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1.
Nat Commun ; 14(1): 2361, 2023 04 24.
Article in English | MEDLINE | ID: covidwho-2298604

ABSTRACT

Since many lateral flow assays (LFA) are tested daily, the improvement in accuracy can greatly impact individual patient care and public health. However, current self-testing for COVID-19 detection suffers from low accuracy, mainly due to the LFA sensitivity and reading ambiguities. Here, we present deep learning-assisted smartphone-based LFA (SMARTAI-LFA) diagnostics to provide accurate decisions with higher sensitivity. Combining clinical data learning and two-step algorithms enables a cradle-free on-site assay with higher accuracy than the untrained individuals and human experts via blind tests of clinical data (n = 1500). We acquired 98% accuracy across 135 smartphone application-based clinical tests with different users/smartphones. Furthermore, with more low-titer tests, we observed that the accuracy of SMARTAI-LFA was maintained at over 99% while there was a significant decrease in human accuracy, indicating the reliable performance of SMARTAI-LFA. We envision a smartphone-based SMARTAI-LFA that allows continuously enhanced performance by adding clinical tests and satisfies the new criterion for digitalized real-time diagnostics.


Subject(s)
COVID-19 , Deep Learning , Humans , Smartphone , COVID-19 Testing , Algorithms
2.
Nat Commun ; 14(1): 1520, 2023 03 18.
Article in English | MEDLINE | ID: covidwho-2275685

ABSTRACT

Highly sensitive rapid testing for COVID-19 is essential for minimizing virus transmission, especially before the onset of symptoms and in asymptomatic cases. Here, we report bioengineered enrichment tools for lateral flow assays (LFAs) with enhanced sensitivity and specificity (BEETLES2), achieving enrichment of SARS-CoV-2 viruses, nucleocapsid (N) proteins and immunoglobulin G (IgG) with 3-minute operation. The limit of detection is improved up to 20-fold. We apply this method to clinical samples, including 83% with either intermediate (35%) or low viral loads (48%), collected from 62 individuals (n = 42 for positive and n = 20 for healthy controls). We observe diagnostic sensitivity, specificity, and accuracy of 88.1%, 100%, and 91.9%, respectively, compared with commercial LFAs alone achieving 14.29%, 100%, and 41.94%, respectively. BEETLES2, with permselectivity and tunability, can enrich the SARS-CoV-2 virus, N proteins, and IgG in the nasopharyngeal/oropharyngeal swab, saliva, and blood serum, enabling reliable and sensitive point-of-care testing, facilitating fast early diagnosis.


Subject(s)
COVID-19 , Humans , COVID-19/diagnosis , SARS-CoV-2 , COVID-19 Testing , Sensitivity and Specificity , Polymerase Chain Reaction , Immunoglobulin G
3.
Biosens Bioelectron ; 222: 114965, 2023 Feb 15.
Article in English | MEDLINE | ID: covidwho-2242175

ABSTRACT

A simple, affordable point of care test (POCT) is necessary for on-site detection of coronavirus disease 2019 (COVID-19). The lateral flow assay (LFA) has great potential for use in POCT mainly because of factors such as low time consumption, low cost, and ease of use. However, it lacks sensitivity and limits of detection (LOD), which are essential for early diagnostics. In this study, we proposed a non-powered preconcentrator (NPP) based on nanoelectrokinetics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Antigen (Ag) lateral flow assay. The non-powered preconcentrator is composed of glass fiber-based composite paper and ion permselective material, and it can be simply operated by force balancing gravitational, capillary, and depletion-induced forces. The proposed approach helps enrich the SARS-CoV-2 viral nucleocapsid (N) proteins based on a 10-min operation, and it improved the LOD by up to 10-fold. The corresponding virus enrichment, which was evaluated using the reverse-transcriptase polymerase chain reaction (RT-PCR), revealed an improvement in ΔCt values > 3. We successfully demonstrated the enhancement of the NPP-assisted LFA, we extended to applying it to clinical samples. Further, we demonstrated an affordable, easy-to-implement form of LFA by simply designing NPP directly on the LFA buffer tube.


Subject(s)
Biosensing Techniques , COVID-19 , Humans , COVID-19/diagnosis , SARS-CoV-2 , COVID-19 Testing , Limit of Detection , Sensitivity and Specificity
4.
Front Immunol ; 13: 1038712, 2022.
Article in English | MEDLINE | ID: covidwho-2198885

ABSTRACT

Comprehensive assessment of SARS-CoV-2 antibodies against antigenic epitopes and cross-neutralization on variants is essential to monitor after infection or vaccination. From 32 COVID-19 patients and 40 vaccinated individuals [20 Oxford-AstraZeneca (AZ) and 20 Pfizer-BioNTech (BNT)], 348 serial sera are collected until 40 days after infection and 3 months after homologous booster vaccination. Antibody levels were monitored using a multiplex-bead assay including variant spike antigens, Roche (S1/RBD total) and a surrogate virus neutralization test (GenScript). Anti-S/S1/RBD levels were higher than anti-S2/N levels from 2 weeks after infection and were higher in severe infection (P < 0.05). Vaccination showed highest antibody levels after 1-month booster and had consistently high levels in the order of anti-full S, anti-RBD, anti-S1 and anti-S2. Infection induced higher anti-S2/N levels than prime vaccination (P < 0.05). Three months after BNT/BNT vaccination, antibody levels against S1/RBD and 23 variant antigens were higher than post-infection or AZ groups (P < 0.05). Regarding intraindividual changes from post-prime to post-boost vaccination, boost induced a 1.1- to 3.9-fold increase on multiplex-bead assay, 22.8- to 24.2-fold on Roche assay and 22.8- to 24.2-fold on GenScript assay. Post-prime levels by multiplex-bead assay predicted post-boost levels, but Roche and GenScript results were not predictive in the AZ group. The kinetics of SARS-CoV-2 antibody levels vary depending on the antigenic epitopes, assay kit, disease severity or vaccine type. Assessing seroconversion using multiplex-bead assays may contribute to monitoring the disease course, adjusting vaccination strategies, and accelerating vaccination efficacy.


Subject(s)
COVID-19 , ChAdOx1 nCoV-19 , Humans , Epitopes , BNT162 Vaccine , SARS-CoV-2 , COVID-19/prevention & control , Antibodies, Viral , Vaccination
5.
Korean J Intern Med ; 37(4): 851-863, 2022 07.
Article in English | MEDLINE | ID: covidwho-1862980

ABSTRACT

BACKGROUND/AIMS: The risk factors and clinical impacts of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remain controversial, and no data have been reported in Korea. This study aimed to investigate the epidemiology and importance of CAPA diagnostic efforts and to identify the predictors of CAPA and the impacts on clinical outcomes. METHODS: Between January 2020 and May 2021, data of severely to critically ill COVID-19 patients were extracted from seven hospitals of the Catholic Medical Center through a clinical data warehouse. Corticosteroid use was subcategorized into total cumulative dose, early 7-day dose, mean daily dose, and duration of use. RESULTS: A total of 2,427 patients were screened, and 218 patients were included. CAPA was diagnosed in 4.6% (10/218) of all hospitalized and 11.2% (10/89) of intensive care unit patients. Total cumulative dose (over 1,000 mg as methylprednisolone) and daily high-dose corticosteroid use (over 60 mg/day) were independent predictors but not early 7-day high-dose corticosteroid use (over 420 mg/week) (odds ratio [OR], 1.731; 95% confidence interval [CI], 0.350 to 8.571) nor prolonged use (OR, 2.794; 95% CI, 0.635 to 13.928). In-hospital overall mortality was 11.9% (26 of 218). CAPA itself did not affect the outcome; rather, daily high-dose steroid use significantly increased the 30-day mortality (hazard ratio, 5.645; 95% CI, 1.225 to 26.091). CONCLUSION: CAPA was not uncommon, especially in critically ill patients. Daily high-dose corticosteroid use was the predictor of CAPA and associated with high mortality rates. High-dose corticosteroids use after early inflammatory phase should be avoided, and active surveillance methods for CAPA are essential for those high-risk patients.


Subject(s)
COVID-19 , Pulmonary Aspergillosis , Adrenal Cortex Hormones/adverse effects , COVID-19/complications , Critical Illness , Humans , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Pulmonary Aspergillosis/epidemiology , Retrospective Studies , Risk Factors
6.
J Med Internet Res ; 23(2): e26257, 2021 02 22.
Article in English | MEDLINE | ID: covidwho-1574035

ABSTRACT

BACKGROUND: As the COVID-19 pandemic continues, an initial risk-adapted allocation is crucial for managing medical resources and providing intensive care. OBJECTIVE: In this study, we aimed to identify factors that predict the overall survival rate for COVID-19 cases and develop a COVID-19 prognosis score (COPS) system based on these factors. In addition, disease severity and the length of hospital stay for patients with COVID-19 were analyzed. METHODS: We retrospectively analyzed a nationwide cohort of laboratory-confirmed COVID-19 cases between January and April 2020 in Korea. The cohort was split randomly into a development cohort and a validation cohort with a 2:1 ratio. In the development cohort (n=3729), we tried to identify factors associated with overall survival and develop a scoring system to predict the overall survival rate by using parameters identified by the Cox proportional hazard regression model with bootstrapping methods. In the validation cohort (n=1865), we evaluated the prediction accuracy using the area under the receiver operating characteristic curve. The score of each variable in the COPS system was rounded off following the log-scaled conversion of the adjusted hazard ratio. RESULTS: Among the 5594 patients included in this analysis, 234 (4.2%) died after receiving a COVID-19 diagnosis. In the development cohort, six parameters were significantly related to poor overall survival: older age, dementia, chronic renal failure, dyspnea, mental disturbance, and absolute lymphocyte count <1000/mm3. The following risk groups were formed: low-risk (score 0-2), intermediate-risk (score 3), high-risk (score 4), and very high-risk (score 5-7) groups. The COPS system yielded an area under the curve value of 0.918 for predicting the 14-day survival rate and 0.896 for predicting the 28-day survival rate in the validation cohort. Using the COPS system, 28-day survival rates were discriminatively estimated at 99.8%, 95.4%, 82.3%, and 55.1% in the low-risk, intermediate-risk, high-risk, and very high-risk groups, respectively, of the total cohort (P<.001). The length of hospital stay and disease severity were directly associated with overall survival (P<.001), and the hospital stay duration was significantly longer among survivors (mean 26.1, SD 10.7 days) than among nonsurvivors (mean 15.6, SD 13.3 days). CONCLUSIONS: The newly developed predictive COPS system may assist in making risk-adapted decisions for the allocation of medical resources, including intensive care, during the COVID-19 pandemic.


Subject(s)
COVID-19/diagnosis , COVID-19/mortality , Age Factors , Aged , Critical Care/statistics & numerical data , Dementia/epidemiology , Female , Humans , Kidney Failure, Chronic/epidemiology , Length of Stay/statistics & numerical data , Male , Middle Aged , Pandemics , Prognosis , Proportional Hazards Models , ROC Curve , Republic of Korea/epidemiology , Retrospective Studies , Risk Factors , Severity of Illness Index , Survival Rate
8.
Mol Diagn Ther ; 25(5): 617-628, 2021 09.
Article in English | MEDLINE | ID: covidwho-1328680

ABSTRACT

BACKGROUND AND OBJECTIVE: Since the initial coronavirus disease outbreak in late 2019 (COVID-19), reverse-transcription real-time polymerase chain reaction (RT-qPCR) has become the gold standard test to detect severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). However, a more sensitive and accurate diagnostic tool was required. Therefore, droplet digital polymerase chain reaction (ddPCR) was suggested as an alternative method. Here, we evaluated the performance of ddPCR to detect SARS-CoV-2 and compared it to the performance of RT-qPCR. METHODS: The analytical performances, including limit of blank and limit of detection, were established using positive and negative SARS-CoV-2 reference materials. A total of 366 RNA extracts (173 positive and 193 negative by RT-qPCR) were collected from four institutions and tested with a Bio-Rad SARS-CoV-2 ddPCR kit that detects the SARS-CoV-2 genome using primers for N1 and N2. RESULTS: Limit of blank was set at 0, and the limits of detection of N1 and N2 were 1.99 copies/µL and 5.18 copies/µL, respectively. Linearity was evaluated using serial dilution samples, which demonstrated good results (R2: 0.999, linear range: 5.88-6825.25 copies/µL for N1 and R2: 0.999, 5.53-5855.47 copies/µL for N2). The results of ddPCR and RT-qPCR revealed substantial agreement (Cohen's kappa: 0.639, p < 0.01). The 63 samples with positive ddPCR but negative RT-qPCR showed low copy numbers, and 55% of them had COVID-19-related symptoms. CONCLUSIONS: Droplet digital polymerase chain reaction demonstrated excellent sensitivity for SARS-Cov-2 detection and consistently agreed with the results from conventional RT-qPCR. Furthermore, ddPCR provided quantitative data that can be used to monitor changes in the viral load of patients with COVID-19.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , RNA, Viral/genetics , SARS-CoV-2/genetics , COVID-19/virology , COVID-19 Nucleic Acid Testing/standards , Calibration , Humans , Limit of Detection , Nasopharynx/virology , Reference Values
9.
Ann Lab Med ; 41(6): 577-587, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1264321

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays have high clinical utility in managing the pandemic. We compared antibody responses and seroconversion of coronavirus disease 2019 (COVID-19) patients using different immunoassays. METHODS: We evaluated 12 commercial immunoassays, including three automated chemiluminescent immunoassays (Abbott, Roche, and Siemens), three enzyme immunoassays (Bio-Rad, Euroimmun, and Vircell), five lateral flow immunoassays (Boditech Med, SD biosensor, PCL, Sugentech, and Rapigen), and one surrogate neutralizing antibody assay (GenScript) in sequential samples from 49 COVID-19 patients and 10 seroconversion panels. RESULTS: The positive percent agreement (PPA) of assays for a COVID-19 diagnosis ranged from 84.0% to 98.5% for all samples (>14 days after symptom onset), with IgM or IgA assays showing higher PPAs. Seroconversion responses varied across the assay type and disease severity. Assays targeting the spike or receptor-binding domain protein showed a tendency for early seroconversion detection and higher index values in patients with severe disease. Index values from SARS-CoV-2 binding antibody assays (three automated assays, one LFIA, and three EIAs) showed moderate to strong correlations with the neutralizing antibody percentage (r=0.517-0.874), and stronger correlations in patients with severe disease and in assays targeting spike protein. Agreement among the 12 assays was good (74.3%-96.4%) for detecting IgG or total antibodies. CONCLUSIONS: Positivity rates and seroconversion of SARS-CoV-2 antibodies vary depending on the assay kits, disease severity, and antigen target. This study contributes to a better understanding of antibody response in symptomatic COVID-19 patients using currently available assays.


Subject(s)
Antibodies, Viral/analysis , COVID-19 Testing/methods , COVID-19/diagnosis , SARS-CoV-2/immunology , COVID-19/pathology , COVID-19/virology , Humans , Immunoassay , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Immunoglobulin M/analysis , Reagent Kits, Diagnostic , SARS-CoV-2/isolation & purification , Sensitivity and Specificity , Severity of Illness Index
10.
British journal of haematology ; 2020.
Article | WHO COVID | ID: covidwho-291287

ABSTRACT

Hematologic patients are immunocompromised, particularly susceptible to life-threatening viral infections (Cho, et al 2018). Regarding the world-wide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the first case was diagnosed in Korea on January 20, 2020 (Kim, et al 2020, Wang, et al 2020). With spreading of COVID-19, the number of new COVID-19 cases had increased exponentially with peak of 909 new infections on February 29 in Korea (Korean Society of Infectious Diseases, et al 2020). The World Health Organization declared COVID-19 pandemic on March 11, and as of May 6, 2020, more than 3.5 million cases have been confirmed around the world.

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