Typhoid Fever In Vietnam Research Articles

The Control of Typhoid Fever in Vietnam.

.Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a diminishing public health problem in Vietnam, and this process may represent a prototype for typhoid elimination in Asia. Here, we review typhoid epidemiology in Vietnam over 20 years and assess the potential drivers associated with typhoid reduction. In the 1990s, multidrug resistant S. Typhi were highly prevalent in a sentinel hospital in southern Vietnam. A national typhoid incidence rate of 14.7/100,000 population per year was estimated around the new millennium. The Vietnamese government recognized the public health issue of typhoid in the 1990s and initiated vaccine campaigns to protect the most vulnerable members of the population. At their peak, these campaigns immunized approximately 1,200,000 children in 35 provinces. Concurrently, Vietnam experienced unprecedented economic development from 1998 to 2014, with the gross national income per capita increasing from $360 to $1,890 over this period. More recent typhoid incidence data are not available, but surveillance suggests that the current disease burden is negligible. This trajectory can be considered a major public health success. However, a paucity of systematic data makes it difficult to disaggregate the roles of immunization and water, sanitation, and hygiene (WASH) interventions in typhoid reduction in Vietnam. Given the limitations of typhoid vaccines, we surmise the practical elimination of typhoid was largely driven by economic development and improvement in general population living standards. Better designed WASH intervention studies with clinical endpoints and systematic incidence data are essential to glean a greater understanding of contextual factors that impact typhoid incidence reduction.

Letter: chronic Salmonella typhi carrier status and gall‐bladder cancer – authors’ reply

We thank Dr Arya and colleagues for their interest in our article1, 2 and highlighting the relationship between HLA and susceptibility to typhoid fever. The momentum for the implementation of personalised medicine in clinical practice is gaining. Recently, HLA genetic screening has been used to prevent carbamazepine-induced toxic effects among persons of Han Chinese descent3 and hypersensitivity to abacavir.4 Similarly, Ivacaftor, an orally available CFTR modulator that is specific for the G551D mutation has come up as a potential treatment for cystic fibrosis,5 thiopurine methyltransferase enzyme activity is predictive of azathioprine related life-threatening myelotoxicity in inflammatory bowel disease6 and reduced-function of CYP2C19 genotype has been related to adverse clinical outcomes among patients treated with clopidogrel.7 Imperial College of Science investigated the association between class II and class III major histocompatibility complex and typhoid fever in Vietnam. It is interesting to see that HLADRB1* 0301/6/8, HLA-DQB1*0201-3 and TNFA*2 (-308)) were associated with susceptibility to typhoid fever and HLA-DRB1*04, HLA-DQB1*0401/2 and TNFA*1 (-308) were linked with disease resistance.8 It would be a good strategy to utilize this characteristic to help prevent typhoid in this cohort of patients, especially in South East Asia. The endemic regions for typhoid can implement more stringent vaccination policies to reduce the health care burden of chronic Salmonella typhi carrier status-related gall-bladder cancer with the help of HLA screening. Another strategy would be to identify the HLA association between chronic Salmonella typhi carriage and gall-bladder cancer. However, whether this will be a cost-effective strategy is a question for the future. We suggest further research in this area to determine this association with the help of genome-wide association studies and animal studies. The authors’ declarations of personal and financial interests are unchanged from those in the original article.2

Risk factors for the development of severe typhoid fever in Vietnam.

BackgroundTyphoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. Age, sex, prolonged duration of illness, and infection with an antimicrobial resistant organism have been proposed risk factors for the development of severe disease or fatality in typhoid fever.MethodsWe analysed clinical data from 581 patients consecutively admitted with culture confirmed typhoid fever to two hospitals in Vietnam during two periods in 1993–1995 and 1997–1999. These periods spanned a change in the antimicrobial resistance phenotypes of the infecting organisms i.e. fully susceptible to standard antimicrobials, resistance to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole (multidrug resistant, MDR), and intermediate susceptibility to ciprofloxacin (nalidixic acid resistant). Age, sex, duration of illness prior to admission, hospital location and the presence of MDR or intermediate ciprofloxacin susceptibility in the infecting organism were examined by logistic regression analysis to identify factors independently associated with severe typhoid at the time of hospital admission.ResultsThe prevalence of severe typhoid was 15.5% (90/581) and included: gastrointestinal bleeding (43; 7.4%); hepatitis (29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12; 2.1%); intestinal perforation (6; 1.0%); haemodynamic shock (5; 0.9%), and death (3; 0.5%). Severe disease was more common with increasing age, in those with a longer duration of illness and in patients infected with an organism exhibiting intermediate susceptibility to ciprofloxacin. Notably an MDR phenotype was not associated with severe disease. Severe disease was independently associated with infection with an organism with an intermediate susceptibility to ciprofloxacin (AOR 1.90; 95% CI 1.18-3.07; p = 0.009) and male sex (AOR 1.61 (1.00-2.57; p = 0.035).ConclusionsIn this group of patients hospitalised with typhoid fever infection with an organism with intermediate susceptibility to ciprofloxacin was independently associated with disease severity. During this period many patients were being treated with fluoroquinolones prior to hospital admission. Ciprofloxacin and ofloxacin should be used with caution in patients infected with S. Typhi that have intermediate susceptibility to ciprofloxacin.

Role of vaccination in preventing typhoid fever: experience from Vietnam

Background: Improvements in water and sanitation are essential to reducing the burden of many infectious diseases, most notably that of diarrhea and enteric fevers. Vietnam has considerable burden of enteric diseases including typhoid fever. The objective of this study was to retrospectively review epidemiological data on typhoid fever and environmental data that are often considered to be associated with typhoid fever in Vietnam over a period of 10 years from 1991 to 2001 to understand the trend and environmental risk factors of typhoid fever in Vietnam. Methods: Government of Vietnam collects data on typhoid fever by provinces. This government data was collected as part of the Existing Data Collection study under the Diseases of the Most Impoverished (DOMI) program of the International Vaccine Institute conducted between 1999 and 2007 and was retrospectively analyzed. In addition, the government provincial data on urbanization, water and sanitation status was compared for all provinces against incidence of reported typhoid fever and plotted in scatter diagram for the risk factor analysis. Retrospective data on typhoid vaccine coverage was collected from the National Institute of Hygiene and Epidemiology. Results: The annual incidence of typhoid fever in Vietnam varied over the first five years increasing from an incidence rate of 12/100,000 in 1991 to over 40/100,000 in 1995 and decreasing during the later five years from 35/100,000 in 1996 to 12/100,000 in 2001. There was seasonal variation with peak incidence from May to August. On the risk factor analysis for typhoid, urbanization, access to clean water, or access to sanitation were not statistically related to typhoid fever incidence. Conclusion: Based on the review of 10-year typhoid fever incidence data coinciding with the introduction of typhoid fever vaccine in Vietnam, improvement in water and sanitation alone did not appear to be significantly related to the reduction in the incidence of typhoid fever. The Government of Vietnam started typhoid vaccination in high-risk districts from 1997 which have contributed in reduction of typhoid fever in these districts. It is important to complement the preventive efforts with introduction of vaccines in the short to intermediate term to effectively control typhoid fever.

A TNF region haplotype offers protection from typhoid fever in Vietnamese patients

The genomic region surrounding the TNF locus on human chromosome 6 has previously been associated with typhoid fever in Vietnam (Dunstan et al. in J Infect Dis 183:261-268, 2001). We used a haplotypic approach to understand this association further. Eighty single nucleotide polymorphisms (SNPs) spanning a 150 kb region were genotyped in 95 Vietnamese individuals (typhoid case/mother/father trios). A subset of data from 33 SNPs with a minor allele frequency of >4.3% was used to construct haplotypes. Fifteen SNPs, which tagged the 42 constructed haplotypes were selected. The haplotype tagging SNPs (T1-T15) were genotyped in 380 confirmed typhoid cases and 380 Vietnamese ethnically matched controls. Allelic frequencies of seven SNPs (T1, T2, T3, T5, T6, T7, T8) were significantly different between typhoid cases and controls. Logistic regression results support the hypothesis that there is just one signal associated with disease at this locus. Haplotype-based analysis of the tag SNPs provided positive evidence of association with typhoid (posterior probability 0.821). The analysis highlighted a low-risk cluster of haplotypes that each carry the minor allele of T1 or T7, but not both, and otherwise carry the combination of alleles *12122*1111 at T1-T11, further supporting the one associated signal hypothesis. Finally, individuals that carry the typhoid fever protective haplotype *12122*1111 also produce a relatively low TNF-alpha response to LPS.

Host Susceptibility and Clinical Outcomes in Toll‐like Receptor 5–Deficient Patients with Typhoid Fever in Vietnam

Toll-like receptor 5 (TLR5) mediates innate immune responses to bacterial pathogens by binding to flagellin. A polymorphism in the TLR5 gene introduces a premature stop codon (TLR5(392STOP)) that is associated with susceptibility to legionnaires disease. Here we investigated whether TLR5(392STOP) was associated with typhoid fever. The frequency of TLR5(392STOP) was not significantly different in 565 patients with typhoid fever and 281 ethnically matched control subjects. Furthermore, TLR5 deficiency had no measurable effect on a number of clinical parameters associated with typhoid fever, including fever clearance time, pathogen burden, disease severity, or age at acquisition of disease. TLR5 may not play an important role in TLR-stimulated innate immune responses to human infection with Salmonella enterica serovar Typhi. Initiation of these responses may rely on other TLRs that recognize different bacterial ligands.

Molecular analysis of incHI1 antimicrobial resistance plasmids from Salmonella serovar Typhi strains associated with typhoid fever.

The first outbreak of multidrug-resistant (MDR) typhoid fever in Vietnam was in 1993, and by 1995 nearly 90% of cases were MDR. Plasmid HCM1, sequenced in full, is an incHI1 plasmid from Salmonella enterica serovar Typhi strain CT18, isolated in Vietnam in 1993. Restriction analysis shows that pHCM1 shares a restriction fragment length polymorphism (RFLP) pattern with plasmids isolated from the first outbreak and 10 of 17 MDR plasmids isolated from sporadic cases occurring at the same time in Vietnam. A core region of pHCM1 has significant DNA sequence similarity to plasmid R27, isolated in 1961 from S. enterica in the United Kingdom. There are five regions of DNA in pHCM1 which are not present in R27. Two of these are putative acquisition regions; the largest is 34.955 kbp in length and includes sequences of several antibiotic resistance genes and several insertion sequences. The borders of this region are defined by two identical IS10 left elements, associated with an inversion of DNA or with a truncated Tn10 element. The second, smaller region is 14.751 kbp and carries a trimethoprim resistance gene dfr14A cassette associated with a class 1 integrase. In 1993 to 1994, restriction analysis revealed some variations in the structures of Salmonella serovar Typhi MDR plasmids which were mapped to the two putative acquisition regions and three smaller variable regions. In 1996 a single RFLP type, RFLP7, was found to carry the dfrA7 and sul-1 genes, which were not present on R27 or pHCM1. This plasmid type appears to have a selective advantage over other plasmids with the same resistance phenotype.

Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam.

The influence of genes of the major histocompatibility complex (MHC) class II and class III loci on typhoid fever susceptibility was investigated. Individuals with blood culture-confirmed typhoid fever and control subjects from 2 distinct geographic locations in southern Vietnam were genotyped for HLA-DRB1 and HLA-DQB1 alleles, the gene that encodes tumor necrosis factor (TNF)-alpha (TNFA [-238] and TNFA [-308]), the gene that encodes lymphotoxin-alpha, and alleles of the TNF-alpha microsatellite. HLA-DRB1*0301/6/8, HLA-DQB1*0201-3, and TNFA*2 (-308) were associated with susceptibility to typhoid fever, whereas HLA-DRB1*04, HLA-DQB1*0401/2, and TNFA*1 (-308) were associated with disease resistance. The frequency of all possible haplotypes of the 3 individually associated loci were estimated and were found to be significantly different in typhoid case patients and control subjects (chi2=55.56, 32 df; P=.006). Haplotypes that were either protective (TNFA*1 [-308].DRB1*04) or predisposed individuals to typhoid fever (TNFA*2 [-308].DRB1*0301) were determined. This report identifies a genetic association in humans between typhoid fever and MHC class II and III genes.

Value of a single-tube widal test in diagnosis of typhoid fever in Vietnam.

The diagnostic value of an acute-phase single-tube Widal test for suspected typhoid fever was evaluated with 2,000 Vietnamese patients admitted to an infectious disease referral hospital between 1993 and 1998. Test patients had suspected typhoid fever and a blood culture positive for Salmonella typhi (n= 1,400) or Salmonella paratyphi A (n = 45). Control patients had a febrile illness for which another cause was confirmed (malaria [n = 103], dengue [n = 76], or bacteremia due to another microorganism [n = 156] or tetanus (n = 265). An O-agglutinin titer of >/=100 was found in 18% of the febrile controls and 7% of the tetanus patients. Corresponding values for H agglutinins were 8 and 1%, respectively. The O-agglutinin titer was >/=100 in 83% of the blood culture-positive typhoid fever cases, and the H-agglutinin titer was >/=100 in 67%. The disease prevalence in investigated patients in this hospital was 30.8% (95% confidence interval, 26.8 to 35.1%); at this prevalence, an elevated level of H agglutinins gave better positive predictive values for typhoid fever than did O agglutinins. With a cutoff titer of >/=200 for O agglutinin or >/=100 for H agglutinin, the Widal test would diagnose correctly 74% of the blood culture-positive cases of typhoid fever. However, 14% of the positive results would be false-positive, and 10% of the negative results would be false-negative. The Widal test can be helpful in the laboratory diagnosis of typhoid fever in Vietnam if interpreted with care.

Quantitative bacteriology of Typhoid fever in Vietnam

Quantitative bacteriology of Typhoid fever in Vietnam

Thermosensitive H1 Plasmids Determining Citrate Utilization

Twelve thermosensitive H1 plasmids from strains of Salmonella typhi that had caused outbreaks of chloramphenicol-resistant typhoid fever in Vietnam, Thailand and India mediated citrate utilization (Cit+) in a prototrophic Escherichia coli K12 strain but not in the S. typhi strains from which they were derived. Four H1 plasmids from a similar outbreak in Mexico differed from the Far Eastern plasmids in not mediating citrate utlization but in mediating mercury resistance. H1 plasmids resembling the Far Eastern and the Mexican plasmids in regard to citrate utilization and mercury resistance were found in sewage in Britain. Citrate utilization was transferred to eight pathogenic strains of E. coli and to one strain each of Shigella flexneri and Shigella sonnei. Cultures of Cit+ bacteria grew more rapidly in citrate media at 28 degrees C than at 37 degrees C. Plasmid mutants that were more efficient at utilizing citrate were present in all such cultures--they grew equally well or better at 37 degrees C than at 28 degrees C. None of 222 strains of E. coli or Shigella that contained a variety of different plasmids were able to utilize citrate. This property was not transferred to the prototrophic E. coli K12 strain from Citrobacter (3 strains), Salmonella (39 strains), Proteus (44 strains), Klebsiella pneumoniae (33 strains) or Pseudomonas aeruginosa (44 strains).

On the Pathogenesis of Typhoid Fever

E fever in this century, typhoid fever was common in the United States and interest in it was great. As its incidence decreased as a result of safe water supplies and improved sewage disposal, knowledge of the disease has ceased to be of general concern. Indeed, many physicians are no longer familiar with the clinical presentations of patients with typhoid fever. Butler and co-workers in this issue of theArchives(p 407) present a study of patients with typhoid fever in Vietnam where the disease is still common. Their study aims to resolve some of the unknown fundamental information on the pathogenesis of the symptoms and signs of typhoid fever. The authors attempt to identify whether circulating endotoxin exists in this disease; if so, is it the basis of the prolonged fever? In addition, as Butler and his colleagues demonstrate, this Gram-negative rod infection produces a coagulopathy that fortunately causes