Polymorphisms in proinflammatory genes and susceptibility to typhoid fever and paratyphoid fever.

Host genetic factors are thought to contribute to susceptibility and outcome in infectious diseases. A polymorphism in a proinflammatory gene, tumor necrosis factor-alpha (TNFA - 308), was recently found to be associated with susceptibility to typhoid fever. As the observation was made in hospitalized patients, a potential confounder could be that the TNFA polymorphism is associated with the severity of established illness resulting in hospital admission rather than susceptibility to disease. We tested whether the association with TNFA - 308 is present also in typhoid fever patients enrolled in a community-based case-control study in an endemic area in Indonesia. Common polymorphisms in other proinflammatory genes were assayed as well. Samples of patients with blood culture-confirmed typhoid fever (n = 90) and paratyphoid fever (n = 26) and fever controls (n = 337) were compared with those of community controls (n = 322). In these groups, we analyzed polymorphisms in TNFA by PCR and RFLP, polymorphisms of IFNG, IL1A, IL1B, IL1R1, TNFRSF1A, CASP1, and CRP by Sequenom MassArray (San Diego, CA), and polymorphisms in IL12B and IFNGR1 by fragment length analysis. The IL1R1 polymorphisms were nearly absent in the Indonesian population. The TNFA - 308 polymorphism was not associated with typhoid fever (OR 0.35, 95% CI 0.1-1.0) in this population. The polymorphisms at TNFA - 238 or in IFNG, IL1A, IL1B, IL12B, TNFRSF1A, IFNGR1, CASP1, and CRP were also not associated with typhoid or paratyphoid fever. We conclude that polymorphisms in proinflammatory genes do not contribute to susceptibility to typhoid fever and, in view of earlier findings, suggest that the TNFA - 308 polymorphism is likely related to severity of established disease rather than to susceptibility per se.

Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR).

The cystic fibrosis transmembrane conductance regulator (CFTR) is the affected protein in cystic fibrosis (CF). The high rate of CF carriers has led to speculation that there must be, similar to the sickle cell haemoglobin advantage in malaria, a selective advantage for heterozygotes. Such a selective advantage may be conferred through reduced attachment of Salmonella typhi to intestinal mucosa, thus providing resistance to typhoid fever. We tested this hypothesis by genotyping patients and controls in a typhoid endemic area in Indonesia for two highly polymorphic markers in CFTR and the most common CF mutation. We found an association between genotypes in CFTR and susceptibility to typhoid fever (OR=2.6). These analyses suggest that the role CFTR plays in vitro in S. typhi infection is also important for infection in the human population.

Identification of typhoid fever and paratyphoid fever cases at presentation in outpatient clinics in Jakarta, Indonesia.

In Jakarta, Indonesia, over 80% of patients with typhoid fever or paratyphoid fever are treated in outpatient settings. In a community-based prospective passive surveillance study, we identified 59 typhoid, 23 paratyphoid fever and 259 non-enteric fever outpatients, all blood culture-confirmed. We compared their symptoms with the aim of developing a clinical prediction rule that may help direct empirical antibiotic treatment to cases with suspected (para)typhoid fever, rather than all febrile patients, or refer patients for additional diagnostic tests. Paratyphoid fever (Salmonella paratyphi A) could not be distinguished clinically from typhoid fever. Decisions on empirical antibiotic treatment and advice on hygiene measures in patients with suspected (para)typhoid fever should take into account chills and absence of cough in the first week of fever and delirium in the second week of illness. This prediction rule increases the likelihood of (para)typhoid fever from 1:10 in the first week to, at most, 2:3 in the second week of a febrile illness. However, we were not able to propose a robust clinical prediction rule that could be used as absolute screening method for decisions on additional diagnostic tests, because of the low sensitivity of presenting symptoms in (para)typhoid fever.

A survey of the supply and bacteriologic quality of drinking water and sanitation in Jakarta, Indonesia.

We assessed the water supply, water quality and human waste disposal and their association with diarrheal illness in Jatinegara, East-Jakarta, where part of the area has been involved in the Kampung Improvement Program (KIP). Three hundred seventy-eight households, randomly selected in the study area, were visited and questioned about water source, sanitation and diarrheal illness during the previous 3 months. Microbiological quality of drinking water was assessed. The water sources were boreholes (243; 64%), the water mains (77; 20%), bottled water (45; 12%), and vendors or dug wells (243; 4%). Fecal coliforms were isolated in 56% of the samples [median 23 (IQR 6-240) /100 ml in the contaminated samples]. Only 2 (3%) of the water mains' samples contained >100 fecal coliforms/100 ml, compared to 57 (24%) groundwater samples. Most residents used private toilets with drainage into on-site septic tanks, yet in over one quarter of households human excreta was disposed of into rivers or gutters. KIP areas lagged behind in environmental hygiene. Diarrheal episodes, reported in one third of the households, were significantly associated with water contaminated with >100 fecal coliforms/100 ml [OR 2.4 (95% CI: 1.4-4.2)], but no association with water source or environmental contamination was found. Significantly, all individuals reported boiling water before consumption.

Risk factors for typhoid and paratyphoid fever in Jakarta, Indonesia.

CONTEXT: The proportion of paratyphoid fever cases to typhoid fever cases may change due to urbanization and increased dependency on food purchased from street vendors. For containment of paratyphoid a different strategy may be needed than for typhoid, because risk factors for disease may not coincide and current typhoid vaccines do not protect against paratyphoid fever. OBJECTIVE: To determine risk factors for typhoid and paratyphoid fever in an endemic area. DESIGN, SETTING, AND PARTICIPANTS: Community-based case-control study conducted from June 2001 to February 2003 in hospitals and outpatient health centers in Jatinegara district, Jakarta, Indonesia. Enrolled participants were 1019 consecutive patients with fever lasting 3 or more days, from which 69 blood culture-confirmed typhoid cases, 24 confirmed paratyphoid cases, and 289 control patients with fever but without Salmonella bacteremia were interviewed, plus 378 randomly selected community controls. MAIN OUTCOME MEASURES: Blood culture-confirmed typhoid or paratyphoid fever; risk factors for both diseases. RESULTS: In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%) Salmonella paratyphi A infections. Paratyphoid fever among cases was independently associated with consumption of food from street vendors (comparison with community controls: odds ratio [OR], 3.34; 95% confidence interval [CI], 1.41-7.91; with fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding (comparison with community controls: OR, 4.52; 95% CI, 1.90-10.73; with fever controls: OR, 3.25; 95% CI, 1.31-8.02). By contrast, independent risk factors for typhoid fever using the community control group were mostly related to the household, ie, to recent typhoid fever in the household (OR, 2.38; 95% CI, 1.03-5.48); no use of soap for handwashing (OR, 1.91; 95% CI, 1.06-3.46); sharing food from the same plate (OR, 1.93; 95% CI, 1.10-3.37), and no toilet in the household (OR, 2.20; 95% CI, 1.06-4.55). Also, typhoid fever was associated with young age in years (OR, 0.96; 95% CI, 0.94-0.98). In comparison with fever controls, risk factors for typhoid fever were use of ice cubes (OR, 2.27; 95% CI, 1.31-3.93) and female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal contamination of drinking water was not associated with typhoid or paratyphoid fever. We did not detect fecal carriers among food handlers in the households. CONCLUSIONS: In Jakarta, typhoid and paratyphoid fever are associated with distinct routes of transmission, with the risk factors for disease either mainly within the household (typhoid) or outside the household (paratyphoid).