January 25, 2024

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COVID: Ventilation/Transmission

Integrated Genomic and Social Network Analyses of Severe Acute Respiratory Syndrome Coronavirus 2 Transmission in the Healthcare Setting
These are the results of a retrospective cross-sectional analyses of viral genomics from all available SARS-CoV-2 viral samples collected at UC San Diego Health and social network analysis using the electronic medical record to derive temporospatial overlap of infections among related viromes and supplemented with contact tracing data. In short, they looked at whether infection prevention measures designed to mitigate transmission were adequate in protecting healthcare workers (HCWs) and patients from acquiring SARS-CoV-2. The outcome measure was any instance of healthcare transmission, defined as cases with closely related viral genomes and epidemiological connection within the healthcare setting during the infection window. Between November 2020 through January 2022, 12,933 viral genomes were obtained from 35,666 patients and HCWs. University of California San Diego Health (UCSDH) consists of two campuses: the older Hillcrest campus, established in 1966, consists of a 381-bed hospital that contains multiple shared patient rooms and the newer 418-bed La Jolla campus, built between 1993 and 2016, that has a majority of single-occupancy rooms. During the study period (November 2020 through January 2022), there were 15,333 adult admissions at the Hillcrest campus and 20,765 at the La Jolla campus. Most healthcare pair transmission events occurred at the older Hillcrest campus; 79% (11 pairs) during the second and third waves and 75% (18 pairs) during Omicron, in contrast to 21% (3 pairs) and 21% (5 pairs) at the La Jolla campus, respectively. The rate of SARS-CoV-2 transmissions per 1000 admissions was 2.54 at Hillcrest compared with 0.63 at the La Jolla campus (χ2 test; P < .001). Additionally, most patients who either acquired or transmitted SARS-CoV-2 in the hospital were in a shared room during part of their stay. They did not identify a single transmission event from exposures via open doors of COVID-19 patients or from patients being placed in nonnegative-pressure rooms, except for exposure to roommates or their direct healthcare providers. Further, no instance of transmission from COVID-19 patients in the intensive care unit to HCWs was identified. Summary: The majority of healthcare-associated transmission events happened either between HCWs when there were breaks in masking protocol or in the setting of shared patient rooms in a hospital with older infrastructure. They suggest that airborne infectious isolation rooms with negative-pressure differential are not indispensable to safely managing patients infected with SARS-CoV-2. They found that masking for source control is effective. However, given that there are inevitable lapses in adherence to infection prevention protocols, healthcare facilities could further benefit by expanding mitigation measures, including enhancing ventilation and air exchanges in all spaces during a future respiratory virus pandemic and supporting single occupancy rooms.

COVID: Early Viral Stage

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19
These are the results of a phase 2–3, double-blind, randomized, placebo-controlled trial. Authors assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy endpoint was the time to sustained resolution of symptoms, defined as the absence of 11 COVID–19–related symptoms for two consecutive days. Safety and changes in viral load were also assessed. They looked at a total of 1,208 patients enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, −35.8 hours [95% CI, −60.1 to −12.4]; P=0.006). On day five, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], −1.51±0.14 log10 copies per milliliter; 95% CI, −1.79 to −1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate.
Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro
The authors look at persistence of infectious SARS-CoV-2 in several permissive cell lines after treatment with high doses of nirmatrelvir or ensitrelvir in vitro. Nirmatrelvir is the protease inhibitor in Paxlovid and ensitrelvir is the Japanese protease inhibitor known as Xocova. They will also be using remdesivir in these assays. The three different permissive cell lines are Huh7-ACE2, A549-ACE2 and Vero-TMPRSS2. They examined the persistence of infectious virus in Huh7-ACE2 for three consecutive days after treatment with each drug (nirmatrelvir, ensitrelvir, or remdesivir) the decay half- lives of the infectivity were calculated to be 23.9h for nirmatrelvir and 26.7h for ensitrelvir. In distinct contrast, remdesivir-treated cells had no measurable infectivity at all time points assessed. They say that this initial finding suggested that while nirmatrelvir or ensitrelvir could block the main viral protease, a replication-competent form of the virus can persist intracellularly. Similar results with other cell types and more time points and a different viral variant. They look further into this phenomenon by examining levels of SARS-CoV-2 genomic RNA (gRNA) and nucleocapsid protein (NP) in infected cells treated with nirmatrelvir or remdesivir. Here Huh7-ACE2 were infected with SARS-CoV-2 at 0.5 MOI for 6h after which the virus was removed and replaced with growth media supplemented with either 20 μM nirmatrelvir or 1 μM remdesivir. (A) Infectivity decay post removal of nirmatrelvir or remdesivir. Authors state that, “our studies on SARS-CoV-2-infected cells in vitro suggest that there is an intermediary form of the virus that is blocked at the stage of polypeptide cleavage by nirmatrelvir or ensitrelvir. The nature of this viral intermediate is yet unclear, but it decays slowly with a half- life of approximately one day. “
Remdesivir Reduced Mortality in Immunocompromised Patients Hospitalized for COVID-19 Across Variant Waves: Findings from Routine Clinical Practice
Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITMHealthcare Database. Patients who received remdesivir within two days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods. A total of 19,184 remdesivir patients were matched to 11,213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval, .62–.78) and 28 days (HR, 0.75; 95% CI, .68–.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods.

COVID: The Late Phase/PASC/Long COVID

Persistent Complement Dysregulation with Signs of Thromboinflammation in Active Long Covid
Investigators followed 39 healthy controls and 113 COVID-19 patients for up to one year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At six-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. They measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally. They found that Long Covid patients exhibited increased complement activation during acute disease, which also persisted at six-month follow-up. They also looked at antithrombin III and their data suggested that in general there was more cleavage and found serum levels of vWF was increased with a decrease in ADAMS13, which regulates vWF. Increased monocyte-platelet aggregates were also found. Also elevated levels of CD41-hi monocytes. While overall serum positivity for CMV- and EBV-specific IgG and, thus, prevalence of CMV or EBV infection, did not differ between patients with and patients without six-month Long Covid, both anti-CMV and anti-EBV IgG were increased in six-month Long Covid patients.