Evaluation of a simple and rapid dipstick assay for the diagnosis of typhoid fever in Indonesia

To support the clinical diagnosis of typhoid fever in Indonesia, where most hospitals and health centres have no facilities for culture, a rapid dipstick assay for the detection of Salmonella typhi-specific IgM antibodies was evaluated on serum samples from 127 patients clinically suspected of having typhoid fever. In a single blood sample collected on admission to hospital, the sensitivity of the dipstick assay was 69.8% when compared with bone marrow culture and 86.5% when compared with blood culture. The specificity as calculated for the group of patients with suspected typhoid fever but a negative culture result was calculated to be 88.9%. Of 80 patients with febrile illnesses other than typhoid fever, reactivity was observed in only three patients with dengue haemorrhagic fever. The assay uses stabilised components that can be stored outside the refrigerator, does not require special equipment, and may be of use in remote health facilities that have no culture facilities.     

Diagnostic usefulness of Vi-indirect fluorescent antibody test(Vi-IFAT) for typhoid fever--a prospective study

Although the confirmative diagnosis of typhoid fever is by culture of the causative organism, usually from blood, a serological test is still necessary to provide a more rapid method of diagnosis. The indirect fluorescent antibody test, using a Salmonella typhi Vi antigen and a FITC-conjugated rabbit anti-human polyvalent immunoglobulin, was evaluated for the diagnosis of typhoid fever. Serum specimens were collected from patients with febrile diseases on admission. Of the 32 patients with titers of 1:64 or more, 22 were confirmed to have typhoid fever by blood culture and 7 had fever of undetermined origin that was considered to be typhoid fever clinically. Three patients were diagnosed to have salmonellosis other than typhoid fever. Of the 121 patients with titers of 1:32 or less, 105 patients had non-typhoidal febrile disease, 15 patients had fever of undetermined origin, and one patient was confirmed to have typhoid fever by blood culture. When a Vi antibody titer of 1:64 or more was taken as serological evidence for the diagnosis of typhoid fever, the sensitivity and specificity were 95.7% and 97.2%, respectively. The incidence of positive test results following fever onset was 70.0% within 1 week of fever onset, 88.9% from 1 to 2 weeks, and 100% after 2 weeks. In conclusion, the Vi-indirect fluorescent antibody test(Vi-IFAT) can be employed as a useful serologic test in the diagnosis of typhoid fever.     

昆明市官渡区2008~2017年伤寒、副伤寒流行特征分析

目的 分析2008~2017年官渡区伤寒、副伤寒流行特征,为制定有效的防控策略提供科学依据。方法 统计“中国疾病预防控制信息系统”中 2008~2017年官渡区伤寒、副伤寒病例数据,对其进行描述流行病学分析。结果 2008~2017年官渡区共报告伤寒、副伤寒1407例,年均发病率为15.92/10万,主要以伤寒为主,伤寒、副伤寒构成比为1.41∶1,发病季节性明显,每年3月份发病开始上升,5~10月份为高发季节,9月份达高峰,11月份开始下降,官渡区伤寒、副伤寒各个街道均有病例报告,关上街道发病居官渡区第1位,金马街道和小板桥街道发病交错排位第2位和第3位。各年龄组均有发病,主要集中于10~40岁组人群,男性发病多于女性,男女之比为1.12∶1。发病人数最多的职业是学生,其次是家务及待业和农民,每年占总发病数的37%~68%。结论 近10年官渡区伤寒、副伤寒发病仍维持较高的发病水平,发病呈散发状态,高危人群为学生、家务及待业、农民,应加强疫情监测。针对性采取综合措施,进一步降低伤寒、副伤寒的发病率。     

Vaccination against typhoid fever in travellers: a cost-effectiveness approach

Analysis of data on the incidence of typhoid fever and the costs of vaccination of travellers to the developing world indicates that vaccination may not be cost-effective for travel to countries with a moderate-to-high endemicity. It may be reasonable to selectively vaccinate travellers to countries with a very high incidence of typhoid fever, and particularly those who are visiting relatives or who will be in close contact with the local population. Vaccination of travellers on standard tourist itineraries is probably not necessary. The basic preventative measure for typhoid fever should be the avoidance of potentially contaminated food and drink.     

Early diagnosis of typhoid fever by the detection of salivary IgA

BACKGROUND:/AIMS: Current diagnostic methods for typhoid fever have low sensitivity and specificity. This study aimed to develop an enzyme linked immunosorbent assay (ELISA) with greater sensitivity and specificity. METHODS: The ELISA was developed and evaluated on patients with acute typhoid infection, febrile controls, and healthy controls. A sequential study on patients with culture confirmed typhoid was also carried out to determine the time period of maximum sensitivity. RESULTS: The ELISA detected anti-Salmonella typhi lipopolysaccharide (LPS) salivary IgA antibodies. A six month follow up study of patients with culture confirmed typhoid fever showed that the test shows maximum efficiency during the second and third weeks of fever and enables detection of the acute infection during the early phase. CONCLUSIONS: This ELISA can detect typhoid fever during the early phase of infection and is most efficient during the second and third weeks of fever, the time at which patients normally present for treatment. Because the sensitivity of the assay is subsequently greatly reduced, it will be useful for the diagnosis of acute infection.     

Typhoid Fever in Nineteenth-Century Colombia: Between Medical Geography and Bacteriology

This paper analyses how the Colombian medical elites made sense of typhoid fever before and during the inception of bacteriological ideas and practices in the second half of the nineteenth century. Assuming that the identity of typhoid fever has to be understood within the broader concerns of the medical community in question, I show how doctors first identified Bogotá’s epidemics as typhoid fever during the 1850s, and how they also attached specificity to the fever amongst other continuous fevers, such as its European and North American counterparts. I also found that, in contrast with the discussions amongst their colleagues from other countries, debates about typhoid fever in 1860–70 among doctors in Colombia were framed within the medico-geographical scheme and strongly shaped by the fear of typhoid fever appearing alongside ‘paludic’ fevers in the highlands. By arguing in medico-geographical and clinical terms that typhoid fever had specificity in Colombia, and by denying the medico-geographical law of antagonism between typhoid and paludic fevers proposed by the Frenchman Charles Boudin, Colombian doctors managed to question European knowledge and claimed that typhoid fever had distinct features in Colombia. The focus on paludic and typhoid fevers in the highlands might explain why the bacteriological aetiology of typhoid fever was ignored and even contested during the 1880s. Anti-Pasteurian arguments were raised against its germ identity and some physicians even supported the idea of spontaneous origin of the disease. By the 1890s, Pasteurian knowledge had come to shape clinical and hygienic practices. Keywords : Typhoid Fever, Medical Geography, Bacteriology, Colombia, History of Medicine, Fevers     

伤寒杆菌“H”、“O”抗体的ELISA检测及临床应用

目前伤寒病的诊断仍依赖血培养和Wi-dal氏反应,前者的阳性率受病人应用抗生素的影响;而后者在病程的后期才出现阳性,且敏感性较低。为寻求敏感而特异的伤寒杆     

Inefficacy of the commercial live oral Ty 21a vaccine in the prevention of typhoid fever

The efficacy of the live oral typhoid fever vaccine Ty 21a marketed in Switzerland in 1981 was investigated. Forty-seven Swiss travellers to Third World countries contracted typhoid fever in 1982 and 1983; 20 (43 %) of these persons had been vaccinated with Ty 21a. The incidence of typhoid fever in vaccinees was 1.1 per 10,000 doses of Ty 21a vaccine sold, which was similar to the incidence of 0.9 per 10,000 doses for the ineffective killed Ty 2 vaccine. Comparison of the incidence of vaccination in patients with typhoid fever in 1983 and in healthy travellers to India revealed vaccination efficacy rates which were not significantly different from zero. It is suggested that Ty 21a vaccine in the form marketed in Switzerland in 1981–1983 is not sufficiently potent or heat-stable, so that the doses of viable bacteria ingested were too low.     

Detection of urinary Vi antigen as a diagnostic test for typhoid fever

Since Vi antigen is limited primarily to Salmonella typhi, it has been thought that detection of the antigen may be a useful method for diagnosing acute typhoid fever. The slide coagglutination method and enzyme-linked immunosorbent assay have recently been suggested as ways to detect small quantities of Vi antigen in urine. In Santiago, Chile, we compared the results of these two methods in patients with acute typhoid fever, paratyphoid fever, and other febrile illnesses and in afebrile control subjects. Using a cut-off value that maximally separated typhoid patients from controls, the enzyme-linked immunosorbent assay was positive in 62.4% of 141 patients with culture-proven typhoid infections and in 13.2% of 159 afebrile control subjects. The enzyme-linked immunosorbent assay was false positive in 64.7% of 34 culture-proven paratyphoid A or B patients and 47.1% of 21 patients with other nontyphoidal febrile illnesses. The coagglutination test was positive in 34% of typhoid patients, 14% of afebrile control subjects, and 46% of febrile control subjects. We conclude that these tests when performed with the Vi antibodies employed in this study are of little value for the diagnosis of typhoid fever in this setting.     

Changing characteristics of typhoid fever in Taiwan.

Typhoid fever, a systemic disease caused by Salmonella typhi, is classically characterized by fever and abdominal symptoms. Although now considered uncommon, it seems to have re-emerged in Taiwan in recent years. We conducted a retrospective study of the clinical characteristics and microbiologic findings in 24 confirmed cases of typhoid fever treated over a 7-year period at a medical center in northern Taiwan. There were 11 males and 13 females, including 15 adults (over 18 years in age) and 9 children. Their mean age was 24.7 years (range, 9 months to 58 years). Twelve patients had recently returned from abroad, mostly from Southeast Asia. The most common complaints were fever (24/24), diarrhea (18/24), abdominal pain (10/24), and cough (10/24). The average duration of fever before diagnosis was 14.1 days, with a maximum of 30 days. Relative bradycardia was noted in 6 patients. Leukopenia was noted in 2 patients. S. typhi was isolated from blood culture in 20 cases, from stool culture in 3 cases, and from bone marrow culture in 1 case. Widal test was only positive initially in 7/18 cases. Fever of unknown origin was the most common initial diagnosis. Typhoid or enteric fever was impressed initially in only 2 cases. Almost all isolates of S. typhi were susceptible to antibiotics currently used for typhoid fever, with only 1 isolate resistant to chloramphenicol. All patients survived after antibiotic treatment. Only 1 patient developed recurrence after a 10-day course of ceftriaxone. In conclusion, the diagnosis of typhoid fever is often challenging due to non-specific symptoms and lack of an immediate confirmatory test. It is important to include this disease in the differential diagnosis of febrile patients with abdominal symptoms.     

Evaluation of passive bacterial agglutination for the diagnosis of typhoid fever.

We evaluated the reliability of a passive bacterial agglutination test to detect Salmonella typhi somatic antigen(s) in the sera of patients with typhoid fever. It was positive in 32 of 33 bacteriologically proven typhoid fever cases. Among 13 patients with a presumptive diagnosis of typhoid fever, 11 were positive by passive bacterial agglutination. The serum of one patient with paratyphoid A was also positive. Among 50 febrile patients without typhoid fever, one was persistently positive during the course of illness; 49 were negative. The sensitivity, specificity, and accuracy indices of the passive bacterial agglutination test were over 95%. The positive and negative predictive values were 94 and 98%, respectively.     

Immunological studies in typhoid fever. II. Cell-mediated immune responses and lymphocyte subpopulations in patients with typhoid fever.

The development of the cell-mediated immune response (CMIR) to antigens prepared from Salmonella typhi was investigated in patients suffering from typhoid fever and in normal healthy subjects. The leucocyte migration inhibition test, blast transformation of lymphocytes and active rosette-forming cells were used for detecting CMIR. Peripheral blood lymphocytes were analysed for the numbers and proportions of B lymphocytes, T lymphocytes and their subpopulations with receptors for IgM (T micro) or IgG (T gamma) and cells with Fc receptors for IgG. These parameters were correlated with the duration and the severity of illness. The uncomplicated cases of typhoid fever were found to have an intact CMIR as compared to the complicated cases. The ratio of T lymphocyte subpopulations was grossly imbalanced in typhoid patients, the numbers of T lymphocytes and their subpopulations were further altered in he complicated cases as compared to uncomplicated cases. The present study demonstrates a depressed state of CMIR in complicated patients with typhoid fever. CMIR may thus emerge as the cardinal point for recovery in typhoid fever rather than the specific antibodies. The study further demonstrates that imbalance within the subsets of T lymphocytes may be responsible for the depressed state of CMIR in complicated cases of typhoid fever.     

Comparison of passive haemagglutination test with Widal agglutination test for serological diagnosis of typhoid fever in an endemic area.

A passive haemagglutination test, using sheep red blood cells sensitised with Salmonella typhi lipopolysaccharide, was compared with the Widal test for the serological diagnosis of typhoid fever in an endemic area. The results obtained on sera from 152 patients with bacteriologically confirmed typhoid and 183 patients who did not have typhoid were analysed in terms of sensitivity, specificity, simplicity, and rapidity of the respective tests. The passive haemagglutination test was found to be more sensitive (80%) than the S typhi O antigen (71%) but marginally less sensitive than the H antigen (82%) of the Widal test. The false positive rate on control sera was 1.2% and 6.6%, respectively, for the Widal O and H antigens, and 1.6% for the passive haemagglutination test. Our findings indicate that the passive haemagglutination test is comparable with the Widal test for the serological diagnosis of typhoid fever in endemic areas, but is more simple, rapid, and economic. The passive haemagglutination test may be a useful alternative to the Widal test for the serological diagnosis of typhoid fever in busy microbiology laboratories in areas in which the disease is endemic.     

Decreased Gut-associated IgA Levels in Patients with Typhoid Fever

Gut and serum immune responses were studied in twenty-two patients with bacteriologically proved typhoid fever at different stages of the illness and six volunteers after parenteral immunizations with heat-killed typhoid vaccine. Whereas the former group had some specific antibodies in their intestinal aspirates and significant specific antibody responses in their sera, the latter could only mount a serum antibody response. Moreover, the intestinal IgA levels in the patients remained significantly decreased throughout the whole course of the illness, but a rise of IgG and IgM was observed in their jejunal secretions. In contrast, the levels of all the three major classes of serum immunoglobulins IgG, IgM and IgA were raised in the patients, as opposed to the volunteers, in whom only IgG and IgM levels were increased. It was inferred that the subjects with deficit of intestinal IgA, and thus lacking protective mucosal barrier, are more prone to develop typhoid fever.     

Radial counter-immunoelectrophoresis for rapid sero-diagnosis of typhoid fever

Serum samples were collected from 24 confirmed cases of typhoid fever and 23 normal healthy controls. Convalescent sera from the patients were obtained, wherever possible, one week after the first sample. In all, 13 paired sera, 11 acute phase only and 23 normal serum samples were tested for ability to elicit precipitins to Salmonella typhi by radial counter-immunoelectrophoresis using cellulose acetate membranes. In addition, conventional counter-immunoelectrophoresis (CIE) was performed using agar-gel layer for comparison. One of 24 acute phase sera gave positive results whereas all 13 convalescent sera were positive by both methods. The radial CIE test may be useful for rapid sero-diagnosis of typhoid fever as it takes only 4 min and can be used to screen large numbers of serum samples from patients suspected of typhoid fever.     

Immunological study of typhoid: immunoglobulins, C3, antibodies, and leukocyte migration inhibition in patients with typhoid fever and TAB-vaccinated individuals

The development of humoral and cell-mediated immune responses to Salmonella typhi antigens and immunoglobulin and C₃ levels were determined in patients suffering from typhoid fever, TAB-vaccinated individuals, and appropriate controls. In 45 patients with typhoid, a significant elevation of immunoglobulin M (IgM) level was noted from the first week of illness onwards. Eighteen TAB-vaccinated persons also showed a significant elevation of IgM levels. In typhoid sera, the anti-O and anti-H antibodies were mostly 2-mercaptoethanol (2-ME) sensitive. The rise of IgM level correlated well with the 2-ME-sensitive anti-O and anti-H antibodies seen in typhoid patients. The anti-O antibodies in the TAB-vaccinated group were almost entirely 2-ME sensitive, but both 2-ME-sensitive and -resistant anti-H antibodies were detected in the TAB group. A marked increas in C₃ level was also noted in patients with typhoid. The cell-mediated immunity (CMI), as measured by leukocyte migration inhibition tests, was demonstrable in 15 of 22 patients with typhoid. On the other hand, only 8 of the 20 normal subjects, 5 of the 16 fever control cases, and 6 of the 18 TAB-vaccinated individuals gave a positive CMI. The latter three groups were comparable with each other but were significantly different from the typhoid patients. It was concluded that TAB-vaccination did not induce CMI even though it induced the development of antibodies, the latter being comparable with those of the patients with typhoid. The significance of these findings is discussed.     

Salmonella typhi disease in HIV-infected patients: case reports and literature review

Two patients with AIDS and severe immunodeficiency developed typhoid fever. The diagnosis was confirmed by isolation of Salmonella typhi from blood cultures, while Widal's serum test isolates proved in vitro sensitive to all tested antimicrobial agents, and complete recovery was obtained with i.v. cotrimoxazole and piperacillin treatment. Unlike complications by non-tiphoid Salmonellae, S. typhi infection has been infrequently reported in the context of AIDS: to our knowledge, only five cases of typhoid fever have been described in HIV-infected living industrialized countries. Medical history and epidemiological information may play an important role in prompting the search for an S. typhi infection in patients coming from endemic regions, since most of the sign and symptoms of typhoid fever may mimic those of a sepsis. Or other AIDS-related complications     

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.     

Evaluation of Serological Diagnostic Tests for Typhoid Fever in Papua New Guinea Using a Composite Reference Standard

Typhoid fever remains a major global health problem. A major impediment to improving outcomes is the lack of appropriate diagnostic tools, which have not significantly improved in low-income settings for 100 years. We evaluated two commercially available rapid diagnostic tests (Tubex and TyphiDot), a prototype (TyphiRapid TR-02), and the commonly used single-serum Widal test in a previously reported high-burden area of Papua New Guinea. Samples were collected from 530 outpatients with axillary temperatures of ≥37.5°C, and analysis was conducted on all malaria-negative samples (n = 500). A composite reference standard of blood culture and PCR was used, by which 47 participants (9.4%) were considered typhoid fever positive. The sensitivity and specificity of the Tubex (51.1% and 88.3%, respectively) and TyphiDot (70.0% and 80.1%, respectively) tests were not high enough to warrant their ongoing use in this setting; however, the sensitivity and specificity for the TR-02 prototype were promising (89.4% and 85.0%, respectively). An axillary temperature of ≥38.5°C correlated with typhoid fever (P = 0.014). With an appropriate diagnostic test, conducting typhoid fever diagnosis only on patients with high-grade fever could dramatically decrease the costs associated with diagnosis while having no detrimental impact on the ability to accurately diagnose the illness.     

Immunoproteomic Analysis of Antibody in Lymphocyte Supernatant in Patients with Typhoid Fever in Bangladesh

We have previously shown that an assay based on detection of anti-Salmonella enterica serotype Typhi antibodies in supernatant of lymphocytes harvested from patients presenting with typhoid fever (antibody in lymphocyte supernatant [ALS] assay) can identify 100% of patients with blood culture-confirmed typhoid fever in Bangladesh. In order to define immunodominant proteins within the S. Typhi membrane preparation used as antigen in these prior studies and to identify potential biomarkers unique to S. Typhi bacteremic patients, we probed microarrays containing 2,724 S. Typhi proteins with ALS collected at the time of clinical presentation from 10 Bangladeshis with acute typhoid fever. We identified 62 immunoreactive antigens when evaluating both the IgG and IgA responses. Immune responses to 10 of these antigens discriminated between individuals with acute typhoid infection and healthy control individuals from areas where typhoid infection is endemic, as well as Bangladeshi patients presenting with fever who were subsequently confirmed to have a nontyphoid illness. Using an ALS enzyme-linked immunosorbent assay (ELISA) format and purified antigen, we then confirmed that immune responses against the antigen with the highest immunoreactivity (hemolysin E [HlyE]) correctly identified individuals with acute typhoid or paratyphoid fever in Dhaka, Bangladesh. These observations suggest that purified antigens could be used with ALS and corresponding acute-phase activated B lymphocytes in diagnostic platforms to identify acutely infected patients, even in areas where enteric fever is endemic.