Grief in Chronic Illness: A Case Study of CFS/ME

Abstract:

This paper points to a more expansive conception of grief by arguing that the losses of illness can be genuine objects of grief.

I argue for this by illuminating underappreciated structural features of typical grief — that is, grief over a bereavement — which are shared but under-recognized. I offer a common chronic illness, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), as a striking case study.

I then use this analysis to highlight some clinical challenges that arise should this claim receive uptake in clinical practice.

Extant literature on CFS/ME tells us that rates of comorbid depression are atypically high. If one accepts that people with CFS/ ME can grieve over losses associated with the condition, and that grief can be easily mistaken for depression in this context, this might suggest that rates of comorbid depression are inflated.

I show, however, that the challenge of distinguishing between healthy and pathological grief arises in its place, and is just as tricky to solve.

Source: Byrne, Eleanor Alexandra. Grief in Chronic Illness: A Case Study of CFS/ME. Journal of Consciousness Studies, Volume 29, Numbers 9-10, September 2022, pp. 175-200(26). https://www.ingentaconnect.com/contentone/imp/jcs/2022/00000029/f0020009/art00009

Symptomatology and microbiology of the gastrointestinal tract in post-COVID conditions

Abstract:

Post-COVID conditions, also known as post-acute sequelae of SARS-CoV-2 (PASC), refer to the persistence of symptoms in COVID-19 long-haulers. Various manifestations of post-COVID conditions are general symptoms and/or manifestations of damage in multiple organs. Besides, SARS-CoV-2 can involve the gastrointestinal tract, resulting in sequelae such as diarrhea, abdominal pain, nausea, anorexia, vomiting, constipation, abdominal distension, acid reflux, and/or gastrointestinal bleeding.
Previous investigations point to SARS-CoV-2 entry into enterocytes enhances by the angiotensin-converting enzyme 2 (ACE2) receptors. Interestingly, ACE2 receptors are abundantly expressed in the gut, implying infection with SARS-CoV-2 might occur through this route as well as in the respiratory tract. According to mounting evidence, SARS-CoV-2 RNA has been identified in fecal specimens of patients with COVID-19 during and beyond the acute phase.
In addition, studies have shown gut microbiome composition is altered in patients with PASC, hence, another putative mechanism linked to gastrointestinal symptoms is gut dysbiosis. The presence of the gut-lung axis in COVID-19 might have major implications for disease pathogenesis and treatment.
This review discussed the prevalence of gastrointestinal symptoms and pathophysiology underlying possible infection of the gut in patients with PASC. Also, SARS-COV-2 induced NLRP3 inflammasome-dependent inflammatory pathways are briefly addressed.
Source: Norouzi Masir M, Shirvaliloo M. Symptomatology and microbiology of the gastrointestinal tract in post-COVID conditions. JGH Open : an Open Access Journal of Gastroenterology and Hepatology. 2022 Aug. DOI: 10.1002/jgh3.12811. PMID: 36247234; PMCID: PMC9538198. https://europepmc.org/article/pmc/pmc9538198 (Full text)

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Source: Apostolou Eirini, Rizwan Muhammad, Moustardas Petros, Sjögren Per, Bertilson Bo Christer, Bragée Björn, Polo Olli, Rosén Anders. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Vol 13, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.949787/full (Full text)

Even mild COVID-19 may have long-term brain impacts

Research presented at the Alzheimer’s Association International Conference suggests even mild cases of COVID-19 may be associated with cognitive deficits months after recovery.

One Argentinian study of 234 seniors who previously had COVID-19 found that more than half showed some degree of cognitive impairment months later. One in three had severe “dementia-like” impairments in memory, attention and executive function — a much higher proportion than the 5%–8% of seniors in the general population who have dementia at a given time.

“This could be the start of a dementia-related epidemic fueled by this latest coronavirus,” stated presenting author Dr. Gabriel de Erausquin of the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio. Researchers will follow the study participants over the next three to five years to see if these problems resolve or worsen.

The study didn’t look at participants’ cognitive performance prior to infection. However, those who lost their sense of smell while sick with COVID-19 tended to have more severe cognitive impairments months later, even if their other symptoms had been mild. According to de Erausquin, “once the virus has affected the olfactory bulb and caused effects there — changes that we can see with imaging — then other places in the brain that are connected to it also become abnormal, either in function or structure or both.”

Other research presented linked SARS-CoV-2 infection with an uptick in biomarkers of brain injury, neuroinflammation and Alzheimer disease. One American study of 310 patients with COVID-19 found that those with new neurological symptoms had higher levels of t-tau, NfL, GFAP, pTau-181, and UCH-L1 in their blood, as well as indicators of inflammation such as C-reactive protein, compared to patients without neurological symptoms. “These findings suggest patients who had COVID-19 may have an acceleration of Alzheimer-related symptoms and pathology,” according to presenting author Dr. Thomas Wisniewski of the New York University Grossman School of Medicine.

Earlier this year, de Erausquin and others reported that brain inflammation, stroke and other common complications of viral infections have longstanding links with neurodegenerative disorders. “Therefore, it seems likely to expect that COVID-19-related cardiovascular and cerebrovascular disease will also contribute to a higher longterm risk of cognitive decline and dementia in recovered individuals.”

Several recent studies have documented cognitive deficits post-COVID but like the research presented at the Alzheimer’s Association conference, data on patients’ performance before infection are lacking.

One British study of 81 337 people in EClinicalMedicine found that those who previously had COVID-19 tended to score lower on measures of intelligence, reasoning, problem-solving and planning than people who were never infected.

“These results accord with reports of long-COVID, where ‘brain fog,’ trouble concentrating and difficulty finding the correct words are common,” according to the authors. People who had been hospitalized and put on ventilators had the greatest impairments, but even those who had relatively mild symptoms showed some deficit.

In another study of 57 Americans receiving inpatient rehabilitation after hospitalization for COVID-19, four in five had mild to severe cognitive impairments. More than half had deficits in working memory, while two in five had impaired processing speed, divided attention, and trouble switching between mental tasks.

Similar deficits have also been noted in patients after recovery from other coronaviruses. A 2020 systematic review and meta-analysis found that delirium was common in the acute stage of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Following up with patients six weeks to 39 months later, more than 15% reported sleep disorders, mood swings, trouble concentrating, impaired memory and other mental challenges.

Based on this growing body of evidence, British researchers warned in March that health systems will likely see an “influx of patients with psychiatric and cognitive problems who were otherwise healthy prior to COVID-19.” They urged doctors to consider detailed cognitive evaluations for anyone reporting new neurological symptoms after infection with SARS-CoV-2.

In the meantime, the Alzheimer’s Association has formed an international consortium to study the long-term effects of COVID-19 on the brain.

“These new data point to disturbing trends showing COVID-19 infections leading to lasting cognitive impairment and even Alzheimer’s symptoms,” stated Heather Snyder of the Alzheimer’s Association. “It is imperative that we continue to study what this virus is doing to our bodies and brains.”

Source: Duong D. Even mild COVID-19 may have long-term brain impacts. CMAJ. 2021 Aug 30;193(34):E1360-E1361. doi: 10.1503/cmaj.1095958. PMID: 34462298; PMCID: PMC8432319.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432319/ (Full text)

Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating multisystem condition with poor prognosis. Studies that examined predictors of ME/CFS outcomes yielded contradictory results. We aimed to explore epidemiological and clinical prognostic factors of ME/CFS using operationalized criteria for recovery/improvement.
Adult ME/CFS patients who attended the Internal Medicine Department of Angers University Hospital, Angers, France between October 2011 and December 2019, and were followed up until December 2020, were included retrospectively. Their medical records were reviewed for data collection. Patients were classified into two groups according to the presence or absence of recovery/improvement (R/I) and compared for epidemiological characteristics, fatigue features, post-exertional malaise severity, clinical manifestations, and comorbidities.
The subgroups of recovered and significantly improved patients were then compared. 168 patients were included. Recovery and improvement rates were 8.3% and 4.8%, respectively. Older age at disease onset was associated with R/I (OR 1.06 [95% CI 1.007–1.110] (p = 0.028)), while diagnostic delay was inversely associated with R/I (OR 0.98 [95% CI 0.964–0.996] (p = 0.036)). The study findings confirmed the poor prognosis of ME/CFS and the deleterious effect of diagnostic delay on disease progression. Interestingly, being older at disease onset was associated with better outcomes, which offers hope to patients for recovery/improvement even at an advanced age.
Source: Ghali A, Lacout C, Fortrat J-O, Depres K, Ghali M, Lavigne C. Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics. 2022; 12(10):2540. https://doi.org/10.3390/diagnostics12102540  https://www.mdpi.com/2075-4418/12/10/2540 (Full text available as PDF file)

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

Abstract:

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury.

Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients.

The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

Source: Xu, Sw., Ilyas, I. & Weng, Jp. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00998-0 https://www.nature.com/articles/s41401-022-00998-0 (Full text)

New‑onset neuropsychiatric sequelae and ‘long‑COVID’ syndrome (Review)

Abstract:

The ongoing coronavirus disease 2019 (COVID‑19) pandemic has had a widespread impact on individuals’ mental health through indirect psychological and social mechanisms, related to factors such as fear of infection or death, social isolation, lack of social support and financial instability.
The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection has also been associated with the development or recurrence of neuropsychiatric symptoms, both during the acute phase, as well as during the post‑acute ‘long‑COVID’ phase. In addition to the COVID‑19 survivors with a mental health history that are at a high risk of experiencing a range of neuropsychiatric symptoms following resolution of acute COVID‑19, there is accumulating evidence that a diagnosis of COVID‑19 may also be associated with new‑onset neuropsychiatric morbidity among survivors without pre‑existing mental health disorders.
In particular, studies investigating the incidence of post‑acute neuropsychiatric sequelae, based mostly on retrospective cohort study designs and data from national health registries, have reported the development of new‑onset manifestations, including depression, anxiety, psychotic symptoms, sleep disturbances and fatigue. Nevertheless, when COVID‑19 survivors were compared with SARS‑CoV‑2‑negative controls and especially survivors of other disorders (such as influenza), the findings regarding the risk of incident neuropsychiatric manifestations varied among studies.
While there is evidence of an association between SARS‑CoV‑2 infection and the subsequent occurrence of new‑onset neuropsychiatric symptoms, especially among patients with increased disease severity, further research using methodological approaches less susceptible to confounding bias is required to establish causal relationships.
Source: Efstathiou, V., Stefanou, M., Demetriou, M., Siafakas, N., Katsantoni, E., Makris, M., Tsivgoulis, G., Zoumpourlis, V., Kympouropoulos, S. P., Tsoporis, J. N., Spandidos, D. A., Ferentinos, P., Smyrnis, N., Rizos, E.”New‑onset neuropsychiatric sequelae and ‘long‑COVID’ syndrome (Review)”. Experimental and Therapeutic Medicine 24.5 (2022): 705. https://www.spandidos-publications.com/10.3892/etm.2022.11641 (Full text available as PDF file)

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

Abstract:

Background: Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients.

Methods: A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D.

Results: Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05).

Conclusions: Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.

Source: Patel, M.A., Knauer, M.J., Nicholson, M. et al. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol Med 28, 122 (2022). https://doi.org/10.1186/s10020-022-00548-8 https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00548-8 (Full text)

Increased levels of inflammatory molecules in blood of Long COVID patients point to thrombotic endotheliitis

Abstract:

The prevailing hypotheses for the persistent symptoms of Long COVID have been narrowed down to immune dysregulation and autoantibodies, widespread organ damage, viral persistence, and fibrinaloid microclots (entrapping numerous inflammatory molecules) together with platelet hyperactivation. Here we demonstrate significantly increased concentrations of Von Willebrand Factor, platelet factor 4, serum amyloid A, alpha-2-antiplasmin E-selectin, and platelet endothelial cell adhesion molecule-1, in the soluble part of the blood.

It was noteworthy that the mean level of alpha-2-antiplasmin exceeded the upper limit of the laboratory reference range in Long COVID patients, and the other 5 were significantly elevated in Long COVID patients as compared to the controls. This is alarming if we take into consideration that a significant amount of the total burden of these inflammatory molecules has previously been shown to be entrapped inside fibrinolysis-resistant microclots (thus decreasing the apparent level of the soluble molecules). We also determined that by individually adding E-selectin and PECAM-1 to healthy blood, these molecules may indeed be involved in protein-protein interactions with plasma proteins (contributing to microclot formation) and platelet hyperactivation. This investigation was performed as a laboratory model investigation and the final exposure concentration of these molecules was chosen to mimic concentrations found in Long COVID.

We conclude that presence of microclotting, together with relatively high levels of six inflammatory molecules known to be key drivers of endothelial and clotting pathology, points to thrombotic endotheliitis as a key pathological process in Long COVID. This has implications for the choice of appropriate therapeutic options in Long COVID.

Source: Simone Turner, Caitlin Naidoo, Thomas Usher, Arneaux Kruger, Chantelle Venter, Gert J Laubscher, M Asad Khan, Douglas B Kell, Etheresia Pretorius. Increased levels of inflammatory molecules in blood of Long COVID patients point to thrombotic endotheliitis. medRxiv 2022.10.13.22281055; doi: https://doi.org/10.1101/2022.10.13.22281055 (Full text available as PDF file)

New symptoms and prevalence of postacute COVID-19 syndrome among nonhospitalized COVID-19 survivors

Abstract:

The aim of this study was to assess postacute coronavirus disease 2019 (COVID-19) syndrome (PACS) symptoms according to the onset of the infection while evaluating the effect of COVID-19 vaccination on the symptoms of PACS. We conducted a retrospective single-center cohort study in which nonhospitalized COVID-19 survivors and healthy controls were compared for the occurrence of PACS.

The total number of patients in this study was 472. At 6–12 and > 12 months after the infection, COVID-19 survivors had a significantly higher incidence of posttraumatic stress disorder (PTSD) and anxiety than the non-COVID-19 cohort. Furthermore, depression, cognitive deficit, tics, impaired quality of life and general health impairment were significantly more prevalent among COVID-19 survivors at < 6 months, 6–12 months and > 12 months than in the non-COVID-19 cohort. However, respiratory symptoms were significantly more prevalent among COVID-19 survivors only in the first 6 months after infection.

In addition, cognitive deficit (OR = 0.15; 95% CI 0.03–0.87) and impaired quality of life (B = − 2.11; 95% CI − 4.21 to − 0.20) were significantly less prevalent among vaccinated COVID-19 survivors than among nonvaccinated survivors.

Longitudinal studies are needed to establish the time that should elapse after COVID-19 infection for the symptoms of PACS to appear. Randomized clinical trials are needed to assess the possibility that COVID-19 vaccines might relieve PACS symptoms.

Source: Albtoosh, A.S., Toubasi, A.A., Al Oweidat, K. et al. New symptoms and prevalence of postacute COVID-19 syndrome among nonhospitalized COVID-19 survivors. Sci Rep 12, 16921 (2022). https://doi.org/10.1038/s41598-022-21289-y  (Full text)