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Igiri B E, Okoduwa S I R, Munirat S A, Otu-Bassey I B, Bashir A, Onyiyioza O M, et al . Diversity in Enteric Fever Diagnostic Protocols and Recommendation for Composite Reference Standard. Iran J Med Microbiol 2023; 17 (1) :22-38
URL: http://ijmm.ir/article-1-1584-en.html
Diversity in Enteric Fever Diagnostic Protocols and Recommendation for Composite Reference Standard
Bernard Egwu Igiri1 , Stanley Irobekhian Reuben Okoduwa 2, Shaibu Ahmed Munirat3 , Iquo Bassey Otu-Bassey4 , Abdullahi Bashir3 , Otori Mercy Onyiyioza3 , Idongesit Asuquo Enang5 , Ugochi Judith Okoduwa5
1- Directorate of Research and Development, Nigerian Institute of Leather and Science Technology, Zaria, Nigeria
2- Directorate of Research and Development, Nigerian Institute of Leather and Science Technology, Zaria, Nigeria , siroplc@gmail.com
3- Department of Microbiology, Ahmadu Bello University, Zaria, Nigeria
4- Department of Medical Laboratory Sciences, University of Calabar, Calabar, Nigeria
5- Industrial and Environmental Pollution Department, National Research Institute for Chemical Technology, Zaria, Nigeria
Keywords: Typhoid fever, Lipopolysaccharides, Metabolomics, Composite reference standard, Biomarkers, Sensitivity
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Introduction


Enteric fever (EF), commonly called typhoid fever (TF) is a systemic infectious illness triggered by Salmonella Typhi and Salmonella Paratyphi A, which if left untreated could cause substantial ill health and death. The disease causes serious public health challenges, with approximately 12,000,000 to 27,000,000 cases annually (1, 2). The estimated death varies between 129,000 to 223,000 annually (3, 4) with overwhelming affliction in poor countries, with a worldwide projection of 11.9 million cases and 120 000–220 000 mortality yearly (5, 6). The prevalence of TF has been reported to be high in preschool children and infants (6-9). In Africa, it has been observed that the burden of the disease is significantly high (6, 10).
Lack of suitable diagnostic tests, as well as effective antibiotic treatment, could result in TF death (11). With respect to the absence of decisive diagnostic protocols, the disease could lead to fatal complications such as intestinal perforations (12). The diagnostic accuracy of TF is a major challenge. The gap in TF diagnosis has led to under-diagnosis, imprecise disease burden estimates, inaccurate, and over-diagnosis that could result in inappropriate and excessive intake of antibiotics (13, 14). Various diagnostic techniques have been employed, including blood culture and bone marrow which were recommended to be gold-standard diagnostic tests (15, 16). Bone marrow techniques are the most sensitive and specific assay for enteric fever, though invasive with medical complications and required skilled personnel and expert equipment (17). Blood culture is the most frequently used technique among culture-based methods (18). Blood and bone marrow culture sensitivity has been quantified at 40-80% and >80% respectively (17, 18).
Rapid and accurate enteric fever diagnosis is significant and could reduce mortality, and ill health and control the spread of the ailment (19-23). Widal test is mostly utilized because it is readily available and affordability but lacks sensitivity and specificity and is not very reliable (24-27). However, this cheap and quick Widal test is the reason for the extensive report on typhoid fever prevalence in different regions of Nigeria (14). Numerous serology-based rapid assays for enteric fever are accessible, such as TUBEX, Typhidot, and Multi-Test Dipstick. Enzyme-linked immunosorbent assay (ELISA) and hemagglutination are serological tests that are utilized for Salmonella enterica serova Typhi O and H antigens with poor sensitivity and specificity (28). Research findings for the best enteric fever diagnostic techniques are being carried out by many research groups globally, with elusive results (29). Novel diagnostic techniques for enteric fever are in progress that could mitigate this deficit. New point-of-care technologies such as Loop-Mediated Isothermal Amplification, rapid magneto-DNA nanoparticle assay, Polymerase Chain Reaction (PCR) and Typhidot have been established (30-34). Emerging typhoid diagnostic techniques based on protein biomarkers, metabolite biomarkers, nucleic acid biomarkers and genomics are among the utmost examined methods, and are presented in the subsequent section. Researchers have searched for specific biomarkers for acute typhoid fever patients, enabling scholars to distinguish patients with other ailments as well as people that are hale and hearty.
The use of gold-standard tests with imperfect diagnostic accuracy could bring about newer and better techniques (35). The development of a CRS is an alternative technique to improve accuracy due to the lack of a perfect reference standard test (36). CRS is the combination of more than one imperfect technique aimed at increasing diagnostic accuracy. The knowledge of sensitivity as well as specificity of formerly detected S. Typhi is significant in providing data and hence creating very accurate diagnostic techniques for enteric fever. Consequently, this study involved the evaluation of existing evidence concerning the sensitivity, specificity, as well as emerging diagnostic techniques of enteric fever.  This study anticipated that the result will help to provide informative resources for researchers that want to improve enteric fever diagnostic tests. However, the finding proposed the adoption of harmonised CRS as a suitable standardized composite reference which would help to enhance assurance in the prevalence appraisals of enteric fever infections.

 

Materials and Methods

2.1.   Research design

The research design was a quantitative method with a survey approach which involves five respective steps: identification of studies; selection of articles; quality assessment of studies; extraction of data; and data analysis. Relevant literature published between January 2010 and December 2021 were retrieved.

2.2. Search Strategy for Identification of Relevant Articles of Diagnostic Protocols of Typhoid Fever

An electronic search approach was used to find out articles in English that assessed enteric fever diagnostic protocols among humans. Published peer-reviewed articles on the diagnostic protocol for enteric fever were identified from Google scholar, PubMed, and MEDLINE databases. The search words were sensitivity or specificity of typhoid diagnosis, Typhidot test, biomarkers of typhoid fever and Widal test for trials in progress.

2.3. Search Outcome and Selection of Studies

In all, four hundred and thirty-two (432) articles were identified and screened (Figure 1). 379 articles were excluded after reviewing the articles based on the following: duplicates 99, misleading titles and abstract 105, articles without Widal and rapid diagnostic test 98, and articles that do not meet quality criteria 77. The data obtained from the chosen sources were gathered and summarized using detection assays, biological specimens, classification studies on typhoid fever diagnosis, year of publication, specificity and sensitivity

 Figure 1. Flowchart of published peer-reviewed journals detected through databases and included in the analysis.
Figure 1. Flowchart of published peer-reviewed journals detected through databases and included in the analysis.

 

2.4 Inclusion and Exclusion Criteria

Studies in the English language were included without restrictions on the country, age, demographics, or time. Cross-sectional studies with paired comparative studies, prospective cohort studies, and retrospective studies were included. Also, Studies that reported on classifications of typhoid diagnosis were included.  Studies that do not meet quality criteria were excluded.

2.5 Ethics Statement

Studies included were those that were given approval by an institutional ethics review committee and in addition obtained informed consent from all their participants. Ethics approval was not requisite for the present study as it was based on secondary data generated from primary sources.

2.6 Statistical Analysis

Microsoft Excel and Statistical Package for Social Science (SPSS) version 25.0 were used to enter data obtained using descriptive analysis. The results are presented as percentages. An independent sample t-test was utilized to find differences in the mean percentage specificity and sensitivity of diagnostic tests. P < 0.05 was used for the statistical significance level.

 
 

Results

3.1. Characteristics of Diagnostic Protocols for Enteric Fever

Results of the synthesis collected in the literature review are presented in this section. Of the 432 searched articles, 53(12.3%) articles met the inclusion criteria with 13,036 participants (Table 1). Exactly 35 studies use the Widal test, 6 use TUBEX, 15 use Typhidot (Typhidot, Typhidot-M, and TyphiRapid-Tr02), 1 use Diazo test, 2 use Enterocheck WB®, 6  use PCR, 1 use ONSITE Typhoid Combo, 1 use Multi-test dipstick, and 2 use Panbio ELISA. Forty (40) studies used the gold standard for comparison. All of the diagnostic tests were developed to identify S. Typhi infection and Paratyphi. Six (6) studies utilized antibody detection.  Lipopolysaccharides (LPS), distending toxin subunit B (CdtB), flagellin, hemolysin E (HlyE), and 50 kDa outer were the most commonly studied antigen. Many of the studies were done to detect antibodies presence using blood serum samples while few studies uses saliva (Table 3). The use of laboratory diagnosis is required to confirm typhoid fever. However, they are several diagnostic protocols for typhoid fever. (Table 2)

3.2. Enteric fever serological diagnosis

Kauffman–White classification is used for serological identification of Salmonella enterica serovars. The Widal test (WT) has a moderate average diagnostic accuracy in the diagnosis of TF, according to the study. The average sensitivity of 53.8%  (Figure 2), average specificity of 55% (Figure 3), average PPV of 57.8% (Figure 4), and average NPV of 55.6% (Figure 5) were determined using the Widal test while 29.4%, 28%, 29.5%, and 27.8% was determined using Typhidot respectively. There was statistical evidence to demonstrate that there was a significant difference between the Widal test and Typhidot. The diagnostic accuracy of Widal was moderate compared to others. Lipopolysaccharides (LPS) O, VI, and flagellar H antigens are frequently used to identify S. Typhi from S. Paratyphi. Widal test is the most commonly used serological test to measure the bacterial O and H antigens agglutination (37, 38). Agglutinating antibodies against flagella (H) and lipopolysaccharide (LPS) (O) antigens of S. Typhi are measured using WT (39). This technique is unreliable and has low specificity and sensitivity (26). Several rapid diagnostic tests (RDTs) have been demonstrated as a rapid diagnostic assay for the assessment of enteric fever-specific immunodominant antigens (3). Tubex test can be used to identify anti-O2 antibodies in S. Paratyphi and anti-O9 IgM antibodies in S. Typhi (40, 41). Typhidot can be utilized to identify IgG and IgM antibodies against the 50-kDa outer membrane protein of S. Typhi (42, 43). IgM is the appropriate marker for detecting acute infection amongst individuals that do not previously have typhoid fever. The serological tests that are currently available cannot reliably diagnose enteric fever as lots of the antigens are being shared amongst various Salmonella serovars. The serological diagnosis of enteric fever relied on identifying antibodies against Salmonella LPS or flagellum and this brings causes high false-positive results (44).

3.3. Culture-based Diagnosis for Enteric Fever

The culture technique is the reference standard and is used for the characterization of disease-causing organisms for antibiotic resistance genes. Blood culture techniques confirmed Salmonella infection (n = 36), stool culture-confirmed (n =11), PCR confirmed (n=1) and bone marrow culture (n = 2) (Table 1). Several gold standard techniques have been utilized to assess enteric fever diagnosis and blood culture is ultimately used. The major problem in assessing the accuracy of enteric fever diagnosis is the absence of a perfect gold standard. Meyer et al. (45) revealed that no particular test protocol of TF has adequately good performance and recommended the use of the most recent techniques as useful for the composite reference standards.
Enteric fever decisive diagnosis involves the isolation of Salmonella species in blood and/or bone marrow (46). For the period of the first two weeks of TF infection, where the bacteria burden is highest, a 5 to 10 ml blood sample is necessary for school-age children and the elderly (47, 48). A small volume of blood (2 to 4 mL) is utilized to diagnose preschool children (46) and could be associated with underdiagnosis amongst younger people (49). Culture-based diagnosis is often affected because of the intake of antibiotic treatment before diagnosis (50, 51). This drawback is overwhelmed by the use of bone marrow techniques as bacteria in the bone marrow are not killed by the treatment of antibiotics (50, 52). Urine, stool, rose spot and duodenal bile are biological samples that could also be used for the cultural isolation of Salmonella species.

3.4. Nucleic Acid Detection-based Diagnosis for Enteric Fever

Polymerase chain reaction (PCR) is a nucleic acid technique utilized to detect Salmonella serovar-specific DNA. This technique requires extracting DNA from the blood of the patient and amplification of the DNA sequences. PCR technique is a non-culture-based technique used to detect S. Typhi and S. Paratyphi A flagellin genes (53, 54). Laboratory methods to lyse the erythrocytes have revealed interesting outcomes (55) and the extraction of DNA from samples could generate increased yield, thus improving sensitivity and specificity (56). Loop-mediated isothermal amplification (LAMP) is a technique that targets specific S. Typhi genes at a constant temperature (57, 58). The most frequently used target genes for TF diagnosis are cytotoxin (clyA), flagellin (fliC), heat-shock protein (groEL), 16s rRNA, Vi polysaccharide (viaB), as well as other genes that are conserved. Because of the absence of reference standard techniques, assay accuracy usually relied on the findings of blood culture. Several investigations revealed a sensitivity of 40–100% and specificity of approximately 100% only if the study is carryout under optimum conditions (59-67). 
Transcriptomics require the measurement of gene expression in a given cellular compartment at a specific time. The transcript mRNA is measured and quantified by the quantity of mRNA transcribed from genomic DNA using microarrays and RNAseq high-throughput molecular technology. A small quantity of whole blood samples can be used to produce gene expression profiles (68). Therefore, transcriptomic is being used for human transcriptional response to several illnesses (69-74) as well as other different immune perturbations (68, 74-76). The human challenge model is the source of various gene expression datasets, allowing the interrogation of the human transcriptional responses to S. Paratyphi A and S. Typhi (33, 73, 77). This technique uses the response of the host as a possible biomarker to detect typhoid fever individuals (78).  Host genes can also be detected by the use of microarray analysis. Five host genes (PSME2, STAT1, WARS, ALDH1A1, and SLAMF8) were investigated and were able to detect TF with 88% specificity and 97% sensitivity (77). A new technique such as miniature NMR has been proposed that uses magneto-DNA probes in identifying bacterial mRNA (32).

3.5. Protein Biomarkers

Modified proteomics and immune screening are high-throughput techniques which have been utilized to detect immunodominant antigen signatures associated with TF (30, 44, 79, 80).  In Nigeria, investigations on children with acute enteric fever based on proteome microarray tested IgM, IgG ELISAs, and IgA using HlyE proteins as well as S. Typhi LPS (81, 82). This study recognized putative serodiagnostic biomarkers such as invasion (SipC), bacterial cell surface (OmpA) as well as proteins (26). Other studies of S. Typhi proteome arrays have shown HlyE as a suitable serodiagnostic biomarker based on IgG and IgA responses (26, 30, 44, 81) OmpA is also a valuable biomarker from proteomic screening (30). Salmonella Typhi proteome array screening has detected N-acetyl muramoyl-L-alanine amidase (t2002, STY0927) as a new putative biomarker which is used in the catabolism of peptidoglycans.
Liquid chromatography–mass spectrometry (LC–MS) has been used to detect several hundred Salmonella antigens. Western blotting is a conventional method for the differential diagnostic potential of acute TF (83). ELISA and immunodot blot techniques used in the evaluation of IgA titers against membrane components of S. Typhi and S. Paratyphi showed 78–97% specificity and 100% sensitivity (84-86). TPTest is a valuable tool used to differentiate acute infection from convalescence in disease diagnosis (86).

3.6. Metabolite Biomarkers

Metabolomics is a technique for scientific research and was developed to identify as well as quantify small quantities of chemicals in complex biological samples (87). Progress has been made to validate the diagnosis of TF by using diagnostic metabolites in blood plasma (88). This technique is useful for several infectious diseases, detecting signatures of inflammatory disease, urinary tract infections and viral infections (89-91). Furthermore, it could forecast disease outcomes, development, and even commencement, as was recorded in tuberculosis (92). This technique was used to produce metabolites by 2-dimensional gas chromatography with time-of-flight mass spectrometry from 50 typhoid fever patients (25 having S. Typhi and 25 having S. Paratyphi A) against 25 febrile controls (88). It has been identified and validated that significant and reproducible metabolomics signatures could separate typhoid and other febrile illness with asymptomatic controls in a Nepali patient cohort (88, 93). This diagnosis compares the metabolites profiles of healthy and infected persons with typhoid and paratyphoid. The threshold is determined to single out those with acute typhoid fever (94). Following acute infection with S. Typhi, a specific interferon signature that alters tryptophan catabolic pathways is generated (33).

3.7. Genomics

This technique has allowed for S. Typhi genome sequencing and assisted in the recognition of specific gene targets. DNA markers that are S. Typhi specific have been identified with the application of nucleic acid sequence alignment tools (BLASTn) and genome database. The primer designed for amplifying specific gene sequences was authenticated using S. Typhi, non-Typhi Salmonella and non-Salmonella clinical isolates (21).


Table 1. Diversity of Typhoid fever diagnostic protocols and accuracy values

Diagnostic tests Study design Sample size (13,036) Gold Standard Country Prev1 (%) Sen2 (%) Spec3 (%) PPV4 (%) NPV5 (%) Ref
Widal Cross-sectional 372 Stool culture Ethiopia 56.2 80 44.5 3.8 98.8 (95)
Widal Cross-sectional 95 Stool culture Ethiopia 68.4 84.2 35.5 24.6 90 (96)
Widal Randomized design 125 Stool Culture Nigeria 17.6 78.3 93.6 68.2 98.1 (97)
Widal Cross sectional 158 Stool Culture Tanzania 81 81.5 18.3 10.1 89.7 (98)
Widal Prospective study 810 Blood and stool culture Nigeria NR 49.1 90.7 46.2 91.6 (99)
Widal Cross-sectional 91 Stool culture Nigeria 62.5 71.4 66.7 83.3 50 (100)
Widal NR 71 PCR India NR 50 50 92.8 39.5 (63)
Widal Comparative study 112 Stool culture Cameroon 57.1 40.9 32.4 6.44 28.1 (101)
Widal Cross-sectional 158 Blood and stool culture NR 81 81.5 18.3 10.1 89.7 (98)
Widal Retrospective study 100 Blood Culture India NR 71.4 47.3 9.25 95.7 (102)
Widal Prospective study 270 Blood culture Ethiopia 32.6 71.4 68.4 5.7 98.9 (102)
Widal Prospective study 163 Blood culture India 54 65.4 89.8 NR NR (103)
Widal Cross-sectional 271 Blood culture Nigeria 45.76 35 51 17 73 (104)
Widal Cross-sectional 100 Blood culture 100 NR 58 85 NR NR (105)
Widal Prospective study 40 immunochromatographic test India 67.6 90 81.25 NR NR (106)
Widal Cross-Sectional 558 Stool culture Cameroon 57.17 94.44 48.35 21.32 98.33 (107)
Widal Comparative study 71 Blood culture Bangladesh 59.15 100 89.9 NR NR (108)
TUBEX Retrospective study 179 Blood culture South Pacific ocean NR 77.6 60.5 32.2 91.5 (109)
Widal Cross-sectional study 158 Stool culture NR 81 81.5 18.3 10.1 89.7 (98)
Widal Randomized 125 Stool culture Nigeria 17.6 78.3 93.6 68.2 98.1 (97)
Typhidot Comparative study 140 Blood culture Egypt 30 93.3 90.6 82.3 96.6 (110)
Widal Comparative study 140 Blood culture Egypt 28 86.7 89.5 79.5 93.4 (110)
TUBEX Comparative study 139 Blood culture Tanzanian NR 79 89 NR NR (111)
TUBEX Retrospective study 970 Blood culture Pakistan 1.86 41.9 96 31.6 97.3 (112)
Typhidot Retrospective study 42 Blood culture NR NR 92.7 NR 97.4 NR (113)
Typhidot Cross-sectional 211 Blood culture NR 95.9 95.9 26.5 30.3 96 (114)
Typhidot Prospective study 500 NR Cambodia 63.6 63.6 82.9 26.4 95.9 (96)
Typhidot Retrospective study 145 Blood culture NR 32.4 26.7 61.5 7.4 87.9 (115)
Multiplex PCR Prospective study 680 Blood culture Bangladesh 20 95 92.9 NR NR (63)
Enterocheck Prospective study 145 Blood culture NR NR 85.5 88.6 51.1 97.7 (13)
Widal Prospective study 80 Blood culture India 62.5 71 62 91 31 (116)
clyA qPCR NR NR Blood culture Pakistan NR 28.57 ≥90 NR NR (117)
RT PCR NR NR Blood & bone marrow Nepal NR 53.9 100 NR NR (67)
PCR NR NR Blood culture India NR 100 76.9 NR NR (66)
PCR NR NR Blood culture Malaysia NR 100 100 NR NR (118)
PCR Comparative study 76 Blood culture NR NR 100 86.5 NR NR (21)
Widal 88.6 62.5
Widal Comparative study 105 Blood culture India 45.7 34.1 42.8 NR NR (119)
Typhidot 74.3 92.6 37.5
Typhidot NR 124 Blood culture NR 97.36 96 89.5 95 NR (120)
Widal 73.68 72 87 87
Widal Comparative study 140 Blood culture Egypt 35 86.7 89.5 79.5 93.4 (121)
Typhidot 36.5 93.3 90.6 82.3 96.6
Widal Comparative study 100 NR India 48.1 NR NR 94 NR (110)
Widal 26 52
Widal Comparative study - Blood culture New Delhi 57 57 83 NR NR (122)
Typhidot 79 79 87.5
ONSITE Typhoid Combo NR 136 NR Zimbabwe NR 100 94.4 63.2 100 (123)
TUBEX 100 94.1 63.2 100
Typhidot NR 97 Blood and bone marrow Pakistan 70 70 77 89 NR (124)
Widal 54 55 81 89
Widal Prospective study 100 Blood culture India NR 68 86 94 57 (23)
Typhidot 85 100 100 75
Typhidot Comparative study 2699 Blood culture India NR 97.3 88.1 97.4 87.8 (43)
Enteroscreen 98.2 92 96.2 82.3
Widal Comparative study 1371 Blood culture Nepal NR 84.1 52.7 25.3 94.5 (125)
ELISA 95.5 94.7 77.7 99.1
Typhidot M Prospective study 145 Blood culture India 90 100 100 92.1 (126)
Diazo test NR 86.7 85.7 83.9 88.2
Widal 40 91.4 80 NR
Panbio ELISA Prospective study 144 NR NR 84 78 80 68.4 87.4 (127)
Widal 98 76.6 69 98.6
Typhidot 98 76.6 98.6 69
TUBEX NR 500 Blood culture New Guinea 15 51.1 88.3 0.31 0.95 (128)
Typhidot 23 70 80.1 0.26 0.96
TyphiDot Rapid (TR-02) 22 89.4 85 0.38 0.99
Widal 8 51.1 95.8 0.56 0.95
Multi-test Dipstick Prospective study 80 NR Vietnam NR 89 50 85 60 (129)
Typhidot 79 89 96 59
TUBEX 78 94 98 59
Widal 64 76 88 48

1. Prev = Prevalence 2. Sen = Sensitivit 3. Spec = Specificity 4. PPV = positive predictive value 5. NPV = Negative predictive value, NR = Not reported
 

Figure 2. The mean percentage sensitivity of typhoid fever diagnostic techniques 
Figure 2. The mean percentage sensitivity of typhoid fever diagnostic techniques
 
Figure 3. Mean percentage specificity of typhoid fever diagnostic techniques. 
Figure 3. Mean percentage specificity of typhoid fever diagnostic techniques.
 
Figure 4. Mean percentage positive predictive value of typhoid fever diagnostic technique.
Figure 4. Mean percentage positive predictive value of typhoid fever diagnostic technique.
 
Figure 5. Mean percentage negative predictive value of enteric fever diagnostic techniques.
Figure 5. Mean percentage negative predictive value of enteric fever diagnostic techniques.

 

Table 2. Enteric fever diagnostic protocols

Diagnostic protocols Limitations Advantages Adjustments*
Bone marrow/blood/
bile/stool/culture		 i. Low sensitivity: ~80% bone marrow culture, ~50% blood culture, moderate sensitivity and specificity for bile and stool culture ii. Collection of bone marrow sample is invasive.  iii.   Waste of time (48 h). iv. Require trained personnel and infrastructure 100% specificity for blood/bone marrow. ii. Isolated enteric fever could be utilized for successive antibiotic susceptibility tests/molecular characterization i. Use of larger sample volume ii. Lyse blood cells to release bacteria.
Serological tests i. Cross-reactivity. ii. Moderate sensitivity and specificity i. Most serological assays are simple, rapid, and cheap ii. Quick turnaround time i. Use of isolated or cultured bacteria
Bacterial nucleic acid
detection		 i. Moderate sensitivity and specificity. i. Nucleic acid assays could also identify non-culturable/dead bacteria i. Nucleic acids of bacterial can be enhanced by removing human DNA and transient culture

* Success rates of assay can be enhanced by modifications.
 
Table 3. Characteristics of included studies that utilized antibody detection

Technique Biomarker Sensitivity (%) Specificity (%) Sample No of Samples Reference
ELISA Anti-LPS IgA 89.2 100 Saliva 37 Positive S. Typhi blood culture, (130)
IC-LFT Anti-LPS (IgG IgM)
and anti-flagellin
(IgG IgM)		 68.8 71.1 Serum 80 Positive S. Typhi blood culture and 256 negative S. Typhi
blood culture		 (131)
ELISA Anti-CdtB IgM 100 83.3 Serum 100 Positive S. Typhi blood culture and 12 healthy controls (132)
ELISA Anti-HlyE (IgG
IgM and IgA)		 70 100 Serum 50 Positive S. Typhi blood culture and 6 positive S. Paratyphi A
blood culture		 (133)
Dot-EIA Anti-50 kDa (IgG
IgA IgM)		 90.9 and 100 (Saliva) 85.4 and 100 (Serum) Saliva,
serum		 11 Positive S. Typhi blood culture and 43 non-typhoid fever patients (134)
ELISA Anti-HlyE (IgG IgA
IgM) and anti-YncE
(IgG IgA IgM)		 83 98 Serum 115 acute typhoid cases, 95 healthy controls, 117  food
handlers		 (135)
ELISA Anti-HlyE IgA,
anti-MP IgA and
anti-LPS IgA		 90 (HlyE), 90 (LPS),  90 (MP) 87 (HlyE), 77 (LPS), 48 (MP) Serum 105 Positive S. Typhi blood culture, 84 healthy controls (82)

ELISA = enzyme-linked immunosorbent assay; HlyE = hemolysin E; LPS = lipopolysaccharides; CdtB = cytolethal distending toxin subunit B; MP = membrane protein; Ig = immunoglobulin; Dot-EIA = dot enzyme immunoassay; YncE = uncharacterized protein
 

Discussion

The study reveals that the practice of combining the existing sensitive and specific techniques could surmount the shortcoming of accuracy that is intrinsic in a single test. The application of composite reference standards could enhance better appraisals for assay performance based on combinations of different assays. The study is aimed at assessing typhoid diagnostic accuracy and the urgent need for the best components of enteric fever CRS in other to establish a standardized composite reference as a novel typhoid protocol. Furthermore, the use of CRS will enhance assurance in the assessment of TF prevalence. An urgent need is required for improved TF diagnostic tests for better evaluations of disease burden and to hasten the approval of novel typhoid vaccines (136, 137). In order to achieve this, standardization and approval of one reference standard based on a composite reference are necessary.

4.1. Challenges and Future Outlook

Identifying real typhoid patients with negative blood cultures is a significant constraint in enteric fever diagnosis (127). About 20mL to 30mL of blood is needed to detect blood-related infections and this poses challenges among the elderly and neonatal patients (128). Additionally, lack of funding support, research capacity, and lack of institutional infrastructure are challenges facing TF diagnosis and other infectious diseases, especially in Nigeria. The absence of a perfect test leads to unwise antibiotic use, resulting in complications, morbidity as well as drug resistance.
It is desirable to develop a diagnostic technique that will require a small volume of blood with rapid and accurate detection. Furthermore, the quality of a reliable future evaluation of enteric fever diagnosis can be improved by the use of CRS because of the lack of a perfect diagnostic technique. This will enhance assurance in prevalence estimates and avoid inappropriate intake of antibiotics by patients that do not need them. It has been anticipated that a computational model using Bayesian probability can be used to estimate the accuracy of TF diagnostic assays (137). Future research should employ a prospective cohort design with CRS as a diagnostic tool. From our outlook, metabolite profiles are the possible upcoming solutions for TF diagnosis. An urgent need is required for researchers to find out a model biomarker(s) that can be uttered in initial infection and show drug-resistance profiles as well as differentiates acute infection from subclinical or chronic infections in widespread regions. The use of CRS as an upgraded reference standard for typhoid fever diagnosis will improve the actual worldwide burden of typhoid widespread.

4.2. Limitations and Strengths of the Study

The limitations in this study arise from the variety of diagnostic techniques employed by several researchers, as well as the way the assays were conducted. Due to this, many research articles could not be included in the study and the analysis was based only on published literature. Regardless of these limitations, the strength of this study is the thorough review of published peer review articles assessing the current trend and performance of various diagnostic protocols for the detection of enteric fever.


 

Conclusion and Recommendations

It is a real possibility to eliminate typhoid fever, but novel diagnostics are necessary and should be factored into a future trajectory for disease control. This study reveals emerging enteric fever diagnostic tests such as protein biomarkers, metabolite biomarkers, nucleic acid biomarkers and genomics. This study found diverse evidence of typhoid diagnostics with a substantial degree of variation in typhoid fever testing. The diversity of enteric fever diagnostic tests lacks flawless reference standards with optimum accuracy, hence the necessity for a synchronized and appropriate standardized composite reference. The principle research outcome of this finding reveals that the diagnostic performance of the Widal test was moderate at a sensitivity of 53.8%. The combination of imperfect tests to determine typhoid fever disease status is a transparent technique to deal with the challenge of imperfect reference standards. However, the study proposes the combinations of peripheral blood culture as well as the Widal test as a composite reference standard which will possibly improve confidence in prevalence estimate.

 

Acknowledgment

The authors are pleased to thank the authors of research articles that were obtained in writing this article. Special thanks go to the members of the Department of Information Technology, SIRONigeria Global Limited, Abuja for their assistance in the downloading of resources and articles used in this study.

Ethical Approval

Not applicable.

Conflicts of Interest

The authors declared no conflicts of interest.

 

Author Contributions

B.E.I. got the concept of the study. S.I.R.O. designed the project and supervised the study. B.E.I. drafted the manuscript. S.I.R.O. and BEI curated and analysed the data obtained as well as the interpretation of the study. S.A.M., I.B.O., O.M.O., I.A.E., and U.J.O. participated in the conduct of data analysis and literature search and sorting. S.I.R.O. and B.E.I. critically reviewed and revised the manuscript for important intellectual content. All authors read through the final version of the manuscript and gave consent for its publication.
 

Funding

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


 

Type of Study: Review Article | Subject: Medical Bacteriology
Received: 2022/01/11 | Accepted: 2022/06/9 | ePublished: 2023/01/20
References
1. Kumar S, Balakrishna K, Singh GP, Batra HV. Rapid detection of Salmonella typhi in foods by combination of immunomagnetic separation and polymerase chain reaction. World J Microbiol Biotechnol. 2005;21(5):625-8. [DOI:10.1007/s11274-004-3553-x]
2. Alba S, Bakker MI, Hatta M, Scheelbeek PFD, Dwiyanti R, Usman R, et al. Risk factors of typhoid infection in the Indonesian archipelago. PloS one. 2016;11(6):e0155286. [DOI:10.1371/journal.pone.0155286] [PMID] [PMCID]
3. Wijedoru L, Mallett S, Parry CM. Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever. Cochrane Database Syst Rev. 2017(5). [DOI:10.1002/14651858.CD008892.pub2] [PMID] [PMCID]
4. Stanaway JD, Reiner RC, Blacker BF, Goldberg EM, Khalil IA, Troeger CE, et al. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;19(4):369-81. [DOI:10.1016/S1473-3099(18)30685-6] [PMID]
5. Buckle GC, Walker CL, Black RE. Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010. J Glob Health. 2012;2(1):010401. [DOI:10.7189/jogh.01.010401] [PMID] [PMCID]
6. Mogasale V, Maskery B, Ochiai RL, Lee JS, Mogasale VV, Ramani E, et al. Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob Health. 2014;2(10):e570-e80. [DOI:10.1016/S2214-109X(14)70301-8] [PMID]
7. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ. 2004;82(5):346-53.
8. Crump JA, Ram PK, Gupta SK, Miller MA, Mintz ED. Part I. Analysis of data gaps pertaining to Salmonella enterica serotype Typhi infections in low and medium human development index countries, 1984-2005. Epidemiol Infect. 2008;136(4):436-48. [DOI:10.1017/S0950268807009338] [PMID] [PMCID]
9. Britto C, Pollard AJ, Voysey M, Blohmke CJ. An Appraisal of the Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-analysis of the Age-Stratified Disease Occurrence. Clin Infect Dis. 2017;64(11):1604-11. [DOI:10.1093/cid/cix229] [PMID] [PMCID]
10. Antillón M, Warren JL, Crawford FW, Weinberger DM, Kürüm E, Pak GD, et al. The burden of typhoid fever in low-and middle-income countries: a meta-regression approach. PLoS Negl Trop Dis. 2017;11(2):e0005376. [DOI:10.1371/journal.pntd.0005376] [PMID] [PMCID]
11. Dutta S, Das S, Mitra U, Jain P, Roy I, Ganguly SS, et al. Antimicrobial resistance, virulence profiles and molecular subtypes of Salmonella enterica serovars Typhi and Paratyphi A blood isolates from Kolkata, India during 2009-2013. PLoS One. 2014;9(8):e101347. [DOI:10.1371/journal.pone.0101347] [PMID] [PMCID]
12. Haque A, Ahmed J, Qureshi Javed A. Early Detection of Typhoid by Polymerase Chain Reaction. Ann Saudi Med. 1999;19(4):337-40. [DOI:10.5144/0256-4947.1999.337] [PMID]
13. Wasihun AG, Wlekidan LN, Gebremariam SA, Welderufael AL, Muthupandian S, Haile TD, et al. Diagnosis and Treatment of Typhoid Fever and Associated Prevailing Drug Resistance in Northern Ethiopia. Int J Infect Dis. 2015;35:96-102. [DOI:10.1016/j.ijid.2015.04.014] [PMID]
14. Igiri BE, Pc I, Gc E, Jimoh O, Ma S, Go I. Diagnostic investigations and prevalence of enteric fever in Ahmadu Bello University Teaching Hospital Shika-Zaria. Clin Microbiol Infect Dis. 2018;3(1):1-5. [DOI:10.15761/CMID.1000131]
15. Vallenas C, Hernandez H, Kay B, Black R, Gotuzzo E. Efficacy of bone marrow, blood, stool and duodenal contents cultures for bacteriologic confirmation of typhoid fever in children. J Pediatr Infect Dis. 1985;4(5):496-8. [DOI:10.1097/00006454-198509000-00011] [PMID]
16. World Health Organisation W. The diagnosis, treatment, and prevention of typhoid Fever 2003 [
17. Mogasale V, Ramani E, Mogasale VV, Park J. What proportion of Salmonella Typhi cases are detected by blood culture? A systematic literature review. Ann Clin Microbiol Antimicrob. 2016;15(1):32. [DOI:10.1186/s12941-016-0147-z] [PMID] [PMCID]
18. Storey HL, Huang Y, Crudder C, Golden A, de los Santos T, Hawkins K. A meta-analysis of typhoid diagnostic accuracy studies: a recommendation to adopt a standardized composite reference. PloS one. 2015;10(11):e0142364. [DOI:10.1371/journal.pone.0142364] [PMID] [PMCID]
19. Zaki SA, Karande S. Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries. 2011;5(05):324-37. [DOI:10.3855/jidc.1405] [PMID]
20. Ugochukwu AI, Amu OC, Nzegwu MA. Ileal perforation due to typhoid fever - Review of operative management and outcome in an urban centre in Nigeria. Int J Surg. 2013;11(3):218-22. [DOI:10.1016/j.ijsu.2013.01.014] [PMID]
21. Goay YX, Chin KL, Tan CLL, Yeoh CY, Ja'afar JaN, Zaidah AR, et al. Identification of Five Novel Salmonella Typhi-Specific Genes as Markers for Diagnosis of Typhoid Fever Using Single-Gene Target PCR Assays. Biomed Res Int. 2016;2016:8905675. [DOI:10.1155/2016/8905675] [PMID] [PMCID]
22. Contini S. Typhoid intestinal perforation in developing countries: Still unavoidable deaths? World J Gastroenterol. 2017;23(11):1925-31. [DOI:10.3748/wjg.v23.i11.1925] [PMID] [PMCID]
23. Parry CM, Wijedoru L, Arjyal A, Baker S. The utility of diagnostic tests for enteric fever in endemic locations. Expert Rev Anti Infect Ther. 2011;9(6):711-25. [DOI:10.1586/eri.11.47] [PMID]
24. Andrews JR, Ryan ET. Diagnostics for invasive Salmonella infections: Current challenges and future directions. Vaccine. 2015;33:C8-C15. [DOI:10.1016/j.vaccine.2015.02.030] [PMID] [PMCID]
25. Maude RR, de Jong HK, Wijedoru L, Fukushima M, Ghose A, Samad R, et al. The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh. Trop Med Int Health. 2015;20(10):1376-84. [DOI:10.1111/tmi.12559] [PMID] [PMCID]
26. Darton TC, Jones C, Dongol S, Voysey M, Blohmke CJ, Shrestha R, et al. Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal. Front Microbiol. 2017;8. [DOI:10.3389/fmicb.2017.02031] [PMID] [PMCID]
27. Olopoenia LA, King AL. Widal agglutination test −100 years later: still plagued by controversy. Postgrad Med J. 2000;76(892):80. [DOI:10.1136/pmj.76.892.80] [PMID] [PMCID]
28. Kantele A, Pakkanen SH, Karttunen R, Kantele JM. Head-to-head comparison of humoral immune responses to Vi capsular polysaccharide and Salmonella Typhi Ty21a typhoid vaccines-a randomized trial. PloS One. 2013;8(4):e60583. [DOI:10.1371/journal.pone.0060583] [PMID] [PMCID]
29. Baker S, Favorov M, Dougan G. Searching for the elusive typhoid diagnostic. BMC Infect Dis. 2010;10(1):45. [DOI:10.1186/1471-2334-10-45] [PMID] [PMCID]
30. Charles Richelle C, Liang L, Khanam F, Sayeed MA, Hung C, Leung Daniel T, et al. Immunoproteomic Analysis of Antibody in Lymphocyte Supernatant in Patients with Typhoid Fever in Bangladesh. Clin Vaccine Immunol. 2014;21(3):280-5. [DOI:10.1128/CVI.00661-13] [PMID] [PMCID]
31. Darton TC, Blohmke CJ, Giannoulatou E, Waddington CS, Jones C, Sturges P, et al. Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans. PLoS Negl Trop Dis. 2015;9(9):e0004029. [DOI:10.1371/journal.pntd.0004029] [PMID] [PMCID]
32. Park KS, Chung HJ, Khanam F, Lee H, Rashu R, Bhuiyan MT, et al. A magneto-DNA nanoparticle system for the rapid and sensitive diagnosis of enteric fever. Sci Rep. 2016;6(1):32878. [DOI:10.1038/srep32878] [PMID] [PMCID]
33. Blohmke CJ, Darton TC, Jones C, Suarez NM, Waddington CS, Angus B, et al. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med. 2016;213(6):1061-77. [DOI:10.1084/jem.20151025] [PMID] [PMCID]
34. Sharma T, Bhatnagar S, Tiwari A. Typhoid Diagnostics: Looking Beneath the Surface. J Clin Diagnostic Res. 2018;12(9). [DOI:10.7860/JCDR/2018/36358.12048]
35. Whiting PF, Rutjes AWS, Westwood ME, Mallett S. A systematic review classifies sources of bias and variation in diagnostic test accuracy studies. J Clin Epidemiol. 2013;66(10):1093-104. [DOI:10.1016/j.jclinepi.2013.05.014] [PMID]
36. Alonzo TA, Pepe MS. Using a combination of reference tests to assess the accuracy of a new diagnostic test. Stat Med. 1999;18(22):2987-3003. https://doi.org/10.1002/(SICI)1097-0258(19991130)18:22<2987::AID-SIM205>3.0.CO;2-B [DOI:10.1002/(SICI)1097-0258(19991130)18:223.0.CO;2-B]
37. Levine MM, Grados O, Gilman RH, Woodward WE, Solis-Plaza R, Waldman W. Diagnostic value of the Widal test in areas endemic for typhoid fever. Am J Trop Med Hyg. 1978;27(4):795-800. [DOI:10.4269/ajtmh.1978.27.795] [PMID]
38. Rodrigues C. The Widal test--more than 100 years old: abused but still used. J Assoc Physicians India. 2003;51:7-8.
39. World Health O. Typhoid vaccines: WHO position paper, March 2018 - Recommendations. Vaccine. 2019;37(2):214-6. [DOI:10.1016/j.vaccine.2018.04.022] [PMID]
40. Lim P-L, Tam Frankie CH, Cheong Y-M, Jegathesan M. One-Step 2-Minute Test To Detect Typhoid-Specific Antibodies Based on Particle Separation in Tubes. J Clin Microbiol. 1998;36(8). [DOI:10.1128/JCM.36.8.2271-2278.1998] [PMID] [PMCID]
41. Tam FCH, Wang M, Dong B, Leung DTM, Ma CH, Lim PL. New rapid test for paratyphoid a fever: usefulness, cross-detection, and solution. Diagn Microbiol Infect Dis. 2008;62(2):142-50. [DOI:10.1016/j.diagmicrobio.2008.07.002] [PMID]
42. Choo KE, Davis TME, Ismail A, Tuan Ibrahim TA, Ghazali WNW. Rapid and reliable serological diagnosis of enteric fever: comparative sensitivity and specificity of Typhidot and Typhidot-M tests in febrile Malaysian children. Acta Trop. 1999;72(2):175-83. [DOI:10.1016/S0001-706X(98)00095-3] [PMID]
43. Bhutta ZA, Mansurali N. Rapid serologic diagnosis of pediatric typhoid fever in an endemic area: a prospective comparative evaluation of two dot-enzyme immunoassays and the Widal test. Am J Trop Med Hyg. 1999;61(4):654-7. [DOI:10.4269/ajtmh.1999.61.654] [PMID]
44. Liang L, Juarez S, Nga TVT, Dunstan S, Nakajima-Sasaki R, Davies DH, et al. Immune profiling with a Salmonella Typhi antigen microarray identifies new diagnostic biomarkers of human typhoid. Sci Rep. 2013;3(1):1043. [DOI:10.1038/srep01043] [PMID] [PMCID]
45. Meyer GJ, Shaffer TW, Erdberg P, Horn SL. Addressing Issues in the Development and Use of the Composite International Reference Values as Rorschach Norms for Adults. J Pers Assess. 2015;97(4):330-47. [DOI:10.1080/00223891.2014.961603] [PMID]
46. Organization WH. Background Document: The Diagnosis, Treatment, and Prevention of Typhoid Fever; World Health Organization Department of Vaccines and Biologicals. Geneva, Switzerland; 2003.
47. Wain J, Bay Phan Van B, Vinh H, Duong Nguyen M, Diep To S, Walsh Amanda L, et al. Quantitation of Bacteria in Bone Marrow from Patients with Typhoid Fever: Relationship between Counts and Clinical Features. J Clin Microbiol. 2001;39(4):1571-6. [DOI:10.1128/JCM.39.4.1571-1576.2001] [PMID] [PMCID]
48. Cockerill FR, III, Wilson JW, Vetter EA, Goodman KM, Torgerson CA, Harmsen WS, et al. Optimal Testing Parameters for Blood Cultures. Clin Infect Dis. 2004;38(12):1724-30. [DOI:10.1086/421087] [PMID]
49. Edelman R, Levine MM. Summary of an international workshop on typhoid fever. Rev Infect Dis. 1986;8(3):329-49. [DOI:10.1093/clinids/8.3.329] [PMID]
50. Farooqui BJ, Khurshid M, Ashfaq MK, Khan MA. Comparative yield of Salmonella typhi from blood and bone marrow cultures in patients with fever of unknown origin. J Clin Pathol. 1991;44(3):258. [DOI:10.1136/jcp.44.3.258] [PMID] [PMCID]
51. Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, et al. Typhoid fever in children aged less than 5 years. The Lancet. 1999;354(9180):734-7. [DOI:10.1016/S0140-6736(98)09001-1] [PMID]
52. Gasem MH, Dolmans WM, Isbandrio BB, Wahyono H, Keuter M, Djokomoeljanto R. Culture of Salmonella typhi and Salmonella paratyphi from blood and bone marrow in suspected typhoid fever. Trop Geogr Med. 1995;47(4):164-7.
53. Zhou L, Jones C, Gibani MM, Dobinson H, Thomaides-Brears H, Shrestha S, et al. Development and evaluation of a blood culture PCR assay for rapid detection of Salmonella Paratyphi A in clinical samples. PloS one. 2016;11(3):e0150576. [DOI:10.1371/journal.pone.0150576] [PMID] [PMCID]
54. Levy H, Diallo S, Tennant Sharon M, Livio S, Sow Samba O, Tapia M, et al. PCR Method To Identify Salmonella enterica Serovars Typhi, Paratyphi A, and Paratyphi B among Salmonella Isolates from the Blood of Patients with Clinical Enteric Fever. J Clin Microbiol. 2008;46(5):1861-6. [DOI:10.1128/JCM.00109-08] [PMID] [PMCID]
55. Boyd MA, Tennant SM, Melendez JH, Toema D, Galen JE, Geddes CD, et al. Adaptation of red blood cell lysis represents a fundamental breakthrough that improves the sensitivity of Salmonella detection in blood. J Appl Microbiol. 2015;118(5):1199-209. [DOI:10.1111/jam.12769] [PMID] [PMCID]
56. Zhou L, Pollard AJ. A novel method of selective removal of human DNA improves PCR sensitivity for detection of Salmonella Typhi in blood samples. BMC Infect Dis. 2012;12(1):164. [DOI:10.1186/1471-2334-12-164] [PMID] [PMCID]
57. Fan F, Du P, Kan B, Yan M. The development and evaluation of a loop-mediated isothermal amplification method for the rapid detection of Salmonella enterica serovar Typhi. PloS One. 2015;10(4):e0124507. [DOI:10.1371/journal.pone.0124507] [PMID] [PMCID]
58. Frickmann H, Wiemer DF, Wassill L, Hinz R, Rojak S, Wille A, et al. Loop-mediated isothermal amplification-based detection of typhoid fever on an automated Genie II Mk2 system - A case-control-based approach. Acta Trop. 2019;190:293-5. [DOI:10.1016/j.actatropica.2018.12.004] [PMID]
59. Nizami SQ, Bhutta ZA, Siddiqui AA, Lubbad L. Enhanced detection rate of typhoid fever in children in a periurban slum in Karachi, Pakistan using polymerase chain reaction technology. Scand J Clin Lab Invest. 2006;66(5):429-36. [DOI:10.1080/00365510600791724] [PMID]
60. Song JH, Cho H, Park MY, Na DS, Moon HB, Pai CH. Detection of Salmonella typhi in the blood of patients with typhoid fever by polymerase chain reaction. J Clin Microbiol. 1993;31(6):1439-43. [DOI:10.1128/jcm.31.6.1439-1443.1993] [PMID] [PMCID]
61. Ali A, Haque A, Haque A, Sarwar Y, Mohsin M, Bashir S, et al. Multiplex PCR for differential diagnosis of emerging typhoidal pathogens directly from blood samples. Epidemiol Infect. 2009;137(1). [DOI:10.1017/S0950268808000654] [PMID]
62. Zhu Q, Lim CK, Chan YN. Detection of Salmonella typhi by polymerase chain reaction. J Appl Bacteriol. 1996;80(3):244-51. [DOI:10.1111/j.1365-2672.1996.tb03216.x] [PMID]
63. Ambati SR, Nath G, Das BK. Diagnosis of typhoid fever by polymerase chain reaction. Indian J Pediatr. 2007;74(10):909-13. [DOI:10.1007/s12098-007-0167-y] [PMID]
64. Kumar A, Arora V, Bashamboo A, Ali S. Detection of Salmonella typhi by polymerase chain reaction: Implications in diagnosis of typhoid fever. Infect Genet Evol. 2002;2(2):107-10. [DOI:10.1016/S1567-1348(02)00090-4] [PMID]
65. Nasrum Massi M, Shirakawa T, Gotoh A, Bishnu A, Hatta M, Kawabata M. Quantitative detection of Salmonella enterica serovar Typhi from blood of suspected typhoid fever patients by real-time PCR. Int J Med Microbiol. 2005;295(2):117-20. [DOI:10.1016/j.ijmm.2005.01.003] [PMID]
66. Nga TVT, Karkey A, Dongol S, Thuy HN, Dunstan S, Holt K, et al. The sensitivity of real-time PCR amplification targeting invasive Salmonellaserovars in biological specimens. BMC Infect Dis. 2010;10(1):125. [DOI:10.1186/1471-2334-10-125] [PMID] [PMCID]
67. Tennant SM, Toema D, Qamar F, Iqbal N, Boyd MA, Marshall JM, et al. Detection of Typhoidal and Paratyphoidal Salmonella in Blood by Real-time Polymerase Chain Reaction. Clin Infect Dis. 2015;61(suppl_4):S241-S50. [DOI:10.1093/cid/civ726] [PMID] [PMCID]
68. Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, et al. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol. 2011;12(8):786-95. [DOI:10.1038/ni.2067] [PMID] [PMCID]
69. Berry MPR, Graham CM, McNab FW, Xu Z, Bloch SAA, Oni T, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466(7309):973-7. [DOI:10.1038/nature09247] [PMID] [PMCID]
70. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC, Jartti T, et al. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med. 2013;10(11):e1001549. [DOI:10.1371/journal.pmed.1001549] [PMID] [PMCID]
71. Subramaniam KS, Spaulding E, Ivan E, Mutimura E, Kim RS, Liu X, et al. The T-Cell Inhibitory Molecule Butyrophilin-Like 2 Is Up-regulated in Mild Plasmodium falciparum Infection and Is Protective During Experimental Cerebral Malaria. J Infect Dis. 2015;212(8):1322-31. [DOI:10.1093/infdis/jiv217] [PMID] [PMCID]
72. Hoang Long T, Lynn David J, Henn M, Birren Bruce W, Lennon Niall J, Le Phuong T, et al. The Early Whole-Blood Transcriptional Signature of Dengue Virus and Features Associated with Progression to Dengue Shock Syndrome in Vietnamese Children and Young Adults. J Virol. 2010;84(24):12982-94. [DOI:10.1128/JVI.01224-10] [PMID] [PMCID]
73. Barton AJ, Hill J, Pollard AJ, Blohmke CJ. Transcriptomics in Human Challenge Models. Front Immunol. 2017;8. [DOI:10.3389/fimmu.2017.01839] [PMID] [PMCID]
74. Blohmke CJ, Hill J, Darton TC, Carvalho-Burger M, Eustace A, Jones C, et al. Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever. Front Immunol. 2017;8. [DOI:10.3389/fimmu.2017.01276] [PMID] [PMCID]
75. Vahey MT, Wang Z, Kester KE, Cummings J, Heppner DG, Jr., Nau ME, et al. Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine. J Infect Dis. 2010;201(4):580-9. [DOI:10.1086/650310] [PMID]
76. Li S, Sullivan NL, Rouphael N, Yu T, Banton S, Maddur MS, et al. Metabolic Phenotypes of Response to Vaccination in Humans. Cell. 2017;169(5):862-77.e17. [DOI:10.1016/j.cell.2017.04.026] [PMID] [PMCID]
77. Blohmke CJ, Muller J, Gibani MM, Dobinson H, Shrestha S, Perinparajah S, et al. Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases. EMBO Mol Med. 2019;11(10):e10431. [DOI:10.15252/emmm.201910431] [PMID] [PMCID]
78. Gliddon HD, Herberg JA, Levin M, Kaforou M. Genome-wide host RNA signatures of infectious diseases: discovery and clinical translation. Immunology. 2018;153(2):171-8. [DOI:10.1111/imm.12841] [PMID] [PMCID]
79. Darton TC, Baker S, Randall A, Dongol S, Karkey A, Voysey M, et al. Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array. Front Microbiol. 2017;8. [DOI:10.3389/fmicb.2017.01794] [PMID] [PMCID]
80. Charles Richelle C, Sheikh A, Krastins B, Harris Jason B, Bhuiyan MS, LaRocque Regina C, et al. Characterization of Anti-Salmonella enterica Serotype Typhi Antibody Responses in Bacteremic Bangladeshi Patients by an Immunoaffinity Proteomics-Based Technology. Clin Vaccine Immunol. 2010;17(8):1188-95. [DOI:10.1128/CVI.00104-10] [PMID] [PMCID]
81. Davies DH, Jain A, Nakajima R, Liang L, Jasinskis A, Supnet M, et al. Serodiagnosis of Acute Typhoid Fever in Nigerian Pediatric Cases by Detection of Serum IgA and IgG Against Hemolysin E and Lipopolysaccharide. Am J Trop Med Hyg. 2016;95(2):431-9. [DOI:10.4269/ajtmh.15-0869] [PMID] [PMCID]
82. Felgner J, Jain A, Nakajima R, Liang L, Jasinskas A, Gotuzzo E, et al. Development of ELISAs for diagnosis of acute typhoid fever in Nigerian children. PLoS Negl Trop Dis. 2017;11(6):e0005679. [DOI:10.1371/journal.pntd.0005679] [PMID] [PMCID]
83. Ansong C, Yoon H, Norbeck AD, Gustin JK, McDermott JE, Mottaz HM, et al. Proteomics Analysis of the Causative Agent of Typhoid Fever. J Proteome Res. 2008;7(2):546-57. [DOI:10.1021/pr070434u] [PMID]
84. Islam K, Sayeed MA, Hossen E, Khanam F, Charles RC, Andrews J, et al. Comparison of the performance of the TPTest, Tubex, Typhidot and Widal immunodiagnostic assays and blood cultures in detecting patients with typhoid fever in Bangladesh, including using a Bayesian latent class modeling approach. PLoS Negl Trop Dis. 2016;10(4):e0004558. [DOI:10.1371/journal.pntd.0004558] [PMID] [PMCID]
85. Sheikh A, Bhuiyan MS, Khanam F, Chowdhury F, Saha A, Ahmed D, et al. Salmonella enterica Serovar Typhi-Specific Immunoglobulin A Antibody Responses in Plasma and Antibody in Lymphocyte Supernatant Specimens in Bangladeshi Patients with Suspected Typhoid Fever. Clin Vaccine Immunol. 2009;16(11):1587-94. [DOI:10.1128/CVI.00311-09] [PMID] [PMCID]
86. Khanam F, Sheikh A, Sayeed MA, Bhuiyan MS, Choudhury FK, Salma U, et al. Evaluation of a typhoid/paratyphoid diagnostic assay (TPTest) detecting anti-Salmonella IgA in secretions of peripheral blood lymphocytes in patients in Dhaka, Bangladesh. PLoS Negl Trop Dis. 2013;7(7):e2316. [DOI:10.1371/journal.pntd.0002316] [PMID] [PMCID]
87. Zurfluh S, Baumgartner T, Meier MA, Ottiger M, Voegeli A, Bernasconi L, et al. The role of metabolomic markers for patients with infectious diseases: implications for risk stratification and therapeutic modulation. Expert Rev Anti Infect Ther. 2018;16(2):133-42. [DOI:10.1080/14787210.2018.1426460] [PMID]
88. Nasstrom E, Thieu N, Dongol S, Karkey A, Vinh P, Thanh T, et al. Salmonella Typhi and Salmonella Paratyphi A elaborate distinct systemic metabolite signatures during enteric fever. eLife. 2014;3:e03100. [DOI:10.7554/eLife.03100] [PMID] [PMCID]
89. Capati A, Ijare OB, Bezabeh T. Diagnostic Applications of Nuclear Magnetic Resonance-Based Urinary Metabolomics. Magn Reson Insights. 2017;10:1178623X17694346. [DOI:10.1177/1178623X17694346] [PMID] [PMCID]
90. French CD, Willoughby RE, Pan A, Wong SJ, Foley JF, Wheat LJ, et al. NMR metabolomics of cerebrospinal fluid differentiates inflammatory diseases of the central nervous system. PLoS Negl Trop Dis. 2018;12(12):e0007045. [DOI:10.1371/journal.pntd.0007045] [PMID] [PMCID]
91. Shrinet J, Shastri JS, Gaind R, Bhavesh NS, Sunil S. Serum metabolomics analysis of patients with chikungunya and dengue mono/co-infections reveals distinct metabolite signatures in the three disease conditions. Sci Rep. 2016;6(1):36833. [DOI:10.1038/srep36833] [PMID] [PMCID]
92. Weiner J, Maertzdorf J, Sutherland JS, Duffy FJ, Thompson E, Suliman S, et al. Metabolite changes in blood predict the onset of tuberculosis. Nat Commun. 2018;9(1):5208. [DOI:10.1038/s41467-018-07635-7] [PMID] [PMCID]
93. Näsström E, Parry CM, Vu Thieu NT, Maude RR, de Jong HK, Fukushima M, et al. Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa. eLife. 2017;6:e15651. [DOI:10.7554/eLife.15651] [PMID] [PMCID]
94. McKinnon LR, Abdool Karim Q. Honing in on enteric fever. eLife. 2014;3:e03545. [DOI:10.7554/eLife.03545] [PMID] [PMCID]
95. Deksissa T, Gebremedhin EZ. A cross-sectional study of enteric fever among febrile patients at Ambo hospital: prevalence, risk factors, comparison of Widal test and stool culture and antimicrobials susceptibility pattern of isolates. BMC Infect Dis. 2019;19(1):288. [DOI:10.1186/s12879-019-3917-3] [PMID] [PMCID]
96. Ameya G, Atalel E, Kebede B, Yohannes B. Comparative study of Widal test against stool culture for typhoid fever suspected cases in southern Ethiopia. Pathol Lab Med Int. 2017;9:1. [DOI:10.2147/PLMI.S124155]
97. Minjibir AA, Diso SU, Ibrahim IS, Abdallah MS, Ali M. Comparative Study of Widal test Against Stool Culture in Diagnosis of Typhoid Fever Suspected Cases in Kano, Northern Nigeria. South Asian Res J Eng Tech. 2020;2(5):39-44. [DOI:10.36346/sarjet.2020.v02i05.001]
98. Mawazo A, Bwire GM, Matee MIN. Performance of Widal test and stool culture in the diagnosis of typhoid fever among suspected patients in Dar es Salaam, Tanzania. BMC Research Notes. 2019;12(1):316. [DOI:10.1186/s13104-019-4340-y] [PMID] [PMCID]
99. Ohanu ME. Typhoid fever among febrile Nigerian patients: Prevalence, diagnostic performance of the Widal test and antibiotic multi-drug resistance. Malawi Med J. 2019;31(3):184-92. [DOI:10.4314/mmj.v31i3.4] [PMID] [PMCID]
100. Ramyi M, Ihuoma O, Ogundeko T, Ameh J, Olorundare F, Adeniyi O, et al. Comparative study on the use of widal test and stool culture in the laboratory diagnosis of salmonella infection in adult and children in jos metropolis, plateau state, Nigeria. Int J Sci Res. 2013;2(12).
101. Wam EC, Arrey CN, Sama LF, Agyingi LA, Wam AN. Comparative study on the use of Widal test to stool culture in the laboratory diagnosis of typhoid fever in Holy Family Hospital Akum, North West Region of Cameroon. Open Microbiol J. 2019;13(1). [DOI:10.2174/1874285801913010073]
102. Lalremruata R, Chadha S, Bhalla P. Retrospective audit of the widal test for diagnosis of typhoid Fever in pediatric patients in an endemic region. J Clin Diagn Res. 2014;8(5):Dc22-5.
103. Andualem G, Abebe T, Kebede N, Gebre-Selassie S, Mihret A, Alemayehu H. A comparative study of Widal test with blood culture in the diagnosis of typhoid fever in febrile patients. BMC Res Notes. 2014;7(1):653. [DOI:10.1186/1756-0500-7-653] [PMID] [PMCID]
104. Maheshwari V, Kaore NM, Ramnani VK, Sarda SA. Comparative evaluation of different diagnostic modalities in the diagnosis of typhoid fever using a composite reference standard; a tertiary hospital based study in central india. J Clin Diagn Res. 2016;10(10):DC01. [DOI:10.7860/JCDR/2016/20426.8684] [PMID] [PMCID]
105. Sharanya K, Lakshmi K, Vinod K, Chitralekha S. Development of Inhouse Immunoblot Method for Detection of Anti Salmonella Antibody and Comparison with Widal Test. J Pure Appl Microbiol. 2018;12(3):1195-200. [DOI:10.22207/JPAM.12.3.19]
106. Shahapur PR, Shahapur R, Nimbal A, Suvvari TK, Silva RGD, Kandi V. Traditional Widal Agglutination Test Versus Rapid Immunochromatographic Test in the Diagnosis of Enteric Fever: A Prospective Study From South India. Cureus. 2021;13(10). [DOI:10.7759/cureus.18474] [PMID] [PMCID]
107. Ousenu K, Ali IM, Sama LF, Ndam MN, Tchouangueu TF, Tume CB. A Cross-Sectional Comparative Study of the Performance of the Widal Test and the Typhidot Immunoassay for Typhoid Fever Diagnosis in the West Region of Cameroon. Can J Infect Dis Med Microbiol. 2021;2021:8279122. [DOI:10.1155/2021/8279122] [PMID] [PMCID]
108. Akter F, Yeasmin M, Alam MZ, Hasan MR, Rahman F, Khandker E, et al. Comparative evaluation of rapid Salmonella Typhi IgM/IgG and Widal test for the diagnosis of enteric fever. IMC J Med Sci. 2020;14(1):18-25. https://doi.org/10.3329/imcjms.v14i1.47452 [DOI:10.3329/imcjms.v10i1.31101]
109. Strobel AG, Airs S, Nguyen C, Vadei TR, Matanitobua S, Kama M, et al. Assessment of Rapid Diagnostic Tests for Typhoid Diagnosis and Assessment of Febrile Illness Outbreaks in Fiji. Am J Trop Med Hyg. 2022;106(2):543. [DOI:10.4269/ajtmh.21-0771] [PMID] [PMCID]
110. Salama RI, Said NM. A Comparative Study of the Typhidot (Dot-EIA) versus Widal Test in Diagnosis of Typhoid Fever among Egyptian Patients. Open J Gastroenterol. 2019;9(06):91. [DOI:10.4236/ojgas.2019.96011]
111. Enabulele O, Awunor SN. Typhoid fever in a Tertiary Hospital in Nigeria: Another look at the Widal agglutination test as a preferred option for diagnosis. Niger Med J. 2016;57(3):145-9. [DOI:10.4103/0300-1652.184057] [PMID] [PMCID]
112. Ley B, Thriemer K, Ame SM, Mtove GM, von Seidlein L, Amos B, et al. Assessment and comparative analysis of a rapid diagnostic test (Tubex®) for the diagnosis of typhoid fever among hospitalized children in rural Tanzania. BMC Infect Dis. 2011;11(1):147. [DOI:10.1186/1471-2334-11-147] [PMID] [PMCID]
113. Khan K, Khalid L, Wahid K, Ali I. Performance of TUBEX® TF in the diagnosis of enteric fever in private tertiary care Hospital Peshawar, Pakistan. J Pakistan Med Associa. 2017;67(5):661.
114. Garg S, Sankhe A, Joshi A, Mehta S. Comparison of Typhidot IgM test and Blood culture in children with clinically compatible enteric fever. Int J Contemp Pediatr. 2018;5(6):2129-32. [DOI:10.18203/2349-3291.ijcp20184270]
115. Javed H, Hussain K, Bashir T, Ullah S, Ijaz U, Khoso I. Diagnostic Accuracy of Typhidot in Patients of Typhoid Fever. Pakistan Armed Forces Med J. 2018;68.
116. Mehmood K, Sundus A, Naqvi IH, Ibrahim MF, Siddique O, Ibrahim NF. Typhidot - A blessing or a menace. Pak J Med Sci. 2015;31(2):439-43. [DOI:10.12669/pjms.312.5934] [PMID] [PMCID]
117. Aziz T, Haque SS. Role of Widal test in the diagnosis of typhoid fever in context to other test. Am J Biochem Biotechnol. 2012;2:16-8. [DOI:10.5923/j.ajb.20120201.04]
118. Khan S, Harish BN, Menezes GA, Acharya NS, Parija SC. Early diagnosis of typhoid fever by nested PCR for flagellin gene of Salmonella enterica serotype Typhi. Indian J Med Res. 2012;136(5):850-4.
119. El-Sayed AKA, El-Shishtawy M, El-Taweel F, El-Mansoury H. Multiplex PCR for diagnosis of Salmonella enterica serovar Typhi. Clin Lab. 2015;61(10):1537-43. [DOI:10.7754/Clin.Lab.2015.150115] [PMID]
120. Narayanappa D, Sripathi R, JagdishKumar K, Rajani HS. Comparative study of dot enzyme immunoassay (Typhidot-M) and Widal test in the diagnosis of typhoid fever. Indian Pediatr. 2010;47(4):331-3. [DOI:10.1007/s13312-010-0062-x] [PMID]
121. Khoharo HK. A comparative study of the typhidot (Dot-EIA) and Widal tests in blood culture positive cases of typhoid fever. Trop Doct. 2011;41(3):136-8. [DOI:10.1258/td.2011.100406] [PMID]
122. Patel RP, Trivedi MB. Study of diagnostic efficacy of widal slide agglutination test against widal tube agglutination test in enteric fever. Indian J Microbiol Res. 2017;4(3):267-9.
123. Sherwal BL, Dhamija RK, Randhawa VS, Jais M, Kaintura A, Kumar M. A comparative study of Typhidot and Widal test in patients of Typhoid fever. J Indian Acad Clin Med. 2004;5(3):244-6.
124. Tarupiwa A, Tapera S, Mtapuri-Zinyowera S, Gumbo P, Ruhanya V, Gudza-Mugabe M, et al. Evaluation of TUBEX-TF and OnSite Typhoid IgG/IgM Combo rapid tests to detect Salmonella enterica serovar Typhi infection during a typhoid outbreak in Harare, Zimbabwe. BMC Res Notes. 2015;8(1):50. [DOI:10.1186/s13104-015-1015-1] [PMID] [PMCID]
125. Adhikari A, Rauniyar R, Raut PP, Manandhar KD, Gupta BP. Evaluation of sensitivity and specificity of ELISA against Widal test for typhoid diagnosis in endemic population of Kathmandu. BMC Infect Dis. 2015;15(1):523. [DOI:10.1186/s12879-015-1248-6] [PMID] [PMCID]
126. Beig FK, Ahmad F, Ekram M, Shukla I. Typhidot M and Diazo test vis-a-vis blood culture and Widal test in the early diagnosis of typhoid fever in children in a resource poor setting. Braz J Infect Dis. 2010;14:589-93. https://doi.org/10.1016/S1413-8670(10)70116-1 [DOI:10.1590/S1413-86702010000600007] [PMID]
127. Anagha K, Deepika B, Shahriar R, Sanjeev K. The easy and early diagnosis of typhoid fever. J Clin Diagn Res. 2012;6(2):198-9.
128. Siba V, Horwood Paul F, Vanuga K, Wapling J, Sehuko R, Siba Peter M, et al. Evaluation of Serological Diagnostic Tests for Typhoid Fever in Papua New Guinea Using a Composite Reference Standard. Clin Vaccine Immunol. 2012;19(11):1833-7. [DOI:10.1128/CVI.00380-12] [PMID] [PMCID]
129. Olsen Sonja J, Pruckler J, Bibb W, Thanh Nguyen Thi M, Trinh Tran M, Minh Nguyen T, et al. Evaluation of Rapid Diagnostic Tests for Typhoid Fever. J Clin Microbiol. 2004;42(5):1885-9. [DOI:10.1128/JCM.42.5.1885-1889.2004] [PMID] [PMCID]
130. Zaka-ur-Rab Z, Abqari S, Shahab T, Islam N, Shukla I. Evaluation of salivary anti-Salmonella typhi lipopolysaccharide IgA ELISA for serodiagnosis of typhoid fever in children. Arch Dis Child. 2012;97(3):236. [DOI:10.1136/adc.2011.300622] [PMID]
131. Das S, Rajendran K, Dutta P, Saha TK, Dutta S. Validation of a new serology-based dipstick test for rapid diagnosis of typhoid fever. Diagn Microbiol Infect Dis. 2013;76(1):5-9. [DOI:10.1016/j.diagmicrobio.2013.01.012] [PMID]
132. Sharma T, Sharma C, Sankhyan A, Bedi SP, Bhatnagar S, Khanna N, et al. Serodiagnostic evaluation of recombinant CdtB of S. Typhi as a potential candidate for acute typhoid. Immunol Res. 2018;66(4):503-12. [DOI:10.1007/s12026-018-9009-4] [PMID]
133. Ong EBB, Ignatius J, Anthony AA, Aziah I, Ismail A, Lim TS. Multi-isotype antibody responses against the multimeric Salmonella Typhi recombinant hemolysin E antigen. Microbiol Immunol. 2015;59(1):43-7. [DOI:10.1111/1348-0421.12211] [PMID]
134. Redhuan NEM, Chin KL, Adnan AS, Ismail A, Balaram P, Phua KK. Salivary Anti-50 kDa Antibodies as a Useful Biomarker for Diagnosis of Typhoid Fever. J Clin Diagn Res. 2017;11(6):Dc10-dc3. [DOI:10.7860/JCDR/2017/21928.10055] [PMID] [PMCID]
135. Franklin F, Chong CW, Chua LH, Anthony AA, Liew MWO, Aziah I, et al. Evaluation of Salmonella Typhi antigen YncE alongside HlyE for the detection of typhoid fever and its carriers. Med Microbiol Immunol. 2020;209(5):593-601. [DOI:10.1007/s00430-020-00667-1] [PMID]
136. Crump JA, Mintz ED. Global Trends in Typhoid and Paratyphoid Fever. Clin Infect Dis. 2010;50(2):241-6. [DOI:10.1086/649541] [PMID] [PMCID]
137. DeRoeck D, Clemens JD, Nyamete A, Mahoney RT. Policymakers' views regarding the introduction of new-generation vaccines against typhoid fever, shigellosis and cholera in Asia. Vaccine. 2005;23(21):2762-74. [DOI:10.1016/j.vaccine.2004.11.044] [PMID]
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