Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever

Lalith Wijedoru; Sue Mallett; Christopher M Parry

doi:10.1002/14651858.CD008892.pub2

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Figure 1

PRISMA flow diagram.

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Figure 2

Summary receiver operating characteristic plot: Enterocheck WB, PanBio, SD Bioline, Mega Salmonella, Multi‐Test Dip‐S‐Tick.

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Figure 3

Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies.

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Figure 4

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.

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Figure 5

Summary ROC Typhidot all test types.

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Figure 6

Forest plots for Typhidot all test types.

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Figure 7

Summary receiver operating characteristic plot of tests: Typhidot and Typhidot‐M by reference test.

Abbreviations: BC: blood culture; BM: bone marrow; BC & PCR: blood culture and polymerase chain reaction.

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Figure 8

Summary receiver operating characteristic plot of test: TUBEX. Reference test: Blood culture. One result per study.

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Figure 9

Forest plot of TUBEX. Reference test blood culture.

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Figure 10

Summary receiver operating characteristic plot: TUBEX by case control design.

Abbreviation: BC: blood culture.

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Figure 11

Summary receiver operating characteristic plot: TUBEX by reference test

Abbreviations: BC: blood culture; BC & PCR: blood culture and polymerase chain reaction.

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Figure 12

Summary receiver operating characteristic plot: KIT all test types. Threshold > 1+.

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Figure 13

Forest plot of tests: KIT Threshold > 1+ by test type. Reference test: blood culture.

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Figure 14

Summary receiver operating characteristic plot: KIT test by threshold > 1+ and > 2+.

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Figure 15

Summary receiver operating characteristic plot: KIT ICT by reference test.

Abbreviations: BC: blood culture; BC & PCR: blood culture and polymerase chain reaction.

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Figure 16

Summary receiver operating characteristic plot: KIT by case control (All test types. Threshold >1+).

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Figure 17

Summary receiver operating characteristic plot: Typhidot versus TUBEX. Paired studies only. One result per index test per study.

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Figure 18

Summary receiver operating characteristic: TUBEX versus KIT. Paired results. One result per index per study.

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Figure 19

Summary receiver operating characteristic plot: Typhidot versus TUBEX tests. One result per index test per study.

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Figure 20

Summary receiver operating characteristic plot: TUBEX versus Test‐it Typhoid (KIT) tests. One result per index test per study.

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Figure 21

Summary receiver operating characteristic: Typhidot versus KIT. No paired studies. One result per index per study.

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Figure 22

Summary receiver operating characteristic plot: Typhidot tests by case control design.

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Test 1

Typhidot. Antibody: IgM or as reported. 1 result per study.

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Test 2

Typhidot. Antibody: IgM or as reported. Reference: BC.

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Test 3

Typhidot. Antibody: IgM or as reported. Reference: BC and BM.

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Test 4

Typhidot. Antibody: IgM or as reported. Reference: BC and PCR.

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Test 5

Typhidot. Antibody: IgM or as reported. Indeterminates reported.

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Test 6

Typhidot. Antibody: IgM or as reported. Indeterminates not reported.

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Test 7

Typhidot‐M. Antibody: IgM.

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Test 8

Typhi rapid Tr‐02. Reference: BC. Antibody: IgM.

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Test 9

Typhi rapid Tr‐02. Reference: BC & PCR. Antibody: IgM.

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Test 10

Typhidot all tests 1 result per study.

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Test 11

TUBEX. Reference:BC.

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Test 12

TUBEX. Reference: BC & PCR.

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Test 13

TUBEX 1 result per study.

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Test 14

KIT ICT. Reference:BC. Threshold > 1+.

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Test 15

KIT ICT. Reference: BC & PCR. Threshold > 1+.

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Test 16

KIT latex agglutination. Threshold > 1+.

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Test 17

KIT Dipstick. Threshold > 1+.

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Test 18

KIT ICT. Threshold > 1+.

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Test 19

KIT all tests. Threshold > 1+. One result per study..

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Test 20

KIT all tests. Threshold > 2+ studies only.

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Test 21

Enterocheck WB.

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Test 22

PanBio.

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Test 23

SD Bioline. Antibody: IgG.

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Test 24

SD Bioline. Antibody: IgM.

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Test 25

SD Bioline Antibody: IgM and IgG.

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Test 26

Mega Salmonella. Antibody: IgG.

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Test 27

Mega Salmonella. Antibody: IgM.

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Test 28

Multi‐Test Dip‐S‐Tick.

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Test 29

Enteroscreen.

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Test 30

Onsite Typhoid Combo CTK Biotech.

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Summary of findings 'Summary of findings' table 1

Review question: to assess the diagnostic accuracy of rapid diagnostic tests (RDTs) for detecting enteric fever in persons living in endemic areas presenting to a healthcare facility with fever

Patients/population: clinically‐suspected enteric fever patients or unselected febrile patients

Role: first test for enteric fever in patients presenting to a healthcare facility with fever in endemic areas

Index tests: all RDTs specifically designed to enteric fever cases applied to patient blood or urine samples

Reference standards: bone marrow culture, peripheral blood culture, peripheral blood culture, and polymerase chain reaction (PCR) on blood

Studies: prospective cohort, retrospective case control

Setting: healthcare facility in enteric fever endemic areas

Index test

Effect (95% confidence interval (CI))

Participants

Total number, number with disease, (number of studies)

Test result

Number of results per 1000 participants tested ¹ (95% CI)

Prevalence 1%

Prevalence 10%

Prevalence 30%

Typhidot

(all types)

Sensitivity 84 (73 to 91)

Specificity 79 (70 to 87)

6928, 982 (22)

8 (7 to 9)

2 (1 to 3)

208 (129 to 297)

782 (693 to 861)

84 (73 to 91)

16 (9 to 27)

189 (117 to 270)

711 (630 to 783)

252 (219 to 273)

48 (27 to 81)

147 (91 to 210)

553 (490 to 609)

Typhidot indeterminants reported or not applicable

Sensitivity 78 (65 to 87)

Specificity 77 (66 to 86)

5555, 662 (13)

8 (7 to 9)

2 (1 to 3)

228 (139 to 337)

762 (653 to 851)

78 (65 to 87)

22 (13 to 35)

207 (126 to 306)

693 (594 to 774)

234 (195 to 261)

66 (39 to 105)

161 (98 to 238)

539 (462 to 602)

Typhidot indeterminate results reported

Sensitivity 66 (59 to 73)

Specificity 81 (58 to 93)

1721, 339 (6)

7 (6 to 7)

3 (3 to 4)

188 (69 to 416)

802 (574 to 921)

66 (59 to 73)

34 (27 to 41)

171 (63 to 378)

729 (522 to 837)

198 (177 to 219)

102 (81 to 123 )

133 (49 to 294)

567 (406 to 651)

TUBEX

Sensitivity 78 (71 to 85)

Specificity 87 (82 to 91)

4885, 627 (14)

8 (7 to 9)

2 (2 to 3)

129 (89 to 178)

861 (812 to 901)

78 (71 to 85)

22 (15 to 29)

117 (81 to 162)

783 (738 to 819)

234 (213 to 255)

66 (45 to 87)

91 (63 to 126)

609 (574 to 637)

Test‐it Typhoid and KIT prototypes (threshold > 1+)

Sensitivity 69 (59 to 78)

Specificity 90 (78 to 93)

2828, 682 (9)

7 (6 to 8)

3 (2 to 4)

99 (69 to 218)

891 (772 to 921)

69 (59 to 78)

31 (22 to 41)

90 (63 to 198)

810 (702 to 837)

207 (177 to 234)

93 (66 to 123)

70 (49 to 154)

630 (546 to 651)

Attributes of tests contributing to benefits and risks

Rapid diagnostic tests (RDTs)²

RDTs are designed to provide test results typically in less than 1 hour, whereas currently used blood culture tests require 48 hours. The technical ability needed to conduct these rapid tests is designed to be lower than typical laboratory based tests, meaning they have the potential to be delivered nearer to the patient, further reducing time to diagnosis. However, some variants of the Typhidot test requires additional laboratory equipment, whereas the TUBEX and Test‐it Typhoid test do not. The TUBEX tests and some variants of Typhidot require cold chain storage. The Test‐it Typhoid test does not. In this Cochrane Review all included rapid tests were used on blood samples. None of the included studies conducted tests on urine samples.

Overall certainty of evidence

Indeterminate results: for the Typhidot index test, there are concerns about studies which do not report indeterminate results (IgM negative and IgG positive). These results can frequently occur and if these results are not included in the analysis this biases study results to be overly‐optimistic.

Case control studies: many of these studies use a case control design. This study design is at risk of overestimating both sensitivity and specificity.

Reference standard: the highest grade of reference standard includes either bone marrow culture or PCR using blood, in addition to blood culture. However using bone marrow as a reference standard is invasive and more severe patients may be selected into these studies. Most included studies use only blood culture, and studies using more than 1 reference standard for example, PCR showed a reduction in RDT sensitivity by 20% to 25%.

Precision: average estimates of both sensitivity and specificity have low precision, due to the heterogeneity between studies.

Paired studies: there are few paired studies, where more than 1 test is used in the same patients. These studies provide the most direct evidence for comparing tests.

Typhidot paired with TUBEX: Total 4245, 484 patients with disease.

Typhidot paired with Test‐it Typhoid and KIT prototypes: no paired studies.

Test‐it Typhoid and KIT prototypes paired with TUBEX: total 127, 64 patients with disease. It remains unclear if the tests were used in the same cohort of patients.

Abbreviations: False Negatives (FN); False Positives (FP); immunoglobulin‐G (IgG); immunoglobulin‐M (IgM); Royal Tropical Institute, Amsterdam (KIT); polymerase chain reaction (PCR); True Negatives (TN); True Positives (TP).

¹We used 2 systematic reviews of bacteraemia in Asia and Africa to inform prevalences of 30% (Asia); 10% (Africa: adults and children) and 1% (Africa: children) (Reddy 2010; Deen 2012).
²Keddy 2011.

Summary of findings 'Summary of findings' table 1

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Table 1. Summary of all index tests

Index Test Name	Manufacturer	Methods	Formats	Biological specimen	Threshold for positivity values	Number of evaluations
TUBEX® TF	IDL Biotech, Bromma, Sweden	Inhibition Binding Magnetic Immunoassay. Detects IgM to S. Typhi O9 antigen. Semi‐quantitative colorimetric.	Mix buffer/reagent into plastic well with patient specimen. 3 minutes for result.	Whole blood, plasma, or serum	Semi‐quantitative colour change scale (0 to 10) provided by manufacturer. Positive if colour change scale ≥ 3.	14
Typhidot®	Malaysian Bio‐Diagnostics Research, Selangor, Malaysia	Dot‐enzyme immunoassay. Detects IgG and IgM to 50 kdA S. Typhi Outer Membrane Protein (OMP) antigen.	Mix serum/whole blood plus reagent incubating commercially‐prepared pre‐dotted antigen filter paper strips. 60 minutes for result.	Whole blood, plasma, or serum	Qualitative: either positive or negative. A positive result is a visible reaction (IgG or IgM) of an intensity equal to or greater than that of the control reaction on the commercially prepared filter paper.	17
Typhidot‐M®	Malaysian Bio‐Diagnostics Research, Selangor, Malaysia	Dot‐enzyme immunoassay. Detects IgM to 50 kdA S. Typhi OMP antigen.	Mix serum/whole blood plus reagent incubating commercially‐prepared pre‐dotted antigen filter paper strips. 60 minutes for result.	Whole blood, plasma, or serum	Qualitative: either positive or negative. Positive as per Typhidot. The absence of any visible spot indicated a negative test result.	6
TyphiRapid Tr‐02 (Typhidot)	Reszon Diagnostics International, Malaysia	Prototype of Typhidot. Immunochromatography assay. Detects IgM to 50 kdA S. Typhi OMP antigen.	Mix serum/whole blood plus buffer/reagent into a well.	Whole blood, plasma, or serum	We were unable to get hold of the manufacturer and are awaiting a response from the study author	1
KIT ICT Test‐It Typhoid^TM	LifeAssay Diagnostics, Cape Town, South Africa	Lateral flow immunochromatographic (ICT) assay. Detects IgM to S. Typhi lipopolysaccharide (LPS) antigen. Semi‐quantitative.	Mix serum/whole blood plus buffer/reagent into lateral flow cassette. Two‐site (test and control) immunoassay on a porous nitrocellulose membrane. 15 minutes for result.	Whole blood, plasma, or serum	Semi‐quantitative result line intensity scale (negative to +4) provided by manufacturer. A positive result is ≥ +1	3
KIT Dipstick Assay	Royal Tropical Institute (KIT), Amsterdam	Detects IgM to S. Typhi LPS antigen. Simplified version of ELISA technique.	Strip of nitrocellulose membrane with immobilized antigen detection band. Serum plus reagent incubated on dipstick for 3 hours at room temperature. Dipsticks rinses with water and dried. >3 hours for result.	Serum	Semi‐quantitative result line intensity scale (negative to +4) provided by manufacturer. A positive result is ≥ +1	5
KIT Dri‐Dot Assay (latex agglutination)	Royal Tropical Institute (KIT), Amsterdam	Detects IgM to S. Typhi LPS antigen. White agglutination card.	Dot of dried detection reagent conjugated to blue latex reagent. Antigen‐activated latex stabilized by drying a drop of latex reagent onto card suspended in serum. Card rotated by hand in near‐horizontal position to further induce agglutination. 30 seconds for result.	Serum	Qualitative: positive or negative. Positive when agglutination was observed within 30 seconds. Negative when no agglutination was observed.	1
SD Bioline Salmonella typhi IgG/IgM Fast	Standard Diagnostics Inc., Gyeonggi, Korea	ICT flow method. Detects IgM and IgG antibodies to unspecified S. Typhi antigens.	4 drops of reagent mixed well with patient specimen. Nitrocellulose strip suspended into with 3 sites (IgM, IgG, and control). 30 minutes for result.	Serum, plasma, or whole blood	Qualitative: positive or negative. Positive if line appears in both control and 1 or both of IgM or IgG test zones.	3
Enterocheck WB®	Zephyr Biologicals, Goa, India	ICT Detects IgM antibodies to S. Typhi LPS antigen.	Two‐site (IgM test, and control) immunoassay cassette on a porous nitrocellulose membrane. 15 minutes for result.	Whole blood, plasma, or serum	Qualitative: positive or negative. Presence of a line in both the test and control zones indicates a positive result.	2
Enteroscreen ®	Zephyr Biologicals, Goa, India	ICT Detects IgM and IgG antibodies to S. Typhi LPS antigen.	Three‐site (IgG, IgM, and control) immunoassay cassette on a porous nitrocellulose membrane. 15 minutes for result.	Whole blood, plasma, or serum	Qualitative: positive or negative. Presence of a line in both the test (IgG, IgM, or both) and control zones indicates a positive result.	1
Multi‐test Dip‐S‐Tick	PanBio Inc., Columbia, Maryland, USA	Tests for five pathogens, including S. Typhi. Dipstick format that detects anti‐O, anti‐H,anti‐Vi, IgM, or IgG antibodies.	Detailed information not available	Heparinized whole blood, serum, or plasma	Detailed information not available	1
Mega Salmonella	Mega Diagnostics, Los Angeles, California, USA	Detect IgG and IgM antibodies to unspecified Salmonella antigens. Quantitatively detected by ELISA with peroxidase‐labelled reagents.	Results read in a microplate ELISA reader.	Whole blood, serum, or plasma	Detailed information not available	1
OnSite Typhoid IgG/IgM Combo	CTK Biotech Inc., San Diego, California, USA	Lateral flow immunoassay. Detects IgG and IgM antibodies against recombinant O and H S. Typhi antigens.	Three‐site (IgG, IgM, and control) immunoassay cassette on a porous nitrocellulose membrane. 15 minutes for result.	Whole blood, serum, or plasma	Qualitative: positive or negative. Presence of a line in both the test (IgG, IgM, or both) and control zones indicates a positive result.	2
Abbreviations: immunochromatographic (ICT); immunoglobulin‐G (IgG); immunoglobulin‐M (IgM); Tropical Institute, Amsterdam (KIT); lipopolysaccharide (LPS); outer membrane protein (OMP).

Table 1. Summary of all index tests

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Typhidot. Antibody: IgM or as reported. 1 result per study Show forest plot	17	3691

2 Typhidot. Antibody: IgM or as reported. Reference: BC Show forest plot	15	3466

3 Typhidot. Antibody: IgM or as reported. Reference: BC and BM Show forest plot	2	225

4 Typhidot. Antibody: IgM or as reported. Reference: BC and PCR Show forest plot	1	500

5 Typhidot. Antibody: IgM or as reported. Indeterminates reported Show forest plot	6	1721

6 Typhidot. Antibody: IgM or as reported. Indeterminates not reported Show forest plot	11	1970

7 Typhidot‐M. Antibody: IgM Show forest plot	6	3334

8 Typhi rapid Tr‐02. Reference: BC. Antibody: IgM Show forest plot	1	500

9 Typhi rapid Tr‐02. Reference: BC & PCR. Antibody: IgM Show forest plot	1	500

10 Typhidot all tests 1 result per study Show forest plot	22	6928

11 TUBEX. Reference:BC Show forest plot	14	4885

12 TUBEX. Reference: BC & PCR Show forest plot	1	500

13 TUBEX 1 result per study Show forest plot	14	4885

14 KIT ICT. Reference:BC. Threshold > 1+ Show forest plot	2	709

15 KIT ICT. Reference: BC & PCR. Threshold > 1+ Show forest plot	2	800

16 KIT latex agglutination. Threshold > 1+ Show forest plot	1	425

17 KIT Dipstick. Threshold > 1+ Show forest plot	5	1394

18 KIT ICT. Threshold > 1+ Show forest plot	3	1009

19 KIT all tests. Threshold > 1+. One result per study. Show forest plot	9	2828

20 KIT all tests. Threshold > 2+ studies only Show forest plot	5	1607

21 Enterocheck WB Show forest plot	2	533

22 PanBio Show forest plot	1	144

23 SD Bioline. Antibody: IgG Show forest plot	3	1669

24 SD Bioline. Antibody: IgM Show forest plot	3	1590

25 SD Bioline Antibody: IgM and IgG Show forest plot	1	300

26 Mega Salmonella. Antibody: IgG Show forest plot	1	177

27 Mega Salmonella. Antibody: IgM Show forest plot	1	177

28 Multi‐Test Dip‐S‐Tick Show forest plot	1	75

29 Enteroscreen Show forest plot	1	1521

30 Onsite Typhoid Combo CTK Biotech Show forest plot	2	436

Table Tests. Data tables by test

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