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All participants underwent 3 nucleic acid tests, and the results of each nucleic acid test were verified by 2 COVID-19 nucleic acid test kits

Diagnosis of Acute Respiratory Syndrome Coronavirus 2 Infection by Detection of Nucleocapsid Protein

medRxiv, (2020)

Cited by: 7|Views227
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Abstract

BACKGROUND Nucleic acid test and antibody assay have been employed in the diagnosis for SARS-CoV-2 infection, but the use of viral antigen for diagnosis has not been successfully developed. Theoretically, viral antigen is the specific marker of the virus and precedes antibody appearance within the infected population. There is a clear ne...More

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Introduction
  • Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was named by the world health organization in 2019, causing COVID-19[1].
  • SARS-CoV-2 is an enveloped RNA virus widely distributed in humans, other mammals and birds that cause respiratory, intestinal, liver and neurological diseases[2, 3].
  • Common symptoms in people infected with SARS-CoV-2 virus include respiratory symptoms, fever, cough, and in more severe cases, infection can lead to pneumonia and severe acute respiratory syndrome [4, 5].
  • The known routes of corona virus disease-19(COVID-19) transmission are respiratory droplets and contact transmission, while aerosol and fecal-oral transmission require further clarification[6]
Highlights
  • Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was named by the world health organization in 2019, causing COVID-19[1]
  • Viral antigen is the specific marker of the virus and precedes antibody appearance within the infected people
  • Our study enrolled 239 participants based on diagnostic criteria for suspected severe acute respiratory syndrome-CoV-2 infection
  • All participants underwent 3 nucleic acid tests, and the results of each nucleic acid test were verified by 2 COVID-19 nucleic acid test kits
  • It is of noteworthy that in this study cohort the earliest patient with fever in 3 days were identified by N antigen detection
  • In the double blind evaluation clinical trial with the nucleic acid test as the golden standard, we found that the nucleic acid detection rate was 87%, and the detection rate of N antigen of severe acute respiratory syndrome-CoV-2 was 68 % and 98% separately, depending on the CT value. 100% of nucleocapsid protein positive and negative participants accord with nucleic acid test
Methods
  • The authors included a cohort of 239 participants with suspected SARS-CoV-2 infection from 7 centers for the study.
  • The authors measured nucleocapsid protein in nasopharyngeal swab samples in parallel with the nucleic acid test.
  • Nucleic acid test was taken as the reference standard, and statistical evaluation was taken in blind.
  • The authors detected nucleocapsid protein in 20 urine samples in another center, employing nasopharyngeal swab nucleic acid test as reference standard
Results
  • The authors developed a fluorescence immunochromatographic assay for detecting nucleocapsid protein of SARS-CoV-2 in nasopharyngeal swab sample and urine within 10 minutes. 100% of nucleocapsid protein positive and negative participants accord with nucleic acid test for same samples.
  • 100% of nucleocapsid protein positive and negative participants accord with nucleic acid test for same samples.
  • The authors performed nucleocapsid protein (N antigen) detection of SARS-CoV-2 in nasopharyngeal swab samples in parallel with nucleic acid test in multiple centers.
  • As shown in Figure 2, among the 239 patients with COVID-19 nucleic acid positive results, 141 were SARS-CoV-2 N antigen positive, the positive rate was 68%.
  • Among the 31 patients with COVID-19 nucleic acid negative results, 31 were N antigen negative, with a positive rate of 100%.
  • It is of noteworthy that in this study cohort the earliest patient with fever in 3 days were identified by N antigen detection
Conclusion
  • Those findings indicate that nucleocapsid protein assay is an accurate, rapid, early and simple method for diagnosis of COVID-19.
  • Appearance of nucleocapsid protein in urine coincides the finding of the SARS-CoV-2 invading kidney and might be of diagnostic value
Tables
  • Table1: Nucleocapsid antigen in urine compared by nucleic acid assay in nasopharyngeal swab. Examination of nucleocapsid antigen in urine compared by nucleic acid assay in nasopharyngeal swab. 14 0f 19(73.6%) the nucleic acid assay in nasopharyngeal swab positive patients exhibits nucleocapsid antigen positive in urine in same day. 1 nucleic acid assay positive patient exhibited nucleocapsid antigen positive in urine
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Funding
  • Role of funding source This research was supported by grants from National Key R&D Program of China (2016YFA0502204); Chongqing Health Commission COVID-19 Project (2020ZX01)
Study subjects and analysis
participants with suspected SARS-CoV-2 infection from 7 centers for: 239
There is a clear need of detection of viral antigen for rapid and early diagnosis. METHODS We included a cohort of 239 participants with suspected SARS-CoV-2 infection from 7 centers for the study. We measured nucleocapsid protein in nasopharyngeal swab samples in parallel with the nucleic acid test

urine samples: 20
Nucleic acid test was taken as the reference standard, and statistical evaluation was taken in blind. We detected nucleocapsid protein in 20 urine samples in another center, employing nasopharyngeal swab nucleic acid test as reference standard. RESULTS We developed a fluorescence immunochromatographic assay for detecting nucleocapsid protein of SARS-CoV-2 in nasopharyngeal swab sample and urine within 10 minutes. 100% of nucleocapsid protein positive and negative participants accord with nucleic acid test for same samples

participants with suspected SARS-CoV-2 infection from 7 centers for: 239
Appearance of nucleocapsid protein in urine coincides our finding of the SARS-CoV-2 invading kidney and might be of diagnostic value. We included a cohort of 239 participants with suspected SARS-CoV-2 infection from 7 centers for the study. We measured nucleocapsid protein in nasopharyngeal swab samples in parallel with the nucleic acid test

urine samples: 20
Nucleic acid test was taken as the reference standard, and statistical evaluation was taken in blind. We detected nucleocapsid protein in 20 urine samples in another center, employing nasopharyngeal swab nucleic acid test as reference standard.We included a cohort of 239 participants with suspected SARS-CoV-2 infection from 7 centers for the study. We measured nucleocapsid protein in nasopharyngeal swab samples in parallel with the nucleic acid test

urine samples: 20
Nucleic acid test was taken as the reference standard, and statistical evaluation was taken in blind. We detected nucleocapsid protein in 20 urine samples in another center, employing nasopharyngeal swab nucleic acid test as reference standard.

participants with suspected SARS-CoV-2 infection from 7 centers for: 239
There is a clear need of detection of viral antigen for rapid and early diagnosis. METHODS We included a cohort of 239 participants with suspected SARS-CoV-2 infection from 7 centers for the study. Nucleic acid test was taken as the reference standard, and statistical evaluation was taken in blind

participants with suspected SARS-CoV-2 infection from 7 centers: 239
Here, we report a fluorescence immunochromatographic assay for detecting nucleocapsid protein of SARS-CoV-2 in nasopharyngeal swab sample and urine within 10 minutes, and evaluated it’s significance in diagnosis of COVID-19. Methods Study Design A total of 239 participants with suspected SARS-CoV-2 infection from 7 centers, including General Hospital of Central Theater Command, Wuhan N0.7 People’s Hospital, Wuhan Pulmonary Hospital,Hubei maternal and child hospital,Taikang Hospital,Hanyang Hospital and Wuguo Hospital, were employed in this clinical trial for diagnosis. Nucleic acid test were taken as golden standard

urine samples: 20
Statistical evaluation was taken in blind based a four-grid table. We detected nucleocapsid protein in 20 urine samples in Southwest hospital in Chongqing, employing parallel nasopharyngeal swab nucleic acid test as reference standard for the same day. This study was approved by the Ethics Commission of participated hospitals

participants: 239
Exclusion criteria: contaminated samples; duplicate samples; unclear sample; samples with missing information from the original records of clinical trials; duplicate samples; samples conditions do not meet the program requirements. Participants Medical records of 239 participants in Wuhan and 20 participants in Chongqing were collected and retrospectively analyzed. Nucleic acid test of SARS-CoV-2 Specimen collected from nasopharyngeal swab were collected from all participants

nasal swab samples: 100
The fluorescent results will then be read by the immunofluorescence analyzer. Cut-off value was determined by testing 100 nasal swab samples of healthy people and calculated as the mean value of the fluorescence signal plus 5 SD. Nucleocapsid Protein Detection Procedure Nasopharyngeal swab samples or urine were diluted and mixed well with 500μl saline solution, 100μl of which was then added to the sample well of the test card

participants: 239
Clinical features and COVID-19 nucleic acid detection. Our study enrolled 239 participants based on diagnostic criteria for suspected SARS-CoV-2 infection. All participants underwent 3 nucleic acid tests, and the results of each nucleic acid test were verified by 2 COVID-19 nucleic acid test kits

patients: 208
All participants underwent 3 nucleic acid tests, and the results of each nucleic acid test were verified by 2 COVID-19 nucleic acid test kits. As shown in Fig 2A, among the 239 suspected COVID-19 patients, COVID-19 nucleic acid cycle threshold (CT value) of 208 patients≤40, while 31 patients>40, indicating 208 patients tested positive for nucleic acid and 31 patients tested negative for nucleic acid, As shown in Fig 2B, among the 239 suspected COVID-19 patients, COVID-19 nucleic acid cycle threshold (CT value) of 56 patients≤30, while 31 patients >40. 2

patients with COVID-19 nucleic acid positive results: 239
We performed nucleocapsid protein (N antigen) detection of SARS-CoV-2 in nasopharyngeal swab samples in parallel with nucleic acid test in multiple centers. As shown in Figure 2, among the 239 patients with COVID-19 nucleic acid positive results, 141 were SARS-CoV-2 N antigen positive, the positive rate was 68%. Meanwhile, among the 31 patients with COVID-19 nucleic acid negative results, 31 were N antigen negative, with a positive rate of 100%

patients with COVID-19 nucleic acid negative results: 31
As shown in Figure 2, among the 239 patients with COVID-19 nucleic acid positive results, 141 were SARS-CoV-2 N antigen positive, the positive rate was 68%. Meanwhile, among the 31 patients with COVID-19 nucleic acid negative results, 31 were N antigen negative, with a positive rate of 100%. In order to investigate the sensitivity and specificity of antigen detection methods from a clinical perspective, our study selected CT value ≤40 and ≤30 (Higher virus titer) as the nucleic acid positive group while CT value > 40 was used as the nucleic acid negative group

patients: 208
A) Description of the fluorescence immunochromatographic strip. (B) Test device. (C) ID chip. (D) Immunofluorescence analyzer. Proportion of participants with nucleic acid detection at different cutoff value. (A) Among 239 suspected COVID-19 participants, nucleic acid cycle threshold (CT value) of 208 patients≤40, while 31 participants >40. (B) Nucleic acid cycle threshold (CT value) of 56 patients ≤30, while 31 participants >40. Comparison between nucleic acid detection and N antigen detection. (A) Comparison of nucleic acid and N antigen detection among participants with nucleic acid detection CT value ≤40. (B) Comparison of nucleic acid and N antigen detection

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Author
Bo Diao
Bo Diao
Kun Wen
Kun Wen
Jian Chen
Jian Chen
Yueping Liu
Yueping Liu
Zilin Yuan
Zilin Yuan
Chao Han
Chao Han
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