ABSTRACT
The SARS-CoV-2 Omicron variant continues to evolve, with new BQ and XBB subvariants now rapidly expanding in Europe/US and Asia, respectively. As these new subvariants have additional spike mutations, they may possess altered antibody evasion properties. Here, we report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals who were boosted with a WA1/BA.5 bivalent mRNA vaccine. Compared to the ancestral strain D614G, serum neutralizing titers against BQ and XBB subvariants were lower by 13-81-fold and 66-155-fold, respectively, far beyond what had been observed to date. A panel of monoclonal antibodies capable of neutralizing the original Omicron variant, including those with Emergency Use Authorization, were largely inactive against these new subvariants. The spike mutations that conferred antibody resistance were individually studied and structurally explained. Finally, the ACE2-binding affinities of the spike proteins of these novel subvariants were found to be similar to those of their predecessors. Taken together, our findings indicate that BQ and XBB subvariants present serious threats to the efficacy of current COVID-19 vaccines, render inactive all authorized monoclonal antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.
ABSTRACT
Transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of natural selection along a transmission chain. Many viruses exhibit tight bottlenecks, and studies of early SARS-CoV-2 lineages identified a bottleneck of 1-3 infectious virions. While increased force of infection, host receptor binding, or immune evasion may influence bottleneck size, the relationship between transmissibility and the transmission bottleneck is unclear. Here, we compare the transmission bottleneck of non-variant-of-concern (non-VOC) SARS-CoV-2 lineages to those of the Alpha, Delta, and Omicron variants. We sequenced viruses from 168 individuals in 65 multiply infected households in duplicate to high depth of coverage. In 110 specimens collected close to the time of transmission, within-host diversity was extremely low. At a 2% frequency threshold, 51% had no intrahost single nucleotide variants (iSNV), and 42% had 1-2 iSNV. In 64 possible transmission pairs with detectable iSNV, we identified a bottleneck of 1 infectious virion (95% CI 1-1) for Alpha, Delta, and Omicron lineages and 2 (95% CI 2-2) in non-VOC lineages. The latter was driven by a single iSNV shared in one non-VOC household. The tight transmission bottleneck in SARS-CoV-2 is due to low genetic diversity at the time of transmission, a relationship that may be more pronounced in rapidly transmissible variants. The tight bottlenecks identified here will limit the development of highly mutated VOC in typical transmission chains, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive their evolution.
ABSTRACT
Neutralizing antibody plays a key role in protective immunity against COVID-19. As increasingly distinct variants circulate, debate continues regarding the value of adding novel variants to SARS-CoV-2 vaccines. In this study, we have analyzed live virus neutralization titers against WA1, Delta, BA.1, BA.2, and BA.5 in 187 hospitalized patients infected with Delta or Omicron strains. This information will be useful in selection of the SARS-CoV-2 strains to include in an updated vaccine. Our results show that unvaccinated Delta infected patients made a highly biased neutralizing antibody response towards the infecting Delta strain with slightly lower responses against the WA1 strain, but with strikingly lower titers against BA.1, BA.2, and BA.5. Delta infected patients that had been previously vaccinated with the WA1 containing COVID vaccine made equivalent responses to WA1 and Delta strains, but still had very low neutralizing antibody responses to Omicron strains. In striking contrast, both unvaccinated and vaccinated Omicron patients exhibited a more balanced ratio of Omicron virus neutralization compared to neutralization of ancestral strains. Interestingly, Omicron patients infected with BA.1 or BA.2 had detectable neutralizing antibody titers to BA.5, but these titers were lower than neutralization titers to BA.1 and BA.2. Taken together, these results suggest that inclusion of the Omicron BA.5 strain in a SARS-CoV-2 vaccine would be beneficial in protection against the widely circulating BA.5 variant. DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
ABSTRACT
BackgroundThe reliability of sequence-based inference of SARS-CoV-2 transmission is not clear. Sequence data from infections among household members can define the expected genomic diversity of a virus along a defined transmission chain. MethodsSARS-CoV-2 cases were identified prospectively among 2,369 participants in 706 households. Specimens with an RT-PCR cycle threshold [≤]30 underwent whole genome sequencing. Intrahost single nucleotide variants (iSNV) were identified at [≥]5% frequency. Phylogenetic trees were used to evaluate the relationship of household and community sequences. ResultsThere were 178 SARS-CoV-2 cases in 706 households. Among 147 specimens sequenced, 106 yielded a whole genome consensus with coverage suitable for identifying iSNV. Twenty-six households had sequences from multiple cases within 14 days. Consensus sequences were indistinguishable among cases in 15 households, while 11 had [≥]1 consensus that differed by 1-2 mutations. Sequences from households and the community were often interspersed on phylogenetic trees. Identification of iSNV improved inference in 2 of 15 households with indistinguishable consensus sequences and 6 of 11 with distinct ones. ConclusionsIn multiple infection households, whole genome consensus sequences differed by 0-1 mutations. Identification of shared iSNV occasionally resolved linkage, but the low genomic diversity of SARS-CoV-2 limits the utility of "sequence-only" transmission inference. SummaryHigh depth of coverage whole genome sequencing can identify SARS-CoV-2 transmission chains in settings where there is strong epidemiologic linkage but is not reliable as a stand-alone method for transmission inference.
ABSTRACT
Objectives: To compare the effectiveness of a primary COVID-19 vaccine series plus a booster dose with a primary series alone for the prevention of Omicron variant COVID-19 hospitalization. Design: Multicenter observational case-control study using the test-negative design to evaluate vaccine effectiveness (VE). Setting: Twenty-one hospitals in the United States (US). Participants: 3,181 adults hospitalized with an acute respiratory illness between December 26, 2021 and April 30, 2022, a period of SARS-CoV-2 Omicron variant (BA.1, BA.2) predominance. Participants included 1,572 (49%) case-patients with laboratory confirmed COVID-19 and 1,609 (51%) control patients who tested negative for SARS-CoV-2. Median age was 64 years, 48% were female, and 21% were immunocompromised; 798 (25%) were vaccinated with a primary series plus booster, 1,326 (42%) were vaccinated with a primary series alone, and 1,057 (33%) were unvaccinated. Main Outcome Measures: VE against COVID-19 hospitalization was calculated for a primary series plus a booster and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. VE analyses were stratified by immune status (immunocompetent; immunocompromised) because the recommended vaccine schedules are different for these groups. The primary analysis evaluated all COVID-19 vaccine types combined and secondary analyses evaluated specific vaccine products. Results: Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71-82%), and for a primary series alone was 44% (95% CI: 31-54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients. Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.
ABSTRACT
Accurate estimates of total burden of SARS-CoV-2 are needed to inform policy, planning and response. We sought to quantify SARS-CoV-2 cases, hospitalizations, and deaths by age in Michigan. COVID-19 cases reported to the Michigan Disease Surveillance System were multiplied by age and time-specific adjustment factors to correct for under-detection. Adjustment factors were estimated in a model fit to incidence data and seroprevalence estimates. Age-specific incidence of SARS-CoV-2 hospitalization, death, and vaccination, and variant proportions were estimated from publicly available data. We estimated substantial under-detection of infection that varied by age and time. Accounting for under-detection, we estimate cumulative incidence of infection in Michigan reached 75% by mid-November 2021, and over 87% of Michigan residents were estimated to have had [≥]1 vaccination dose and/or previous infection. Comparing pandemic waves, the relative burden among children increased over time. Adults [≥]80 years were more likely to be hospitalized or die if infected in fall 2020 than if infected during later waves. Our results highlight the ongoing risk of periods of high SARS-CoV-2 incidence despite widespread prior infection and vaccination. This underscores the need for long-term planning for surveillance, vaccination, and other mitigation measures amidst continued response to the acute pandemic.
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ObjectivesTo characterize the clinical severity of COVID-19 caused by Omicron, Delta, and Alpha SARS-CoV-2 variants among hospitalized adults and to compare the effectiveness of mRNA COVID-19 vaccines to prevent hospitalizations caused by each variant. DesignA case-control study of 11,690 hospitalized adults. SettingTwenty-one hospitals across the United States. ParticipantsThis study included 5728 cases hospitalized with COVID-19 and 5962 controls hospitalized without COVID-19. Cases were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: Alpha (March 11 to July 3, 2021), Delta (July 4 to December 25, 2021), and Omicron (December 26, 2021 to January 14, 2022). Main Outcome MeasuresVaccine effectiveness was calculated using a test-negative design for COVID-19 mRNA vaccines to prevent COVID-19 hospitalizations by each variant (Alpha, Delta, Omicron). Among hospitalized patients with COVID-19, disease severity on the WHO Clinical Progression Ordinal Scale was compared among variants using proportional odds regression. ResultsVaccine effectiveness of the mRNA vaccines to prevent COVID-19-associated hospitalizations included: 85% (95% CI: 82 to 88%) for 2 vaccine doses against Alpha; 85% (95% CI: 83 to 87%) for 2 doses against Delta; 94% (95% CI: 92 to 95%) for 3 doses against Delta; 65% (95% CI: 51 to 75%) for 2 doses against Omicron; and 86% (95% CI: 77 to 91%) for 3 doses against Omicron. Among hospitalized unvaccinated COVID-19 patients, severity on the WHO Clinical Progression Scale was higher for Delta than Alpha (adjusted proportional odds ratio [aPOR] 1.28, 95% CI: 1.11 to 1.46), and lower for Omicron than Delta (aPOR 0.61, 95% CI: 0.49 to 0.77). Compared to unvaccinated cases, severity was lower for vaccinated cases for each variant, including Alpha (aPOR 0.33, 95% CI: 0.23 to 0.49), Delta (aPOR 0.44, 95% CI: 0.37 to 0.51), and Omicron (aPOR 0.61, 95% CI: 0.44 to 0.85). ConclusionsmRNA vaccines were highly effective in preventing COVID-19-associated hospitalizations from Alpha, Delta, and Omicron variants, but three vaccine doses were required to achieve protection against Omicron similar to the protection that two doses provided against Delta and Alpha. Among adults hospitalized with COVID-19, Omicron caused less severe disease than Delta, but still resulted in substantial morbidity and mortality. Vaccinated patients hospitalized with COVID-19 had significantly lower disease severity than unvaccinated patients for all the variants.
ABSTRACT
The first cluster of SARS-CoV-2 cases with lineage B.1.1.7 in the state of Michigan was identified through intensive university-led surveillance sampling and targeted sequencing. A collaborative investigation and response was conducted by the local and state health departments, and the campus and athletic medicine COVID-19 response teams, using S-gene target failure screening and rapid genomic sequencing to inform containment strategies. A total of 50 cases of B.1.1.7-lineage SARS-CoV-2 were identified in this outbreak, which was due to three coincident introductions of B.1.1.7-lineage SARS-CoV-2, all of which were genetically distinct from lineages which later circulated in the broader community. This investigation demonstrates the successful implementation of a genomically-informed outbreak response which can be extended to university campuses and other settings at high risk for rapid emergence of new variants.
ABSTRACT
COVID-19 has had high incidence at institutions of higher education (IHE) in the United States, but the transmission dynamics in these settings are not well understood. It remains unclear to what extent IHE-associated outbreaks have contributed to transmission in nearby communities. We implemented high-density prospective genomic surveillance to investigate these dynamics at the University of Michigan-Ann Arbor and the surrounding community during the Fall 2020 semester (August 16th -November 24th). We sequenced complete SARS-CoV-2 genomes from 1659 individuals, including 468 students, representing 20% of cases in students and 25% of total confirmed cases in Washtenaw County over the study interval. Phylogenetic analysis identified over 200 introductions into the student population, most of which were not related to other student cases. There were two prolonged transmission clusters among students that spanned across multiple on-campus residences. However, there were very few genetic descendants of student clusters among non-students during a subsequent November wave of infections in the community. We conclude that outbreaks at the University of Michigan did not significantly contribute to the rise in Washtenaw County COVID-19 incidence during November 2020. These results provide valuable insights into the distinct transmission dynamics of SARS-CoV-2 among IHE populations and surrounding communities.
ABSTRACT
BackgroundAs SARS-CoV-2 vaccination coverage increases in the United States (US), there is a need to understand the real-world effectiveness against severe Covid-19 and among people at increased risk for poor outcomes. MethodsIn a multicenter case-control analysis of US adults hospitalized March 11 - May 5, 2021, we evaluated vaccine effectiveness to prevent Covid-19 hospitalizations by comparing odds of prior vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with Covid-19 and hospital-based controls who tested negative for SARS-CoV-2. ResultsAmong 1210 participants, median age was 58 years, 22.8% were Black, 13.8% were Hispanic, and 20.6% had immunosuppression. SARS-CoV-2 lineage B.1.1.7 was most common variant (59.7% of sequenced viruses). Full vaccination (receipt of two vaccine doses [≥]14 days before illness onset) had been received by 45/590 (7.6%) cases and 215/620 (34.7%) controls. Overall vaccine effectiveness was 86.9% (95% CI: 80.4 to 91.2%). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.3%; 95% CI: 78.9 to 99.7%). Among 45 patients with vaccine-breakthrough Covid hospitalizations, 44 (97.8%) were [≥]50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (59.2%; 95% CI: 11.9 to 81.1%) than without immunosuppression (91.3%; 95% CI: 85.5 to 94.7%). ConclusionDuring March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing Covid-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.
ABSTRACT
Understanding viral load in patients infected with SARS-CoV-2 is critical to epidemiology and infection control. Previous studies have demonstrated that SARS-CoV-2 RNA can be detected for many weeks after symptom onset. The clinical significance of this finding is unclear and, in most patients, likely does not represent active infection. There are, however, patients who shed infectious virus for weeks. Detection of subgenomic RNA transcripts expressed by SARS-CoV-2 has been proposed to represent productive infection and may be a tractable marker for monitoring infectivity. Here, we use RT-PCR to quantify total and subgenomic nucleocapsid (N) and envelope (E) transcripts in 190 SARS-CoV-2 positive samples collected on hospital admission. We relate these findings to duration of symptoms. We find that all transcripts decline at the same rate; however, subgenomic E becomes undetectable before other transcripts. In Kaplan-Meier analysis the median duration of symptoms to a negative test is 14 days for sgE and 25 days for sgN. There is a linear decline in subgenomic RNA compared to total RNA suggesting subgenomic transcript copy number is highly dependent on copy number of total transcripts. The mean difference between total N and subgenomic N is 16-fold (4.0 cycles) and the mean difference between total E and sub-genomic E is 137-fold (7.1 cycles). This relationship is constant over duration of symptoms allowing prediction of subgenomic copy number from total copy number. Although Subgenomic E is undetectable at a time that may more closely reflect the duration of infectivity, its utility in determining active infection may be no more useful than a copy number threshold determined for total transcripts.
ABSTRACT
The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2500 COVID-19 cases associated with this variant have been detected in the US since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight the primary ports of entry for B.1.1.7 in the US and locations of possible underreporting of B.1.1.7 cases. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.
ABSTRACT
Analysis of SARS-CoV-2 genetic diversity within infected hosts can provide insight into the generation and spread of new viral variants and may enable high resolution inference of transmission chains. However, little is known about temporal aspects of SARS-CoV-2 intrahost diversity and the extent to which shared diversity reflects convergent evolution as opposed to transmission linkage. Here we use high depth of coverage sequencing to identify within-host genetic variants in 325 specimens from hospitalized COVID-19 patients and infected employees at a single medical center. We validated our variant calling by sequencing defined RNA mixtures and identified a viral load threshold that minimizes false positives. By leveraging clinical metadata, we found that intrahost diversity is low and does not vary by time from symptom onset. This suggests that variants will only rarely rise to appreciable frequency prior to transmission. Although there was generally little shared variation across the sequenced cohort, we identified intrahost variants shared across individuals who were unlikely to be related by transmission. These variants did not precede a rise in frequency in global consensus genomes, suggesting that intrahost variants may have limited utility for predicting future lineages. These results provide important context for sequence-based inference in SARS-CoV-2 evolution and epidemiology.
ABSTRACT
We describe a case of chronic COVID-19 in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing replication of infectious SARS-CoV-2 virus for at least 119 days. The patient had three admissions related to COVID-19 over a four-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.
ABSTRACT
BackgroundSARS-CoV-2 has become a global pandemic. Given the challenges in implementing widespread SARS-CoV-2 testing, there is increasing interest in alternative surveillance strategies. MethodsWe tested nasopharyngeal swabs from 821 decedents in the Wayne County Medical Examiners office for SARS-CoV-2. All decedents were assessed by a COVID-19 checklist, and decedents flagged by the checklist (237) were preferentially tested. A random sample of decedents not flagged by the checklist were also tested (584). We statistically analyzed the characteristics of decedents (age, sex, race, and manner of death), differentiating between those flagged by the checklist and not and between those SARS-CoV-2 positive and not. ResultsDecedents were more likely to be male (70% vs 48%) and Black (55% vs 36%) than the catchment population. Seven-day average percent positivity among flagged decedents closely matched the trajectory of percent positivity in the catchment population, particularly during the peak of the outbreak (March and April). After a lull in May to mid-June, new positive tests in late June coincided with increased case detection in the catchment. We found large racial disparities in test results: despite no statistical difference in the racial distribution between those flagged and not, SARS-CoV-2 positive decedents were substantially more likely to be Black (89% vs 51%). SARS-CoV-2 positive decedents were also more likely to be older and to have died of natural causes, including of COVID-19 disease. ConclusionsDisease surveillance through medical examiners and coroners could supplement other forms of surveillance and may serve as a possible early outbreak warning sign.
ABSTRACT
Supply shortages of N95 respirators during the coronavirus disease 2019 (COVID-19) pandemic have motivated institutions to develop feasible and effective N95 respirator reuse strategies. In particular, heat decontamination is a treatment method that scales well and can be implemented in settings with variable or limited resources. Prior studies using multiple inactivation methods, however, have often focused on a single virus under narrowly defined conditions, making it difficult to develop guiding principles for inactivating emerging or difficult-to-culture viruses. We systematically explored how temperature, humidity, and virus deposition solutions impact the inactivation of viruses deposited and dried on N95 respirator coupons. We exposed four virus surrogates across a range of structures and phylogenies, including two bacteriophages (MS2 and phi6), a mouse coronavirus (murine hepatitis virus, MHV), and a recombinant human influenza A virus subtype H3N2 (IAV), to heat treatment for 30 minutes in multiple deposition solutions across several temperatures and relative humidities (RH). We observed that elevated RH was essential for effective heat inactivation of all four viruses tested. For heat treatments between 72{degrees}C and 82{degrees}C, RH greater than 50% resulted in > 6-log10 inactivation of bacteriophages and RH greater than 25% resulted in > 3.5-log10 inactivation of MHV and IAV. Furthermore, deposition of viruses in host cell culture media greatly enhanced virus inactivation by heat and humidity compared to other deposition solutions such as phosphate buffered saline, phosphate buffered saline with bovine serum albumin, and human saliva. Past and future heat treatment methods or technologies must therefore explicitly account for deposition solutions as a factor that will strongly influence observed virus inactivation rates. Overall, our data set can inform the design and validation of effective heat-based decontamination strategies for N95 respirators and other porous surfaces, especially for emerging or low-titer viruses that may be of immediate public health concern such as SARS-CoV-2. ImportanceShortages of personal protective equipment, including N95 respirators, during the coronavirus disease 2019 (COVID-19) pandemic have highlighted the need to develop effective decontamination strategies for their reuse. This is particularly important in healthcare settings for reducing exposure to respiratory viruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Although several treatment methods are available, a widely accessible strategy will be necessary to combat shortages on a global scale. We demonstrate that the combination of heat and humidity inactivates viruses similar in structure to SARS-CoV-2, namely MS2, phi6, influenza A virus, and mouse coronavirus, after deposition on N95 respirators, and achieves the United States Food and Drug Administration guidelines to validate N95 respirator decontamination technologies. We further demonstrate that depositing viruses onto surfaces when suspended in culture media can greatly enhance observed inactivation, adding caution to how heat and humidity treatments methods are validated.
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BackgroundSevere COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment. MethodsWe assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). Findings154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. InterpretationIn this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings. KEY POINTSO_ST_ABSQuestionC_ST_ABSCan therapy with the IL-6 receptor antagonist tocilizumab improve outcomes in patients with severe COVID-19 illness requiring mechanical ventilation? FindingsIn this observational, controlled study of 154 patients, receipt of tocilizumab was associated with a 45% reduction in the hazard of death, despite twice the frequency of superinfection (54% vs 26%), both of which were statistically significant findings. MeaningTocilizumab therapy may improve survival in patients with COVID-19 illness requiring mechanical ventilation. These results can inform clinical practice pending the results of randomized clinical trials.
ABSTRACT
ImportanceFiltering facepiece respirators, including N95 masks, are a critical component of infection prevention in hospitals. Due to unprecedented shortages in N95 respirators, many healthcare systems have explored reprocessing of N95 respirators. Data supporting these approaches are lacking in real hospital settings. In particular, published studies have not yet reported an evaluation of multiple viruses, bacteria, and fungi along with respirator filtration and fit in a single, full-scale study. ObjectiveWe initiated a full-scale study to evaluate different N95 FFR decontamination strategies and their impact on respirator integrity and inactivating multiple microorganisms, with experimental conditions informed by the needs and constraints of the hospital. MethodsWe explored several reprocessing methods using new 3M 1860 N95 respirators, including dry (<10% relative humidity) and moist (62-66% relative humidity) heat (80-82 {degrees}C) in the drying cycle of industrial instrument washers, ethylene oxide (EtO), pulsed xenon UV (UV-PX), hydrogen peroxide gas plasma (HPGP), and vaporous hydrogen peroxide (VHP). Respirator samples were treated and analyzed for biological indicator inactivation using four viruses (MS2, phi6, influenza A virus, murine hepatitis virus), three bacteria (Escherichia coli, Staphylococcus aureus, Geobacillus stearothermophilus), and the fungus Aspergillus niger. The impact of different application media was also evaluated. In parallel, decontaminated respirators were evaluated for filtration integrity and fit. ResultsVHP resulted in >2 log10 inactivation of all tested biological indicators. The combination of UV-PX + moist heat resulted in >2 log10 inactivation of all biological indicators except G. stearothermohphilus. Greater than 95% filtration efficiency was maintained following 2 (UV-PX + <10% relative humidity heat) or 10 (VHP) cycles of treatment, and proper fit was also preserved. UV-PX + dry heat was insufficient to inactivate all biological indicators. Although very effective at virus decontamination, HPGP resulted in decreased filtration efficiency after 3 cycles, and EtO treatment raised potential toxicity concerns. The observed inactivation of viruses with UV-PX, heat, and hydrogen peroxide treatments varied as a function of which culture media (PBS buffer or DMEM) they were deposited in. Conclusions and RelevanceHigh levels of biological indicator inactivation were achieved following treatment with either moist heat or VHP. These same treatments did not significantly impact mask filtration or fit. Hospitals have a variety of scalable options to safely reprocess N95 masks. Beyond value in the current Covid-19 pandemic, the broad group of microorganisms and conditions tested make these results relevant in potential future pandemic scenarios.
