June 27, 2024

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COVID: Pre-exposure Period/Transmission/Testing

Human SARS-CoV-2 Challenge Uncovers Local and Systemic Response Dynamics
Investigators report on results from single-cell multi-omic profiling of nasopharyngeal swabs and blood, looking at abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Explanation of terms:
- Abortive infection - People get exposed to a pathogen, they remain PCR-negative, they remain seronegative, but they did have a detectable innate immune response.
- Transient infection – People get a positive PCR but not more than one quantifiable detections of viral RNA over time
- Sustained infection - At least two quantifiable detections of viral RNA over time.
The investigators report detecting activation of MAIT cells and certain monocyte responses that occur during early and abortive infections. These mucosal-associated invariant T (MAIT) cells are a subset of T cells that are found in the blood and are enriched in many tissues. MAIT cells express a semi-invariant T cell receptor restricted by the MHC class I-related (MR1) molecule. During sustained infections that lead to disease, symptomatic COVID-19, they observed an immediate and new APR in ciliated cells at the site of infection. In addition, they described a distinct cell state for activated conventional T cells that harbour SARS-CoV-2-specific TCRs, and showed that this signature can be projected onto patient cohort data to identify disease-specific T cell responses. In sustained infections, they saw global activation of interferon signalling that affected all circulating immune cells. The activation of interferon signalling in blood preceded widespread activation at the site of inoculation. The activation of interferon signalling at days five to seven after inoculation coincides with global immune infiltration and a peak of detectable virally infected cells. This relatively slow immune infiltration at the site of inoculation is in contrast to the immediate immune infiltration observed in infections that were only transiently detectable. Their data suggest that individuals with high HLA-DQA2 expression (MHC class II) are better at preventing the onset of a sustained viral infection.
Cannabis, Tobacco Use, and COVID-19 Outcomes
In this study of over 72,000 patients they report that current tobacco smoking was significantly associated with increased risk of hospitalization (odds ratio [OR], 1.72; 95% CI, 1.62-1.82; P < .001), ICU admission (OR, 1.22; 95% CI, 1.10-1.34; P < .001), and all-cause mortality (OR, 1.37, 95% CI, 1.20-1.57; P < .001) after adjusting for other factors. Cannabis use was also significantly associated with increased risk of hospitalization (OR, 1.80; 95% CI, 1.68-1.93; P < .001) and ICU admission (OR, 1.27; 95% CI, 1.14-1.41; P < .001) but not with all-cause mortality (OR, 0.97; 95% CI, 0.82-1.14, P = .69) They did adjust for a number of factors including vaccination, comorbidity, diagnosis date, and demographic factors.

COVID: Active Vaccination/Immunity

Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19
These are the results of a test-negative case-control study performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19–associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. Among 2,854 cases and 15,345 controls (median [IQR] age, 56 [37-72] years; 10,658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission.
Adjunctive Statin Therapy in Patients with Covid-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
The authors systematically searched Medline, Embase, Cochrane, and ClinicalTrial.gov databases from March 2020 to late April 2024 for randomized controlled trials (RCTs) comparing statin versus no statin use in patients hospitalized with COVID-19. They pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) applying a random-effects model. They ended up including 7 RCTs comprising 4,262 patients, of whom 2,645 (62%) were randomized to receive statin therapy. Although individual studies included in this meta-analysis have not found any statistically significant difference in overall death, they reported that performing a pooled analysis, compared with no statin, statin use significantly reduced case-fatality rate (RR 0.88; 95% CI 0.80-0.98; I2=0%), so a 12% reduction. There was, however, no statistically significant difference between the two groups in length of hospital stay, elevation of liver enzymes, and C-reactive protein levels.
Nirmatrelvir and Ritonavir for Inpatients with Severe or Critical COVID-19 Beyond Five Days of Symptom Onset: A Propensity Score-matched, Multicenter, Retrospective Cohort Study
A propensity score-matched cohort was constructed by using multicenter data from 6,695 adult inpatients with COVID-19 from December 2022 to February 2023 in China after the epidemic control measures were lifted across the country. The symptom onset of 1,870 enrolled severe or critical inpatients was beyond five days, and they received either Nmr/r plus standard treatment or only standard care. In the Nmr/r group, on Day 7, the number of patients with an improvement in Sequential Organ Failure Assessment (SOFA) score ≥ 2 was much greater than that in the standard treatment group (P = 0.024) without a significant decrease in glomerular filtration rate (P = 0.815). Additionally, the rate of new intubation was lower (P = 0.004) and the no intubation days were higher (P = 0.003) in the first seven days in the Nmr/r group. Other clinical benefits were limited. The authors point out that this study is preliminary and randomized controlled trials to these findings are needed.

COVID: The Late Phase/PASC/Long COVID

Fecal Microbiota Transplantation for Sleep Disturbance in Post-acute COVID-19 Syndrome
Between September 22, 2022 and May 22, 2023, researchers recruited 60 PASC patients with insomnia defined as Insomnia Severity Index (ISI) ≥ 8 and assigned them to the FMT group (FMT at weeks 0, 2, 4 and 8; n=30) or the control group (n=30). The primary outcome was clinical remission defined by an ISI of less than eight at 12 weeks. Secondary outcomes included changes in the Pittsburgh Sleep Quality Index (PSQI), Generalised Anxiety Disorder-7 scale (GAD-7), Epworth Sleepiness Scale (ESS), Multidimensional Fatigue Inventory (MFI), blood cortisol and melatonin, and gut microbiome analysis on metagenomic sequencing. At week 12, more patients in the FMT than the control group had insomnia remission (37.9% vs 10.0%; p=0.018). The FMT group showed a decrease in ISI score (p<0.0001), Pittsburgh Sleep Quality Index (PSQI) (p<0.0001), Generalised Anxiety Disorder-7 scale (GAD-7) (p=0.0019), ESS (p=0.0057) and blood cortisol concentration (p=0.035) from baseline to week 12, but there was no significant change in the control group. There was enrichment of bacteria such as Gemmiger formicilis and depletion of microbial pathways producing menaquinol derivatives after FMT. Gut microbiome profile resembled that of the donor in FMT responders but not in non-responders at week 12. There was no serious adverse event.
Precision Symptom Phenotyping Identifies Early Clinical and Proteomic Predictors of Distinct COVID-19 Sequela
This study identifies three symptom-based clusters:
Cluster 1 (Sensory) was characterized by a higher frequency of sensory symptoms such as loss of smell and/or taste; Cluster 2 (Fatigue/Difficulty thinking) was characterized by a higher frequency of fatigue (including mental and physical fatigue) and difficulty thinking (e.g., brain fog), and Cluster 3 (Difficulty breathing/Exercise intolerance) was characterized by a higher frequency of difficulty breathing symptoms (e.g., shortness of breath) and exercise intolerance (e.g., difficulty exercising).