Meta-analysis of rapid direct-to-PCR assays for the qualitative detection of SARS-CoV-2

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic present significant challenges to current diagnostic and therapeutic patient care pathways including whether new in vitro diagnostic tests can accurately identify and rule out current SARS-CoV-2 infection. The gold standard diagnostic test to identify a current SARS-CoV-2 infection is a central laboratory-based molecular assay employing reverse transcription polymerase chain reaction (RT-PCR) with very high accuracy of detection; however, which typically requires 1-2 days turn-around for results. Rapid RT-PCR assays and systems have been developed which can be deployed locally (near-patient or point of care (POC)), provide faster results and not impact on already stressed central laboratory capacity. Rapid test results can be returned within the same clinical encounter, facilitating timely decisions that optimise the patient care pathway and support more rapid COVID-19 diagnosis, isolation and contract tracing activities1. Direct-to-PCR is an evolution of RT-PCR in which the patient sample is added directly to an amplification reaction without being subjected to prior nucleic acid extraction, purification, or quantification to reduce the time and monetary resources required to process samples. Rapid, direct-to-PCR systems further increase the speed of testing by combining rapid PCR instruments with direct-to-PCR assays, to generate results in less than two hours. This appears to be the first meta-analysis assessing the accuracy of rapid direct-to-PCR in the detection of SARS-CoV-2. In total, 1,144 unique records were identified and screened using search string evaluation, 49 full-text reports and/or supplemental materials were assessed for inclusion. This resulted in 16 studies, reporting 22 datasets with 5322 patient samples (of which 2220 were identified as positive according to centralised laboratory testing) included in the analysis. The overall percentage agreement (OPA) between the rapid direct RT-PCR and gold standard centralised laboratory RT-PCR was 95.10% with 91.22% positive percent agreement (PPA) and 98.16% negative percent agreement (NPA). When compared to commercially available tests were considered, these were assessed to be 96.95% OPA, 94.78 % PPA and 98.34 % NPA. Furthermore, the Cohens kappa statistical coefficient k = 0.94 (0.96 for commercial only), and Youden Index = 0.893 (0.924 for commercial only) indicate an almost perfect agreement. These results therefore indicate that direct-to-PCR assays performance is equivalent to the standard centralised laboratory PCR systems for the detection of SARS-CoV-2. ObjectivesTo assess the efficacy of rapid direct-to-PCR assays and systems for the detection of SARS-CoV-2 in the hospital, care home and medical research population from November 2020 to July 2021. Search methodsInitial electronic searches of the Cochrane COVID-19 Study Register (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on the 30th of April 2021, with a further search undertaken on 8th July 2021 (PRISMA flow diagram, Figure 2). O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/21256745v3_fig2.gif" ALT="Figure 2"> View larger version (26K): org.highwire.dtl.DTLVardef@14e69fcorg.highwire.dtl.DTLVardef@1105ea2org.highwire.dtl.DTLVardef@1b50b5corg.highwire.dtl.DTLVardef@fce6b7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 2.C_FLOATNO PRISMA flowchart C_FIG Selection criteriaStudies, published in English, of subjects with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection were included. Commercially available and research use only rapid direct-to-PCR assays (without RNA extraction and purification reporting results within two hours) were included in the study. Data collection, extraction and analysisStudies were screened independently, in duplicate with any disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability were undertaken independently in duplicate. Where studies were not publicly available, sites that undertook in-service evaluations of rapid direct-to-PCR system were contacted and asked to supply anonymised datasets. Both reviewers independently performed data extraction and verification and calculated 2x2 contingency tables with the number of true positives, false positives, false negatives and true negatives. They resolved any disagreements by discussion and by review with the third reviewer. Main resultsIn total, 22 study cohorts were included (described in 16 study reports, including 5 unpublished reports), reporting results for 5322 samples (of which 2220 were confirmed SARS-CoV-2, as determined by central laboratory testing). Studies were mainly from Europe and North America and evaluated eight commercially available direct-to-PCR assay kits/cartridges, and six developed from other reagents. ConclusionsThis appears to be the first meta-analysis assessing the accuracy of rapid direct-to-PCR in the detection of SARS-CoV-2. In total, 1,144 unique records were identified and screened using search string evaluation, 49 full-text reports and/or supplemental materials were assessed for inclusion. This resulted in 16 studies reporting 21 datasets with 5322 patient samples (2220 positive) included in the analysis. The overall agreement between the commercially available rapid direct RT-PCR and gold standard centralised laboratory RT-PCR was 96.9% with 94.8% PPA and 98.4% NPA. Furthermore, the Cohens kappa statistical coefficient k = 0.96, indicating an almost perfect agreement and Youden Index = 0.93. These results show that direct-to-PCR assays performance is equivalent to the gold standard centralised laboratory RT-PCR systems for the detection of SARS-CoV-2. Plain language summaryO_ST_ABSWhat is a rapid direct-to-PCR test for diagnosing COVID-19?C_ST_ABSRapid direct-to-PCR tests are rapid tests that aim to confirm or rule out the presence of SARS-CoV-2 within 2 hours without complicated processing of the sample. How accurate is a rapid direct-to-PCR test for diagnosing COVID-19?We compared the accuracy of rapid direct-to-PCR tests with gold standard centralised laboratory RT-PCR for the detection of SARS-CoV-2 and found that direct-to-PCR was as accurate as standard RT-PCR assays. Why is this question important?People with suspected COVID-19 need to know quickly whether they are infected, so that they can self-isolate, inform close contacts and possibly receive treatment. Currently, COVID-19 infection is confirmed by a laboratory test called RT-PCR, which uses specialist equipment and often takes at least 24 hours to produce a result. If they are accurate, faster diagnosis could allow people to take appropriate action more rapidly, with the potential to reduce the spread of COVID-19.1 What did we aim to find out?Our goal was to determine if commercially available and research use rapid direct-to-PCR tests are accurate enough to detect SARS-CoV-2 in comparison to gold standard laboratory RT-PCR. What did we do?We looked for studies that measured the accuracy of any commercially produced and research use rapid direct-to-PCR tests, in people tested for COVID-19 using RT-PCR. People could be tested in hospital or in the community. Studies could test people with or without symptoms. Tests had to use minimal equipment, be performed safely without risking infection from the sample, and have results available within two hours of the sample being collected. What we found?We include 22 studies in the review. They investigated a total of 5322 nose or throat samples; COVID-19 was confirmed in 2220 of these samples. The studies investigated 15 different direct-to-PCR tests. They took place mainly in Europe and North America. What did we find?Although overall results for diagnosing and ruling out COVID-19 were good (91.2% of infections correctly diagnosed and 98.3% correctly ruled out), we noted a difference in COVID-19 detection between tests, especially those available as commercial kits versus ones assembled from reagents from different sources. However, we cannot be certain about whether results will remain the same in a real-world setting. We could not investigate differences in people with or without symptoms, nor time since symptoms-onset because the studies did not consistently provide enough clinical information about their participants. How reliable were the results of the studies?In general, the studies included followed rigorous methods, in accordance with the tests intended use to detect COVID-19 and included at least two independent results to confirm or rule out COVID-19 infection. The results from different test brands varied and few studies compared multiple rapid-PCR tests. Most of the studies did not provide sufficient information to determine whether the detection levels would vary in people with COVID-19 symptoms versus without symptoms. What does this mean?On average the rapid direct-to-PCR were shown to be equivalent to gold standard laboratory-based RT-PCR tests and several direct-to-PCR tests show very high accuracy. However, for most of the tests, more evidence is needed particularly in people without symptoms, on the accuracy of repeated testing, and testing in non-healthcare settings such as schools (including self-testing).

Psychotropic Prescription In Antenatal Depression, Anxiety And Adjustment Disorders In Singapore

@#Objective: This is the first Singaporean study to examine prescribing practices among clinicians treating women with antenatal psychiatric conditions. This study aims to describe the characteristics of pregnant women who were prescribed psychotropic for new-onset antenatal psychiatric conditions. It also examines psychotropic prescription patterns and explores associations between antidepressant/benzodiazepine prescription and clinical characteristics. Methods: Pregnant women who were seen by psychiatrists from the Mental Wellness Service at the Kandang Kerbau (KK) Women’s and Children’s Hospital over a four-year period for new-onset antenatal psychiatric conditions, and who were prescribed psychotropic medication, were eligible for inclusion in the study. Demographic and obstetric information, psychiatric diagnoses and prescription of psychotropic were recorded in a database. Descriptive analyses were performed and associations between antidepressant/benzodiazepine prescription and clinical characteristics were studied. Results: A total of 110 patients were included in the study. The majority of the subjects were diagnosed with antenatal depression. Most of the subjects were prescribed an antidepressant in combination with Promethazine. Low-dose Dothiepin was the antidepressant of choice. Subjects with antenatal depression were more likely to be prescribed antidepressants (odds ratio (OR) 5.30, 95% confidence interval (CI) 2.29-12.27; p<0.01) while subjects with an adjustment disorder were less likely to be prescribed antidepressants (OR 0.11, 95% CI 0.02-0.52; p=0.001). No significant associations were found between antidepressant prescription and diagnoses of antenatal anxiety or mixed depression-anxiety. Nulliparous subjects were less likely to be prescribed an antidepressant or benzodiazepine, compared to subjects with a history of previous births (OR 0.35, 95% CI 0.16-0.79; p=0.01 and OR 0.91, 95% CI 0.84-0.98; p=0.03 respectively). Conclusions: Future studies of psychotropic prescription for pregnant psychiatric patients should examine severity of symptoms at presentation, timing of first presentation in relation to gestational age, patients’ willingness to accept medication and response to psychotherapy. More studies are needed to explore the association between parity and antidepressant prescription.

Antenatal Anxiety: Prevalence and Patterns in a Routine Obstetric Population

INTRODUCTION@#Expectant mothers may appear anxious even during healthy pregnancies. Unfortunately, little is known about antenatal anxiety, and affected women may remain undetected and untreated. This study aimed to examine the prevalence, incidence, course and associations of high state anxiety in routine obstetric care.@*MATERIALS AND METHODS@#This was an observational prospective cohort study at a large maternity unit. Obstetric outpatients with low-risk singleton pregnancies were recruited during first trimester consultations. Participants provided sociodemographic data and completed the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale. The STAI was re-administered at each subsequent trimester.@*RESULTS@#Prevalence and incidence of  high state anxiety among 634 completers were 29.5% (95% CI 25.6%-33.6%) and 13.9% (95% CI 9.9%-18.0%), respectively. Anxiety was persistent in 17.0% (95% CI 14.3%-20.2%) and transient in 26.3% (95% CI 23.1%-29.9%). Only persistently anxious participants had high mean second trimester state anxiety scores. Odds for anxiety of greater persistence increased by 29% (95% CI 24%-35%) per 1-point increase in first trimester depression scores, and decreased by 36% (95% CI 7%-56%) with tertiary education.@*CONCLUSION@#Antenatal anxiety symptoms are common even in normal pregnancies, especially among women with depression and lower education. Our study indicates value in exploring diagnostic criteria and quantitative measures for antenatal anxiety.

Patterns and predictors of treatment outcome for antenatal major depression

<p><b>INTRODUCTION</b>Antenatal major depression is a relatively common and potentially debilitating illness, but knowledge of its treatment outcomes and strategies is still lacking. This study aimed to explore the clinical profiles and treatment outcomes of patients with antenatal major depression, to look for patterns and associations that could guide subsequent research and clinical applications.</p><p><b>METHODS</b>From May 2006 to November 2010, 118 consecutive patients with antenatal major depression were naturalistically assessed over eight months of individualised therapy, and their characteristics were assessed as potential predictors of treatment outcome.</p><p><b>RESULTS</b>All participants accepted supportive counselling and case management, although only 51 (43.2%) participants accepted low-dose antidepressant therapy. Overall, 95 (80.5%) of them were successfully discharged, while 12 (10.2%) required extended treatment into the postnatal period. An equation for prognosticating the need for extended treatment was obtained using multiple logistic regression analysis, which incorporated three predictors: previous depression (odds ratio [OR] 12.4, 95% confidence interval [CI] 1.40-110; p = 0.024); maternal age < 26 years or > 35 years (OR 6.88, 95% CI 1.67-28.4; p = 0.008); and no use of antidepressant (OR 6.94, 95% CI 0.79-60.9; p = 0.080). Among participants with previous depression and at either extreme of maternal age, the number needed to treat with antidepressants to avert extended treatment was three.</p><p><b>CONCLUSION</b>The majority of women with antenatal major depression recovered after receiving short-term treatment. Those with previous depression and who were of relative extreme maternal age were most likely to benefit from antidepressant treatment to expedite recovery.</p>

Antenatal Depression In A High-Risk Pregnancy

Objective: This case report highlights antenatal depression as a common condition with potentially grave outcomes if left untreated. However, treatment options can be limited by the need to protect the fetus from medication-induced side effects. Methods: We report a young female obstetric patient who was carrying twins conceived through assisted reproduction, and her pregnancy was complicated by placenta previa major and repeated antepartum hemorrhages, which necessitated multiple admissions and strict bed rest. She became intensely depressed and anxious, developed suicidal ideation and refused examinations that were necessary to her physical health. She was referred to a psychiatrist and was given low-dose medication, supportive counseling, and case management. Results: She responded well to treatment, showing marked improvement in her mood and cooperation with obstetric care. Her twins were delivered at 35 weeks’ gestation in good health. Her progress was maintained into the postpartum period. Conclusions: This case of antenatal depression was successfully treated using a combination of medication, case management and psychological support. It adds to evidence that this illness benefits from early identification and is highly treatable.

The maternal infant dyadic relationship-looking beyond postpartum depression

Postpartum mental illness arises from a culmination of factors at the time of the motherhood transition, and bears impact on maternal wellbeing, as well as the infant. Whilst traditional psychiatric approach focuses primarily on symptomatology, diagnostic assessment, and treatment aimed largely at symptoms relief, the infant’s wellbeing and development is of key concern. And thus follows the need to address the space between mother and infant – the dyadic experience. Understanding the world of the infant, the nature of mother-infant bonding, and possible disorders allows us to care better for mothers with perinatal mental illness. Methods: Literature review of the evidence and possible approaches to addressing the mother-infant relational disorder will be discussed based on case reports. In particular, the Watch Wait and Wonder technique, an infant/child-led psychotherapy will be demonstrated with case studies. Results: The case studies demonstrate important themes of mother-infant bonding difficulties common to mothers with postpartum mental illness. Therapy specifically addressing these issues can enable mothers to process feelings of ambivalence and conflicts that hamper the development of the dyadic relationship. Conclusion: The maternal-infant dyadic relationship is a key focus in postpartum mental illness, and mental healthcare for postpartum depression and other illness should consider interventions as needed.

Postnatal depression: a family medicine perspective

The prevalence of postnatal depression (PND) was reported to be 6.8% in an obstetric setting in Singapore. Since primary care physicians are the healthcare clinicians most likely to interact with postnatal mothers in Singapore, they are in the best position to screen for PND and help new mothers. PND affects the well-being of the mother, her baby and those around her. If left untreated, depression can result in lasting adverse outcomes such as unfavourable parenting practices, impaired mother-infant bonding, impaired intellectual and emotional development of the infant, maternal suicide, and even infanticide. The Edinburgh Postnatal Depression Scale and the Patient Health Questionnaire-2 are effective screening tools that can be easily used in primary care settings for screening at-risk mothers. Herein, we discuss the management options available in primary care settings, as well as share some local resources available to mothers and the benefits of timely intervention.

Understanding maternal mental illness: psychiatric autopsy of a maternal death

Maternal mental illness is a significant public health concern, with established adverse outcomes on both mother and infant, such as impaired mother-infant bonding and infant cognitive and emotional development. In severe cases, maternal mortality and infanticide can tragically occur. This is a report on the suicide of a mother who jumped to her death at three months postpartum. She suffered from puerperal psychosis with bipolar features, with onset at six weeks postpartum. The case highlights the burden of maternal mental illness in our community as well as the need for resources and services to care well for mothers. With a better understanding of its presentation and risk factors, early identification and intervention can reduce morbidity and mortality.