January 11, 2024

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COVID

The Death Rate of COVID-19 Infection in Different SARS-CoV-2 Variants was Related to C-reactive Protein Gene Polymorphisms
This study examined whether the single nucleotide polymorphisms in CRP rs1205 were associated with COVID-19 mortality among various severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) variants. They did genotyping and found that certain polymorphisms in 2,023 deceased and 2,307 recovered patients were significantly different between the recovered and the deceased patients. In all three variants they examined, COVID-19 mortality rates were associated with a particular genotype. More science to suggest polymorphisms within the CRP gene may relate to serum CRP levels and mortality among COVID-19 patients. They do humbly suggest that a replication of these results is needed. The risk correlation with different genotypes and death varied between different SARS-CoV-2 variants. So with Delta certain genotypes had only a small increase in a correlation with death while for some genotypes this might double with Omicron BA-5.

COVID: Active Vaccination/Immunity

Early COVID-19 Vaccine Effectiveness of XBB.1.5 Vaccine against Hospitalization and Admission to Intensive Care, the Netherlands, 9 October to 5 December 2023
In the Netherlands, the 2023 seasonal COVID-19 vaccination campaign started on 2 October, targeting persons aged 60 years and older, healthcare workers, pregnant women and medical risk groups. It used the monovalent XBB.1.5 Comirnaty vaccine (Pfizer-BioNTech). All residents of the Netherlands aged 60 years and older received a personal invitation for vaccination by post between 2 October and the end of November. Up to 17 December 2023, 48.2% of residents aged 60 and older had received the 2023 seasonal COVID-19 vaccination. They then extracted hospitalizations with admission dates between 9 October and 5 December 2023 from the National Intensive Care Evaluation (NICE) COVID-19 database on 11 December 2023, to account for registration delay. This dataset contained around 55% of all COVID-19 hospitalizations during the study period in the Netherlands. Based on their analysis: The VE against hospitalization was estimated at 70.7% (95% CI: 66.6–74.3). VE against ICU admission was estimated at 73.3% (95% CI: 42.2–87.6). The VE against hospitalization estimate was slightly lower for the age groups 60–74 years (68.3%; 95% CI: 58.3–75.9) and 85 years and older (66.0%; 95% CI: 56.4–73.5) than for persons aged 75 to 84 years (73.9%; 95% CI: 68.5–78.4), but these differences were not statistically significant.

COVID: Early Viral Phase

SARS-CoV-2 Antiviral Prescribing Gaps Among Non-Hospitalized High-Risk Adults
Here we read that within a multi-state clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among non-hospitalized SARS-CoV-2-infected patients with risk factors for severe COVID-19. Among 3,247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers.
Proportion of Hospitalizations Preventable with Increased Oral SARS-CoV-2 Antiviral Treatment
In this investigation they estimated the proportion of hospitalizations that could have been averted had all eligible high-risk adults with SARS-CoV-2 infection in a clinical cohort been treated with an oral SARS-CoV-2 antiviral agent early in infection. Among 3,037 patients with risk factors for progressing to severe COVID-19, 946 (31.1%) received an oral antiviral prescription (834 nirmatrelvir and 112 molnupiravir). Only 3.0% of treated patients vs 9.1% of untreated patients were hospitalized (adjusted risk ratio [RR]=0.27; 95% confidence interval [CI]: 0.18-0.41). If all patients had been treated, an estimated 63.3% (95% CI: 50.4-75.1) of hospitalizations within 30 days could have been prevented. This finding is attributed to large gaps in treatment and a strong protective association of antiviral treatment with subsequent hospitalization.
SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals
To enhance current understanding of rebound, CDC reviewed SARS-CoV-2 rebound studies published during February 1, 2020– November 29, 2023. No statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment. Depending on the definition used, the prevalence of rebound varied. No hospitalizations or deaths were reported among outpatients who experienced rebound, because COVID-19 signs and symptoms were mild. The potential for rebound should not deter clinicians from prescribing lifesaving antiviral treatments when indicated to prevent morbidity and mortality from COVID-19.
Evaluation of SARS-CoV-2 RNA Rebound After Nirmatrelvir/Ritonavir Treatment in Randomized, Double-Blind, Placebo-Controlled Trials — United States and International Sites, 2021–2022
Rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19–related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration’s determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19.
Evaluating fluvoxamine for the outpatient treatment of COVID-19: A systematic review and meta-analysis
Nine RCT studies (N = 5861) were included in this review. So let us start w the Forest plots for hospitalizations incidence of hospitalization (based on 5 RCTs 100mg PO BID, N = 3433; RR 0.75, 95% CI 0.58–0.97) From the Authors: “While we concur that drugs with stronger supporting evidence should be prioritized over fluvoxamine for clinical practice, it is our view that there remains a need for low-cost alternatives to these more established antiviral therapies, especially in resource-constrained areas where the use of drugs like nirmatrelvir/ritonavir is costly or logistically prohibitive. As an old, generic medication, fluvoxamine is widely available and costs as low as $1 per day—substantially cheaper than the $530/course for nirmatrelvir/ritonavir, and $700/course for molnupiravir.
Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate
Three highlights from the authors:
1. Hydroxychloroquine was prescribed in hospitalized patients with Covid-19 despite the low-level evidence.
2. Subsequently, HCQ use was associated with an 11% increase in the mortality rate in a meta-analysis of randomized trials.
3. These findings illustrate the hazard of drug repurposing with low-level evidence for the management of future pandemics.
Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: A randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU)
In this pragmatic, non-blinded trial, authors looked at 387 patients aged 40–90 years who were randomized to receive treatment with SoC plus doxycycline (n = 192) or SoC only (n = 195) in six hospitals in India. The primary outcome was the need for ICU admission as judged by the attending physicians. Among the 387 participants, 77 or (19.9%) developed critical disease needing ICU admission. They reported that doxycycline was associated with a risk reduction of being judged by their physicians to require admission to the local ICU from the regular medical ward. Subtly there is that only about half or 46 people so 59.7% actually went to the ICU after their doctor felt they needed to go. Well-matched controls to treated, lots of ivermectin, steroids, antivirals, and antibiotics other than doxycycline being used with over 80% in both groups. Thirty-nine of 387 study participants (10.1%) died during the trial, and this was the same, with about 10% dying in the doxycycline groups and ab out 10% dying in the no doxycycline group. The authors suggest they are trying to use doxycycline to target the cytokine storm. To summarize for doxycycline: no compelling data for reduction of need for hospitalization of death and this one study suggesting an impact on the providers perception of need for ICU stay.

COVID: The Late Phase/PASC/Long COVID

Muscle Abnormalities Worsen after Post-exertional Malaise in Long COVID
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with Long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), authors provide new insights into the pathophysiology of post-exertional malaise in patients with Long COVID. They show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with Long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from Long COVID and other post-infectious diseases. Initially all participants performed a cardiopulmonary exercise test on a cycle ergometer. Maximal oxygen uptake (V̇O2max) and peak power output were substantially lower in Long COVID patients. They found that the cardiovascular system was not compromised in Long COVID patients, suggesting that the cardiovascular system does not explain the limited exercise capacity in patients with Long COVID. They also found that the lower V̇O2max in patients was not due to submaximal effort during the exercise test. Next, they assessed skeletal muscle structure and function to explain the lower exercise capacity in patients. Capillary density and the capillary-to-fiber ratio were not different between groups. Compared to healthy controls, they observed a higher proportion of highly fatigable glycolytic fibers in the vastus lateralis muscle in Long COVID patients along with a lower cross-sectional area of fatigue-resistant type I fibers in females. Succinate dehydrogenase (SDH) activity (a marker for mitochondrial content) correlated with V̇O2max in healthy controls, but not in patients. While patients had a significantly lower oxidative phosphorylation capacity, no differences were observed in SDH activity, suggestive of qualitatively lower mitochondrial respiration rather than a lower mitochondrial enzyme activity. Collectively, the data suggested that the lower exercise capacity in Long COVID patients is associated with a greater proportion of high-fatigable glycolytic fibers and lower mitochondrial function, with a possible additional limitation of a lower capillarization and the ventilatory system. They then obtained vastus lateralis muscle biopsies before and one day after the induction of post-exertional malaise. All Long COVID patients experienced post-exertional malaise following maximal exercise, despite considerable heterogeneity in exercise capacity. Symptoms included muscle pain, greater severity of fatigue, and cognitive symptoms up to seven days after maximal exercise. They measured mitochondrial respiration and metabolomic signatures in skeletal muscle before and one day after the induction of post-exertional malaise. It has been hypothesized that amyloid-containing deposits in the circulation can block local perfusion in Long COVID, causing ischemia-reperfusion injury. They studied whether amyloid-containing deposits were present in the skeletal muscle of Long COVID patients and whether the indication of post-exertional malaise changed the concentration. They demonstrate that the concentration of amyloid-containing deposits was greater in the skeletal muscle of Long COVID patients at baseline. Visualizing amyloid-containing deposits together with capillaries or lymph vessels revealed that the skeletal amyloid-containing deposits were not located in capillaries or lymphatic vessels, but rather next to capillaries and in the extracellular matrix between muscle fibers. This is important and led them to conclude that post-exertional malaise cannot be explained by the hypothesis that these deposits block vessel perfusion, causing local tissue hypoxia. They found that a larger percentage of Long COVID patients displayed small atrophic fibers and focal necrosis, which increased significantly after exercise, indicating an exacerbated tissue damage response in patients with Long COVID. They explored the infiltration of immune cells (macrophages, T- and B-cells) in skeletal muscle upon exhaustive exercise. More Long COVID patients had CD68+ macrophage infiltration in skeletal muscle compared to healthy controls. To determine whether viral remnants play a role in the differential immune response in skeletal muscle in Long COVID upon induction of post-exertional malaise, they stained all muscle sections for SARS-CoV-2 nucleocapsid protein. They found that the amount of SARS-CoV-2 nucleocapsid protein was not different between groups, before and after adjusting for time since the latest infection. The ventilatory and central cardiovascular system did not limit exercise capacity in Long COVID patients, but these results confirm previous reports of a peripheral impairment in skeletal muscle metabolism in Long COVID patients. They demonstrated that Long COVID is associated with a lower skeletal muscle oxidative phosphorylation capacity. The occurrence of more IIA/X hybrid fibers and rare I/IIA hybrid fibers in patients with Long COVID suggests that the pathophysiology of Long COVID includes a fiber-type shift towards a less oxidative, more glycolytic phenotype. These findings did not support the hypothesis of chronic tissue hypoxia due to vessel blockage contributing to the development of skeletal muscle-related symptoms in long COVID or post-exertional malaise.
Features of Acute COVID-19 Associated with Post-acute Sequelae of SARS-CoV-2 Phenotypes: Results from the IMPACC Study
Here 1,164 participants were enrolled between May 5, 2020 and March 19, 2021 and followed up to 28 days while hospitalized. Of the 702 participants who survived hospitalization and were alive and on study at three months post-discharge, 590 (84%) completed at least one quarterly set of surveys post-discharge (survey respondent cohort). A number of interesting findings, such as a correlation between high viral burden and low antibody levels early in disease. They also reported that during hospitalization, 76% of participants received oxygen therapy, 68% received steroids and 64% received remdesivir. Among the 52% of participants who reported symptoms 12 weeks post-infection and beyond, 29% reported shortness of breath, 21% reported muscle aches or pain, and 20% reported cough. Use of remdesivir and steroids in the inpatient period was not associated with a decrease in PASC prevalence.