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Journal of Clinical Microbiology, April 2002, p. 1464-1469, Vol. 40, No. 4
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.4.1464-1469.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evaluation of Eight Rapid Screening Tests for Acute Leptospirosis in Hawaii

Paul V. Effler,^1* April K. Bogard,¹ Harry Y. Domen,² Alan R. Katz,³ Henry Y. Higa,² and David M. Sasaki¹

Epidemiology Branch, Communicable Disease Division, Hawaii State Department of Health, Honolulu, Hawaii 96813 ,¹ Medical Microbiology Branch, State Laboratories Division, Hawaii State Department of Health, Pearl City, Hawaii 96782,² Department of Public Health Sciences and Epidemiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96822³

Received 30 July 2001/ Returned for modification 29 November 2001/ Accepted 30 December 2001

Top Abstract Introduction Materials and Methods Results Discussion References

 
Leptospirosis is a major public health problem throughout the world. Clinical recognition of leptospirosis is challenging, and the definitive serologic diagnostic assay, the microscopic agglutination test, is time-consuming and difficult to conduct. Various serologic screening tests have been developed, but their performance among ill persons in the United States has not been established. Eight screening tests were compared using 379 serum samples obtained in 1998 and 1999 from a series of 236 patients (33 with confirmed infection). The median number of days between illness onset and specimen collection was 9. The overall sensitivity, by specimen, for each test was as follows: indirect hemagglutination assay (MRL Diagnostics, Cypress, Calif.), 29%; INDX Leptospira Dip-S-Tick (PanBio InDx, Inc., Baltimore, Md.), 52%; Biognost IgM IFA test (Bios GmbH Labordiagnostik, Gräfelfing, Germany), 40%; Biolisa IgM ELISA (Bios GmbH, Labordiagnostik), 48%; Leptospira IgM ELISA (PanBio Pty Ltd., Brisbane, Australia), 36%; SERION ELISA classic Leptospira (Institut Virion•Serion GmbH, Würzburg, Germany), 48%; LEPTO Dipstick(Organon-Teknika, Ltd., Amsterdam, The Netherlands), 34%; Biosave latex agglutination test (LATEX; Bios GmbH Labordiagnostik), 86%. Test specificity ranged from 85 to 100% among all tests except LATEX, for which the specificity was significantly lower, at 10%. Test sensitivity was particularly low (<25%) for all tests (except LATEX) on specimens collected during the first week of illness. This is the most comprehensive field trial of leptospirosis screening tests reported to date. The data indicate that immunoglobulin M detection tests have limited utility for diagnosing leptospirosis during the initial evaluation of patients seen in Hawaii, a time when important therapeutic decisions are made. Improved leptospirosis screening tests are needed.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Leptospirosis is a major public health problem throughout the world, particularly in the tropics (6, 9). Infections from Hawaii account for the majority of all reported leptospirosis acquired in the United States each year, with an annual incidence rate approximately 100 times that of the mainland (1; R. Burr and D. Sasaki, Int. Conf. Emerg. Infect. Dis. 1998, poster from session 21, board 5, p. 131, 1998).

Clinical recognition of leptospirosis is difficult because leptospires can affect many different organ systems, resulting in a wide variety of clinical presentations. Consequently, leptospirosis is often misdiagnosed as influenza, aseptic meningitis, encephalitis, dengue fever, hepatitis, or gastroenteritis. Timely diagnosis of leptospirosis is essential because prompt, specific treatment, as early in the illness as possible, is important to ensuring a favorable clinical outcome (3).

The Hawaii State Laboratories Division (SLD) routinely makes leptospirosis testing available to the local medical community, but laboratory confirmation is challenging. The sensitivity of blood cultures is low, and culture isolation requires special media and up to 6 weeks of incubation (13). The definitive serologic diagnostic assay, the microscopic agglutination test (MAT), is a time-consuming, difficult test requiring technical expertise and the maintenance of multiple live serovars (4). Moreover, because a fourfold rise in titer between acute- and convalescent-phase samples is necessary for serologic confirmation, the MAT is not useful for guiding clinical management early in the course of illness.

In response to the challenges inherent with definitively diagnosing leptospirosis by MAT or cultures, various screening tests have been developed. Currently, the U.S. Food and Drug Administration (FDA) has approved two, the indirect hemagglutination assay (IHA) and the immunoglobulin M (IgM) dot enzyme-linked immunosorbent assay (ELISA), for commercial use. Previous reports have found the licensed screening tests to be highly sensitive and useful for diagnosing patients suspected of having acute leptospirosis (10; PanBio InDx, Inc., summary of safety and effectiveness data [submitted to the FDA 2001]] [http://www.fda.gov/cdrh/pdf/k002024.pdf]). In our experience, however, the IHA was not as sensitive as it was described to be in other geographic settings (5). This finding prompted us to attempt to identify a screening test which might perform better in our environment. Here we present the findings of a head-to-head comparison of eight different screening tests among patients evaluated for leptospirosis in Hawaii.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patient samples. During the study period (1 June 1998 through 28 February 1999) physicians in Hawaii considering a diagnosis of leptospirosis were encouraged to submit acute- and convalescent-phase patient sera to the Hawaii State Department of Health for culture and serologic diagnosis. Blood cultures were performed at the Hawaii SLD on acute-phase specimens, and a battery of eight screening tests were performed on acute- and convalescent-phase specimens. Aliquots of serum specimens were forwarded to the Centers for Disease Control and Prevention (CDC) for MAT testing.

Leptospirosis patients were classified as "confirmed" if they had a clinically compatible illness and (i) isolation of Leptospira spp. from a clinical specimen, or (ii) an increase of fourfold or more in the Leptospira MAT titer between acute- and convalescent-phase serum specimens studied at the same laboratory (18).

Leptospirosis patients were classified as "probable" if they had a clinically compatible illness and a Leptospira MAT titer of 1:200 in one or more serum specimens without a fourfold rise in titer or a positive culture (2).

To be eligible for the study, MAT results on paired serum specimens needed to be available for a patient, and at least one of the specimens must have been collected during the first 6 weeks following illness onset. Of 395 patients initially evaluated for leptospirosis, only one specimen was provided for 154 patients and no specimens were collected within 6 weeks of onset for 5 other patients, leading these 159 patients to be excluded. Culture and MAT results were subsequently reviewed for the remaining 236 patients to determine the case status for each patient. Because the leptospirosis screening tests we evaluated primarily detect IgM antibody and are intended to identify acute infections, only the screening test results from specimens collected <42 days after illness onset were included in the assessment of the test's performance. The final sample for the screening test evaluation consisted of 93 patients with the first of paired specimens and 143 patients with both specimens, for a total of 379 specimens.

Fifty-eight specimens were obtained from 33 patients with confirmed leptospirosis, 30 specimens were obtained from 19 patients with probable leptospirosis infection, and 291 specimens were obtained from 184 patients without leptospirosis infection as determined by MAT. The prevalence of confirmed or probable leptospirosis was thus 22% (52 of 236 patients) in our population.

Of patients with confirmed leptospirosis, 25 patients (76%) had a fourfold rise in MAT titer, 1 patient (3%) was confirmed by culture only, and 7 patients (21%) had both a fourfold rise in titer and a positive culture. Seven (37%) of the patients with probable leptospirosis had at least one MAT titer of 1:800. The median number of days between illness onset and specimen collection was 9 (mean = 14 days): 4 days for the first of the paired specimens (mean = 7 days) and 24 days for the second specimens (mean = 25 days).

Laboratory methods. (i) Cultures. Blood cultures and serogrouping of isolates were performed as previously described with one minor variation (18). Inoculated blood cultures were incubated for 6 weeks and examined weekly, instead of weekly examinations for 5 weeks followed by monthly examinations for 4 months.

(ii) MAT. The presence of antibodies to Leptospira antigens was determined by the MAT as previously described (4, 5). Twenty-one serovars representing 17 serogroups were used in the test battery.

Screening tests. All screening tests were performed by a single, experienced serologist at the SLD who was unaware of the MAT result for any given specimen at the time the screening tests were performed.

(i) IHA. A commercially available IHA, purchased from MRL Diagnostics (Cypress, Calif.), was performed at the SLD as previously described (5, 11). Results from three samples were excluded from the analysis because of nonspecific reactivity.

(ii) D-ELISA. A commercially available IgM Dot ELISA (INDX Leptospira Dip-S-Tick) (D-ELISA) was donated by PanBio InDx, Inc. (Baltimore, Md.), and performed at the SLD as previously described (10).

(iii) IFA. An IgM indirect fluorescent-antibody (IFA) assay kit (Biognost) was donated by Bios GmbH Labordiagnostik (Gräfelfing, Germany), and the assay was performed by the SLD as described in the package insert.

(iv) B-ELISA. An IgM ELISA test (Biolisa) (B-ELISA) was donated by Bios GmbH Labordiagnostik and performed by the SLD as previously described (20).

(v) P-ELISA. A commercially available IgM ELISA (Leptospira IgM ELISA) (P-ELIAS) was donated by PanBio Pty Ltd. (Brisbane, Australia) and performed at the SLD as previously described (19) but with the following variances as recommended in the test insert: (i) an incubation temperature of 37°C was used instead of room temperature, and (ii) our test results were expressed in PanBio units, i.e., a ratio (sample absorbance/mean IgM calibrator absorbance) multiplied by a factor of 10. As recommended by the manufacturer's technical representative (Peter Devine, personal communication, 1999) PanBio units of <10 were considered negative, while values of 10 were considered positive.

(vi) S-ELISA. An IgM ELISA (SERION ELISA classic Leptospira) (S-ELISA) was donated by Institut Virion•Serion GmbH (Würzburg, Germany) and performed at the SLD as described in the package insert.

(vii) DIPSTICK. An IgM Dipstick test (LEPTO Dipstick) (DIPSTICK) was donated by Organon-Teknika, Ltd. (Amsterdam, The Netherlands), and performed by the SLD as previously described (7).

(viii) LATEX. A latex agglutination test (Biosave) (LATEX) was donated by Bios GmbH Labordiagnostik and performed by the SLD according to instructions in the package insert.

Data analyses. The sensitivity of the screening test was defined as the proportion of all specimens obtained from patients with leptospirosis as determined by MAT or culture that were positive with the screening test. Specificity was defined as the proportion of all specimens obtained from patients without leptospirosis that were negative with the screening test. The positive predictive value (PPV) was defined as the proportion of specimens with positive results on the screening test which were obtained from patients with leptospirosis. The negative predictive value (NPV) was defined as the proportion of specimens with negative results on the screening test which were obtained from patients without leptospirosis. An assessment of each screening test's sensitivity, specificity, PPV, and NPV was performed when all patients with confirmed or probable leptospirosis were classified as having leptospirosis and also when patients with probable leptospirosis were excluded from the analysis.

Proportions and 95% confidence intervals (95% CIs) for proportions were calculated with the Fleiss quadratic equation using Microsoft Excel software. The chi-square test for linear trend was calculated using EpiInfo software (version 6). Linear trend lines in graphs were obtained using routine formatting options in Excel software.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The sensitivity, specificity, PPV, and NPV for each of the eight leptospirosis screening tests are shown in Table 1. With the exception of the LATEX test, whose test performance characteristics were quite different from the others in all parameters evaluated, point estimates of the sensitivities ranged from 26 to 51% for the analyses that included both confirmed and probable cases. Generally, sensitivities increased slightly when probable cases were removed from the analysis.

View this table: [in this window] [in a new window]

TABLE 1. Sensitivities, specificities, PPVs, and NPVs of leptospirosis screening tests performed on sera from patients evaluated in Hawaii, 1998 to 1999

Point estimates for specificity ranged from 85 to 100% among seven of the eight screening tests and were not affected by the exclusion of sera from probable leptospirosis cases. The specificity of LATEX was significantly lower, at 10%.

The point estimates of sensitivity for each test by number of days after illness onset that the specimen was obtained are presented in Fig. 1. Overall, sensitivity was low (<25%) for all tests (except LATEX) on specimens collected during the first week of illness. Sensitivity increased for all tests on specimens collected 7 through 13 days post-illness onset, and the observed difference between specimens collected during the first and second weeks post-illness onset was statistically significant (P < 0.05) for all tests but LATEX (P = 0.09).

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FIG. 1. Sensitivities of eight different leptospirosis screening tests as they performed in testing of specimens from confirmed and probable cases of leptospirosis diagnosed in Hawaii from 1 June 1998 through 28 February 1999.

Test specificity, however, was notably higher for all tests early in illness (except LATEX), with point estimates of >80% among samples collected within the first week following illness onset and >90% for specimens collected during the second week post-illness onset (Fig. 2).

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FIG. 2. Specificities of eight different leptospirosis screening tests as they performed in testing of specimens from confirmed and probable cases of leptospirosis diagnosed in Hawaii from 1 June 1998 through 28 February 1999.

Trends in the proportion of each screening test that were positive, compiled on the basis of the MAT titer in the tested specimen, are presented in Fig. 3. Specimens with higher MAT titers were significantly more likely to test positive in each of the screening tests (chi-square test for linear trend P < 0.0005) except LATEX (P = 0.07).

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FIG. 3. Proportion of leptospirosis screening test results that were positive versus the height of the MAT titer for specimens collected in Hawaii from 1 June 1998 through 28 February 1999. All titers are reciprocals of the numbers shown on the x axis.

Top Abstract Introduction Materials and Methods Results Discussion References

 
This is the most comprehensive field trial of leptospirosis screening tests reported to date, allowing for direct comparison of eight different tests as they performed on a series of patient specimens collected in the course of routine clinical practice in Hawaii.

In this study, the LATEX test was found to be highly sensitive, but the specificity and PPV of this test were unacceptably low, precluding further consideration of this screening test in our setting. Of the remaining tests, the highest point estimates for sensitivity on specimens collected during the 6 weeks after illness onset barely exceeded 50%, and 95% CIs did not surpass 65%. All tests were particularly insensitive for testing of samples collected within the first week following illness onset. Unfortunately, it is during this time frame that important therapeutic decisions are likely to be made in the evaluation of patients with a leptospirosis-compatible illness.

During the second week post-illness onset, test sensitivities improved significantly for all but one of the tests. Still, when we analyzed test parameters and combined the results for specimens collected during the first 2 weeks post-illness onset, the overall test sensitivities remained low, ranging from 12 to 32% (analysis not shown).

Test specificity was higher for all tests (excluding LATEX), even among those samples collected within the first week following illness. NPVs were also respectable during the first 6 days post-illness onset, ranging from 74 to 78% and remaining ca. 85% or higher for each of the next four weeks (data not shown).

Some of the screening tests included in this study have been evaluated elsewhere. Although the specificities of these tests are uniformly high, there is greater variability in reported sensitivities. In our evaluation, the estimates of overall sensitivity were generally lower than those reported previously (10, 14, 15, 19; M. D. S. Bajani, D. A. Ashford, S. L. Bragg, C. Woods, T. Aye, R. A. Spiegel, B. D. Plikaytis, and R. S Weyant, Int. Conf. Emerg. Infect. Dis. 2000, poster of session 48, board 24, p. 119, 2000).

There are several possible explanations for the variability in screening test sensitivity observed between studies. First, differences in reported test sensitivity may be attributable to differences in the case definitions used or dissimilar methods of case recruitment (5). Leptospirosis surveillance in Hawaii is community based; physicians suspecting leptospirosis submit serum samples from individuals treated as inpatients or outpatients. In this study, 31% of the patients were hospitalized, and the "gold standard" for evaluating the screening tests was the MAT and/or culture; in other evaluations patients were drawn from hospitalized cases only or were confirmed using an IgM ELISA test (10, 11).

Second, selection of the control population may also influence the results of screening test evaluations. Lijmer et al. report that studies using a diseased population and a separate control group significantly overestimate the diagnostic performance of screening tests compared to studies using a single clinical population (12). The optimal design for assessing the accuracy of a diagnostic test is a prospective comparison of the "test and the reference test in a consecutive series of patients from a clinically relevant population," i.e., "a group of patients covering the spectrum of disease that is likely to be encountered in use of the test" (12). The population enrolled in our study fits this description. Thus, differences in overall test sensitivity observed in our assessment and those that used other means to identify noncases may be secondary to differences in study design (7, 16, 19, 20; Bajani et al., Abstr. Int. Conf. Emerg. Infect. Dis. 2000)).

A third explanation for reported differences in leptospirosis screening test performance is that test sensitivity may be affected by the prevalence of the various different infecting serogroups. Screening tests for leptospirosis use broad-reacting antigens to detect the patient's immune response to the infecting leptospires. Because the prevalence of enzootic leptospiral serogroups varies geographically, there may be a fair degree of variability in the antigenic characteristics of the pathogen causing infection between one location and another. The screening test's sensitivity in any given setting is therefore dependent on the ability of test antigens to detect antibodies produced against the site-specific leptospiral serovars (8). Therefore, laboratories need to validate the performance of screening tests in the setting in which they are to be used.

A fourth possible explanation for the variations in test sensitivity observed in our study compared to others is laboratory error. We believe it is unlikely, however, that laboratory errors produced reduced estimates of test sensitivity for each of seven different tests, while major, anticipated patterns in test sensitivity (e.g., substantial improvement in test sensitivity between acute- and convalescent-phase sera and a positive correlation between antibody titers as determined by MAT and the proportion of all screening tests that are positive) were preserved (17).

The main limitation of this study is the relatively small sample size, which resulted in sensitivity estimates with 95% CIs that are necessarily wide. Unfortunately, extension of the study period to enroll more patients was not possible due to the considerable resources required.

When initiating this evaluation it was our intent to identify a screening test that might be more sensitive than the IHA—the only FDA-licensed test at that time. In Hawaii, the ELISA-based tests performed reasonably well for diagnosing recent infection if the specimen was obtained 7 days after illness onset. Although no single test was clearly superior, two tests (D-ELISA and B-ELISA) had significantly higher sensitivities in the analysis which included confirmed and probable patients, compared to the IHA. Both these ELISAs had acceptable specificities as well, but the sensitivities during the first week of illness were still suboptimal.

Leptospirosis screening tests that are sensitive and specific early in the acute phase of illness would be of great benefit to patients and physicians. Conversely, poorly performing screening tests may adversely impact clinical management, because a false-negative screening test result might discourage physicians from further considering leptospirosis and appropriate treatment might not be initiated (5). We concur with Faine et al. that "better bedside tests are required," ones which can recognize leptospirosis "earlier than serological methods" (6). Diagnostic strategies based on leptospiral antigen detection or nucleic acid amplification techniques are alternatives to be explored.

 
We thank Chester Wakida, Kristin Mills, Erik Cremer, and Jo Manea from the Hawaii State Department of Health for assistance with the case investigations. We are also very grateful to Robbin Weyant, Sandra Bragg, and Tin Aye of the CDC/WHO Collaborating Center for Leptospirosis, Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, for supporting the State of Hawaii by providing microscopic agglutination testing on all samples. With the exception of the IHA, which was purchased by the Hawaii State Department of Health, all screening test kits were donated by the manufacturers, for which we are grateful.

Financial support was provided through cooperative agreement U50/CCU912395-03 from the CDC, U.S. Public Health Service, Atlanta, Ga.

 
* Corresponding author. Mailing address: Hawaii State Department of Health, 1250 Punchbowl St., Room 444, Honolulu, HI 96813. Phone: (808) 586-4586. Fax: (808) 586-8347. E-mail: pveffler{at}mail.health.state.hi.us.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Journal of Clinical Microbiology, April 2002, p. 1464-1469, Vol. 40, No. 4
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.4.1464-1469.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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