Long COVID Patient Symptoms and its Evaluation and Management

Abstract:

While the acute case burdens and deaths from the COVID-19 pandemic (in Nepal approaching 700,000 and 10,000 respectively) have been costly, the characteristics and potentially huge dimensions of the chronic disease sequelae of this infectious disease are only slowly becoming apparent. We reviewed Pub Med, major medical meeting and medical journal, and investigative journalist materials seeking to frame and describe COVID-19 chronic disease.

The consequences of COVID-19 infections follow major organ damage, and induction of immunological and hormonal systems dysfunction. The first injuries are consequent to direct viral effects on tissues, and vasculitis, endothelialitis, thrombosis and inflammatory events. Pulmonary, cardiac, brain, and kidney tissues incur function-limiting damage, with dyspnea, arrythmias, decreased exercise capacity, cognitive dysfunction, and decreased glomerular filtration rates.

The second process is characterized by immune dysregulation and autoimmunity, and dysfunction of hormonal regulation systems, with high, fluctuating levels of physical and mental fatigue, multiple-site pain and ache, and non-restorative sleep, in 10-30% of cases.

This communication proposes evaluation and management of chronic COVID-19 patients with efficient assessment of commonest symptoms, targeted physical examination and organ function testing, and interventions based on specific organ functional status, and experience with similar chronic immune syndromes, such as myalgic encephalomyelitis.

Source: Sundar Shrestha D, Love R. Long COVID Patient Symptoms and its Evaluation and Management. JNMA J Nepal Med Assoc. 2021 Aug 12;59(240):823-831. doi: 10.31729/jnma.6355. PMID: 34508486. https://pubmed.ncbi.nlm.nih.gov/34508486/

Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis

Abstract:

Background: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination.

Methods and findings: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination.

Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010).

Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results.

Conclusions: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

Source: Krogsgaard LW, Petersen I, Plana-Ripoll O, Bech BH, Lützen TH, Thomsen RW, Rytter D. Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis. PLoS Med. 2021 Sep 8;18(9):e1003768. doi: 10.1371/journal.pmed.1003768. Epub ahead of print. PMID: 34495975. https://pubmed.ncbi.nlm.nih.gov/34495975/

COVID-19 Symptoms Over Time: Comparing Long-Haulers to ME/CFS

Abstract:

Introduction: Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group. 278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences from an average of 21.7 weeks prior.

Methods: We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.

Results: Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.

Conclusions: These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.

Source: Jason LA, Islam M, Conroy K, Cotler J, Torres C, Johnson M, Mabie B. COVID-19 Symptoms Over Time: Comparing Long-Haulers to ME/CFS. Fatigue. 2021;9(2):59-68. doi: 10.1080/21641846.2021.1922140. Epub 2021 May 5. PMID: 34484973; PMCID: PMC8411893. https://pubmed.ncbi.nlm.nih.gov/34484973/

Report on the 2021 IACFS/ME research and clinical conference

The recently held 3-day virtual conference (8/19–8/21) of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) resembled our in-person meetings in that we offered the full range of meeting events including new research talks, poster sessions, professional workshops (shortened), clinical symposia, and patient/public talks. We also were honored to have a timely keynote speaker, NIH physician-scientist, Dr. Avi Nath, who addressed ME/CFS and Long COVID.

Clearly, the virtual medium has many advantages, particularly convenience and cost, although technical limitations preclude much of the meet-and-greet and networking that are standard at our in-person conferences. We expect our 2022 conference at Stony Brook University to be in-person. Our NIH conference grant will be used to cover the travel costs of new, early stage and/or under-represented investigators in the ME/CFS field. More information on applying for the 2022 travel award will be posted in the fall.

Our final participation figures (378 attendees) were comparable to our in-person conferences. Attendees included 223 Professionals (60%) and 155 Patient/ Public (67% attended all 3 days). Forty-five percent rated the conference as “Excellent” and 81% Excellent or Very Good. About 55% said there was nothing in particular that they disliked. The online format was liked by 71%, and the availability of conference recordings was liked by 77%. Eighty-six percent were interested in future virtual meetings. Most suggestions were scattered among different items like wanting more breaks, longer talks, a list of attendees, improved sound, etc. For some of these suggestions, there are good reasons not to implement them. For example, attendees like their confidentiality and 60% preferred the shorter day with breaks that could be taken anytime with viewing later. An additional 100+ individuals did not attend live and are interested in the conference recording which we expect will be available in early to mid-September. Our membership has now increased to 221.

Read the rest of this article HERE.

Source: Fred Friedberg (2021) Report on the 2021 IACFS/ME research and clinical conference, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1976560

Asthenic disorders as a manifestation of chronic fatigue syndrome

Abstract:

The article explains the changes in terminology and diagnostic criteria for asthenic disorders as manifestations of chronic fatigue syndrome CFS (myalgic encephalomyelitis). Chronic fatigue syndrome is defined as neuroimmune endocrine dysfunction with a purely clinical diagnosis. Probably, viral infections can play a leading role in the pathogenesis. Published diagnostic criteria reveal possible correlations between chronic fatigue syndrome and COVID-19 disease. A promising strategy for the therapy and rehabilitation of patients is the use of smart peptides, a representative of which is the drug cortexin.

Source: Putilina MV. Astenicheskie rasstroistva kak proyavlenie sindroma khronicheskoi ustalosti [Asthenic disorders as a manifestation of chronic fatigue syndrome]. Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(8):125-130. Russian. doi: 10.17116/jnevro2021121081125. PMID: 34481448. [Abstract in English, Russian] https://pubmed.ncbi.nlm.nih.gov/34481448/

Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Long Covid

BURLINGAME, Calif., Sept. 2, 2021 /PRNewswire/ — Cortene Inc. announces publication of its InTiME clinical trial in which a short subcutaneous infusion of its experimental drug, CT38, achieved sustained symptom improvement in ME/CFS. The company intends to test CT38 in Long Covid, the post-acute stage of COVID-19 infection, which is considered by many to be the latest trigger for ME/CFS.

Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS. “The conventional approach would be to block the overactive pathway,” said Sanjay Chanda, PhD, Cortene’s Chief Development Officer. “Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”

CT38 was subcutaneously infused at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. CT38 treatment was safe and generally well-tolerated. It was associated with significant reduction in mean 28-day, total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by 26% (p < 0.01, n = 7).

“Infusing CT38 is known to cause temporary cardiovascular changes and InTiME revealed that patients were significantly more sensitive to these changes than healthy subjects from a previous safety study,” said Hunter Gillies, MD, InTiME’s medical monitor. “These data support there being a pathological hypersensitivity in the CRFR2 pathway. Given that InTiME showed i) dose-dependent improvements in TDSS; and ii) additional infusions provide additional benefit, the next trial should test CT38 using longer or additional infusions. While infusion rates are somewhat limited by tolerability, it is total exposure at low rates that appears to drive symptom improvement.”

“The persistent improvement in symptoms over weeks using a limited exposure is encouraging. Many patients are still showing signs of improvement almost 2 years after treatment,” said Lucinda Bateman, MD, founder and Medical Director of the Bateman Horne Center, scientific advisor to Cortene, and the Principal Investigator of the InTiME study. “In fact, a few patients expressed a desire for ‘just a little bit more drug’.”

Full details of the trial have been peer reviewed and published in Frontiers in Systems Neuroscience, Acute corticotropin-releasing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis / chronic fatigue syndrome. The publication explains how the CRFR2 pathway controls homeostasis (maintaining biological system stability), how this pathway can become disrupted at the neuronal level leading to the individual symptoms of ME/CFS and how these same symptoms manifest in many other chronic diseases. Cortene plans to conduct additional trials in patients with ME/CFS and other diseases with similar symptoms using well-tolerated infusion rates and greater total exposure.

To view the full publication, please visit https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full.

About ME/CFS
ME/CFS is an unexplained, life-long disease, usually triggered by infection, physical/mental trauma, or chemical exposure. Symptoms include diminished physical capacity, pain, sleep issues, cognitive impairment, orthostatic intolerance, among many others, which worsen with innocuous stimulation (referred to as post-exertional malaise) and are not improved by sleep. ME/CFS afflicts 3 million Americans. There are no approved therapeutics and quality of life is worse than in most chronic diseases.

About InTiME
InTiME was a proof-of-concept, single-site, open-label interventional trial, with patients blind as to dose, to investigate the safety and efficacy of CT38 in ME/CFS patients. Efficacy was assessed by a variety of endpoints, including patient-reported daily symptoms scores for each of 13 symptoms, general health (via SF-36), and continuous Fitbit™ monitoring. The primary endpoint was the change in the mean total daily symptom score over the 28-day periods immediately prior to the first treatment (pre-treatment) and immediately prior to exit from the trial (post-treatment).

About CT38
A proprietary peptide agonist, selective/specific for Corticotropin-Releasing Factor Receptor Type 2 (CRFR2).

About Cortene
Cortene Inc. (http://corteneinc.com, @CorteneInc) is a biopharmaceutical startup headquartered in Burlingame, CA, developing therapeutics for treating disorders related to disrupted homeostasis.

Contact: Michael Corbett, CBO, 408-373-7300, mcorbett@corteneinc.com, @CorteneInc on twitter.

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03613129.

Source: Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman. Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Syst. Neurosci., 01 September 2021. https://doi.org/10.3389/fnsys.2021.69824 https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full (Full text)

Chronic Fatigue Syndrome and Cardiovascular Disease: JACC State-of-the-Art Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medically unexplained illness characterized by severe fatigue limiting normal daily activities for at least 6 months accompanied by problems with unrefreshing sleep, exacerbation of symptoms following physical or mental efforts (postexertional malaise [PEM]), and either cognitive reports or physiological evidence of orthostatic intolerance in the form of either orthostatic tachycardia and/or hypocapnia.

Although rarely considered to have cardiac dysfunction, ME/CFS patients frequently have reduced stroke volume with a significant inverse relation between cardiac output and PEM severity. Magnetic resonance imaging of ME/CFS patients compared with normal control subjects found significantly reduced stroke, end-systolic, and end-diastolic volumes together with reduced end-diastolic wall mass. Another cardiovascular abnormality is reduced nocturnal blood pressure assessed by 24-hour monitoring. Autonomic dysfunction is also frequently observed with postural orthostatic tachycardia and/or hypocapnia. Two consecutive cardiopulmonary stress tests may provide metabolic data substantiating PEM.

Source: Natelson BH, Brunjes DL, Mancini D. Chronic Fatigue Syndrome and Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Sep 7;78(10):1056-1067. doi: 10.1016/j.jacc.2021.06.045. PMID: 34474739. https://pubmed.ncbi.nlm.nih.gov/34474739/

Meet The Scientist: A conversation with Professor Chris Ponting

Professor Chris Ponting is Chair of Medical Bioinformatics at Edinburgh University and a Principal Investigator at the MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine. His research group has made substantial contributions to protein science, evolutionary biology, genetics and genomics. He has served on the editorial boards of numerous medical journals including Genome Research, Genome Biology, Human Molecular Genetics, Annual Review of Genomics and Human Genetics and Trends in Genetics. He is a Fellow of the Academy of Medical Sciences and is Principal Investigator for the Decode ME study over the next 4 years.

Professor Ponting took time out from his busy schedule to talk about the Decode ME study that seeks to understand the causes of ME. In turn, this should help with the discovery of effective treatments for ME which are so desperately needed.

The study will be the largest ever biomedical study of ME as it needs 20,000 participants. If you would like to register an interest in participating in the study then please use the link below.

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Read the rest of this interview HERE. 

Source: ME Association. July 29, 2020