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Improved Influenza Diagnostics through Thermal Contrast Amplification.

ABSTRACT: Influenza poses a serious health threat and creates an economic burden for people around the world. The accurate diagnosis of influenza is critical to the timely clinical treatment of patients and the control of outbreaks to protect public health. Commercially available rapid influenza diagnostic tests (RIDTs) that are operated by visual readout are widely used in clinics to screen influenza infections, but RIDTs suffer from imperfect analytical sensitivity, especially when the virus concentration in the sample is low. Fortunately, the sensitivity can be simply improved through an add-on signal amplification step, i.e., thermal contrast amplification (TCA). To demonstrate the advantage of TCA for influenza diagnosis, we conducted a prospective cohort study on 345 clinical specimens collected for influenza A and B testing during the 2017-2018 influenza season. All samples were tested using the Quidel QuickVue Influenza A + B test, followed by a TCA readout, and then confirmatory polymerase chain reaction testing. Through the TCA detecting sub-visual weak positives, TCA reading improved the overall influenza sensitivity by 53% for influenza A and 33% for influenza B over the visual RIDTs readings. Even though the specificity was compromised slightly by the TCA protocol (relative decrease of 0.09% for influenza A and 0.01% for influenza B), the overall performance was still better than that achieved by visual readout based on comparison of their plots in receiver operating characteristic space and F1 scores (relative increase of 14.5% for influenza A and 12.5% for influenza B). Performing a TCA readout on wet RIDTs also improved the overall TCA performance (relative increase in F1 score of 48%). Overall, the TCA method is a simple and promising way to improve the diagnostic performance of commercial RIDTs for infectious diseases, especially in the case of specimens with low target analytes.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7999055 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Detection of human immunodeficiency virus (HIV) p24 protein at a single pg/ml concentration in point-of-care (POC) settings is important because it can facilitate acute HIV infection diagnosis with a detection sensitivity approaching that of laboratory-based assays. However, the limit of detection (LOD) of lateral flow immunoassays (LFAs), the most prominent POC diagnostic platform, falls short of that of laboratory protein detection methods such as enzyme-linked immunosorbent assay (ELISA). Here, we report the development and optimization of a thermal contrast amplification (TCA) LFA that will allow ultrasensitive detection of 8 pg/ml p24 protein spiked into human serum at POC, approaching the LOD of a laboratory test. To achieve this aim, we pursued several innovations as follows: (a) defining a new quantitative figure of merit for LFA design based on the specific to nonspecific binding ratio (BR); (b) using different sizes and shapes of gold nanoparticles (GNPs) in the systematic optimization of TCA LFA designs; and (c) exploring new laser wavelengths and power regimes for TCA LFA designs. First, we optimized the blocking buffer for the membrane and running buffer by quantitatively measuring the BR using a TCA reader. The TCA reader interprets the thermal signal (i.e., temperature) of GNPs within the membrane when irradiated by a laser at the plasmon resonance wavelength of the particle. This process results in higher detection and quantitation of GNPs than in traditional visual detection (i.e., color intensity). Further, we investigated the effect of laser power (30, 100, 200 mW), GNP size and shape (30 and 100 nm gold spheres, 150 nm gold-silica shells), and laser wavelength (532, 800 nm). Applying these innovations to a new TCA LFA design, we demonstrated that 100 nm spheres with a 100 mW 532 nm laser provided the best performance (i.e., LOD = 8 pg/ml). This LOD is significantly better than that of the current colorimetric LFA and is in the range of the laboratory-based p24 ELISA. In summary, this TCA LFA for p24 protein shows promise for detecting acute HIV infection in POC settings.

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Improved Influenza Diagnostics through Thermal Contrast Amplification.

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