Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 20
Filter
2.
Cell Reports Medicine ; : 100583, 2022.
Article in English | ScienceDirect | ID: covidwho-1735052

ABSTRACT

Summary The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England, USA. We compare logistic growth rates during each variant’s respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% CI 3.1-10.9) times more viral RNA copies/mL than Alpha infections during their respective emergence. Overall, our evidence suggests that Delta’s enhanced transmissibility can be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on underlying population attributes and sequencing data availability.

3.
J Infect Dis ; 225(7): 1115-1117, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1704419
4.
Nat Med ; 2022 Feb 07.
Article in English | MEDLINE | ID: covidwho-1671607

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated a clear need for high-throughput, multiplexed and sensitive assays for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses and their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (mCARMEN), which combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable the identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants.

5.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1649048

ABSTRACT

Isolation guidelines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are largely derived from data collected prior to the emergence of the delta variant. We followed a cohort of ambulatory patients with postvaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole-genome sequencing, and viral culture. All delta variant infections in our cohort were symptomatic, compared with 64% of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared with non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support US CDC isolation guidelines as of November 2021, which recommend isolation for 10 days or until symptom resolution and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/genetics , COVID-19/metabolism , SARS-CoV-2/physiology , Virus Replication , Virus Shedding/physiology , Adult , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , Time Factors
6.
Clin Infect Dis ; 73(12): 2248-2256, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1592977

ABSTRACT

BACKGROUND: Isolation of hospitalized persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19) reduces nosocomial transmission risk. Efficient evaluation of PUIs is needed to preserve scarce healthcare resources. We describe the development, implementation, and outcomes of an inpatient diagnostic algorithm and clinical decision support system (CDSS) to evaluate PUIs. METHODS: We conducted a pre-post study of CORAL (COvid Risk cALculator), a CDSS that guides frontline clinicians through a risk-stratified COVID-19 diagnostic workup, removes transmission-based precautions when workup is complete and negative, and triages complex cases to infectious diseases (ID) physician review. Before CORAL, ID physicians reviewed all PUI records to guide workup and precautions. After CORAL, frontline clinicians evaluated PUIs directly using CORAL. We compared pre- and post-CORAL frequency of repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs), time from NAAT result to PUI status discontinuation, total duration of PUI status, and ID physician work hours, using linear and logistic regression, adjusted for COVID-19 incidence. RESULTS: Fewer PUIs underwent repeated testing after an initial negative NAAT after CORAL than before CORAL (54% vs 67%, respectively; adjusted odd ratio, 0.53 [95% confidence interval, .44-.63]; P < .01). CORAL significantly reduced average time to PUI status discontinuation (adjusted difference [standard error], -7.4 [0.8] hours per patient), total duration of PUI status (-19.5 [1.9] hours per patient), and average ID physician work-hours (-57.4 [2.0] hours per day) (all P < .01). No patients had a positive NAAT result within 7 days after discontinuation of precautions via CORAL. CONCLUSIONS: CORAL is an efficient and effective CDSS to guide frontline clinicians through the diagnostic evaluation of PUIs and safe discontinuation of precautions.


Subject(s)
Anthozoa , COVID-19 , Animals , Humans , Nucleic Acid Amplification Techniques , Odds Ratio , SARS-CoV-2
7.
Cell ; 185(3): 485-492.e10, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1588148

ABSTRACT

An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , COVID-19/transmission , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/virology , Child , Child, Preschool , Contact Tracing/methods , Disease Outbreaks , Female , Genome, Viral , Humans , Infant , Infant, Newborn , Male , Massachusetts/epidemiology , Middle Aged , Molecular Epidemiology , Phylogeny , SARS-CoV-2/classification , Vaccination , Whole Genome Sequencing , Young Adult
8.
Nat Microbiol ; 7(1): 108-119, 2022 01.
Article in English | MEDLINE | ID: covidwho-1574813

ABSTRACT

The global spread and continued evolution of SARS-CoV-2 has driven an unprecedented surge in viral genomic surveillance. Amplicon-based sequencing methods provide a sensitive, low-cost and rapid approach but suffer a high potential for contamination, which can undermine laboratory processes and results. This challenge will increase with the expanding global production of sequences across a variety of laboratories for epidemiological and clinical interpretation, as well as for genomic surveillance of emerging diseases in future outbreaks. We present SDSI + AmpSeq, an approach that uses 96 synthetic DNA spike-ins (SDSIs) to track samples and detect inter-sample contamination throughout the sequencing workflow. We apply SDSIs to the ARTIC Consortium's amplicon design, demonstrate their utility and efficiency in a real-time investigation of a suspected hospital cluster of SARS-CoV-2 cases and validate them across 6,676 diagnostic samples at multiple laboratories. We establish that SDSI + AmpSeq provides increased confidence in genomic data by detecting and correcting for relatively common, yet previously unobserved modes of error, including spillover and sample swaps, without impacting genome recovery.


Subject(s)
DNA Primers/standards , SARS-CoV-2/genetics , Sequence Analysis/standards , COVID-19/diagnosis , DNA Primers/chemical synthesis , Genome, Viral/genetics , Humans , Quality Control , RNA, Viral/genetics , Reproducibility of Results , Sequence Analysis/methods , Whole Genome Sequencing , Workflow
9.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1556107

ABSTRACT

Isolation guidelines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are largely derived from data collected prior to the emergence of the delta variant. We followed a cohort of ambulatory patients with postvaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole-genome sequencing, and viral culture. All delta variant infections in our cohort were symptomatic, compared with 64% of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared with non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support US CDC isolation guidelines as of November 2021, which recommend isolation for 10 days or until symptom resolution and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/genetics , COVID-19/metabolism , SARS-CoV-2/physiology , Virus Replication , Virus Shedding/physiology , Adult , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , Time Factors
10.
J Neurol Sci ; 430: 120023, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1446884

ABSTRACT

OBJECTIVE: Little is known about CSF profiles in patients with acute COVID-19 infection and neurological symptoms. Here, CSF was tested for SARS-CoV-2 RNA and inflammatory cytokines and chemokines and compared to controls and patients with known neurotropic pathogens. METHODS: CSF from twenty-seven consecutive patients with COVID-19 and neurological symptoms was assayed for SARS-CoV-2 RNA using quantitative reverse transcription PCR (RT-qPCR) and unbiased metagenomic sequencing. Assays for blood brain barrier (BBB) breakdown (CSF:serum albumin ratio (Q-Alb)), and proinflammatory cytokines and chemokines (IL-6, IL-8, IL-15, IL-16, monocyte chemoattractant protein -1 (MCP-1) and monocyte inhibitory protein - 1ß (MIP-1ß)) were performed in 23 patients and compared to CSF from patients with HIV-1 (16 virally suppressed, 5 unsuppressed), West Nile virus (WNV) (n = 4) and 16 healthy controls (HC). RESULTS: Median CSF cell count for COVID-19 patients was 1 white blood cell/µL; two patients were infected with a second pathogen (Neisseria, Cryptococcus neoformans). No CSF samples had detectable SARS-CoV-2 RNA by either detection method. In patients with COVID-19 only, CSF IL-6, IL-8, IL-15, and MIP-1ß levels were higher than HC and suppressed HIV (corrected-p < 0.05). MCP-1 and MIP-1ß levels were higher, while IL-6, IL-8, IL-15 were similar in COVID-19 compared to WNV patients. Q-Alb correlated with all proinflammatory markers, with IL-6, IL-8, and MIP-1ß (r ≥ 0.6, p < 0.01) demonstrating the strongest associations. CONCLUSIONS: Lack of SARS-CoV-2 RNA in CSF is consistent with pre-existing literature. Evidence of intrathecal proinflammatory markers in a subset of COVID-19 patients with BBB breakdown despite minimal CSF pleocytosis is atypical for neurotropic pathogens.


Subject(s)
COVID-19 , Inflammation/virology , RNA, Viral/cerebrospinal fluid , Blood-Brain Barrier , COVID-19/physiopathology , Case-Control Studies , Chemokines , Cytokines , Humans , SARS-CoV-2
11.
Science ; 371(6529)2021 02 05.
Article in English | MEDLINE | ID: covidwho-1388436

ABSTRACT

Analysis of 772 complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from early in the Boston-area epidemic revealed numerous introductions of the virus, a small number of which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, whereas other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread. The two events also differed substantially in the genetic variation they generated, suggesting varying transmission dynamics in superspreading events. Our results show how genomic epidemiology can help to understand the link between individual clusters and wider community spread.


Subject(s)
COVID-19/epidemiology , Genome, Viral , Phylogeny , SARS-CoV-2/genetics , Boston/epidemiology , COVID-19/transmission , Disease Outbreaks , Epidemiological Monitoring , Humans
12.
Clin Infect Dis ; 74(7): 1275-1278, 2022 Apr 09.
Article in English | MEDLINE | ID: covidwho-1345718

ABSTRACT

The impact of coronavirus disease 2019 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of severe acute respiratory syndrome coronavirus 2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, the higher cycle thresholds, repeat negative tests, and inability to culture virus raise questions about their clinical significance.


Subject(s)
COVID-19 , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Health Personnel , Humans , Incidence , Prospective Studies , SARS-CoV-2 , Vaccination
13.
J Clin Pathol ; 74(8): 496-503, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1247388

ABSTRACT

Developing and deploying new diagnostic tests are difficult, but the need to do so in response to a rapidly emerging pandemic such as COVID-19 is crucially important. During a pandemic, laboratories play a key role in helping healthcare providers and public health authorities detect active infection, a task most commonly achieved using nucleic acid-based assays. While the landscape of diagnostics is rapidly evolving, PCR remains the gold-standard of nucleic acid-based diagnostic assays, in part due to its reliability, flexibility and wide deployment. To address a critical local shortage of testing capacity persisting during the COVID-19 outbreak, our hospital set up a molecular-based laboratory developed test (LDT) to accurately and safely diagnose SARS-CoV-2. We describe here the process of developing an emergency-use LDT, in the hope that our experience will be useful to other laboratories in future outbreaks and will help to lower barriers to establishing fast and accurate diagnostic testing in crisis conditions.


Subject(s)
COVID-19 Nucleic Acid Testing , COVID-19/diagnosis , Emergency Service, Hospital , Laboratories, Hospital , Real-Time Polymerase Chain Reaction , SARS-CoV-2/genetics , COVID-19/virology , Humans , Predictive Value of Tests , Reproducibility of Results
16.
Clin Infect Dis ; 73(12): 2248-2256, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1075482

ABSTRACT

BACKGROUND: Isolation of hospitalized persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19) reduces nosocomial transmission risk. Efficient evaluation of PUIs is needed to preserve scarce healthcare resources. We describe the development, implementation, and outcomes of an inpatient diagnostic algorithm and clinical decision support system (CDSS) to evaluate PUIs. METHODS: We conducted a pre-post study of CORAL (COvid Risk cALculator), a CDSS that guides frontline clinicians through a risk-stratified COVID-19 diagnostic workup, removes transmission-based precautions when workup is complete and negative, and triages complex cases to infectious diseases (ID) physician review. Before CORAL, ID physicians reviewed all PUI records to guide workup and precautions. After CORAL, frontline clinicians evaluated PUIs directly using CORAL. We compared pre- and post-CORAL frequency of repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs), time from NAAT result to PUI status discontinuation, total duration of PUI status, and ID physician work hours, using linear and logistic regression, adjusted for COVID-19 incidence. RESULTS: Fewer PUIs underwent repeated testing after an initial negative NAAT after CORAL than before CORAL (54% vs 67%, respectively; adjusted odd ratio, 0.53 [95% confidence interval, .44-.63]; P < .01). CORAL significantly reduced average time to PUI status discontinuation (adjusted difference [standard error], -7.4 [0.8] hours per patient), total duration of PUI status (-19.5 [1.9] hours per patient), and average ID physician work-hours (-57.4 [2.0] hours per day) (all P < .01). No patients had a positive NAAT result within 7 days after discontinuation of precautions via CORAL. CONCLUSIONS: CORAL is an efficient and effective CDSS to guide frontline clinicians through the diagnostic evaluation of PUIs and safe discontinuation of precautions.


Subject(s)
Anthozoa , COVID-19 , Animals , Humans , Nucleic Acid Amplification Techniques , Odds Ratio , SARS-CoV-2
17.
J Neurol Sci ; 421: 117308, 2021 02 15.
Article in English | MEDLINE | ID: covidwho-1033825

ABSTRACT

We evaluated the incidence, distribution, and histopathologic correlates of microvascular brain lesions in patients with severe COVID-19. Sixteen consecutive patients admitted to the intensive care unit with severe COVID-19 undergoing brain MRI for evaluation of coma or neurologic deficits were retrospectively identified. Eleven patients had punctate susceptibility-weighted imaging (SWI) lesions in the subcortical and deep white matter, eight patients had >10 SWI lesions, and four patients had lesions involving the corpus callosum. The distribution of SWI lesions was similar to that seen in patients with hypoxic respiratory failure, sepsis, and disseminated intravascular coagulation. Brain autopsy in one patient revealed that SWI lesions corresponded to widespread microvascular injury, characterized by perivascular and parenchymal petechial hemorrhages and microscopic ischemic lesions. Collectively, these radiologic and histopathologic findings add to growing evidence that patients with severe COVID-19 are at risk for multifocal microvascular hemorrhagic and ischemic lesions in the subcortical and deep white matter.


Subject(s)
Brain Injuries/diagnostic imaging , COVID-19/diagnostic imaging , Magnetic Resonance Imaging/methods , Microvessels/diagnostic imaging , Severity of Illness Index , Brain/blood supply , Brain/diagnostic imaging , Brain Injuries/etiology , COVID-19/complications , Humans , Intensive Care Units/trends , Male , Microvessels/injuries , Middle Aged , Retrospective Studies
18.
Nat Commun ; 11(1): 5921, 2020 11 20.
Article in English | MEDLINE | ID: covidwho-939436

ABSTRACT

The COVID-19 pandemic has highlighted that new diagnostic technologies are essential for controlling disease transmission. Here, we develop SHINE (Streamlined Highlighting of Infections to Navigate Epidemics), a sensitive and specific diagnostic tool that can detect SARS-CoV-2 RNA from unextracted samples. We identify the optimal conditions to allow RPA-based amplification and Cas13-based detection to occur in a single step, simplifying assay preparation and reducing run-time. We improve HUDSON to rapidly inactivate viruses in nasopharyngeal swabs and saliva in 10 min. SHINE's results can be visualized with an in-tube fluorescent readout - reducing contamination risk as amplification reaction tubes remain sealed - and interpreted by a companion smartphone application. We validate SHINE on 50 nasopharyngeal patient samples, demonstrating 90% sensitivity and 100% specificity compared to RT-qPCR with a sample-to-answer time of 50 min. SHINE has the potential to be used outside of hospitals and clinical laboratories, greatly enhancing diagnostic capabilities.


Subject(s)
Betacoronavirus/isolation & purification , CRISPR-Associated Proteins/metabolism , Molecular Diagnostic Techniques/methods , Biological Assay , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Fluorescence , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2
19.
bioRxiv ; 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-637849

ABSTRACT

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.

20.
Cell ; 183(3): 739-751.e8, 2020 10 29.
Article in English | MEDLINE | ID: covidwho-758650

ABSTRACT

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.


Subject(s)
Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Spike Glycoprotein, Coronavirus/physiology , Spike Glycoprotein, Coronavirus/ultrastructure , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , Betacoronavirus/pathogenicity , COVID-19 , Cells, Cultured , Coronavirus Infections/virology , Female , Genetic Variation , HEK293 Cells , Humans , Male , Models, Molecular , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Conformation , Protein Processing, Post-Translational , Receptors, Coronavirus , Receptors, Virus/metabolism , SARS-CoV-2 , Species Specificity
SELECTION OF CITATIONS
SEARCH DETAIL