ABSTRACT
The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.
Subject(s)
COVID-19 , Breakthrough PainABSTRACT
Many regions have experienced successive epidemic waves of COVID-19 since the emergence of SARS-CoV-2 with heterogeneous differences in mortality. Elucidating factors differentially associated with mortality between epidemic waves may inform clinical and public health strategies. We examined clinical and demographic data among patients admitted with COVID-19 during the first (March-June 2020) and second (December 2020-March 2021) epidemic waves at an academic medical center in New York City. Hospitalized patients (N=4631) had lower mortality during the second wave (14%) than the first (23%). Patients in the second wave had a lower 30-day mortality (Hazard Ratio (HR) 0.52, 95% CI 0.44, 0.61) than those in the first wave. The mortality decrease persisted after adjusting for confounders except for the volume of COVID-19 admissions (HR 0.88, 95% CI 0.70, 1.11), a measure of health system strain. Several demographic and clinical patient factors were associated with an increased risk of mortality independent of wave.
Subject(s)
COVID-19 , DeathABSTRACT
COVID-19 is associated with prolonged hospitalization and a high risk of intubation, which raises concern for bacterial co-infection and antimicrobial resistance. Previous research has shown a wide range of bacterial pneumonia rates for COVID-19 patients in a variety of clinical and demographic settings, but none have compared hospitalized COVID-19 patients to patients testing negative for SARS-CoV-2 in similar care settings. We performed a retrospective cohort study on hospitalized patients with COVID-19 testing from 10 March 2020 to 31 December 2020. A total of 19,219 patients were included, of which 3,796 tested positive for SARS-CoV-2. We found a 2.6-fold increase (p < 0.001) in respiratory culture ordering in COVID-19 patients. On a per-patient basis, COVID-19 patients were 1.5-fold more likely than non-COVID patients to have abnormal respiratory cultures (46.8% vs. 30.9%, p <0.001), which was primarily driven by patients requiring intubation. Among patients with pneumonia, a significantly higher proportion of COVID-19 patients had ventilator-associated pneumonia (VAP) relative to non-COVID patients (85.7% vs 55.1%, p <0.001), but a lower proportion had community-acquired (12.2% vs 22.1%, p < 0.01) or hospital-acquired pneumonia (2.1% vs. 22.8%, p < 0.001). There was also a significantly higher proportion of respiratory cultures positive for MRSA, K. pneumoniae, and antibiotic-resistant organisms in COVID-19 patients. Increased rates of respiratory culture ordering for COVID-19 patients therefore appear to be clinically justified for patients requiring intubation, but further research is needed to understand how SARS-CoV-2 increases the risk of VAP.
Subject(s)
Coinfection , Pneumonia , Pneumonia, Ventilator-Associated , COVID-19 , Pneumonia, BacterialABSTRACT
The identification of the Omicron variant (B.1.1.529.1 or BA.1) of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in Botswana in November 20211 immediately raised alarms due to the sheer number of mutations in the spike glycoprotein that could lead to striking antibody evasion. We2 and others3-6 recently reported results in this Journal confirming such a concern. Continuing surveillance of Omicron evolution has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K mutation (BA.1+R346K) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike mutations while lacking 13 spike mutations found in BA.1. We therefore extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.12,3,5,6. These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)7, which had retained appreciable activity against BA.1 and BA.1+R346K2-4,6 . This new finding shows that no presently approved or authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant.
Subject(s)
Coronavirus InfectionsABSTRACT
The Omicron (B.1.1.529) variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally1. It is expected to become dominant in the coming weeks2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies4. This concern is amplified by the findings from our study. We found B.1.1.529 to be markedly resistant to neutralization by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 18 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.
Subject(s)
COVID-19ABSTRACT
The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Two monoclonal antibody (mAb) therapeutics have received emergency use authorization, and more are in the pipeline. Furthermore, multiple vaccine constructs have shown promise, including two with ~95% protective efficacy against Covid-19. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple potent mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.
Subject(s)
COVID-19ABSTRACT
Molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the gold standard for diagnosis of coronavirus disease 2019 (COVID-19), but the test clinical performance is poorly understood. From 3/10/2020-5/1/2020 NewYork-Presbyterian laboratories performed 27,377 SARS-CoV-2 molecular assays from 22,338 patients. Repeat testing was performed in 3,432 patients, of which 2,413 had negative and 1,019 had positive first day results. Repeat-tested patients were more likely to be older, male, African-American or Hispanic, and to have severe disease. Among the patients with initially negative results, 18.6% became positive upon repeat-testing. Only 58.1% of any-time positive patients had a result of "detected" on the first test. The clinical sensitivity of COVID-19 molecular assays is estimated between 66.2 % and 95.6%, depending on the unknown number of false negative results in single-tested patients. Conversion to a negative result is unlikely to occur before 15 to 20 days after initial testing or 20-30 days after the onset of symptoms, with 50% conversion occurring at 28 days after initial testing. Forty-nine initially-positive patients converted to negative and then back to positive in subsequent days. Conversion from first day negative to positive results increased linearly with each day of testing, reaching 25% probability in 20 days. In summary, our study provides estimates of the clinical performance of SARS-CoV-2 molecular assays and suggests time frames for appropriate repeat testing, namely 15 to 20 days after a positive test and the same or next 2 days after a negative test in a patient with high suspicion for COVID-19.
Subject(s)
COVID-19ABSTRACT
Background and Aims: No medications are proven to improve clinical outcomes in COVID-19. Famotidine is commonly used for gastric acid suppression but has recently gained attention as an antiviral that may inhibit SARS-CoV-2 replication. This study tested whether famotidine use is associated with improved clinical outcomes in patients with COVID-19 initially hospitalized to a non-intensive care setting. Methods: This was retrospective cohort study conducted among consecutive hospitalized patients with COVID-19 infection from February 25 to April 13, 2020 at a single medical center. The primary exposure was famotidine, received within 24 hours of hospital admission. The primary outcome was intubation or death. Propensity score matching was used to balance the baseline characteristics of patients who did and did not use famotidine. Results: 1,620 hospitalized patients with COVID-19 were identified including 84 (5.1%) who received famotidine within 24 hours of hospital admission. 340 (21%) patients met the study composite outcome of death or intubation. Use of famotidine was associated with reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21-0.85) and also with reduced risk for death alone (aHR 0.30, 95% CI 0.11-0.80). After balancing baseline patient characteristics using propensity score matching, these relationships were unchanged (HR for famotidine and death or intubation 0.43, 95% CI 0.21-0.88). Proton pump inhibitors, which also suppress gastric acid, were not associated with reduced risk for death or intubation. Conclusion: Famotidine use is associated with reduced risk of intubation or death in hospitalized COVID-19 patients. Randomized controlled trials are warranted to determine whether famotidine therapy improves outcomes in hospitalized COVID-19 patients.
Subject(s)
COVID-19 , DeathABSTRACT
A surge of patients with coronavirus disease 2019 (COVID-19) presenting to New York City hospitals in March 2020 led to a sharp increase in the utilization of blood cultures, which overwhelmed the capacity of automated blood culture instruments. We sought to evaluate the utilization and diagnostic yield of blood cultures during the COVID-19 pandemic to determine prevalence and common etiologies of bacteremia, and to inform a diagnostic approach to relieve blood culture overutilization. We performed a retrospective cohort analysis of 88,201 blood cultures from 28,011 patients at a multicenter network of hospitals within New York City to evaluate order volume, positivity rate, time to positivity, and etiologies of positive cultures in COVID-19. Ordering volume increased by 34.8% in the second half of March 2020 compared to the first half of the month. The rate of bacteremia was significantly lower among COVID-19 patients (3.8%) than COVID-19 negative patients (8.0%) and those not tested (7.1%), p < 0.001. COVID-19 patients had a high proportion of organisms reflective of commensal skin microbiota, reducing the bacteremia rate to 1.6% when excluded. More than 98% of all positive cultures were detected within 4 days of incubation. Bloodstream infections are very rare for COVID-19 patients, which supports the judicious use of blood cultures in the absence of compelling evidence for bacterial co-infection. Clear communication with ordering providers is necessary to prevent overutilization of blood cultures during COVID-19 surges, and laboratories should consider shortening the incubation period from 5 days to 4 days to free additional capacity.
Subject(s)
COVID-19 , Bacteremia , Bacterial InfectionsABSTRACT
Objective: To characterize patients with coronavirus disease 2019 (COVID-19) in a large New York City (NYC) medical center and describe their clinical course across the emergency department (ED), inpatient wards, and intensive care units (ICUs). Design: Retrospective manual medical record review. Setting: NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC), a quaternary care academic medical center in NYC. Participants: The first 1000 consecutive patients with laboratory-confirmed COVID-19. Methods: We identified the first 1000 consecutive patients with a positive RT-SARS-CoV-2 PCR test who first presented to the ED or were hospitalized at NYP/CUIMC between March 1 and April 5, 2020. Patient data was manually abstracted from the electronic medical record. Main outcome measures: We describe patient characteristics including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition. Results: Among the first 1000 patients, 150 were ED patients, 614 were admitted without requiring ICU-level care, and 236 were admitted or transferred to the ICU. The most common presenting symptoms were cough (73.2%), fever (72.8%), and dyspnea (63.1%). Hospitalized patients, and ICU patients in particular, most commonly had baseline comorbidities including of hypertension, diabetes, and obesity. ICU patients were older, predominantly male (66.9%), and long lengths of stay (median 23 days; IQR 12 to 32 days); 78.0% developed AKI and 35.2% required dialysis. Notably, for patients who required mechanical ventilation, only 4.4% were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at 3-4 and 9 days. As of April 30, 90 patients remained hospitalized and 211 had died in the hospital. Conclusions: Hospitalized patients with COVID-19 illness at this medical center faced significant morbidity and mortality, with high rates of AKI, dialysis, and a bimodal distribution in time to intubation from symptom onset.