Impact of direct disk-diffusion testing on time to optimal antibiotic therapy

We evaluated the impact of preliminary blood-culture antibiotic susceptibility testing on time to optimal antibiotic therapy in a cohort of 503 patients with monomicrobial bloodstream infections. The median time from blood-culture collection to optimal antibiotics was 17 hours earlier in the preliminary antibiotic susceptibility testing group.

Predictors of low spike antibody response in patients with systemic rheumatic disease after an initial course of COVID-19 vaccination.

BACKGROUND: Patients with rheumatic disease may mount a suboptimal serologic response to COVID-19 vaccination. We evaluated predictors of low antibody response in a clinic-based cohort. METHODS: We conducted a cross-sectional study using electronic health record (EHR) data at Brigham and Women's Hospital, Boston, MA. Patients with systemic rheumatic disease that had SARS-CoV-2 spike antibody (Ab) tested using the Roche Elecsys immunoassay, February-August 2021, after 2 doses of mRNA vaccine or 1 dose of adenovirus vector vaccine were identified. Demographics, systemic rheumatic disease, vaccination dates, and disease-modifying antirheumatic drugs (DMARDs) were extracted. The primary outcome was low spike Ab (≤ 200 U/mL). Logistic regression models estimated predictors of low spike Ab. RESULTS: Among 382 patients, the mean age was 57 years, 77% were female, and 37% had low spike Ab. Older age (OR 1.03, 95% CI [1.02, 1.05]), SLE (OR 4.81 [2.08, 8.43], reference: inflammatory arthritis), prednisone (OR 1.67 [1.03, 2.74]), and rituximab (OR 22.91 [9.85, 53.29]) were significantly associated with higher odds of low spike Ab. Use of csDMARD monotherapy (OR 0.12 [0.04, 0.33]) and JAK inhibitors (OR 0.41 [0.18, 0.92]) were associated with significantly lower odds for low spike Ab. After adjusting for systemic rheumatic disease and DMARDs, SLE and rituximab remained significantly associated with low spike Ab. CONCLUSIONS: Over a third of patients with systemic rheumatic disease with spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. SLE and rituximab were significant risk factors for low spike Ab. KEY POINTS: • More than one-third of patients with systemic rheumatic disease that had spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. • Diagnosis of SLE, use of prednisone, and use of rituximab were significantly associated with greater odds of low spike antibodies. • These data underscore the importance of additional doses of COVID-19 vaccine and prophylactic Evusheld in immunosuppressed patients with systemic rheumatic disease as recommended by the US Centers for Disease Control.

Prevalence, Clinical Characteristics, and Outcomes of Sepsis Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Versus Other Pathogens in Hospitalized Patients With COVID-19

IMPORTANCE: The prevalence and causes of sepsis in patients hospitalized with COVID-19 are poorly characterized. OBJECTIVES: To investigate the prevalence, clinical characteristics, and outcomes of sepsis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) versus other pathogens in patients hospitalized with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, retrospective chart review of 200 randomly selected patients hospitalized with COVID-19 at four Massachusetts hospitals between March 2020 and March 2021. MAIN OUTCOMES AND MEASURES: The presence or absence of sepsis was determined per Sepsis-3 criteria (infection leading to an increase in Sequential Organ Failure Assessment score by ≥ 2 points above baseline). Sepsis episodes were assessed as caused by SARS-CoV-2, other pathogens, or both. Rates of organ dysfunction and in-hospital death were also assessed. RESULTS: Sepsis was present in 65 of 200 COVID-19 hospitalizations (32.5%), of which 46 of 65 sepsis episodes (70.8%) were due to SARS-CoV-2 alone, 17 of 65 (26.2%) were due to both SARS-CoV-2 and non-SARS-CoV-2 infections, and two of 65 (3.1%) were due to bacterial infection alone. SARS-CoV-2–related organ dysfunction in patients with sepsis occurred a median of 1 day after admission (interquartile range, 0–2 d) and most often presented as respiratory (93.7%), neurologic (46.0%), and/or renal (39.7%) dysfunctions. In-hospital death occurred in 28 of 200 COVID-19 hospitalizations (14.0%), including two of 135 patients without sepsis (1.5%), 16 of 46 patients with sepsis (34.8%) due to SARS-CoV-2 alone, and 10 of 17 patients with sepsis (58.8%) due to both SARS-CoV-2 and bacterial pathogens. CONCLUSIONS: Sepsis occurred in one in three patients hospitalized with COVID-19 and was primarily caused by SARS-CoV-2 itself, although bacterial infection also contributed in a quarter of sepsis cases. Mortality in COVID-19 patients with sepsis was high, especially in patients with mixed SARS-CoV-2 and bacterial sepsis. These findings affirm SARS-CoV-2 as an important cause of sepsis and highlight the need to improve surveillance, recognition, prevention, and treatment of both viral and bacterial sepsis in hospitalized patients with COVID-19.

The Effect of Vaccine Type and SARS-CoV-2 Lineage on Commercial SARS-CoV-2 Serologic and Pseudotype Neutralization Assays in mRNA Vaccine Recipients.

The use of anti-spike (S) serologic assays as surrogate measurements of SARS-CoV-2 vaccine induced immunity will be an important clinical and epidemiological tool. The characteristics of a commercially available anti-S antibody assay (Roche Elecsys anti-SARS-CoV-2 S) were evaluated in a cohort of vaccine recipients. Levels were correlated with pseudotype neutralizing antibodies (NAb) across SARS-CoV-2 variants. We recruited adults receiving a two-dose series of mRNA-1273 or BNT162b2 and collected serum at scheduled intervals up to 8 months post-first vaccination. Anti-S and NAb levels were measured, and correlation was evaluated by (i) vaccine type and (ii) SARS-CoV-2 variant (wild-type, Alpha, Beta, Gamma, and three constructs Day 146*, Day 152*, and RBM-2). Forty-six mRNA vaccine recipients were enrolled. mRNA-1273 vaccine recipients had higher peak anti-S and NAb levels compared with BNT162b2 (P < 0.001 for anti-S levels; P < 0.05 for NAb levels). When anti-S and NAb levels were compared, there was good correlation (all r values ≥ 0.85) in both BNT162b2 and mRNA-1273 vaccine recipients across all evaluated variants; however, these correlations were nonlinear in nature. Lower correlation was identified between anti-S and NAb for the Beta variant (r = 0.88) compared with the wild-type (WT) strain (r = 0.94). Finally, the degree of neutralizing activity at any given anti-S level was lower for each variant compared with that of the WT strain, (P < 0.001). Although the Roche anti-S assay correlates well with NAb levels, this association is affected by vaccine type and SARS-CoV-2 variant. These variables must be considered when interpreting anti-S levels. IMPORTANCE We evaluated anti-spike antibody concentrations in healthy mRNA vaccinated individuals and compared these concentrations to values obtained from pseudotype neutralization assays targeting SARS-CoV-2 variants of concern to determine how well anti-spike antibodies correlate with neutralizing titers, which have been used as a marker of immunity from COVID-19 infection. We found high peak anti-spike concentrations in these individuals, with significantly higher levels seen in mRNA-1273 vaccine recipients. When we compared anti-spike and pseudotype neuralization titers, we identified good correlation; however, this correlation was affected by both vaccine type and variant, illustrating the difficulty of applying a "one size fits all" approach to anti-spike result interpretation. Our results support CDC recommendations to discourage anti-spike antibody testing to assess for immunity after vaccination and cautions providers in their interpretations of these results as a surrogate of protection in COVID-vaccinated individuals.

Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus 2: A Narrative Review.

Diagnostic testing to identify persons infected with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019. In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies. In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons. Real-time reverse transcriptase polymerase chain reaction-based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics. However, point-of-care technologies and serologic immunoassays are rapidly emerging. Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation. Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity. These challenges may be even greater in low-resource settings. Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS-CoV-2 infection. Here, the authors review the current array of tests for SARS-CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions.

Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.

The Effect of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Mitigation Strategies on Seasonal Respiratory Viruses: A Tale of 2 Large Metropolitan Centers in the United States.

To assess the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on seasonal respiratory viruses, absolute case counts and viral reproductive rates from 2019-2020 were compared against previous seasons. Our findings suggest that the public health measures implemented to reduce SARS-CoV-2 transmission significantly reduced the transmission of other respiratory viruses.

Prospective Clinical Assessments of Hospitalized Patients With Positive SARS-CoV-2 PCR Tests for Necessity of Isolation.

We prospectively assessed 536 hospitalized patients with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction tests for infectiousness based on symptoms, cycle thresholds, and SARS-CoV-2 history, with repeat testing and serologies in select cases. One hundred forty-eight (28%) patients were deemed noninfectious, most with evidence of prior infection, and managed on standard precautions without evidence of transmission.

Estimating epidemiologic dynamics from cross-sectional viral load distributions.

Estimating an epidemic's trajectory is crucial for developing public health responses to infectious diseases, but case data used for such estimation are confounded by variable testing practices. We show that the population distribution of viral loads observed under random or symptom-based surveillance-in the form of cycle threshold (Ct) values obtained from reverse transcription quantitative polymerase chain reaction testing-changes during an epidemic. Thus, Ct values from even limited numbers of random samples can provide improved estimates of an epidemic's trajectory. Combining data from multiple such samples improves the precision and robustness of this estimation. We apply our methods to Ct values from surveillance conducted during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in a variety of settings and offer alternative approaches for real-time estimates of epidemic trajectories for outbreak management and response.

How SARS-CoV-2 Transformed the Clinical Laboratory: Challenges and Lessons Learned.

The COVID-19 pandemic has made a devastating impact on global health and continues to challenge healthcare infrastructure and delivery. The clinical laboratories were no exception as they are responsible for diagnostic testing that dictates many clinical, infection control, and public health decisions. Information technology and laboratory management tools are critical assets for maintaining and adapting operations in response to crises. When utilized effectively, they promote the integration between the clinical laboratory specialties (e.g., chemistry, hematology, microbiology, and molecular pathology). During the COVID-19 pandemic, our systems and processes were strained due to high testing volumes, demand for rapid turnaround times, supply chain constraints, and constantly evolving testing algorithms and result interpretations as our knowledge of the virus and of diagnostics increased over time. In this report, we describe those challenges and subsequent adaptations made by each clinical laboratory section. We hope these details help to provide potential solutions and approaches for other hospitals facing COVID-19 surges or other future pandemics.

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review.

Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation.

Duration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectivity: When Is It Safe to Discontinue Isolation?

Defining the duration of infectivity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has major implications for public health and infection control practice in healthcare facilities. Early in the pandemic, most hospitals required 2 negative RT-PCR tests before discontinuing isolation in patients with Covid-19. Many patients, however, have persistently positive RT-PCR tests for weeks to months following clinical recovery, and multiple studies now indicate that these generally do not reflect replication-competent virus. SARS-CoV-2 appears to be most contagious around the time of symptom onset, and infectivity rapidly decreases thereafter to near-zero after about 10 days in mild-moderately ill patients and 15 days in severely-critically ill and immunocompromised patients. The longest interval associated with replication-competent virus thus far is 20 days from symptom onset. This review summarizes evidence-to-date on the duration of infectivity of SARS-CoV-2, and how this has informed evolving public health recommendations on when it is safe to discontinue isolation precautions.