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.
SummaryHost genetic factors may contribute to susceptibility to and outcome in infectious diseases. Recently polymorphisms in PARK2/PACRG , a gene cluster linked to ubiquitination and proteasome-mediated protein degradation, were found to be associated with manifest infection by M. leprae . Here, we address whether these polymorphisms are associated with susceptibility to infection with Salmonella typhi and S. paratyphi A, intracellular pathogens that upon infection of humans share with mycobacteria aspects of the hosts' immune response. The polymorphisms of PARK_e01( − − − − 697) , PARK2_e01( − − − − 2599) , rs1333955 and rs1040079 were analysed by polymerase chain reaction and restriction fragment length polymorphism in a case-control study of typhoid and paratyphoid fever patients in an endemic area in Jakarta, Indonesia. For this study, samples were obtained from patients with blood culture-confirmed typhoid fever ( n = = = = 90), paratyphoid fever ( n = = = = 26) and fever controls ( n = = = = 337) in a passive, community-based surveillance and compared to those of randomly selected community controls ( n = = = = 322) from the same city area. The PARK2_e01( − − − − 2599) allele T was significantly associated with typhoid and paratyphoid fever (OR: 1·51, 95%CI: 1·02-2·23) but the other polymorphisms, PARK2_e01( − − − − 697) , rs1333955 and rs1040079 , were not associated. Although within the PARK2/PACRG gene cluster the PARK2_e01( − − − − 2599) allele T was most strongly associated with leprosy (OR ∼ ∼ ∼ ∼ 3-5), the association with typhoid is much less strong. Our findings suggest that this polymorphism in PARK2/PACRG plays a small but significant role in susceptibility to the intracellular pathogens S. typhi and S. paratyphi .
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.
In a previous risk factor study in Jakarta we identified purchasing street food as an independent risk factor for paratyphoid. Eating from restaurants, however, was not associated with disease. To explain these findings we compared 128 street food-vendors with 74 food handlers from restaurants in a cross-sectional study in the same study area. Poor hand-washing hygiene and direct hand contact with foods, male sex and low educational level were independent characteristics of street vendors in a logistic regression analysis. Faecal contamination of drinking water (in 65 % of samples), dishwater (in 91 %) and ice cubes (in 100 %) was frequent. Directly transmittable pathogens including S. typhi (n = 1) and non-typhoidal Salmonella spp. (n = 6) were isolated in faecal samples in 13 (7 %) vendors; the groups did not differ, however, in contamination rates of drinking water and Salmonella isolation rates in stools. Poor hygiene of street vendors compared to restaurant vendors, in combination with faecal carriage of enteric pathogens including S. typhi, may help explain the association found between purchasing street food and foodborne illness, in particular Salmonella infections. Public health interventions to reduce transmission of foodborne illness should focus on general hygienic measures in street food trade, i.e. hand washing with soap, adequate food-handling hygiene, and frequent renewal of dishwater.
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.
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