The long-COVID-19 in older adults: facts and conjectures

The coronavirus disease-19 (COVID-19) has greatly affected the overall health of the elderly population through direct biological (infection-related) and indirect psychosocial (quarantine- and isolation-related) effects. Because the severe form of COVID-19 most frequently targets this population, the prevalence of long-term sequelae is expected to rise consequentially in people ≥ 65 years old. The prominent neuropsychiatric consequences of COVID-19 and the cognitive frailty seen in older adults can both have a negative impact on their mental health.

To explore the behavioral, neurological, and psychosocial consequences of COVID-19, we conducted separate studies on different populations of older adult people residing in Lombardy – the Italian epicenter of the first pandemic wave in spring 2020. In one study, we found that behavioral changes (i.e., delirium) were a frequent symptom of COVID-19, manifesting at disease onset and preceding the typical symptoms in about 1/3 (36.8%) of cases, particularly in patients with neurocognitive disorders (NCD), such as dementia (major-NCD) or mild cognitive impairment (mild-NCD). Delirium was also associated with short-term mortality and potential long-term cognitive sequelae (Poloni et al., 2020).

To uncover the neuropathology underlying behavioral changes and their possible effects over time, we compared 9 brains of elderly patients who had died of COVID-19 (with and without dementia) with 6 brains from age-matched non-COVID controls. The main finding was an excessive innate immune response, represented by microglial hyperactivation. Although we observed severe inflammatory changes especially in the brainstem, we did not find neuropathological evidence suggestive of SARS-CoV-2 replication in the brain (Gagliardi et al., 2021; Poloni et al., 2021).

In a study evaluating the psychosocial consequences of the lockdown due to the pandemic (Carlos et al., 2021), we observed that those with mild-moderate dementia were unable to cope and adapt to the life changes caused by the restrictions and consequently suffered from depression and cognitive decline. Before COVID, patients with dementia normally engaged in habitual daily activities. The disruption of said routines, the inability to engage in new activities, and the incapability to use modern technologies all triggered psychological distress and some degree of cognitive and motor regression (Figure 1A). Although lockdown (the sternest form of quarantine in history) protected them from COVID-19, the social seclusion and the inability to access primary care treatment – aggravated by an unprepared and unequipped primary care health sector – caused further complications (Carlos et al., 2021). Moreover, the general effects of the pandemic in terms of loss of “individual freedom”, economic crisis, and mass media conditioning should not be overlooked due to their possible impact on mental health.

Source: Poloni, Tino Emanuele; Medici, Valentina; Zito, Antonio; Carlos, Arenn Faye The long-COVID-19 in older adults, Neural Regeneration Research: December 2022 – Volume 17 – Issue 12 – p 2679-2681 doi: 10.4103/1673-5374.339483 https://journals.lww.com/nrronline/Fulltext/2022/12000/The_long_COVID_19_in_older_adults__facts_and.27.aspx (Full text)

Development of a Mouse Model for Chronic Fatigue Syndrome

Abstract:

The purpose of this study was to develop a clinically relevant mouse model of CFS to allow for the testing of underlying mechanisms and development of novel treatment interventions.

Mice were injected with either lipopolysaccharide (LPS) or Poly I:C systemically (0.1- 1.0 mg/kg LPS, i.p. or 0.6-6mg/kg Poly I:C) and compared to a vehicle control injection.

To test for fatigue-like behaviors, we examined voluntary wheel running (VWR) and open field activity.

To test for pain-like behaviors, muscle withdrawal thresholds (MWT) and mechanical sensitivity of the paw.

Measurements were assessed before and up to 1 week after injection of LPS or Poly I:C.

Differences in voluntary running wheel data were assessed using mixed model analysis for differences between dose, time and an interaction between dose and time.

Differences in open field parameters, MWT, and paw sensitivity between groups were assessed using repeated measures ANOVAs.

Running wheel activity was reduced after injection of either LPS or Poly I:C (χ2=15.4; p=0.003).

LPS reduced running wheel activity on days 1-3 for the 1.0 mg/kg dose of LPS and on Day 1 for Poly I:C when compared to vehicle (p<0.001).

Lower doses of LPS showed faster recovery to baseline.

For the open field testing, LPS reduced in distance travelled (F=9.1; p<0.001), increase in time standing still (F=6.5, p=0.001) but not time in center (F= 1.1, p=0.36) 24h after infection.

Post-hoc testing (Tukey’s test) showed a significant difference between the vehicle and the 1.0 mg/kg group of LPS (p=0.001).

Similar reductions were observed for the 6 mg/kg group of Poly I:C (p<0.001). For pain behaviors, there was no difference between groups in the MWT or paw sensitivity (p>0.05) for either LPS or Poly I:C.

These results show that a single injection of an infectious agent reduces physical activity and exploratory behavior, but does not produce pain behaviors.

Source: Adam Janowski, Joseph Lesnak, Ashley Plumb, Lynn Rasmussen, Kathleen Sluka. Development of a Mouse Model for Chronic Fatigue Syndrome. The Journal of Pain 23 (5): 12. https://www.sciencedirect.com/science/article/abs/pii/S152659002200092X

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers.

The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network.

We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which were established in CFAS-D patients.

PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks.

MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA.

The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease.

Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus.

In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

Source: Michael Maes, Marta Kubera and Magdalena Kotańska. Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Frontiers in Psychiatry 13: 822382. https://www.frontiersin.org/articles/10.3389/fpsyt.2022.822382/full  (Full text)

Breast Implant-Associated Immunological Disorders

Abstract:

Background: Breast implants are commonly placed postbreast cancer reconstruction, cosmetic augmentation, and gender-affirming surgery. Breast implant illness (BII) is a systemic complication associated with breast implants. Patients with BII may experience autoimmune symptoms including fatigue, difficulty concentrating, hair loss, weight change, and depression. BII is poorly understood, and the etiology is unknown. The purpose of this literature review is to characterize BII autoimmune disorders and determine possible causes for its etiology.

Methods: The PubMed, Google Scholar, Embase, Web of Science, and OVID databases were interrogated from 2010 to 2020 using a query strategy including search term combinations of “implants,” “breast implant illness,” “autoimmune,” and “systemic illness.”

Results: BII includes a spectrum of autoimmune symptoms such as fatigue, myalgias/arthralgias, dry eyes/mouth, and rash. A review of epidemiological studies in the past ten years exhibited evidence affirming an association between breast implants and autoimmune diseases. The most commonly recognized were Sjogren’s syndrome, rheumatoid arthritis, systemic sclerosis, chronic fatigue syndrome, and Raynaud’s syndrome. Explantation resulted in alleviation of symptoms in over 50% of patients, strengthening the hypothesis linking breast implants to BII. Studies have shown that silicone is a biologically inert material and unlikely to be the cause of these symptoms. This is supported by the fact that increased risk of autoimmune disease was also reported in patients with other implantable biomaterials such as orthopedic implants. Recent studies shed light on a possible role of bacterial biofilm and subsequent host-pathogen interactions as a confounding factor to this problem.

Conclusion: BII could be dependent on biofilm infection and the microenvironment around the implants. The true pathophysiology behind these complaints must be further investigated so that alternative treatment regimens other than explantation can be developed. Translational significance of these studies is not limited to breast implants but extends to other implants as well.

Source: Suh LJ, Khan I, Kelley-Patteson C, Mohan G, Hassanein AH, Sinha M. Breast Implant-Associated Immunological Disorders. J Immunol Res. 2022 May 4;2022:8536149. doi: 10.1155/2022/8536149. PMID: 35571560; PMCID: PMC9095406. https://pubmed.ncbi.nlm.nih.gov/35571560/

Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: Studies have demonstrated immune dysfunction in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, evidence is varied. The current study used network analysis to examine relationships between cytokines among a sample of pediatric participants with ME/CFS.

Methods: 10,119 youth aged 5-17 in the Chicagoland area were screened for ME/CFS; 111 subjects and controls were brought in for a physician examination and completed a blood draw. Youth were classified as controls (Cs, N = 43), ME/CFS (N = 23) or severe (S-ME/CFS, N = 45). Patterns of plasma cytokine networks were analyzed.

Results: All participant groups displayed a primary network of interconnected cytokines. In the ME/CFS group, inflammatory cytokines IL-12p70, IL-17A, and IFN-γ were connected and included in the primary membership, suggesting activation of inflammatory mechanisms. The S-ME/CFS group demonstrated a strong relationship between IL-17A and IL-23, a connection associated with chronic inflammation. The relationships of IL-6 and IL-8 in ME/CFS and S-ME/CFS participants also differed from Cs. Together, these results indicate pro-inflammatory responses in our illness populations.

Discussion: Our data imply biological differences between our three participant groups, with ME/CFS and S-ME/CFS participants demonstrating an inflammatory profile. Examining co-expression of cytokines may aid in the identification of a biomarker for pediatric ME/CFS.

Source: Jason LA, Gaglio CL, Furst J, Islam M, Sorenson M, Conroy KE, Katz BZ. Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chronic Illn. 2022 May 16:17423953221101606. doi: 10.1177/17423953221101606. Epub ahead of print. PMID: 35570777.  https://pubmed.ncbi.nlm.nih.gov/35570777/

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.

Read the rest of this article HERE.

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)