Chagas disease serological test performance in United States blood donor specimens

Whitman, Jeffrey D.; Bulman, Christina; Gunderson, Emma L.; Irish, Amanda M.; Townsend, Rebecca L.; Stramer, Susan L.; Sakanari, Judy; Bern, Caryn

doi:10.1101/730754

Cited by 6 publications

(9 citation statements)

References 27 publications

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“…Each cartridge was assigned a semi-quantitative score (0 for negative, 1 to 6 for positive) for test line intensity by two independent readers blinded to specimen status and to each other’s scores (eFigure 1). 17 For some cartridges (DeepBlue, UCP, Bioperfectus), the positive control indicator failed to appear after addition of diluent in a significant fraction of tests. For these tests, two further drops of diluent were added to successfully recover control indicators in all affected tests.…”

Section: Methodsmentioning

confidence: 99%

“…For specificity, we included 108 pre-COVID-19 plasma specimens from eligible blood donors collected prior to July 2018. 17 We assessed cross-reactivity using 52 specimens from 2020: 50 with test results for other respiratory viruses (Biofire FilmArray; BioFire Diagnostics, Salt Lake City, UT), and 32 with negative results by SARS-CoV-2 RT-PCR. We based minimum sample size calculations on expected binomial exact 95% confidence limits.…”

Section: Methodsmentioning

confidence: 99%

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Test performance evaluation of SARS-CoV-2 serological assays

Whitman

2020

Preprint

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247

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Background Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data. Method We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies. The specimen set comprised 128 plasma or serum samples from 79 symptomatic SARS-CoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system. Results Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.7-94.8%. No consistent cross-reactivity was observed. Conclusion Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Test performance evaluation of SARS-CoV-2 serological assays

Whitman

2020

Preprint

Self Cite

247

282

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“…Using Chagas disease seropositive specimens, a panel of 31 peptide motifs was identified that exhibited 100% sensitivity (60/60) and 100% specificity (120/120) in independent validation sets. Remarkably, the Chagas SERA assay exhibited 99.8% specificity (998/1000) amongst sera without known Chagas serostatus, which compares favorably to the combined sensitivity and specificity of individual, FDA-cleared tests 17 . The exceptional specificity of SERA could be expected to yield fewer false positive tests, a feature that may be useful in screening and surveillance studies 21 , particularly when multiple tests are performed in parallel.…”

Section: Discussionmentioning

confidence: 90%

“…Confirmatory testing currently requires the use of three serology tests -two parallel, independent tests, and a third "tie-breaker" test to achieve a specificity of >99%. Thus, a single test with high specificity could streamline confirmatory testing and screening in blood donors and at-risk groups 17 . Our results indicate that NGS-based serology using SERA provides an effective approach to antigen and epitope discovery, and an assay format capable of achieving exceptional diagnostic specificity without multiplexing limitations.…”

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confidence: 99%

Antibody epitope repertoire analysis enables rapid antigen discovery and multiplex serology

Kamath

Reifert

Johnston

et al. 2020

Sci Rep

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The detection of pathogen-specific antibodies remains a cornerstone of clinical diagnostics. Yet, many test exhibit undesirable performance or are completely lacking. Given this, we developed serum epitope repertoire analysis (SERA), a method to rapidly discover conserved, pathogen-specific antigens and their epitopes, and applied it to develop an assay for Chagas disease caused by the protozoan parasite Trypanosoma cruzi. Antibody binding peptide motifs were identified from 28 Chagas repertoires using a bacterial display random 12-mer peptide library and next-generation sequencing (NGS). Thirty-three motifs were selected and mapped to candidate Chagas antigens. In a blinded validation set (n = 72), 30/30 Chagas were positive, 30/30 non-Chagas were negative, and 1/12 Leishmania sp. was positive. After unblinding, a Leishmania cross-reactive epitope was identified and removed from the panel. The Chagas assay exhibited 100% sensitivity (30/30) and specificity (90/90) in a second blinded validation set including individuals with other parasitic infections. Amongst additional epitope repertoires with unknown Chagas serostatus, assay specificity was 99.8% (998/1000). Thus, the Chagas assay achieved a combined sensitivity and specificity equivalent or superior to diagnostic algorithms that rely on three separate tests to achieve high specificity. NGS-based serology via SERA provides an effective approach to discover antigenic epitopes and develop high performance multiplex serological assays.

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“…We recognize that access to CD diagnosis is also problematic in the US [10]. While this topic was not within the scope of this study, creating access to benznidazole will require actions in relation to diagnosis, such as assessment of the four FDA-cleared diagnostic assays [18,33], development of strategies for maternal and newborn screening, education of primary care providers on diagnostic testing, and improvement of linkage to care for seropositive blood donors. Likewise, we did not consider access to nifurtimox, which is still provided by CDC for compassionate use.…”

Section: Discussionmentioning

confidence: 99%

Access to Chagas disease treatment in the United States after the regulatory approval of benznidazole

et al. 2020

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Approximately 300,000 persons in the United States (US) are infected with Trypanosoma cruzi, the protozoan that causes Chagas disease, but less than 1% are estimated to have received antiparasitic treatment. Benznidazole was approved by the US Food and Drug Administration (FDA) for treatment of T. cruzi infection in 2017 and commercialized in May 2018. This paper analyzes factors that affect access to benznidazole following commercialization and suggests directions for future actions to expand access. We applied an access framework to identify barriers, facilitators, and key actors that influence the ability of people with Chagas disease to receive appropriate treatment with benznidazole. Data were collected from the published literature, key informants, and commercial databases. We found that the mean number of persons who obtained benznidazole increased from just under 5 when distributed by the CDC to 13 per month after the commercial launch (from May 2018 to February 2019). Nine key barriers to access were identified: lack of multi-sector coordination, failure of health care providers to use a specific order form, lack of an emergency delivery system, high medical costs for uninsured patients, narrow indications for use of benznidazole, lack of treatment guidelines, limited number of qualified treaters, difficulties for patients to make medical appointments, and inadequate evaluation by providers to determine eligibility for treatment. Our analysis shows that access to benznidazole is still limited after FDA approval. We suggest six areas for strategic action for the pharmaceutical company that markets benznidazole and its allied private foundation to expand access to benznidazole in the US. In addition, we recommend expanding the existing researcher-clinician network by including government agencies, companies and others. This paper's approach could be applied to access programs for benznidazole in other countries or for other health products that target neglected populations throughout the world.

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Chagas disease serological test performance in United States blood donor specimens

Cited by 6 publications

References 27 publications

Test performance evaluation of SARS-CoV-2 serological assays

Test performance evaluation of SARS-CoV-2 serological assays

Antibody epitope repertoire analysis enables rapid antigen discovery and multiplex serology

Access to Chagas disease treatment in the United States after the regulatory approval of benznidazole

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