Tag: long covid treatment

Assessment of microbiota in the gut and upper respiratory tract associated with SARS-CoV-2 infection

Abstract:

Background: The human microbiome plays an important role in modulating the host metabolism and immune system. Connections and interactions have been found between the microbiome of the gut and oral pharynx in the context of SARS-CoV-2 and other viral infections; hence, to broaden our understanding of host-viral responses in general and to deepen our knowledge of COVID-19, we performed a large-scale, systematic evaluation of the effect of SARS-CoV-2 infection on human microbiota in patients with varying disease severity.

Results: We processed 521 samples from 203 COVID-19 patients with varying disease severity and 94 samples from 31 healthy donors, consisting of 213 pharyngeal swabs, 250 sputa, and 152 fecal samples, and obtained meta-transcriptomes as well as SARS-CoV-2 sequences from each sample. Detailed assessment of these samples revealed altered microbial composition and function in the upper respiratory tract (URT) and gut of COVID-19 patients, and these changes are significantly associated with disease severity. Moreover, URT and gut microbiota show different patterns of alteration, where gut microbiome seems to be more variable and in direct correlation with viral load; and microbial community in the upper respiratory tract renders a high risk of antibiotic resistance. Longitudinally, the microbial composition remains relatively stable during the study period.

Conclusions: Our study has revealed different trends and the relative sensitivity of microbiome in different body sites to SARS-CoV-2 infection. Furthermore, while the use of antibiotics is often essential for the prevention and treatment of secondary infections, our results indicate a need to evaluate potential antibiotic resistance in the management of COVID-19 patients in the ongoing pandemic. Moreover, a longitudinal follow-up to monitor the restoration of the microbiome could enhance our understanding of the long-term effects of COVID-19.

Source: Li J, Jing Q, Li J, Hua M, Di L, Song C, Huang Y, Wang J, Chen C, Wu AR. Assessment of microbiota in the gut and upper respiratory tract associated with SARS-CoV-2 infection. Microbiome. 2023 Mar 3;11(1):38. doi: 10.1186/s40168-022-01447-0. PMID: 36869345; PMCID: PMC9982190. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9982190/ (Full text)

Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial

Abstract:

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID.

Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2×3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records.

Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed >9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34). Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95%CI, 0.38 to 0.88; P=0·009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within <4 days of symptom onset, the HR for Long COVID was 0.37 (95%CI, 0.15 to 0.95).  No statistical difference in Long COVID occurred in those randomized to either ivermectin (HR=0.99; 95%CI, 0.59 to 1.64) or fluvoxamine (HR=1.36; 95%CI, 0.78 to 2.34).

Interpretations: A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.

Source: Bramante, Carolyn and Buse, John B. and Liebovitz, David and Nicklas, Jacinda and Puskarich, Michael and Cohen, Kenneth R. and Belani, Hrishikesh and Anderson, Blake and Huling, Jared D. and Thompson, Jennifer and Pullen, Matthew and Wirtz, Esteban Lemus and Siegel, Lianne and Proper, Jennifer and Odde, David J. and Klatt, Nichole and Sherwood, Nancy E. and Lindberg, Sarah and Karger, Amy B. and Beckman, Kenneth B. and Erickson, Spencer and Fenno, Sarah and Hartman, Katrina and Rose, Michael and Mehta, Tanvi and Patel, Barkha and Griffiths, Gwendolyn and Bhat, Neeta and Murray, Thomas A. and Boulware, David R., Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial. Available at SSRN: https://ssrn.com/abstract=4375620 or http://dx.doi.org/10.2139/ssrn.4375620

Potential of Black Seeds (Nigella Sativa) in the Management of Long COVID or Post-acute Sequelae of COVID-19 (PASC) and Persistent COVID-19 Symptoms – An Insight

Abstract:

Background: Some individuals may experience symptoms persisting for many months after the recovery from COVID-19 and patients with Long COVID are managed mainly with symptomatic treatment and supportive care.

Objective: This review article focuses on the beneficial effects of black seeds (Nigella Sativa) in the management of long COVID and persistent COVID symptoms.

Methods: The literature was searched in databases such as LitCOVID, Web of Science, Google Scholar, bioRxiv, medRxiv, Science Direct, EBSCO, Scopus, Embase, and reference lists to identify studies, which evaluated various effects of black seeds (N. sativa) related to signs and symptoms of Long COVID.

Results: Black seeds (N. sativa) have shown potential anti-COVID, antiviral, anti-inflammatory, antioxidant, immunomodulatory, antihypertensive, anti-obesity, antidiabetic, antihyperlipidemic, and antiasthmatic properties in various clinical, animal, in-vitro, in-vivo, and in-silico studies, which would help the patients recovered from COVID to mitigate Long COVID complications.

Conclusion: Patients experiencing Long COVID may use black seeds (N. sativa) as adjunctive therapy in combination with symptomatic treatment and supportive care to prevent further deterioration and hospitalization. The safety and efficacy of N. sativa in patients with Long-COVID would further be established by future randomized controlled clinical trials.

Source: Pakkir Maideen NM, Hassan Jumale A, Ramadan Barakat I, Khalifa Albasti A. Potential of Black Seeds (Nigella Sativa) in the Management of Long COVID or Post-acute Sequelae of COVID-19 (PASC) and Persistent COVID-19 Symptoms – An Insight. Infect Disord Drug Targets. 2023 Feb 23. doi: 10.2174/1871526523666230223112045. Epub ahead of print. PMID: 36825730.

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome

Abstract:

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study.

We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822-12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34-9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine.

In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

Source: Zavori L, Molnar T, Varnai R, Kanizsai A, Nagy L, Vadkerti B, Szirmay B, Schwarcz A, Csecsei P. Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome. J Pers Med. 2023 Feb 19;13(2):371. doi: 10.3390/jpm13020371. PMID: 36836605; PMCID: PMC9958557. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958557/ (Full text)

STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol

Abstract:

Introduction: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace.

Methods and analysis: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as “standard of care” in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately.

Ethics and dissemination: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations.

Trial registration number: ISRCTN10665760.

Source: Forshaw D, Wall EC, Prescott G, Dehbi HM, Green A, Attree E, Hismeh L, Strain WD, Crooks MG, Watkins C, Robson C, Banerjee R, Lorgelly P, Heightman M, Banerjee A; STIMULATE-ICP trial team. STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol. PLoS One. 2023 Feb 15;18(2):e0272472. doi: 10.1371/journal.pone.0272472. PMID: 36791116; PMCID: PMC9931100. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931100/ (Full text)

Therapeutic Approaches to Dysautonomia in Childhood, with a Special Focus on Long COVID

Abstract:

Background: Dysautonomia seems to be important for the pathophysiology of psychosomatic diseases and, more recently, for long COVID. This concept may explain the clinical symptoms and could help open new therapeutic approaches.
Methods: We compared our data from an analysis of heart rate variability (HRV) in an active standing test in 28 adolescents who had developed an inappropriate sinus tachycardia (IST, n = 13) or postural orthostatic tachycardia syndrome (POTS, n = 15) after contracting COVID-19 disease and/or vaccination with 64 adolescents from our database who developed dysautonomia due to psychosomatic diseases prior to the COVID-19 pandemic. We prove the effects of our treatment: omega-3 fatty acid supplementation (O3-FA, n = 18) in addition to propranolol (low dose, up to 20-20-0 mg, n = 32) or ivabradine 5-5-0 mg (n = 17) on heart rate regulation and heart rate variability (HRV).
Results: The HRV data were not different between the adolescents with SARS-CoV-2-related disorders and the adolescents with dysautonomia prior to the pandemic. The heart rate increases in children with POTS while standing were significantly lower after low-dose propranolol (27.2 ± 17.4 bpm***), ivabradine (23.6 ± 8.12 bpm*), and O-3-FA (25.6 ± 8.4 bpm*). The heart rate in children with IST while lying/standing was significantly lower after propranolol (81.6 ± 10.1 bpm**/101.8 ± 18.8***), ivabradine (84.2 ± 8.4 bpm***/105.4 ± 14.6**), and O-3-FA (88.6 ± 7.9 bpm*/112.1/14.9*).
Conclusions: The HRV data of adolescents with dysautonomia after COVID-19 disease/vaccination are not significantly different from a historical control of adolescents with dysautonomia due to psychosomatic diseases prior to the pandemic. Low-dose propranolol > ivabradine > omega-3 fatty acids significantly decrease elevated heart rates in patients with IST and the heart rate increases in patients with POTS and may be beneficial in these children with dysautonomia.
Source: Buchhorn R. Therapeutic Approaches to Dysautonomia in Childhood, with a Special Focus on Long COVID. Children. 2023; 10(2):316. https://doi.org/10.3390/children10020316 https://www.mdpi.com/2227-9067/10/2/316 (Full text)

Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome

Abstract:

Long-term neurological complications, persisting in patients who cannot fully recover several months after severe SARS-CoV-2 coronavirus infection, are referred to as neurological sequelae of the long COVID syndrome. Among the numerous clinical post-acute COVID-19 symptoms, neurological and psychiatric manifestations comprise prolonged fatigue, “brain fog”, memory deficits, headache, ageusia, anosmia, myalgias, cognitive impairments, anxiety, and depression lasting several months.
Considering that neurons are highly vulnerable to inflammatory and oxidative stress damages following the overproduction of reactive oxygen species (ROS), neuroinflammation and oxidative stress have been suggested to dominate the pathophysiological mechanisms of the long COVID syndrome. It is emphasized that mitochondrial dysfunction and oxidative stress damages are crucial for the pathogenesis of neurodegenerative disorders. Importantly, antioxidant therapies have the potential to slow down and prevent disease progression.
However, many antioxidant compounds display low bioavailability, instability, and transport to targeted tissues, limiting their clinical applications. Various nanocarrier types, e.g., liposomes, cubosomes, solid lipid nanoparticles, micelles, dendrimers, carbon-based nanostructures, nanoceria, and other inorganic nanoparticles, can be employed to enhance antioxidant bioavailability.
Here, we highlight the potential of phytochemical antioxidants and other neuroprotective agents (curcumin, quercetin, vitamins C, E and D, melatonin, rosmarinic acid, N-acetylcysteine, and Ginkgo Biloba derivatives) in therapeutic strategies for neuroregeneration. A particular focus is given to the beneficial role of nanoparticle-mediated drug-delivery systems in addressing the challenges of antioxidants for managing and preventing neurological disorders as factors of long COVID sequelae.
Source: Akanchise T, Angelova A. Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome. Antioxidants. 2023; 12(2):393. https://doi.org/10.3390/antiox12020393 https://www.mdpi.com/2076-3921/12/2/393 (Full text)

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation

Abstract:

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling.

We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID.

Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

Source: Colzato LS, Elmers J, Beste C, Hommel B. A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation. J Clin Med. 2023 Feb 2;12(3):1198. doi: 10.3390/jcm12031198. PMID: 36769845. https://www.mdpi.com/2077-0383/12/3/1198 (Full text)

Long Covid and Neurodegenerative Disease

Abstract:

Brain fog with compromised ability to concentrate has been the most frequent Long Covid (LC) complaint. This is due to an increased TGF beta/IFN gamma with consequently increased bradykinin (BKN), especially in Caucasian females. Brain and lung blood vessels “leak.” This same ratio is increased in Alzheimer’s disease (AD), but decreased in Parkinson’s disease (PD), because CD4+ and CD8+ T cells are differentially affected by the invading associated viruses, e.g., SARS CoV2, HIV, ….

In Covid-19 CD147 receptors on immune cells are critical in generating the increased TGF beta/IFN gamma and those on endothelial cells, platelets, and erythrocytes are critical to the abnormal microvascular blood flow. ACE2 receptors on pneumocytes and enterocytes enable pulmonary and GI entry, initiating gut dysbiosis.

Epigenetics, methylation, magnesium, vitamin D, the B vitamins, and antioxidants suggest that these issues can be surmounted. Biochemical, physiologic, and epidemiologic data are analyzed to answer these questions. An LC model is presented and discussed in the context of the most recent research. Suggestions to avoid these and other worrisome concerns are included. Other topics discussed include estrogen, the gut microbiome, type 2 diabetes (T2D), and homocysteine.

Source: Chambers, P. Long Covid and Neurodegenerative Disease. Preprints 2023, 2023020027 (doi: 10.20944/preprints202302.0027.v1) https://www.preprints.org/manuscript/202302.0027/v1 (Full text available as PDF file)

 

Compounding for the Treatment of COVID-19 and Long COVID, Part 1: Terminology, Mutations, and Variants

Abstract:

COVID-19 (coronavirus disease 2019), which is caused by the positive-stranded ribonucleic acid virus SARS-CoV-2 (acute respiratory syndrome coronavirus 2), is an extremely contagious airborne illness of pandemic proportions. In the modern era, few diseases other than COVID-19 have produced such severe, prolific, and protean short-term adverse effects and long-term sequelae. In addition, few other pandemics have exhibited a trajectory of morbidity and mortality so affected by social, economic, and political factors as well as individual personal perceptions and beliefs.

Vaccines for the prevention of SARS-CoV-2 infection and treatments for COVID-19 mitigate associated morbidity and mortality, but an increasing array of variants presents challenges to therapeutic effectiveness. As a result, afflicted patients often require customized treatments that address the severity of their infection, the manifestations of disease they exhibit, and their individual pharmacogenomic profile. In such cases, a compounded preparation may offer needed support for recovery.

This article, which is the first in a series on compounding for COVID-19 and long COVID (i.e., the long- term sequelae of SARS-CoV-2 infection), provides information about pertinent viral terminology and a brief overview of SARS-CoV-2 mutations and variants of note. Two formulations for customized compounds that may prove effective in treating the acute and/or long-term effects of COVID-19 when commercial therapies have failed are also provided.

Source: Riepl M. Compounding for the Treatment of COVID-19 and Long COVID, Part 1: Terminology, Mutations, and Variants. Int J Pharm Compd. 2023 Jan-Feb;27(1):12-21. PMID: 36720058. https://pubmed.ncbi.nlm.nih.gov/36720058/