After the virus has cleared-Can preclinical models be employed for Long COVID research?

Abstract:

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics.

After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics.

Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

Source: Jansen EB, Orvold SN, Swan CL, Yourkowski A, Thivierge BM, Francis ME, Ge A, Rioux M, Darbellay J, Howland JG, Kelvin AA. After the virus has cleared-Can preclinical models be employed for Long COVID research? PLoS Pathog. 2022 Sep 7;18(9):e1010741. doi: 10.1371/journal.ppat.1010741. PMID: 36070309; PMCID: PMC9451097. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451097/ (Full text)

Long Covid: where we stand and challenges ahead

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.

Source: Mantovani, A., Morrone, M.C., Patrono, C. et al. Long Covid: where we stand and challenges ahead. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01052-6 https://www.nature.com/articles/s41418-022-01052-6 (Full text)

Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant

Abstract:

This study compared differences in the presence of post-COVID symptoms among vaccinated and non-vaccinated COVID-19 survivors requiring hospitalization due to the Delta (B.1.617.2) variant. This cohort study included hospitalized subjects who had survived SARS-CoV-2 infection (Delta variant) from July to August 2021 in an urban hospital in Madrid, Spain. Individuals were classified as vaccinated if they received full administration (i.e., two doses) of BNT162b2 (“Pfizer-BioNTech”) vaccines. Other vaccines were excluded. Those with just one dose of the BNT162b2 vaccine were considered as non-vaccinated.
Patients were scheduled for a telephone interview at a follow-up around six months after infection for assessing the presence of post-COVID symptoms with particular attention to those symptoms starting after acute infection and hospitalization. Anxiety/depressive levels and sleep quality were likely assessed. Hospitalization and clinical data were collected from medical records. A total comprising 109 vaccinated and 92 non-vaccinated COVID-19 survivors was included.
Vaccinated patients were older and presented a higher number of medical comorbidities, particular cardiorespiratory conditions, than non-vaccinated patients. No differences in COVID-19 onset symptoms at hospitalization and post-COVID symptoms six months after hospital discharge were found between vaccinated and non-vaccinated groups. No specific risk factor for any post-COVID symptom was identified in either group.
This study observed that COVID-19 onset-associated symptoms and post-COVID symptoms six-months after hospitalization were similar between previously hospitalized COVID-19 survivors vaccinated and those non-vaccinated. Current data can be applied to the Delta variant and those vaccinated with BNT162b2 (Pfizer-BioNTech) vaccine.
Source: Fernández-de-las-Peñas C, Ortega-Santiago R, Fuensalida-Novo S, Martín-Guerrero JD, Pellicer-Valero OJ, Torres-Macho J. Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant. Vaccines. 2022; 10(9):1481. https://doi.org/10.3390/vaccines10091481 https://www.mdpi.com/2076-393X/10/9/1481/htm (Full text)

Bias in Exercise Trials for ME/CFS: the Importance of Objective Outcomes and Long-term Follow-up

Sharpe and colleagues recommend that patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) be offered cognitive behavior therapy (CBT) and graded exercise therapy (GET)1, advice that contrasts with recent NICE guidance on ME/CFS.2 The authors argue that “there are many randomized trials indicating the safety and efficacy of these treatments.”1

All of these trials, however, were nonblinded and relied on subjective symptom questionnaires as their main outcomes, a combination that creates a high risk of response bias. Treatment manuals used in these trials included explicit encouragements to raise patients’ expectations of GET and CBT. One patient booklet, for example, informed patients: “You will experience a snowballing effect as increasing fitness leads to increasing confidence in your ability. You will have conquered CFS by your own effort and you will be back in control of your body again.”3 These encouragements were not provided to participants in the control group and might have influenced how patients rated their health. In contrast to what Sharpe and colleagues claim, measuring the expectations of patients before the trial begins, does not address how therapists might have influenced symptom reporting during the trial.

There are further arguments that suggest these trials might have measured response bias rather than improvements in health. There were, for example, no clinically significant differences on objective outcome measures that are less prone to response bias such as employment figures, activity levels, or fitness tests.3 In addition, at long-term follow-up, the control group seemed to perform just as well as participants who received GET or CBT. This could not be explained by additional treatment received after the trial ended.4 These findings are difficult to interpret if patients did indeed rehabilitate successfully following GET or CBT. It is unfortunate that the authors, who were primary researchers in many of these trials, do not address these concerns.

Lastly, Sharpe and colleagues argue that “harm reported from patient community surveys reflects poorly implemented therapy.”1 Patient surveys, however, indicate that ME/CFS patients report harm of GET even if prescribed by a specialist or physiotherapist.5 The authors have previously been challenged for misrepresenting the findings of these surveys.5 Post-exertional malaise or a marked worsening of symptoms when patients exceed their energy limit, is a characteristic feature of ME/CFS.2 There are therefore reasonable safety concerns about treatments such as GET and CBT that try to push patients to exceed their limits.

Read the full article HERE.

Source: Tack, M. Bias in Exercise Trials for ME/CFS: the Importance of Objective Outcomes and Long-term Follow-up. J GEN INTERN MED 37, 3193 (2022). https://doi.org/10.1007/s11606-022-07704-0  (Full text)

Austerity and identity formation: How welfare cutbacks condition narratives of sickness

Abstract:

In recent years, Swedish sick insurance has become more restrictive. In this article, we analyse how people not being granted payments, despite being seriously ill, are affected. Scholarship on identity formation and sickness stress the importance of constructing narratives in order to come to terms with one’s situation. Our analysis of 30 qualitative interviews with people diagnosed with ME/CFS shows that workfare politics conditions such identity formation and often prevents it from taking place.

Interviewees describe extreme stress as a result of their contacts with the Social Insurance Agency (SIA), which results in a perpetual crisis that is renewed with each new denied application. In particular, the sense of not having a future means that it is hard to construct narratives to make sense of one’s situation. To escape the perpetual crisis, some people have politicised their situation, constructing a narrative about themselves as suffering from oppressive politics. Others have escaped by not applying for sick insurance or other social insurances. But generally speaking, the most common effect of being denied sick insurance is an ongoing crisis that leads to deteriorating health.

Source: Altermark N, Plesner Å. Austerity and identity formation: How welfare cutbacks condition narratives of sickness. Sociol Health Illn. 2022 Sep;44(8):1270-1286. doi: 10.1111/1467-9566.13545. Epub 2022 Sep 6. PMID: 36066495. https://onlinelibrary.wiley.com/doi/10.1111/1467-9566.13545 (Full text)

Larger gray matter volumes in neuropsychiatric long-COVID syndrome

Abstract:

Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID. To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20). Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry.

To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and/or initial severity of symptoms of COVID-19 and time since onset of COVID-19 stepwise linear regression analysis was performed. Significantly enlarged GMV in long-COVID patients was present in several clusters (spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres) when compared to controls. Time since onset of COVID-19 was a significant regressor in four of these clusters with an inverse relationship. No associations with clinical symptom burden were found.

GMV alterations in limbic and secondary olfactory areas are present in long-COVID patients and might be dynamic over time. Larger samples and longitudinal data in long-COVID patients are required to further clarify the mediating mechanisms between COVID-19, GMV and neuropsychiatric symptoms.

Source: Besteher B, Machnik M, Troll M, Toepffer A, Zerekidze A, Rocktäschel T, Heller C, Kikinis Z, Brodoehl S, Finke K, Reuken PA, Opel N, Stallmach A, Gaser C, Walter M. Larger gray matter volumes in neuropsychiatric long-COVID syndrome. Psychiatry Res. 2022 Sep 6;317:114836. doi: 10.1016/j.psychres.2022.114836. Epub ahead of print. PMID: 36087363; PMCID: PMC9444315. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444315/ (Full text)

Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function

Summary:

Background: Fatigue with reduced tolerance to exercise is a common persistent long-lasting feature amongst COVID-19 survivors. The assessment of muscle function in this category of patients is often neglected.

Aim: To evaluate the potential impact of a daily supplementation based on amino acids, minerals, vitamins, and plant extracts (Apportal®) on muscle function, body composition, laboratory parameters and self-rated health in a small group of COVID-19 survivors affected by fatigue.

Methods: Thirty participants were enrolled among patients affected by physical fatigue during or after acute COVID-19 and admitted to the post-COVID-19 outpatient service at Fondazione Policlinico Gemelli in Rome between 1st March 2021 and 30th April 2021. All participants were evaluated at first visit (t0) and at control visit (t1), after taking a daily sachet of Apportal® for 28 days. Muscle function was analyzed using hand grip strength test, exhaustion strength time and the number of repetitions at one-minute chair stand test. Body composition was assessed with bioelectrical impedance analysis (BIA). Laboratory parameters, including standard blood biochemistry and ferritin levels, were evaluated at the first visit and during the control visit. A quick evaluation of self-rated health, before COVID-19, at t0 and t1, was obtained through a visual analogue scale (VAS).

Results: Participants aged 60 years and older were 13 (43%). Females represented the 70% of the study sample. Participants hospitalized for COVID-19 with low-flow oxygen supplementation represented the 43.3% of the study sample while 3.3% received noninvasive ventilation (NIV) or invasive ventilation. Hand grip strength improved from 26.3 Kg to 28.9 Kg (p < 0.05) at t1 as compared to t0. The mean time of strength exhaustion increased from 31.7 s (sec) at t0 to 47.5 s at t1 (p < 0.05). Participants performed a higher number of repetitions (28.3 vs. 22.0; p < 0.05) during the one-minute chair stand test at t1 as compared to t0. A trend, although not significant, in reduction of ferritin levels was found after nutritional supplementation (94.4 vs. 84.3, respectively; p = 0.01). The self-rated health status increased by at least 13 points (t0, mean 57.6 ± 5.86; t1, mean 71.4 ± 6.73; p < 0.05).

Conclusion: After 28 days of nutritional supplementation with Apportal® in COVID-19 survivors affected by fatigue with reduced tolerance to exercise, we found a significant improvement in means of muscle strength and physical performance, associated with enhancement of self-rated health status between t0 and t1.

Source: Vincenzo Galluzzo, Maria Beatrice Zazzara, Francesca Ciciarello, Giulia Savera, Cristina Pais, Riccardo Calvani, Anna Picca, Emanuele Marzetti, Francesco Landi, Matteo Tosato, Steering Committee, Francesco Landi, Elisa Gremese, Coordination, Roberto Bernabei, Massimo Fantoni, Antonio Gasbarrini, Field investigators, Gastroenterology team, Serena Porcari, Carlo Romano Settanni, Geriatric team, Francesca Benvenuto, Giulia Bramato, Vincenzo Brandi, Angelo Carfì, Francesca Ciciarello, Sofia Fabrizi, Vincenzo Galluzzo, Maria Rita Lo Monaco, Anna Maria Martone, Emanuele Marzetti, Carmen Napolitano, Francesco Cosimo Pagano, Cristina Pais, Sara Rocchi, Elisabetta Rota, Andrea Salerno, Matteo Tosato, Marcello Tritto, Maria Beatrice Zazzara, Riccardo Calvani, Lucio Catalano, Anna Picca, Giulia Savera, Francesco Paolo Damiano, Alessandra Rocconi, Alessandro Galliani, Giovanni Spaziani, Salvatore Tupputi, Camilla Cocchi, Flavia Pirone, Federica D’Ignazio, Stefano Cacciatore, Infectious disease team, Roberto Cauda, Enrica Tamburrini, A. Borghetti, Simona Di Gianbenedetto, Rita Murri, Antonella Cingolani, Giulio Ventura, E. Taddei, D. Moschese, A. Ciccullo, A. Dusina, Internal Medicine team, Leonardo Stella, Giovanni Addolorato, Francesco Franceschi, Gertrude Mingrone, M.A. Zocco, Microbiology team, Maurizio Sanguinetti, Paola Cattani, Simona Marchetti, Brunella Posteraro, M. Sali, Neurology team, Alessandra Bizzarro, Alessandra Lauria, Ophthalmology team, Stanislao Rizzo, Maria Cristina Savastano, G. Gambini, G.M. Cozzupoli, C. Culiersi, Otolaryngology team, Giulio Cesare Passali, Gaetano Paludetti, Jacopo Galli, F. Crudo, G. Di Cintio, Y. Longobardi, L. Tricarico, M. Santantonio, Pediatric team, Danilo Buonsenso, P. Valentini, D. Pata, D. Sinatti, C. De Rose, Pneumology team, Luca Richeldi, Francesco Lombardi, A. Calabrese, Paolo Maria Leone, Maria Rosaria Calvello, Enrica Intini, Giuliano Montemurro, Psychiatric team, Gabriele Sani, Delfina Janiri, Alessio Simonetti, G. Giuseppin, M. Molinaro, M. odica, Radiology team, Luigi Natale, Anna Rita Larici, Riccardo Marano, Rheumatology team, Annamaria Paglionico, Luca Petricca, Luca Gigante, G. Natalello, A.L. Fedele, M.M. Lizzio, B. Tolusso, Clara Di Mario, S. Alivernini, Vascular team, Angelo Santoliquido, Luca Santoro, Angela Di Giorgio, Antonio Nesci, V. Popolla, Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function, Clinical Nutrition ESPEN, 2022, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2022.08.029. (Full text)

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).

Materials and methods: In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire-Short Form (DSQ-SF).

Results: The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%-79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.

Conclusion: Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.

Source: Rekeland IG, Sørland K, Bruland O, Risa K, Alme K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. PLoS One. 2022 Sep 19;17(9):e0274472. doi: 10.1371/journal.pone.0274472. PMID: 36121803. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274472 (Full text)

Towards a critical psychology of chronic fatigue syndrome: Biopsychosocial narratives and UK welfare reform

Abstract:

Chronic fatigue syndrome, understood as per (bio) psychosocial discourse, is a political construction, serving actors and structures associated with welfare reform, to the detriment of patients.

The condition typically known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling condition characterised by post-exertional malaise, often accompanied by cognitive impairment, pain, sleep disturbance, gastro-intestinal and autonomic dysfunction (Goudsmit et al., 2009). ME/CFS is positioned as having multifactorial aetiology, including a genetic predisposition, precipitated by viral, bacterial and parasitic infection, toxins and stress, perpetuated through neuro-immune and metabolic dysfunction (Cortes Rivera et al., 2019). The dominant conceptualisation of ME/CFS in UK healthcare, generated through a biopsychosocial model with a cognitivebehavioural focus, is that of a psychosocial entity which, whilst possibly precipitated by a virus or other stressor, is perpetuated by ‘maladaptive’ illness beliefs, fear-avoidance behaviours, and social reinforcement (Sharpe et al., 1997; Deary et al., 2007; Harvey & Wessely, 2009). This conceptualisation has been critiqued for lacking empirical support.

Read the rest of this article HERE.

Source: Hunt, Joanne. Towards a critical psychology of chronic fatigue syndrome: Biopsychosocial narratives and UK welfare reform. Journal of Critical Psychology, Counselling and Psychotherapy, Vol. 22, No. 1, 18-28  https://www.researchgate.net/publication/361017759_Towards_a_critical_psychology_of_chronic_fatigue_syndrome_Biopsychosocial_narratives_and_UK_welfare_reform (Full text)

The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

Abstract:

Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID.

Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities.

Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

Source: Kell DB, Pretorius E. The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochem J. 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154. PMID: 36043493. https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury (Full text)