Tag: 2022

Epipharyngeal Abrasive Therapy Down-regulates the Expression of SARS-CoV-2 Entry Factors ACE2 and TMPRSS2

Abstract:

COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa.
In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment.
Source: Imai K, Yamano T, Nishi S, Nishi R, Nishi T, Tanaka H, Tsunoda T, Yoshimoto S, Tanaka A, Hiromatsu K, Shirasawa S, Nakagawa T, Nishi K. Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment. Viruses. 2022; 14(5):907. https://doi.org/10.3390/v14050907  (Full text)

Hormonal trends in patients suffering from long COVID symptoms

Abstract:

Symptoms of long COVID are complex and long-lasting, and endocrine dysfunction might be involved in the underlying mechanisms. In this study, to clarify the hormonal characteristics of long COVID patients, laboratory data for patients who visited the outpatient clinic for long COVID were evaluated. A retrospective analysis was performed for patients who visited Okayama University Hospital during the period from Feb 2021 to Dec 2021 with focus on the interrelationships between major symptoms and endocrine data.

Information and laboratory data were obtained from medical records for 186 patients. The patients had various symptoms, and the most frequent symptoms were general malaise, dysosmia/dysgeusia, hair loss, headache, dyspnea, and sleeplessness. Patients who were suffering from fatigue and dysosmia/dysgeusia were younger, while hair loss was more frequent in older and female patients.

As for the characteristics of patients suffering from general fatigue, the scores of depression and fatigue were positively correlated with serum levels of cortisol and free thyroxin (FT4), respectively. Also, patients suffering from general fatigue had lower levels of serum growth hormone and higher levels of serum FT4, while patients with dysosmia/dysgeusia had a significantly lower level of serum cortisol. Serum thyrotropin (TSH) levels were higher and the ratios of FT4/TSH were lower in the initially severe cases, suggesting occult hypothyroidism. In addition, the ratios of plasma adrenocorticotropin to serum cortisol were decreased in patients with relatively high titers of serum SARS-CoV-2 antibody. Thus, hormonal changes seem to be, at least in part, involved in the persistent symptoms of long COVID.

Source: Sunada N, Honda H, Nakano Y, Yamamoto K, Tokumasu K, Sakurada Y, Matsuda Y, Hasegawa T, Otsuka Y, Obika M, Hanayama Y, Hagiya H, Ueda K, Kataoka H, Otsuka F. Hormonal trends in patients suffering from long COVID symptoms. Endocr J. 2022 Apr 28. doi: 10.1507/endocrj.EJ22-0093. Epub ahead of print. PMID: 35491089. https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ22-0093/_article (Full text)

Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism

Abstract:

Purpose: Apart from the global disease burden of acute COVID-19 disease, the health complications arising after recovery have been recognized as a long-COVID or post-COVID-19 syndrome. Evidences of long-COVID symptoms involving various organ systems are rapidly growing in literature. The objective was to perform a rapid review and evidence mapping of systemic complications and symptoms of long-COVID and underlying pathophysiological mechanisms.

Methods: Publications reporting clinical trials, observational cohort studies, case-control studies, case-series, meta-analysis, and systematic reviews, focusing on the squeal of the disease, consequences of COVID-19 treatment/hospitalization, long-COVID, chronic COVID syndrome, and post acute COVID-19 were reviewed in detail for the narrative synthesis of frequency, duration, risk factors, and pathophysiology.

Results: The review highlights that pulmonary, neuro-psychological, and cardiovascular complications are major findings in most epidemiological studies. However, dysfunctional gastrointestinal, endocrine, and metabolic health are recent findings for which underlying pathophysiological mechanisms are poorly understood. Analysis of the clinical trial landscape suggests that more than 50% of the industry-sponsored trials are focused on pulmonary symptoms. In contrast to the epidemiological trends and academic trials, cardiovascular complications are not a focus of industry-sponsored trials, suggestive of the gaps in the research efforts.

Conclusion: The gap in epidemiological trends and academic trials, particularly concerning cardiovascular complications not being a focus of industry-sponsored trials is suggestive of the gaps in research efforts and longer follow-up durations would help identify other long-COVID-related health issues such as reproductive health and fertility.

Source: Umesh A, Pranay K, Pandey RC, Gupta MK. Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism. Infection. 2022 Apr 30:1–14. doi: 10.1007/s15010-022-01835-6. Epub ahead of print. PMID: 35489015; PMCID: PMC9055372. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055372/ (Full text)

Long COVID: systemic inflammation and obesity as therapeutic targets

Management of the post-COVID-19 condition—often referred to as long COVID—is a challenge for health-care professionals because of the heterogeneity and complexity of its clinical manifestations and the probable need for multidisciplinary management approaches. Identification and understanding of modifiable determinants associated with manifestations of long COVID would help in the adaptation of treatment pathways for particular phenotypes. In The Lancet Respiratory Medicine, the PHOSP-COVID Collaborative Group report the latest results from the UK-based, multicentre, prospective Post-hospitalisation COVID-19 (PHOSP-COVID) study, in which the investigators identified systemic inflammation and obesity as factors that might be associated with long COVID, representing potentially treatable traits in people with more severe post-COVID-19 symptoms.

In the current report, the PHOSP-COVID Collaborative Group found increased levels of several biomarkers related to systemic inflammation and lung damage in individuals with more severe physical and mental health impairments 1 year after hospital discharge. The presence of increased levels of systemic inflammatory biomarkers (eg, cytokines) in individuals with severe acute COVID-19 has been reported previously. Moreover, the use of anti-inflammatory agents such as corticosteroids or interleukin-6 (IL-6)-blocking agents has been found to be associated with positive outcomes in patients hospitalised with acute COVID-19.

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Source: Florencio LL, Fernández-de-Las-Peñas C. Long COVID: systemic inflammation and obesity as therapeutic targets. Lancet Respir Med. 2022 Apr 22:S2213-2600(22)00159-X. doi: 10.1016/S2213-2600(22)00159-X. Epub ahead of print. PMID: 35472305; PMCID: PMC9034853. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034853/ (Full text)

Cardiac tamponade – an unexpected “long COVID-19” complication

Abstract:

Introduction: Year 2020 has been a cornerstone in medical research due to the COVID-19 pandemic
outbreak. The process of understanding the condition brought to light certain organ involvement like
pulmonary or kidney damage or endocrine disbalances, while connection to other types of organ
impairment remain unclear. SARS-CoV-2 has previously been incriminated in cardiac involvement,
ranging from mild symptoms to more severe occurrences such as myocarditis, arrythmias or heart
failure, thus complicating the acute-phase management and worsening patients’ prognosis. Despite being
reported as an acute manifestation in critical COVID-19, cardiac tamponade seems to also occur as a
“long- COVID19” complication. The latter is a distinct yet unclear entity associated with remanent
fatigue or cough, but more severe sequelae like vasculitis or polyneuropathy can occur.

Case report: We report the case of a 42-year-old patient admitted in the intensive care unit for severe
respiratory and renal dysfunction one month after an initial mild episode of COVID-19. RT-PCR for
SARS-CoV-2 on admission was negative. Initial imaging through CT and heart ultrasound revealed the
presence of pericardial effusion but no signs of tamponade were initially obvious. Twelve hours later, the
patient’s state deteriorated with cardiocirculatory failure and signs of obstructive shock. Agents
responsible for severe acute respiratory infection (SARI) such as influenza A and B, adenovirus,
Bordetella pertussis, Mycoplasma pneumoniae, coxsackie virus, Chlamydia pneumoniae or parainfluenza
viruses were ruled out. Surprisingly, RT-PCR testing for SARS-CoV-2 came back positive, although the
initial test was negative. Repeated imaging confirmed massive circumferential pericardial effusion for
which emergency pericardiocentesis was performed. Fluid was an exudate and histopathology reported
chronic inflammation. RT-PCR testing for Mycoplasma tuberculosis in the pericardial tissue came back
negative.

Conclusions: The case is to our knowledge among the first to report cardiac tamponade one month
after mild COVID-19 infection. The aim of this case report is to raise awareness in the medical
community on the possibility of severe complications targeting major organs in the long-COVID-19
phase.

Source: Cobilinschi, Cristian; Melente, Oana Maria; Bologa, Cristina; Cotae, Ana-Maria; Constantinescu, Laura; et al. Cardiac tamponade – an unexpected “long COVID-19” complication. Germs; Bucharest Vol. 12, Iss. 1, (Mar 2022): 112-117. https://www.proquest.com/openview/4b836e7b0259b3a7fe1c40199f4b9c4c/1?pq-origsite=gscholar&cbl=2032454 (Full text)

Long COVID-19: Psychological symptoms in COVID-19 and probiotics as an adjunct therapy

Abstract:

There is an increase in mental health sequelae following COVID-19 infection, with some studies showing a higher prevalence rate of psychiatric sequelae in post-COVID-19 survivors than in the general population. This review discusses the possible causes, prevalence, and risk factors of COVID-19 associated psychological manifestations, namely anxiety, depression, and post-traumatic stress disorder (PTSD).

Although the exact cause is yet to be determined, it is likely multifactorial involving environmental, biological, and psychological factors due to the pandemic. Variation exists for risk factors and prevalence, but the female gender and psychiatric disorder history seem to be consistent risk factors across several studies. While conventional psychotropic medications are the common therapeutic intervention, probiotics could be a potential adjunct treatment to prevent and treat COVID-19 and its associated psychological manifestations. Their anti-inflammatory effects have been seen directly via reducing plasma concentration of proinflammatory cytokines or indirectly via the suppression within the kynurenine pathway and restoration of gut permeability.

Additionally, short-chain fatty acids (SCFAs) are crucial gut microbial metabolites with essential roles, including signaling along the microbiota-gut-brain (MGB) axis, maintaining blood-brain barrier’s (BBB) integrity, neuronal functions, neurotransmitters, and neurotrophic factors modulation.

Source: Angel Yun, Kuan Thye, Loh Teng, Hern Tan, Jodi Woan, Fei Law, Priyia Pusparajah, Vengadesh Letchumanan. Long COVID-19: Psychological symptoms in COVID-19 and probiotics as an adjunct therapy. Progress in Microbes and Molecular Biology. April 20, 2022. https://journals.hh-publisher.com/index.php/pmmb/article/view/616/340 (Full text)

Persistent COVID-19 symptoms at least one month after diagnosis: A national survey

Abstract:

Background: Post-acute COVID-19 syndrome (PACS) is an important healthcare burden. We examined persistent symptoms in COVID-19 patients at least four weeks after the onset of infection, participants’ return to pre-COVID-19 health status and associated risk factors.

Methods: Cross-sectional study was conducted (December 2020 to January 2021). A validated online questionnaire was sent to randomly selected individuals aged more than 14 years from a total of 1397,386 people confirmed to have COVID-19 at least 4 weeks prior to the start of this survey. This sample was drawn from the Saudi ministry of health COVID-19 testing registry system.

Results: Out of the 9507 COVID-19 patients who responded to the survey, 5946 (62.5%) of them adequately completed it. 2895 patients (48.7%) were aged 35-44 years, 64.4% were males, and 91.5% were Middle Eastern or North African. 79.4% experienced unresolved symptoms for at least 4 weeks after the disease onset. 9.3% were hospitalized with 42.7% visiting healthcare facility after discharge and 14.3% requiring readmission. The rates of main reported persistent symptoms in descending order were fatigue 53.5%, muscle and body ache 38.2%, loss of smell 35.0%, joint pain 30.5%, and loss of taste 29.1%. There was moderate correlation between the number of symptoms at the onset and post-four weeks of COVID-19 infection. Female sex, pre-existing comorbidities, increased number of baseline symptoms, longer hospital-stay, and hospital readmission were predictors of delayed return to baseline health state (p < 0.05).

Conclusion: The symptoms of PACS are prevalent after contracting COVID-19 disease. Several risk factors could predict delayed return to baseline health state.

Source: Tleyjeh IM, Kashour T, Riaz M, Amer SA, AlSwaidan N, Almutairi L, Halwani R, Assiri A. Persistent COVID-19 symptoms at least one month after diagnosis: A national survey. J Infect Public Health. 2022 May;15(5):578-585. doi: 10.1016/j.jiph.2022.04.006. Epub 2022 Apr 20. PMID: 35477145; PMCID: PMC9020835. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020835/ (Full text)

Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.

Research Question: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?

Methods: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.

Results: Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.

Interpretation: Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

Abbreviations List: Ca-vO2 (arterial-venous oxygen content difference), iCPET (Invasive cardiopulmonary exercise test), MAP (Mean arterial pressure), mPAP (Mean pulmonary artery pressure), ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome), PASC (Post-acute sequelae of SARS-CoV-2 infection), PAWP (Pulmonary arterial wedge pressure), POTS (Postural orthostatic tachycardia syndrome), Qc (Cardiac output), RAP (Right atrial pressure), SE (Standard error), SFN (Small fiber neuropathy), VE/VCO2 (Ventilatory efficiency), VO2 (Oxygen uptake)

Source: Phillip Joseph, MD, Rosa Pari, MD, Sarah Miller, BS, Arabella Warren, BS, Mary Catherine Stovall, BS, Johanna Squires, MSc, Chia-Jung Chang, PhD, Wenzhong Xiao, PhD, Aaron B. Waxman, MD, PhD, David M. Systrom, MD. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest, Published: May 05, 2022. DOI: https://doi.org/10.1016/j.chest.2022.04.146

Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial

Rationale: One third of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have evidence of small fiber neuropathy (SFN). Neurovascular dysregulation during upright exercise may be associated with impaired venoconstriction resulting in low biventricular filling pressures and impaired arteriolar constriction resulting in a mismatch between perfusion and skeletal muscle metabolism. We hypothesize that pyridostigmine, a reversible acetylcholinesterase inhibitor, may improve vascular regulation and exercise tolerance in ME/CFS by increasing sympathetic outflow.

Methods: 45 subjects (39 women, 6 men) with ME/CFS were assessed. A baseline invasive cardiopulmonary exercise test (iCPET) was performed to confirm presence of low peak exercise RAP (<6.5mmHg). Eligible subjects were blindly administered placebo (n=22) or 60mg pyridostigmine (n=23) at a 1:1 ratio. A second iCPET was performed following a 50 minute combined rest and dosing period. Serial iCPET results were compared to assess changes in oxygen uptake at peak exercise (VO2 max). Secondary outcomes included subject ventilatory efficiency (VE/VCO2), peak hemodynamic response (RAP, PCWP, SV, Qt), systemic gas exchange (Ca-vO2/Hgb), and subjective reporting of dyspnea and fatigue. Results: 39 subjects (all women) were considered in data analysis. There was a significant increase in VO2 max between iCPET 1 and iCPET 2 in the treatment group when compared with the placebo group (p = 0.043).

There was a significant decrease in the placebo group and a significant increase in the treatment group in VO2 (p = 0.008), Qt (p = 0.039), and RAP (p = 0.045) when comparing iCPET 1 peak – rest and iCPET 2 peak – rest between groups. There were no significant differences in peak arteriovenous oxygen content difference (Ca-vO2/Hgb). 38% of subjects had objective evidence of SFN with no statistically significant difference between groups.

Conclusion: Using pyridostigmine as an investigative tool, this study suggests that neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. Additionally, we have new evidence that worsening vascular dysregulation results from prior exercise, which sheds insight into the post exertional malaise that is a hallmark of this syndrome.

Source: M. Stovall, P. Joseph, R. Pari, A. Warren, S. Miller, J. Squires, W. Xiao, A.B. Waxman, D.M. Systrom. Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial. American Journal of Respiratory and Clinical Care Medicine, Vol 205, p A2063, May 2022. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2063

Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study

Abstract:

The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways.

This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores.

Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID.

In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.

Source: Hussein Kadhem Al-Hakeim, Haneen Tahseen Al-Rubaye, Dhurgham Shihab Al-Hadrawi, Abbas F. Almulla, Michael Maes. Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study. medRxiv 2022.04.25.22274251; doi: https://doi.org/10.1101/2022.04.25.22274251 https://www.medrxiv.org/content/10.1101/2022.04.25.22274251v1.full-text  (Full text)