Tag: 2022

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

Abstract:

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.

Source: Bramante CT, Buse JB, Liebovitz D, Nicklas J, Puskarich MA, Cohen K, Belani H, Anderson B, Huling JD, Tignanelli C, Thompson J, Pullen M, Siegel L, Proper J, Odde DJ, Klatt N, Sherwood N, Lindberg S, Wirtz EL, Karger A, Beckman K, Erickson S, Fenno S, Hartman K, Rose M, Patel B, Griffiths G, Bhat N, Murray TA, Boulware DR. Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up. medRxiv [Preprint]. 2022 Dec 23:2022.12.21.22283753. doi: 10.1101/2022.12.21.22283753. PMID: 36597543; PMCID: PMC9810227.  https://www.medrxiv.org/content/10.1101/2022.12.21.22283753v1.full (Full text)

COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients

Abstract:
Background: Better understanding of long-term health effects after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We analyzed large and diverse patient cohort to study health effects related to SARS-CoV-2 infection occurring more than one month post-infection.
Methods: We analyzed 17,487 patients who received diagnoses for SARS-CoV-2 infection in a total of 122 healthcare facilities in the United States prior to April, 14,2022. Patients were propensity score matched with patients diagnosed with the common cold, influenza, or viral pneumonia from March 1, 2020, to April 1, 2021. For each outcome, SARS-CoV-2 was compared to a generic Viral Respiratory Infection (VRI) by predicting diagnoses in the period between 30 and 365 days post-infection. Both COVID-19 and VRI patients were propensity score matched with patients with no record of COVID-19 or VRI and the same methodology was applied. Diagnoses where COVID-19 infection was a significant positive predictor in both COVID-19 vs VRI and COVID-19 vs Control comparisons were considered COVID-19-specific effects.
Results: Compared to common VRIs, SARS-CoV-2 was associated with diagnoses palpitations, hair loss, fatigue, chest pain, dyspnea, joint pain, and obesity in the post-infectious period.
Conclusions: We identify that some diagnoses commonly described as “long COVID” do not appear significantly more frequent post-COVID-19 infection compared to other common VRIs. We also identify sequelae which are specifically associated with a prior SARS-CoV-2 infection.
Source: William I Baskett, MS, Adnan I Qureshi, MD, Daniel Shyu, MD, Jane M Armer, PhD, RN, Chi-Ren Shyu, PhD, COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients, Open Forum Infectious Diseases, 2022;, ofac683, https://doi.org/10.1093/ofid/ofac683 (Full text)

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19

Abstract:

Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals.

Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis.

COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.

Source: Maher AK, Burnham KL, Jones EM, Tan MMH, Saputil RC, Baillon L, Selck C, Giang N, Argüello R, Pillay C, Thorley E, Short CE, Quinlan R, Barclay WS, Cooper N, Taylor GP, Davenport EE, Dominguez-Villar M. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19. Nat Commun. 2022 Dec 26;13(1):7947. doi: 10.1038/s41467-022-35638-y. PMID: 36572683; PMCID: PMC9791976. https://www.nature.com/articles/s41467-022-35638-y (Full text)

Hyperbaric oxygen treatment for long coronavirus disease-19: a case report

Abstract:

Background: The coronavirus disease 2019 pandemic has resulted in a growing population of individuals who experience a wide range of persistent symptoms referred to as “long COVID.” Symptoms include neurocognitive impairment and fatigue. Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy.

Case presentation: A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treatment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity.

Conclusions: We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.

Source: Bhaiyat AM, Sasson E, Wang Z, Khairy S, Ginzarly M, Qureshi U, Fikree M, Efrati S. Hyperbaric oxygen treatment for long coronavirus disease-19: a case report. J Med Case Rep. 2022 Feb 15;16(1):80. doi: 10.1186/s13256-022-03287-w. PMID: 35168680; PMCID: PMC8848789. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848789/ (Full text)

Post-acute sequelae of COVID-19 infection

Highlights:

• Higher post-acute depression/anxiety, DVT & fibromyalgia among COVID-19 patients.
• Higher lung disease and sleep disturbance, when acute-phase hospitalized included.
• No higher risk observed for CVA, MI, HTN, AKI, IHD or diabetes.

Abstract:

To determine if people infected with SARS-CoV-2 were at higher risk of developing selected medical conditions post-recovery, data were extracted from the database of a large health maintenance organization (HMO) in Israel between March 2020 and May 2021. For each condition, a condition-naïve group prior to COVID-19 (PCR-positive) infection were compared to a condition-naïve, non-COVID-19 infected group, matched by gender, age, socioeconomic status, minority group status and number of months visited primary care physician (PCP) in previous year. Diagnosis and recuperation dates for each COVID-19 infected participant were applied to their matched comparison participant (1:1 ratio). Incidence of each condition was measured between date of recuperation and end of study period for each group and Cox regression models developed to determine hazard ratios by group status, controlling for demographic and health variables.

Crude and adjusted incidence rates were higher for the COVID-19 infected group than those not infected with COVID-19 for treatment for depression/anxiety, sleep disturbance, diagnosis of deep venous thrombosis, lung disease and fibromyalgia. Differences in incidence were no longer observed between the two groups for treatment of sleep disturbance, and diagnosis of lung disease when those hospitalized during the acute-phase of illness (any reason) were excluded. No difference was found by COVID-19 infection status for post-acute incidence of diabetes, cerebrovascular accident, myocardial infarction, acute kidney disease, hypertension and ischemic heart disease.

Patients post- COVID-19 infection should be evaluated for depression, anxiety, sleep disturbance, DVT, lung disease and fibromyalgia.

Source: Kertes Jennifer, Shapiro Ben David Shirley,  Porath Avib et al. Post-acute sequelae of COVID-19 infection. Preventive Medicine Reports. Available online 21 December 2022, 102097. https://www.sciencedirect.com/science/article/pii/S2211335522004041 (Full text)

The Rise and Fall of the Psychosomatic Approach to Medically Unexplained Symptoms, Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:

The psychosomatic approach to medically unexplained symptoms, myalgic encephalomyelitis and chronic fatigue syndrome (MUS/ME/CFS) is critically reviewed using scientific criteria. Based on the ‘Biopsychosocial Model’, the psychosomatic theory proposes that patients’ dysfunctional beliefs, deconditioning and attentional biases cause or make illness worse, disrupt therapies, and lead to preventable deaths. The evidence reviewed suggests that none of these psychosomatic hypotheses is empirically supported.

The lack of robust supportive evidence together with the use of fallacious causal assumptions, inappropriate and harmful therapies, broken scientific principles, repeated methodological flaws and an unwillingness to share data all give the appearance of cargo cult science. The psychosomatic approach needs to be replaced by a scientific, biologically grounded approach to MUS/ME/CFS that can be expected to provide patients with appropriate care and treatments. Patients with MUS/ME/CFS and their families have not been treated with the dignity, respect and care that is their human right. Patients with MUS/ME/CFS and their families could consider a class action legal case against the injuring parties.

Source: David F Marks. (2022). The Rise and Fall of the Psychosomatic Approach to Medically Unexplained Symptoms,
Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Arch Epidemiol Pub Health Res, 1(2), 97-143. https://www.opastpublishers.com/peer-review/the-rise-and-fall-of-the-psychosomatic-approach-to-medically-unexplained-symptoms-myalgic-encephalomyelitis-and-chronic–4899.html (Full text available as PDF file)

Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature

Abstract:

The present study aims to provide a critical overview of the literature on the relationships between post-acute COVID-19 infection and cognitive impairment, highlighting the limitations and confounding factors. A systematic search of articles published from 1 January 2020 to 1 July 2022 was performed in PubMed/Medline. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies using validated instruments for the assessment of cognitive impairment were included. Out of 5515 screened records, 72 studies met the inclusion criteria.

The available evidence revealed the presence of impairment in executive functions, speed of processing, attention and memory in subjects recovered from COVID-19. However, several limitations of the literature reviewed should be highlighted: most studies were performed on small samples, not stratified by severity of disease and age, used as a cross-sectional or a short-term longitudinal design and provided a limited assessment of the different cognitive domains. Few studies investigated the neurobiological correlates of cognitive deficits in individuals recovered from COVID-19. Further studies with an adequate methodological design are needed for an in-depth characterization of cognitive impairment in individuals recovered from COVID-19.

Source: Perrottelli A, Sansone N, Giordano GM, Caporusso E, Giuliani L, Melillo A, Pezzella P, Bucci P, Mucci A, Galderisi S. Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature. J Pers Med. 2022 Dec 15;12(12):2070. doi: 10.3390/jpm12122070. PMID: 36556290; PMCID: PMC9781311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781311/ (Full text)

Risk factors, health outcomes, healthcare services utilization, and direct medical costs of long COVID patient

Abstract:

Background: Data on the economic burden of long-COVID are scarce. We aimed to examine the prevalence and medical-costs for treating long-COVID.

Methods: We conducted this historical-cohort study using data of patients with COVID-19 among members of a large health-provider in Israel. Cases were defined according to physician diagnosis (definite long-COVID) or suggestive symptoms given ≥4-weeks from infection (probable cases). Healthcare resource utilization (HCRU) and direct healthcare costs (HCCs) in the period prior to infection and afterwards were compared across study groups.

Findings: Between March 2020, and March 2021, a total of 180,759 COVID-19 patients (mean[SD] age=32.9y [19.0y]; 89,665 [49.6%] females) were identified. Overall, 14,088(7.8%) individuals developed long-COVID (mean[SD] age=40.0y [19.0y]; 52.4% females). Among them, 1,477(10.5%) were definite long-COVID and 12,611(89.5%) were defined as probable long-COVID. Long-COVID was associated with age (AOR=1.058 per year, 95%CI:1.053-1.063), female sex (AOR=1.138;1.098-1.180), smoking (AOR=1.532;1.358-1.727), and symptomatic acute-phase (AOR=1.178;1.133-1.224), primarily muscle-pain and cough. Hypertension was an important risk factor for long-COVID among younger adults. Compared to non-long-COVID patients, definite and probable cases were associated with AORs of 2.47(2.22-2.75) and 1.76(1.68-1.84) for post-COVID hospitalization, respectively. While among non-long COVID patients HCCs decreased from US$ 1400 during 4 months before the infection to US$ 1021, among long-COVID patients HCC increased from $US 2435 to $US 2810.

Interpretation: Long-COVID is associated with a substantial increase in healthcare services utilization and direct-medical costs. Our findings underline the need for timely planning and allocating resources for long-COVID patient-centered care as well as for its secondary-prevention in high-risk patients.

Source: Tene L, Bergroth T, Eisenberg A, Ben David SS, Chodick G. Risk factors, health outcomes, healthcare services utilization, and direct medical costs of long COVID patient. Int J Infect Dis. 2022 Dec 15:S1201-9712(22)00640-3. doi: 10.1016/j.ijid.2022.12.002. Epub ahead of print. PMID: 36529373. https://www.ijidonline.com/article/S1201-9712(22)00640-3/fulltext (Full text)

Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort

Abstract:

Importance: Persistent symptoms after SARS-COV-2 infection, or long-COVID, may occur in anywhere from 10-55% of those who have had COVID-19, but the extent of impact on daily functioning and disability remains unquantified.

Objective: To characterize physical and mental disability associated with long-COVID.

Design: Cross-sectional analysis of baseline data from a cohort study.

Setting: Online US nationwide survey.

Participants: Adults 18 years of age and older who live in the US who either report a history of COVID-19 illness (n=8,874) or report never having had COVID-19 (n=633).

Main outcome and measures: Self-reported mobility disability (difficulty walking a quarter of a mile and/or up 10 stairs, instrumental activities of daily living [IADL] disability (difficulty doing light or heavy housework), and mental fatigue as measured by the Wood Mental Fatigue Inventory (WMFI).

Results: Of 7,926 participants with long-COVID, the median age was 45 years, 84% were female, 89% self-reported white race, and 7.4% self-reported Hispanic/Latino ethnicity. Sixty-five percent of long-COVID participants were classified as having at least one disability, compared to 6% of those with resolved-COVID (n=948) and 14% of those with no-COVID (n=633). Of long-COVID participants, about 1% and 5% were classified as critically physically disabled or mentally fatigued, respectively. Age, prior comorbidity, increased BMI, female gender, hospitalization for COVID-19, non-white race, and multi-race were all associated with significantly higher disability burden. Dizziness at the time of infection (33% non-hospitalized, 39% hospitalized) was associated with all five disability components in both hospitalized and non-hospitalized groups. Heavy limbs, dyspnea, and tremors were associated with four of the five components of disability in the non-hospitalized group, and heavy limbs was associated with four of the five components in the hospitalized group. Vaccination was protective against development of disability.

Conclusion and relevance: We observed a high burden of physical and mental disability associated with long-COVID which has serious implications for individual and societal health that may be partially mitigated by vaccination. Longitudinal characterization and evaluation of COVID-19 patients is necessary to identify patterns of recovery and treatment options.

Source: Lau B, Wentz E, Ni Z, Yenokyan K, Coggiano C, Mehta SH, Duggal P. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort. medRxiv [Preprint]. 2022 Dec 7:2022.12.07.22283203. doi: 10.1101/2022.12.07.22283203. PMID: 36523402; PMCID: PMC9753791. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9753791/ (Full text)

T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID

Abstract:

Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells.

Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.

One Sentence Summary Adaptive immunity is altered in patients with neurologic manifestations of long COVID.

Source: Lavanya Visvabharathy, Barbara A. Hanson, Zachary S. Orban, Patrick H. Lim, Nicole M. Palacio, Millenia Jimenez, Jeffrey R. Clark, Edith L. Graham, Eric M. Liotta, George Tachas, Pablo Penaloza-MacMaster, Igor J. Koralnik. T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID. medRxiv 2021.08.08.21261763; doi: https://doi.org/10.1101/2021.08.08.21261763 https://www.medrxiv.org/content/10.1101/2021.08.08.21261763v4.full-text (Full text)