SARS-CoV-2 laboratory diagnostic methods: a systematic review

Abstract Background The new SARS-CoV-2 is a single-stranded RNA β-coronavirus, and it is comprising by structural proteins (N), (S), (E) and (M). Timely and accurate detection is necessary for spread control of SARS-CoV-2 infection, avoiding inaccurate outcomes. Therefore, in this systematic review, it is purpose to evaluate a set of laboratory diagnostic techniques and methods, analyse their specificity, sensitivity, contributing to improve detection rates and reduce false negative and false positive diagnostic results. Methods In this review, we used literature available on the indexed search database ‘PubMed’, concerning the following keywords: ‘SARS-CoV-2’, ‘Specimen handling’, ‘Cell Culture Technique’, ‘Viral Antigen’, ‘Immunoassay’, ‘NAAT’ according to Medical Subject Headings Mesh and applying the Prisma Diagram methodology. Results DD-PCR and CRISPER had more promising results, but they are unconventional and expensive NAAT methods, the usage of the target RdRp/He gene has exhibited very encouraging results improving sensitivity and specificity. After the onset of symptoms, the sensitivity of the immunoassay varies considering of blood collection day. The antigen detection test showed the highest specificity reached, however is sensitivity is lower compared to NAAT assays. Conclusions In summary, RT-PCR still considered the gold standard and precisely detects the presence of virus RNA, although with some flaws in sensitivity, while the serological tests identify a previous infection by the virus, detecting antibodies, allowing the kinetic and immunological studies, not being able to use as a diagnostic method. The molecular point of care testing equipment’s revelled be the future in the rapid and accurately diagnosis of SARS-CoV-2.

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Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis

BMJ ◽

10.1136/bmj.m2516 ◽

2020 ◽

pp. m2516 ◽

Cited By ~ 111

Author(s):

Mayara Lisboa Bastos ◽

Gamuchirai Tavaziva ◽

Syed Kunal Abidi ◽

Jonathon R Campbell ◽

Louis-Patrick Haraoui ◽

...

Keyword(s):

Systematic Review ◽

Diagnostic Accuracy ◽

Sensitivity And Specificity ◽

Symptom Onset ◽

Serological Test ◽

Point Of Care ◽

Meta Analysis ◽

Risk Of Bias ◽

Serological Tests ◽

Immunoglobulin Class

AbstractObjectiveTo determine the diagnostic accuracy of serological tests for coronavirus disease-2019 (covid-19).DesignSystematic review and meta-analysis.Data sourcesMedline, bioRxiv, and medRxiv from 1 January to 30 April 2020, using subject headings or subheadings combined with text words for the concepts of covid-19 and serological tests for covid-19.Eligibility criteria and data analysisEligible studies measured sensitivity or specificity, or both of a covid-19 serological test compared with a reference standard of viral culture or reverse transcriptase polymerase chain reaction. Studies were excluded with fewer than five participants or samples. Risk of bias was assessed using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). Pooled sensitivity and specificity were estimated using random effects bivariate meta-analyses.Main outcome measuresThe primary outcome was overall sensitivity and specificity, stratified by method of serological testing (enzyme linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs), or chemiluminescent immunoassays (CLIAs)) and immunoglobulin class (IgG, IgM, or both). Secondary outcomes were stratum specific sensitivity and specificity within subgroups defined by study or participant characteristics, including time since symptom onset.Results5016 references were identified and 40 studies included. 49 risk of bias assessments were carried out (one for each population and method evaluated). High risk of patient selection bias was found in 98% (48/49) of assessments and high or unclear risk of bias from performance or interpretation of the serological test in 73% (36/49). Only 10% (4/40) of studies included outpatients. Only two studies evaluated tests at the point of care. For each method of testing, pooled sensitivity and specificity were not associated with the immunoglobulin class measured. The pooled sensitivity of ELISAs measuring IgG or IgM was 84.3% (95% confidence interval 75.6% to 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and of CLIAs was 97.8% (46.2% to 100%). In all analyses, pooled sensitivity was lower for LFIAs, the potential point-of-care method. Pooled specificities ranged from 96.6% to 99.7%. Of the samples used for estimating specificity, 83% (10 465/12 547) were from populations tested before the epidemic or not suspected of having covid-19. Among LFIAs, pooled sensitivity of commercial kits (65.0%, 49.0% to 78.2%) was lower than that of non-commercial tests (88.2%, 83.6% to 91.3%). Heterogeneity was seen in all analyses. Sensitivity was higher at least three weeks after symptom onset (ranging from 69.9% to 98.9%) compared with within the first week (from 13.4% to 50.3%).ConclusionHigher quality clinical studies assessing the diagnostic accuracy of serological tests for covid-19 are urgently needed. Currently, available evidence does not support the continued use of existing point-of-care serological tests.Study registrationPROSPERO CRD42020179452.

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Performance of SARS-CoV-2 Serology tests: Are they good enough?

10.1101/2020.11.13.20229625 ◽

2020 ◽

Author(s):

Isabelle Piec ◽

Emma English ◽

M Annette Thomas ◽

Samir Dervisevic ◽

William D Fraser ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Respiratory Infections ◽

Point Of Care ◽

False Negative ◽

Rapid Test ◽

Diagnostic Sensitivity ◽

Medical Community ◽

Antibody Detection ◽

Serological Tests ◽

Negative Results

AbstractBackgroundIn the emergency of the SARS-CoV-2 pandemic, great efforts were made to quickly provide serology testing to the medical community however, these methods have been introduced into clinical practice without the complete validation usually required by the regulatory organizations.MethodsSARS-CoV-2 patient samples (n=43) were analysed alongside pre-pandemic control specimen (n=50), confirmed respiratory infections (n=50), inflammatory polyarthritis (n=22) and positive for thyroid stimulating immunoglobulin (n=30). Imprecision, diagnostic sensitivity and specificity and concordance were evaluated on IgG serologic assays from EuroImmun, Epitope Diagnostics (EDI), Abbott Diagnostics and DiaSorin and a rapid IgG/IgM test from Healgen.ResultsEDI and EuroImmun imprecision was 0.02-14.0% CV. Abbott and DiaSorin imprecision (CV) ranged from 5.2% - 8.1% and 8.2% - 9.6% respectively. Diagnostic sensitivity of the assays were 100% (CI: 80-100%) for Abbott, EDI and EuroImmun and 95% (CI: 73-100%) for DiaSorin at ≥14 days post PCR. Only the Abbott assay had a diagnostic specificity of 100% (CI: 91-100%). EuroImmun cross-reacted in 3 non-SARS-CoV-2 respiratory infections and 2 controls. The DiaSorin displayed more false negative results and cross-reacted in six cases across all conditions tested. EDI had one cross-reactive sample. The Healgen rapid test showed excellent sensitivity and specificity. Overall, concordance of the assays ranged from 76.1% to 97.9%.ConclusionsSerological tests for SARS-CoV-2 showed good analytical performance. The head-to-head analysis of samples revealed differences in results that may be linked to the use of nucleocapsid or spike proteins. The point of care device tested demonstrated adequate performance for antibody detection.

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Point-of-Care Diagnostic Tests for Detecting SARS-CoV-2 Antibodies: A Systematic Review and Meta-Analysis of Real-World Data

Journal of Clinical Medicine ◽

10.3390/jcm9051515 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1515 ◽

Cited By ~ 17

Author(s):

Matteo Riccò ◽

Pietro Ferraro ◽

Giovanni Gualerzi ◽

Silvia Ranzieri ◽

Brandon Michael Henry ◽

...

Keyword(s):

Systematic Review ◽

Diagnostic Tests ◽

Large Scale ◽

Point Of Care ◽

Meta Analysis ◽

Rapid Diagnostic Tests ◽

Diagnostic Methods ◽

Rt Pcr ◽

Real World Data ◽

Healthcare Facilities

SARS-CoV-2 is responsible for a highly contagious infection, known as COVID-19. SARS-CoV-2 was discovered in late December 2019 and, since then, has become a global pandemic. Timely and accurate COVID-19 laboratory testing is an essential step in the management of the COVID-19 outbreak. To date, assays based on the reverse-transcription polymerase chain reaction (RT-PCR) in respiratory samples are the gold standard for COVID-19 diagnosis. Unfortunately, RT-PCR has several practical limitations. Consequently, alternative diagnostic methods are urgently required, both for alleviating the pressure on laboratories and healthcare facilities and for expanding testing capacity to enable large-scale screening and ensure a timely therapeutic intervention. To date, few studies have been conducted concerning the potential utilization of rapid testing for COVID-19, with some conflicting results. Therefore, the present systematic review and meta-analysis was undertaken to explore the feasibility of rapid diagnostic tests in the management of the COVID-19 outbreak. Based on ten studies, we computed a pooled sensitivity of 64.8% (95%CI 54.5–74.0), and specificity of 98.0% (95%CI 95.8–99.0), with high heterogeneity and risk of reporting bias. We can conclude that: (1) rapid diagnostic tests for COVID-19 are necessary, but should be adequately sensitive and specific; (2) few studies have been carried out to date; (3) the studies included are characterized by low numbers and low sample power, and (4) in light of these results, the use of available tests is currently questionable for clinical purposes and cannot substitute other more reliable molecular tests, such as assays based on RT-PCR.

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Comparison of Serological Tests for the Detection of Natural Heartworm Infection in Cats

Journal of the American Animal Hospital Association ◽

10.5326/0400376 ◽

2004 ◽

Vol 40 (5) ◽

pp. 376-384 ◽

Cited By ~ 37

Author(s):

Paul Berdoulay ◽

Julie K. Levy ◽

Patti S. Snyder ◽

Michael J. Pegelow ◽

Jennifer L. Hooks ◽

...

Keyword(s):

Point Of Care ◽

False Negative ◽

Serological Tests ◽

Male Worm ◽

Single Male ◽

Commercial Laboratory ◽

Heartworm Infection ◽

Antigen Tests ◽

Antibody Tests ◽

Positive Results

Serological tests were performed on 380 cats with necropsy-confirmed heartworm status to compare the performance of currently available commercial laboratory and point-of-care heart-worm serological tests in a heartworm-endemic area. Overall, antigen tests detected 79.3% to 86.2% of heartworm infections and were highly specific. Most cats with false-negative antigen tests had a single male worm. Antibody tests detected 62.1% to 72.4% of heartworm infections and had a wider range of false-positive results (1.4% to 19.1%) than antigen tests (0.3% to 2.0%). Serological tests for feline heartworm infection varied in diagnostic performance. Combining results from antigen and antibody tests achieved greater sensitivity than using either test alone.

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A comparative study of fluorescent microscopy with Ziehl-Neelsen staining and culture for the diagnosis of pulmonary tuberculosis

Kathmandu University Medical Journal ◽

10.3126/kumj.v7i3.2728 ◽

1970 ◽

Vol 7 (3) ◽

pp. 226-230 ◽

Cited By ~ 10

Author(s):

S Laifangbam ◽

HL Singh ◽

NB Singh ◽

KM Devi ◽

NT Singh

Keyword(s):

Mycobacterium Tuberculosis ◽

Fluorescence Microscopy ◽

Pulmonary Tuberculosis ◽

Fluorescent Microscopy ◽

False Negative ◽

Diagnostic Methods ◽

Case Detection ◽

Detection Rates ◽

Auramine O ◽

The Difference

Background: For developing countries with a large number of cases and financial constraints, evaluation of rapid and inexpensive diagnostic methods has great importance. The bacilli in the sputum can be detected microscopically by ZN stain and fluorochrome stain. Objectives : To study the efficacy of fluorescence microscopy in the diagnosis of pulmonary tuberculosis in comparison to Ziehl-Neelsen staining and culture of sputum samples from patients suspected of pulmonary tuberculosis. Materials and methods : 306 sputum samples collected from 102 patients suspected of pulmonary tuberculosis were processed by the Petroff's method, and subjected to Ziehl-Neelsen staining (ZN), fluorescent Auramine-O staining (AO) and culture on modified Lowenstein-Jensen media (gold standard) for detection of Mycobacterium tuberculosis. Positive smears were graded according to Forbes BA et al, and culture isolates were biochemically tested for confirmation of species. Results : Out of 102 patients, 44.1%, 71.6% and 70% were found positive by ZN, AO and culture respectively. AO was found to be superior to ZN on several aspects. The difference in their case detection rates was statistically significant (χ2 = 24.93, p < 0.001). AO was also able to detect more pauci-bacillary cases than ZN. There was more agreement between culture and fluorescence microscopy (95.1%) than with ZN microscopy (69.6%). The percentage of false negative by AO staining was only 2.78% which was in sharp contrast to that of ZN (40.27%). Conclusion: The better case detection rates of AO over ZN were comparable to those found by several studies. Since screening was done under lower power of magnification (400x), fluorescence microscopy has been found to be less time consuming as compared to ZN method (1000x) in the diagnosis of tuberculosis. The tubercle bacilli stood out as bright objects against a dark background in fluorescence microscopy which makes them easily identifiable hence causing less eye-strain. The efficacy of fluorescence microscopy proved to be much higher than conventional light microscopy and comparable to that of culture. Key words: Ziehl-Neelsen staining; Mycobacterium tuberculosis; Auramine-O DOI: 10.3126/kumj.v7i3.2728 Kathmandu University Medical Journal (2009) Vol.7, No.3 Issue 27, 226-230

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High anion gap metabolic acidosis caused by D-lactate

Biochemia Medica ◽

10.11613/bm.2020.011001 ◽

2020 ◽

Vol 30 (1) ◽

pp. 153-157 ◽

Cited By ~ 1

Author(s):

Matthias Weemaes ◽

Martin Hiele ◽

Pieter Vermeersch

Keyword(s):

Lactic Acidosis ◽

Clinical Presentation ◽

Point Of Care ◽

Venous Blood ◽

False Negative ◽

Blood Analysis ◽

Anion Gap ◽

Blood Collection ◽

Urine Organic Acid ◽

Time Of Admission

Introduction: D-lactic acidosis is an uncommon cause of high anion gap acidosis. Materials and methods: A 35-year old woman was admitted to the emergency room with somnolence, drowsiness, dizziness, incoherent speech and drunk appearance. Her past medical history included a Roux-en-Y bypass. Point-of-care venous blood analysis revealed a high anion gap acidosis. Based on the clinical presentation, routine laboratory results and negative toxicology screening, D-lactate and 5-oxoprolinuria were considered as the most likely causes of the high anion gap acidosis. Urine organic acid analysis revealed increased lactate, but no 5-oxoproline. Plasma D-lactate was < 1.0 mmol/L and could not confirm D-lactic acidosis. What happened: Further investigation revealed that the blood sample for D-lactate was drawn 12 hours after admission, which might explain the false-negative result. Data regarding the half-life of D-lactate are, however, scarce. During a second admission, one month later, D-lactic acidosis could be confirmed with an anion gap of 40.7 mmol/L and a D-lactate of 21.0 mmol/L measured in a sample collected at the time of admission. Main lesson: The time of blood collection is of utmost importance to establish the diagnosis of D-lactic acidosis due to the fast clearance of D-lactate in the human body

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Microbiological Laboratory Diagnosis of Human Brucellosis: An Overview

Pathogens ◽

10.3390/pathogens10121623 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1623

Author(s):

Giovanni Di Bonaventura ◽

Silvia Angeletti ◽

Andrea Ianni ◽

Tommasangelo Petitti ◽

Giovanni Gherardi

Keyword(s):

Clinical Symptoms ◽

Early Stage ◽

Point Of Care ◽

Laboratory Diagnosis ◽

Cross Reactivity ◽

Diagnostic Methods ◽

Nucleic Acid Amplification ◽

Human Brucellosis ◽

Microbiological Analysis ◽

Serological Tests

Brucella spp. are Gram-negative, non-motile, non-spore-forming, slow-growing, facultative intracellular bacteria causing brucellosis. Brucellosis is an endemic of specific geographic areas and, although underreported, represents the most common zoonotic infection, with an annual global incidence of 500,000 cases among humans. Humans represent an occasional host where the infection is mainly caused by B. melitensis, which is the most virulent; B. abortus; B. suis; and B. canis. A microbiological analysis is crucial to identifying human cases because clinical symptoms of human brucellosis are variable and aspecific. The laboratory diagnosis is based on three different microbiological approaches: (i) direct diagnosis by culture, (ii) indirect diagnosis by serological tests, and (iii) direct rapid diagnosis by molecular PCR-based methods. Despite the established experience with serological tests and highly sensitive nucleic acid amplification tests (NAATs), a culture is still considered the “gold standard” in the laboratory diagnosis of brucellosis due to its clinical and epidemiological relevance. Moreover, the automated BC systems now available have increased the sensitivity of BCs and shortened the time to detection of Brucella species. The main limitations of serological tests are the lack of common interpretative criteria, the suboptimal specificity due to interspecies cross-reactivity, and the low sensitivity during the early stage of disease. Despite that, serological tests remain the main diagnostic tool, especially in endemic areas because they are inexpensive, user friendly, and have high negative predictive value. Promising serological tests based on new synthetic antigens have been recently developed together with novel point-of-care tests without the need for dedicated equipment and expertise. NAATs are rapid tests that can help diagnose brucellosis in a few hours with high sensitivity and specificity. Nevertheless, the interpretation of NAAT-positive results requires attention because it may not necessarily indicate an active infection but rather a low bacterial inoculum, DNA from dead bacteria, or a patient that has recovered. Refined NAATs should be developed, and their performances should be compared with those of commercial and home-made molecular tests before being commercialized for the diagnosis of brucellosis. Here, we review and report the most common and updated microbiological diagnostic methods currently available for the laboratory diagnosis of brucellosis.

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Utility of Available Methods for Diagnosing SARS-CoV-2 in Clinical Samples

Archives of Pediatric Infectious Diseases ◽

10.5812/pedinfect.103677 ◽

2020 ◽

Vol 8 (3) ◽

Author(s):

Armin Shirvani ◽

Leila Azimi ◽

Roxana Mansour Ghanaie ◽

Masoud Alebouyeh ◽

Fatemeh Fallah ◽

...

Keyword(s):

Point Of Care ◽

Laboratory Diagnosis ◽

Diagnostic Value ◽

Clinical Findings ◽

Diagnostic Methods ◽

Detection Methods ◽

Clinical Samples ◽

Clinical Settings ◽

Rt Pcr ◽

Serological Tests

: The laboratory diagnosis of SARS-CoV-2 should be done to confirm coronavirus disease 2019 (COVID-19) in suspected patients. Although several diagnostic methods have been developed in this regard, their accuracy for clinical application is not very clear yet. To compare the diagnostic value of laboratory tests for the detection of COVID-19 infection, this study provides an upcoming review of the newly developed detection methods. Sensitivity, specificity, detection limit, and turn-around-time of these methods are compared and challenges for their application in clinical settings are reviewed. PubMed and Google Scholar web sites were used for the systematic search until April 9, 2020 to identify the published studies based on the following keywords: “Detection”, “Coronavirus 2019”, “SARS-CoV-2”, and “Sensitivity”. Out of 526 results, a total of 54 articles, including 46 studies on detection methods, were considered eligible for the review. The results showed that most of the proposed tests focused on molecular methods, while immunological and point-of-care tests were investigated in 13 studies. There were also a few commercial automated methods for the qualitative detection of SARS-CoV-2 in clinical samples, most of which are not examined in the current review, as no data about their sensitivity and specificity were presented. Although the assessment of publication biases showed that 64% sensitivity and nearly 100% specificity for RT-PCR are close to reality, most of the related reports for serological methods are not valid and further studies are needed to confirm their utility in clinical settings. Moreover, the RT-PCR test alone cannot act as a gold standard because of bias in measurements. Therefore, antibody tests and other proposed methods could be used as supplementary diagnostic tests to improve RT-PCR accuracy. Although clinical findings are invaluable, in many cases, they can provide more valuable supportive data than serological tests.

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Diagnosis of COVID-19 by Serology in Admitted Patients with Negative RT-PCR Assay

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v20i4.6949 ◽

2021 ◽

Author(s):

Mitra Rezaei ◽

Parvaneh Baghaei ◽

Makan Sadr ◽

Afshin Moniri ◽

Abdolreza Babamahmoodi ◽

...

Keyword(s):

Diagnostic Yield ◽

Serological Test ◽

False Negative ◽

Diagnostic Methods ◽

Rt Pcr ◽

Pcr Assay ◽

Serological Tests ◽

Negative Results ◽

False Negative Results ◽

Polymerase Chain

Considering the increasing prevalence and burden of coronavirus disease 2019 (COVID-19) disease and false-negative results in routine reverse transcription-polymerase chain reaction (RT-PCR) tests, additional diagnostic methods are needed to diagnose active cases of this disease. This prospective study was conducted on patients, in whom clinical and radiological symptoms/signs were in favor of COVID-19 while their first PCR test was negative. Later on, a second RT-PCR was performed and serological evaluation was carried out and results were compared with each other. Out of 707 patients who had been referred to the hospital and were clinically and radiologically suspicious of disease, 137 patients with negative RT-PCR tests entered the study. RT-PCR assay became positive for the second time in 45 (32.8%). Anti-COVID-19 IgM and IgG antibodies were positive in 83 (60.6%) and 86 (62.8%) patients, respectively. Finally, it was determined that serological test was diagnostic in 73% of patients and the diagnostic yield of serology was significantly higher after the first week of illness (54.8% in the first week and 88% after that). Taking advantage of both serological tests and RT-PCR helps in diagnosing 83.9% of cases. Based on the present study, the serology may be useful as a complementary test and in parallel to RT-PCR assay for diagnosis of COVID-19 among admitted symptomatic cases.

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Clinical-Forensic Autopsy Findings to Defeat COVID-19 Disease: A Literature Review

Journal of Clinical Medicine ◽

10.3390/jcm9072026 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2026 ◽

Cited By ~ 7

Author(s):

Francesco Sessa ◽

Giuseppe Bertozzi ◽

Luigi Cipolloni ◽

Benedetta Baldari ◽

Santina Cantatore ◽

...

Keyword(s):

Cause Of Death ◽

Standard Method ◽

Point Of Care ◽

Real Data ◽

Laboratory Diagnosis ◽

Diagnostic Techniques ◽

Diagnostic Methods ◽

Serological Tests ◽

Gold Standard Method ◽

Therapeutic Implications

The severe acute respiratory syndrome (SARS)-CoV-2 was identified for the first time in China, in December 2019. Confirmed cases of COVID-19 have been reported around the world; indeed, this infection has been declared a pandemic. Consequently, the scientific community is working hard to gain useful information about the history of this virus, its transmission, diagnosis, clinical features, radiological findings, research and development of candidate therapeutics as well as vaccines. This review aims to analyze the diagnostic techniques used to ascertain the COVID-19 infection, critically reviewing positive points and criticism for forensic implications, obviously including autopsy. Finally, this review proposes a practical workflow to be applied in the management of corpses during this outbreak of the COVID-19 infection, which could be useful in cases of future infectious disease emergencies. Analyzing the diagnostic methods, to date, virus nucleic acid RT-PCR represents the standard method used to ascertain the COVID-19 infection in living subjects and corpses, even if this technique has several criticisms: mainly, the staff should be highly specialized, working in high-throughput settings, able to handle high workloads and aware of health risks and the importance of the results. Thus, IgG/IgM serological tests have been developed, overcoming RT-qPCR duration, costs, and management, not requiring highly trained personnel. Nevertheless, serological tests present problems; the WHO recommends the use of these new point-of-care immunodiagnostic tests only in research settings. Furthermore, nothing has yet been published regarding the possibility of applying these methods during post-mortem investigations. In light of this scenario, in this review, we suggest a flow chart for the pathologist called on to ascertain the cause of death of a subject with historical and clinical findings of COVID-19 status or without any anamnestic, diagnostic, or exposure information. Indeed, the literature data confirmed the analytical vulnerabilities of the kits used for laboratory diagnosis of COVID-19, particularly during postmortem examinations. For these reasons, autopsy remains the gold standard method to ascertain the exact cause of death (from or with COVID-19 infection, or other causes), to consequently provide real data for statistical evaluations and to take necessary measures to contain the risks of the infection. Moreover, performing autopsies could provide information on the pathogenesis of the COVID-19 infection with obvious therapeutic implications.

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