will help policymakers respond to World Health Organization's updated typhoid fever immunization recommendations.

Suitable disk antimicrobial susceptibility breakpoints defining Salmonella enterica serovar Typhi isolates with reduced susceptibility to fluoroquinolones.

Infections with Salmonella enterica serovar Typhi isolates that have reduced susceptibility to ofloxacin (MIC ≥ 0.25 µg/ml) or ciprofloxacin (MIC ≥ 0.125 µg/ml) have been associated with a delayed response or clinical failure following treatment with these antimicrobials. These isolates are not detected as resistant using current disk susceptibility breakpoints. We examined 816 isolates of S. Typhi from seven Asian countries. Screening for nalidixic acid resistance (MIC ≥ 16 µg/ml) identified isolates with an ofloxacin MIC of ≥0.25 µg/ml with a sensitivity of 97.3% (253/260) and specificity of 99.3% (552/556). For isolates with a ciprofloxacin MIC of ≥0.125 µg/ml, the sensitivity was 92.9% (248/267) and specificity was 98.4% (540/549). A zone of inhibition of ≤28 mm around a 5-µg ofloxacin disc detected strains with an ofloxacin MIC of ≥0.25 µg/ml with a sensitivity of 94.6% (246/260) and specificity of 94.2% (524/556). A zone of inhibition of ≤30 mm detected isolates with a ciprofloxacin MIC of ≥0.125 µg/ml with a sensitivity of 94.0% (251/267) and specificity of 94.2% (517/549). An ofloxacin MIC of ≥0.25 µg/ml and a ciprofloxacin MIC of ≥0.125 µg/ml detected 74.5% (341/460) of isolates with an identified quinolone resistance-inducing mutation and 81.5% (331/406) of the most common mutant (carrying a serine-to-phenylalanine mutation at codon 83 in the gyrA gene). Screening for nalidixic acid resistance or ciprofloxacin and ofloxacin disk inhibition zone are suitable for detecting S. Typhi isolates with reduced fluoroquinolone susceptibility.

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness.

BACKGROUND: Influenza is a major cause of morbidity and hospitalization among children. While less often reported in adults, gastrointestinal symptoms have been associated with influenza in children, including abdominal pain, nausea, vomiting, and diarrhea. METHODS: From September 2005 and April 2008, pediatric patients in Indonesia presenting with concurrent diarrhea and influenza-like illness were enrolled in a study to determine the frequency of influenza virus infection in young patients presenting with symptoms less commonly associated with an upper respiratory tract infection (URTI). Stool specimens and upper respiratory swabs were assayed for the presence of influenza virus. RESULTS: Seasonal influenza A or influenza B viral RNA was detected in 85 (11.6%) upper respiratory specimens and 21 (2.9%) of stool specimens. Viable influenza B virus was isolated from the stool specimen of one case. During the time of this study, human infections with highly pathogenic avian influenza A (H5N1) virus were common in the survey area. However, among 733 enrolled subjects, none had evidence of H5N1 virus infection. CONCLUSIONS: The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

A study of typhoid fever in five Asian countries: disease burden and implications for controls.

OBJECTIVE: To inform policy-makers about introduction of preventive interventions against typhoid, including vaccination. METHODS: A population-based prospective surveillance design was used. Study sites where typhoid was considered a problem by local authorities were established in China, India, Indonesia, Pakistan and Viet Nam. Standardized clinical, laboratory, and surveillance methods were used to investigate cases of fever of >or= 3 days' duration for a one-year period. A total of 441,435 persons were under surveillance, 159,856 of whom were aged 5-15 years. FINDINGS: A total of 21,874 episodes of fever were detected. Salmonella typhi was isolated from 475 (2%) blood cultures, 57% (273/475) of which were from 5-15 year-olds. The annual typhoid incidence (per 100,000 person years) among this age group varied from 24.2 and 29.3 in sites in Viet Nam and China, respectively, to 180.3 in the site in Indonesia; and to 412.9 and 493.5 in sites in Pakistan and India, respectively. Altogether, 23% (96/413) of isolates were multidrug resistant (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole). CONCLUSION: The incidence of typhoid varied substantially between sites, being high in India and Pakistan, intermediate in Indonesia, and low in China and Viet Nam. These findings highlight the considerable, but geographically heterogeneous, burden of typhoid fever in endemic areas of Asia, and underscore the importance of evidence on disease burden in making policy decisions about interventions to control this disease.

The use of typhoid vaccines in Asia: the DOMI experience.

BACKGROUND: Two currently licensed typhoid vaccines have been evaluated in Asia, yet few Asian countries have considered including typhoid vaccines in their vaccination programs. The Diseases of the Most Impoverished (DOMI) Program was initiated to provide evidence to decide on the introduction of typhoid vaccines in Asian countries. METHODS: The centerpiece of the program is a multidisciplinary demonstration project with Vi vaccine in 5 Asian countries. The project includes epidemiologic, economic, sociobehavioral, and policy studies. RESULTS: Policy makers want evidence on which to base their vaccine-related decisions. The DOMI Program has provided updated information on the typhoid fever burden at several Asian sites. Cost-of-illness studies found high costs to governments and individuals. Sociobehavioral studies indicated a positive attitude toward typhoid vaccines. The results of the demonstration projects indicate that mass-immunization campaigns are feasible and acceptable. CONCLUSIONS: The DOMI Program has begun to provide momentum for the evidence-based, rational introduction of typhoid vaccines into the public health programs of several Asian countries.

Adults' perceived prevalence of enteric fever predicts laboratory-validated incidence of typhoid fever in children.

This study was undertaken to develop a model to predict the incidence of typhoid in children based on adults' perception of prevalence of enteric fever in the wider community. Typhoid cases among children, aged 5-15 years, from epidemic regions in five Asian countries were confirmed with a positive Salmonella Typhi culture of the blood sample. Estimates of the prevalence of enteric fever were obtained from random samples of adults in the same study sites. Regression models were used for establishing the prediction equation. The percentages of enteric fever reported by adults and cases of typhoid incidence per 100,000, detected through blood culture were 4.7 and 24.18 for Viet Nam, 3.8 and 29.20 for China, 26.3 and 180.33 for Indonesia, 66.0 and 454.15 for India, and 52.7 and 407.18 for Pakistan respectively. An established prediction equation was: incidence of typhoid (1/100,000= -2.6946 + 7.2296 x reported prevalence of enteric fever (%) (F=31.7, p<0.01; R2=0.992). Using adults' perception of prevalence of disease as the basis for estimating its incidence in children provides a cost-effective behavioural epidemiologic method to facilitate prevention and control of the disease.

A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology.

BACKGROUND: The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. METHODS AND FINDINGS: Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). CONCLUSIONS: Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.

Isolation of Salmonella enterica subspecies enterica serovar Paratyphi B dT+, or Salmonella Java, from Indonesia and alteration of the d-tartrate fermentation phenotype by disrupting the ORF STM 3356.

Salmonella enterica subspecies enterica serovar Paratyphi B [O1,4,(5),12 : Hb : 1,2] can cause either an enteric fever (paratyphoid fever) or self-limiting gastroenteritis in humans. The d-tartrate non-fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT- (S. Paratyphi B) is the causative agent of paratyphoid fever, and the d-tartrate fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT+ (S. Paratyphi B dT+; formerly called Salmonella Java) causes gastroenteritis. S. Java is currently recognized as an emerging problem worldwide. Twelve dT+ S. Java isolates were collected in Indonesia between 2000 and 2002. One-third of them contained Salmonella genomic island 1 (SGI1), which gives the multidrug-resistant phenotype to the bacteria. In this study, a PCR-based method to detect a single nucleotide difference responsible for the inability to ferment d-tartrate, reported elsewhere, was validated. The d-tartrate fermenting phenotype of S. Java was converted to the non-fermenting phenotype by the disruption of the ORF STM 3356, and the d-tartrate non-fermenting phenotype of the ORF STM 3356-disrupted strain and the dT- reference strain was changed to the dT+ phenotype by complementing ORF STM 3356 in trans. The results show that the dT+ phenotype requires a functional product encoded by STM 3356, and support the use of the PCR-based discrimination method for S. Paratyphi B and S. Java as the standard differentiation method.

The burden of diarrhoea, shigellosis, and cholera in North Jakarta, Indonesia: findings from 24 months surveillance.

BACKGROUND: In preparation of vaccines trials to estimate protection against shigellosis and cholera we conducted a two-year community-based surveillance study in an impoverished area of North Jakarta which provided updated information on the disease burden in the area. METHODS: We conducted a two-year community-based surveillance study from August 2001 to July 2003 in an impoverished area of North Jakarta to assess the burden of diarrhoea, shigellosis, and cholera. At participating health care providers, a case report form was completed and stool sample collected from cases presenting with diarrhoea. RESULTS: Infants had the highest incidences of diarrhoea (759/1,000/year) and cholera (4/1,000/year). Diarrhea incidence was significantly higher in boys under 5 years (387/1,000/year) than girls under 5 years (309/1,000/year; p < 0.001). Children aged 1 to 2 years had the highest incidence of shigellosis (32/1,000/year). Shigella flexneri was the most common Shigella species isolated and 73% to 95% of these isolates were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol and tetracycline but remain susceptible to nalidixic acid, ciprofloxacin, and ceftriaxone. We found an overall incidence of cholera of 0.5/1,000/year. Cholera was most common in children, with the highest incidence at 4/1,000/year in those less than 1 year of age. Of the 154 V. cholerae O1 isolates, 89 (58%) were of the El Tor Ogawa serotype and 65 (42%) were El Tor Inaba. Thirty-four percent of patients with cholera were intravenously rehydrated and 22% required hospitalization. V. parahaemolyticus infections were detected sporadically but increased from July 2002 onwards. CONCLUSION: Diarrhoea causes a heavy public health burden in Jakarta particularly in young children. The impact of shigellosis is exacerbated by the threat of antimicrobial resistance, whereas that of cholera is aggravated by its severe manifestations.

Diarrhoea episodes and treatment-seeking behaviour in a slum area of North Jakarta, Indonesia.

Visits to household during a census in an impoverished area of north Jakarta were used for exploring the four-week prevalence of diarrhoea, factors associated with episodes of diarrhoea, and the patterns of healthcare use. For 160,261 urban slum-dwellers, information was collected on the socioeconomic status of the household and on diarrhoea episodes of individual household residents in the preceding four weeks. In households with a reported case of diarrhoea, the household head was asked which form of healthcare was used first. In total, 8,074 individuals (5%)--13% of children aged less than five years and 4% of adults--had a diarrhoea episode in the preceding four weeks. The two strongest factors associated with a history of diarrhoea were a diarrhoea episode in another household member in the four weeks preceding the interview (adjusted odds ratio [OR] 11.1; 95% confidence interval [CI] 10.4-11.8) and age less than five years (adjusted OR 3.4; 95% CI 3.2-3.5). Of the 8,074 diarrhoea cases, 1,969 (25%) treated themselves, 1,822 (23%) visited a public-health centre (PHC), 1,462 (18%) visited a private practitioner or a private clinic, 1,318 (16%) presented at a hospital, 753 (9%) bought drugs from a drug vendor, and 750 (9%) used other healthcare providers, such as belian (traditional healers). Children with diarrhoea were most often brought to a PHC, a private clinic, or a hospital for treatment. Compared to children, adults with diarrhoea were more likely to treat themselves. Individuals from households in the lowest-income group were significantly more likely to attend a PHC for treatment of diarrhoea compared to individuals from households in the middle- and higher-income groups.

Enteric fever burden in North Jakarta, Indonesia: a prospective, community-based study.

INTRODUCTION: We undertook a prospective community-based study in North Jakarta, Indonesia, to determine the incidence, clinical characteristics, seasonality, etiologic agent, and antimicrobial susceptibility pattern of enteric fever. METHODOLOGY: Following a census, treatment centre-based surveillance for febrile illness was conducted for two-years. Clinical data and a blood culture were obtained from each patient. RESULTS: In a population of 160,261, we detected 296 laboratory-confirmed enteric fever cases during the surveillance period, of which 221 (75%) were typhoid fever and 75 (25%)  were paratyphoid fever.  The overall incidence of typhoid and paratyphoid cases was 1.4, and 0.5 per thousand populations per year, respectively. Although the incidence of febrile episodes evaluated was highest among children under 5 years of age at 92.6 per thousand persons per year, we found that the burden of typhoid fever was greatest among children between 5 and 20 years of age. Paratyphoid fever occurred most commonly in children and was infrequent in adults. CONCLUSION: Enteric fever is a public health problem in North Jakarta with a substantial proportion due to paratyphoid fever. The results highlight the need for control strategies against enteric fever.

The cost-effectiveness of typhoid Vi vaccination programs: calculations for four urban sites in four Asian countries.

The burden of typhoid fever remains high in impoverished settings, and increasing antibiotic resistance is making treatment costly. One strategy for reducing the typhoid morbidity and mortality is vaccination with the Vi polysaccharide vaccine. We use a wealth of new economic and epidemiological data to evaluate the cost-effectiveness of Vi vaccination against typhoid in sites in four Asian cities: Kolkata (India), Karachi (Pakistan), North Jakarta (Indonesia), and Hue (Vietnam). We report results from both a societal as well as a public sector financial perspective. Baseline disease burden estimates in the four areas are: 750 cases per year in two Kolkata neighborhoods (pop 185,000); 84 cases per year in the city of Hue (pop 280,000); 298 cases per year in two sub-districts in North Jakarta (pop 161,000), and 538 cases per year in three squatter settlements in Karachi (pop 102,000). We estimate that a vaccination program targeting all children (2-14.9) would prevent 456, 158, and 258 typhoid cases (and 4.6, 1.6, and 2.6 deaths), and avert 126, 44, and 72 disability-adjusted life years (DALYs) over 3 years in Kolkata, North Jakarta and Karachi, respectively. The net social costs would be US$160 and US$549, per DALY averted in Kolkata and North Jakarta, respectively. These programs, along with a similar program in Karachi, would be considered "very cost-effective" (e.g. costs per DALY averted less than per capita gross national income (GNI)) under a wide range of assumptions. Community-based vaccination programs that also target adults in Kolkata and Jakarta are less cost-effective because incidence is lower in adults than children, but are also likely to be "very cost-effective". A program targeting school-aged children in Hue, Vietnam would prevent 21 cases, avert 6 DALYs, and not be cost-effective (US$3779 per DALY averted) because of the low typhoid incidence there.

The high burden of cholera in children: comparison of incidence from endemic areas in Asia and Africa.

BACKGROUND: Cholera remains an important public health problem. Yet there are few reliable population-based estimates of laboratory-confirmed cholera incidence in endemic areas around the world. METHODS: We established treatment facility-based cholera surveillance in three sites in Jakarta (Indonesia), Kolkata (India), and Beira (Mozambique). The annual incidence of cholera was estimated using the population census as the denominator and the age-specific number of cholera cases among the study cohort as the numerator. FINDINGS: The lowest overall rate was found in Jakarta, where the estimated incidence was 0.5/1000 population/year. The incidence was three times higher in Kolkata (1.6/1000/year) and eight times higher in Beira (4.0/1000/year). In all study sites, the greatest burden was in children under 5 years of age. CONCLUSION: There are considerable differences in cholera incidence across these endemic areas but in all sites, children are the most affected. The study site in Africa had the highest cholera incidence consistent with a growing impression of the large cholera burden in Africa. Burden estimates are useful when considering where and among whom interventions such as vaccination would be most needed.

Implementation of good clinical practice guidelines in vaccine trials in developing countries.

The practicalities when applying the ICH GCPs (International Conference on Harmonization 1996 Good Clinical Practices [EU, MHLW, FDA. International Conference on Harmonization Guideline for Good Clinical Practice; 1997] in less developed countries (ldcs) are seldom discussed and we found no guidelines as how to "adapt" them. Below we illustrate how ICH GCP principles can be implemented in different settings. We have recently conducted in Asia (Hechi, China; Karachi, Pakistan; Hue, Vietnam; North Jakarta, Indonesia and Kolkata, India) large-scale cluster-randomized effectiveness evaluations of the Vi polysaccharide typhoid fever vaccine (Vi PS project) among approximately 200,000 individuals(1)[Acosta CJ, Galindo CM, Ali M, Abu-Elyazeed R, Ochiai RL Danovaro-Holliday MC et al. A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design. TMIH 2005;10(12):1219-1228]. There is no doubt on the importance of ICH GCP in its contribution to ethical and scientifically sound clinical research. However, when the ICH GCP is implemented in ldcs some considerations must be made in order to adequately tailor them. Vaccine trials in ldcs are a frequent setting for such challenges because of the increased global interest conducting health research in such countries. The ICH GCP principles are discussed below within the framework of this recent typhoid fever vaccine study experience.

Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones.

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83-->Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.

Salmonella paratyphi A rates, Asia.

Little is known about the causes of enteric fever in Asia. Most cases are believed to be caused by Salmonella enterica serovar Typhi and the remainder by S. Paratyphi A. We compared their incidences by using standardized methods from population-based studies in China, Indonesia, India, and Pakistan.

A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design.

Phase-III vaccine efficacy trials typically employ individually randomized designs intended to ensure that measurements of vaccine protective efficacy reflect only direct vaccine effects. As a result, decisions about introducing newly licensed vaccines into public health programmes often fail to consider the substantially greater protection that may occur when a vaccine is deployed in public health programmes, due to the combination of direct plus indirect vaccine protective effects. Vaccine total protection can be better evaluated with cluster randomized trials. Such a design was considered to generate policy relevant data to accelerate the rationale introduction of the licensed typhoid fever Vi polysaccharide (PS) vaccine in Asia by the Diseases of the Most Impoverished (DOMI) typhoid fever programme. The DOMI's programme multi-country study is one of the largest cluster randomized vaccine trials ever mounted in Asia, which includes approximately 200,000 individuals. Its main objective is to determine the effectiveness of a licensed Vi PS vaccine. The rationale and design of this study are discussed. Preliminary results are presented that determined the final planning of the trial before immunization. Important methodological and practical issues regarding vaccine cluster randomized designs are illustrated.