Long-term Follow-up After Critical COVID-19

Barnett, Michael L.; Sax, Paul E.

doi:10.1001/jama.2022.23700

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…[14][15][16][17] It is important to consider all such analyses when critically evaluating a phase 3 randomized trial. 18,19 Long Covid was a pre-specified secondary outcome of the COVID-OUT trial. It was not possible to elevate it to co-primary outcome because the trial had already begun enrolling before Long Covid was recognized as a disease entity that needed further study, and primary outcomes cannot be changed after enrollment starts.…”

Section: Discussionmentioning

confidence: 99%

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Bramante

Buse

Liebovitz

et al. 2022

Preprint

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Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registration:NCT04510194; IND 152439

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Section: Discussionmentioning

confidence: 99%

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Bramante

Buse

Liebovitz

et al. 2022

Preprint

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“…As described earlier, it is increasingly becoming clear that the IL-6 signalling system is involved not only in systemic aspects of COVID-19 such as COVID-CSs but also in the neuropsychiatric aspects of long-COVID [10,11,[31][32][33]. While in vivo levels of IL-6 are similar in plasma and CSF [30], CSF levels of sIL-6R (~0.5-2 ng/mL, versus ~20-40 ng/mL in plasma) and sgp130 (~30 ng/mL, versus ~300 ng/mL in plasma) have consistently been reported as significantly lower than in the blood [53,54]). While, according to Garbers (2015), IL-6, sIL-6R and sgp130 form a blood-borne 'IL-6 buffer complex' (with 2:2:2 stoichiometry [13]) whose buffering capacity is determined by the sIL-6R concentration [46], this depends on circulating sgp130 levels remaining in excess at all times.…”

Section: Discussionmentioning

confidence: 99%

“…Individuals' cytokine responses to SARS-CoV-2 may influence the likelihood of developing not only acute COVID-19 but also long-COVID: for example, given that IL-6 and sIL-6R are implicated in neuroinflammatory processes in a number of contexts [26][27][28][29], neuropsychiatric long-COVID symptoms may be attributable at least in part to IL-6/sIL-6R signalling [10,11]. This has recently been supported by the REMAP-CAP Long-Term Follow-Up study [30,31], which reported that Tocilizumab significantly improved several aspects of health-related quality of life (including cognitive function) six months after initial SARS-CoV-2 infection, while Tocilizumab was protective against neuropsychiatric symptoms in a cohort of COVID-19 survivors three months after discharge following hospitalisation [32]. This link to IL-6/IL-6R signalling further supports the potential use of the rs2228145 genotype as a predictive biomarker to identify at-risk patients (at risk of long-COVID, in this case), for whom IL-6 signalling blockers such as Tocilizumab could be appropriate therapies.…”

Section: Introductionmentioning

confidence: 89%

The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein

Sarwar,

Aicheler,

Butcher

et al. 2023

COVID

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Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk.

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“…The REMAP-CAP trial evaluated 6 treatment classes for 4689 intensive care COVID-19 patients and confirmed a substantial clinical benefit of the IL-6 receptor antagonists tocilizumab and sarilumab. This same study also was unable to confirm the claimed benefits of convalescent plasma exchange, the anti-malarial hydroxychloroquine (might even be harmful), nor the anti-viral lopinavir and ritonavir (Barnett & Sax, 2023).…”

Section: Hypometabolism and Hypermetabolism In Brain Areas Revealed B...mentioning

confidence: 91%

“…The REMAP-CAP trial found aspirin or P2Y12 inhibitors (antiplatelet agents) demonstrated a high likelihood of improving 180-day mortality. Comparatively, anticoagulation with heparin in noncritical disease of moderate severity, but not in critical disease, improved outcomes (Barnett & Sax, 2023).…”

Section: Hypometabolism and Hypermetabolism In Brain Areas Revealed B...mentioning

confidence: 99%

COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain

Tang

Helmeste

Leonard

2023

Acta Neuropsychiatr.

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There appear to be huge variations and aberrations in the reported data in COVID-19 two years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host’s inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms, and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

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Long-term Follow-up After Critical COVID-19

Cited by 5 publications

References 16 publications

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein

COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain

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