Category: Overlapping Illnesses

Creative Long Covid: A qualitative exploration of the experience of Long Covid through the medium of creative narratives

Abstract:

Background: Healthcare is witnessing a new disease with the emergence of Long Covid; a condition which can result in myriad symptoms, varying in frequency and severity. As new data are emerging to help inform treatment guidelines, the perspectives of those living with Long Covid are essential in informing healthcare practice. The research aimed to collect the narratives of people living with Long Covid to better understand the lived experience of this condition. In attempting to narrate complex or traumatic experiences the arts and humanities can offer alternative ways of expressing embodied narratives, representing rich sources of meaning. Therefore, the research specifically sought to elicit creative expressions from participants with lived experience of Long Covid.

Methods: Data were collected via an online repository where participants could submit their pieces of creative writing. Data were collected between August 2021 and January 2022 and a total of 28 submissions were received from participants. These were mostly written creative narratives. However, a small number were submitted as audio or video files of spoken word poetry or songs. Data collection was stopped once data saturation was achieved.

Results: The submissions were subjected to thematic analysis and five themes were generated. These five themes are Identity, social relationships, symptoms, interaction with healthcare systems and time. The results provide an insight into the experience of Long Covid as detailed by the participants’ creative narratives.

Conclusion: The results from this study provide a unique insight into the lived experience of Long Covid. In relation to clinical practice, the results suggest that adjustment reaction and loss of sense of self could be added as common symptoms.

Patient and public contribution: Before undertaking the research, Long Covid community groups were contacted to discuss the potential value of this study and it was widely supported. One of the leading Long Covid support groups was also involved in disseminating information regarding the project. As part of ongoing work within this project, members of the team are actively disseminating the results within Long Covid communities and seeking to develop arts-based workshops specifically for people with Long Covid.

Source: Pearson M, Singh P, Bartel H, Crawford P, Allsopp G. Creative Long Covid: A qualitative exploration of the experience of Long Covid through the medium of creative narratives. Health Expect. 2022 Sep 23. doi: 10.1111/hex.13602. Epub ahead of print. PMID: 36148648.  https://onlinelibrary.wiley.com/doi/10.1111/hex.13602 (Full text)

Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review

Abstract:

Long COVID is an emergent, heterogeneous, and multisystemic condition with an increasingly important impact also on the pediatric population. Among long COVID symptoms, patients can experience chronic gastrointestinal symptoms such as abdominal pain, constipation, diarrhea, vomiting, nausea, and dysphagia.
Although there is no standard, agreed, and optimal diagnostic approach or treatment of long COVID in children, recently compounds containing multiple micronutrients and lactoferrin have been proposed as a possible treatment strategy, due to the long-standing experience gained from other gastrointestinal conditions. In particular, lactoferrin is a pleiotropic glycoprotein with antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory activities. Moreover, it seems to have several physiological functions to protect the gastrointestinal tract.
In this regard, we described the resolution of symptoms after the start of therapy with high doses of oral lactoferrin in two patients referred to our post-COVID pediatric unit due to chronic gastrointestinal symptoms after SARS-CoV-2 infection.
Source: Morello R, De Rose C, Cardinali S, Valentini P, Buonsenso D. Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review. Children. 2022; 9(10):1446. https://doi.org/10.3390/children9101446 (Full text)

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR).

In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups.

We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients.

Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Source: Franziska Sotzny, Igor Salerno Filgueiras, Claudia Kedor, Helma Freitag, Kirsten Wittke, Sandra Bauer, Nuno Sepúlveda, Dennyson Leandro Mathias da Fonseca, Gabriela Crispim Baiocchi, Alexandre H. C. Marques, Myungjin Kim, Tanja Lange, Desirée Rodrigues Plaça, Finn Luebber, Frieder M. Paulus, Roberta De Vito, Igor Jurisica, Kai Schulze-Forster, Friedemann Paul, Judith Bellmann-Strobl, Rebekka Rust, Uta Hoppmann, Yehuda Shoenfeld, Gabriela Riemekasten, Harald Heidecke, Otavio Cabral-Marques, Carmen Scheibenbogen. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Front. Immunol., 27 September 2022
Sec. Autoimmune and Autoinflammatory Disorders https://doi.org/10.3389/fimmu.2022.981532 (Full text)

Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19

Abstract:

Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets.

To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC.

A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.

Source: Jonathan D. Herman, Caroline Atyeo, Yonatan Zur, Claire E. Cook, Naomi J. Patel, Kathleen M. Vanni, Emily N. Kowalski, Grace Qian, Nancy A. Shadick, Douglas Laffenburger, Zachary S. Wallace, Jeffrey A. Sparks, Galit Alter. Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19. medRxiv 2022.09.25.22280335; doi: https://doi.org/10.1101/2022.09.25.22280335 https://www.medrxiv.org/content/10.1101/2022.09.25.22280335v1.full-text (Full text)

Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study

Abstract:

Background: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households.

Methods: 1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires.

Findings: The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% [95% CI: 30.7-42.4%] vs 14.2% [95% CI: 8.7-21.5%]), infected men (22.9% [95% CI: 17.9-28.5%] vs 10.3% [95% CI: 5.8-16.9%]) and infected adolescent girls (32.1% 95% CI: 17.2-50.5%] vs 8.9% [95%CI: 3.1-19.8%]). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14-18 (9.7% [95% CI: 2.8-23.6%] or in infected children <14 years (girls: 4.3% [95% CI: 1.2-11.0%]; boys: 3.7% [95% CI: 1.1-9.6%]) than in their exposed counterparts (adolescent boys: 0.0% [95% CI: 0.0-6.7%]; girls < 14 years: 2.3% [95% CI: 0·7-6·1%]; boys < 14 years: 0.0% [95% CI: 0.0-2.0%]). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI [1.03-1.20]).

Interpretation: In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful.

Funding: Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.

Source: Haddad A, Janda A, Renk H, Stich M, Frieh P, Kaier K, Lohrmann F, Nieters A, Willems A, Huzly D, Dulovic A, Schneiderhan-Marra N, Jacobsen EM, Fabricius D, Zernickel M, Stamminger T, Bode SFN, Himpel T, Remppis J, Engel C, Peter A, Ganzenmueller T, Hoffmann GF, Haase B, Kräusslich HG, Müller B, Franz AR, Debatin KM, Tönshoff B, Henneke P, Elling R. Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study. EBioMedicine. 2022 Sep 22;84:104245. doi: 10.1016/j.ebiom.2022.104245. Epub ahead of print. PMID: 36155957; PMCID: PMC9495281. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495281/ (Full text)

Tunneling nanotubes provide a route for SARS-CoV-2 spreading

Abstract:

Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represent a major issue in long coronavirus disease. How SARS-CoV-2 gains access to the brain and how infection leads to neurological symptoms are not clear because the principal means of viral entry by endocytosis, the angiotensin-converting enzyme 2 receptor, are barely detectable in the brain.

We report that human neuronal cells, nonpermissive to infection through the endocytic pathway, can be infected when cocultured with permissive infected epithelial cells. SARS-CoV-2 induces the formation of tunneling nanotubes (TNTs) and exploits this route to spread to uninfected cells. In cellulo correlative fluorescence and cryo-electron tomography reveal that SARS-CoV-2 is associated with TNTs between permissive cells. Furthermore, multiple vesicular structures such as double-membrane vesicles, sites of viral replication, are observed inside TNTs between permissive and nonpermissive cells.

Our data highlight a previously unknown mechanism of SARS-CoV-2 spreading, likely used as a route to invade nonpermissive cells and potentiate infection in permissive cells.

Source: Pepe A, Pietropaoli S, Vos M, Barba-Spaeth G, Zurzolo C. Tunneling nanotubes provide a route for SARS-CoV-2 spreading. Sci Adv. 2022 Jul 22;8(29):eabo0171. doi: 10.1126/sciadv.abo0171. Epub 2022 Jul 20. PMID: 35857849; PMCID: PMC9299553.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299553/ (Full text)

Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

Abstract:

While significant attention has been paid to the immunologic determinants of disease states associated with COVID-19, their contributions to post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, it is critical to understand if specific features of the disease are associated with discrete immune processes, and whether those processes may be therapeutically targeted. To this end, we performed wide immunologic and serological characterization of patients in the early recovery phase of COVID-19 across a breadth of symptomatic presentations.

Using high-parameter proteomics screening and applied machine learning (ML), we identify clear signatures of immunologic activity between PASC patients and uncomplicated recovery, dominated by inflammatory cytokine signaling, neutrophil activity, and markers of cell death. Consistent with disease complexity, heterogeneity in plasma profiling reveals distinct PASC subsets with striking divergence in these ongoing inflammatory processes, here termed plasma quiescent (plaq) and inflammatory (infl) PASC.

In addition to elevated inflammatory blood proteomics, inflPASC patients display positive clinical tests of acute inflammation including C-reactive protein and fibrinogen, increased B cell activity with extrafollicular involvement coupled with elevated targeting of viral nucleocapsid protein and clinical autoreactivity. Further, the unique plasma signatures of PASC patients allowed for the creation of refined models with high sensitivity and specificity for the positive identification of inflPASC with a streamlined assessment of 12 blood markers. Additionally, refined ML modeling highlights the unexpected significance of several markers of potential diagnostic or therapeutic use for PASC in general, including the peptide hormone, epiregulin.

In all, this work identifies clear biological signatures of PASC with potential diagnostic and therapeutic potential and establishes clear disease subtypes that are both easily identifiable and highly relevant to ongoing efforts in both therapeutic targeting and epidemiological investigation of this highly complex disease.

Source: Matthew Woodruff, Kevin S Bonham, Fabliha A Anam, Tiffany Walker, Yusho Ishii, Candice Y Kaminski, Martin Runnstrom, Alexander Truong, Adviteeya Dixit, Jenny Han, Richard Ramonell, Natalie S. Haddad, Mark Rudoloph, Arezou Khosroshahi, Scott A Jenks, F. Eun-Hyung Lee, Ignacio Sanz. Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID. medRxiv 2021.09.21.21263845; doi: https://doi.org/10.1101/2021.09.21.21263845.  (Full text available as PDF file)

Effects of SARS-CoV-2 Infection on Attention, Memory, and Sensorimotor Performance

Abstract:

Background: Recovery after SARS-CoV-2 infection is extremely variable, with some individuals recovering quickly, and others experiencing persistent long-term symptoms or developing new symptoms after the acute phase of infection, including fatigue, poor concentration, impaired attention, or memory deficits. Many existing studies reporting cognitive deficits associated with SARS-CoV-2 infection are limited by the exclusive use of self-reported measures or a lack of adequate comparison groups.

Methods: Forty-five participants, ages 18-70, (11 Long-COVID, 14 COVID, and 20 No-COVID) underwent behavioral testing with the NIH Toolbox Neuro-Quality of Life survey and selected psychometric tests, including a flanker interference task and the d2 Test of Attention.

Results: We found greater self-reported anxiety, apathy, fatigue, emotional dyscontrol, sleep disturbance and cognitive dysfunction in COVID compared No-COVID groups. After categorizing COVID patients according to self-reported concentration problems, we observed declining performance patterns in multiple attention measures across No-COVID controls, COVID and Long-COVID groups. COVID participants, compared to No-COVID controls, exhibited worse performance on NIH Toolbox assessments, including the Eriksen Flanker, Nine-Hole Pegboard and Auditory Verbal Learning tests.

Conclusion: This study provides convergent evidence that previous SARS-CoV-2 infection is associated with impairments in sustained attention, processing speed, self-reported fatigue and concentration. The finding that some patients have cognitive and visuomotor dysfunction in the absence of self-reported problems suggests that SARS-CoV-2 infection can have unexpected and persistent subclinical consequences.

Source: O’Connor EE, Rednam N, O’Brien R, O’Brien S, Rock P, Levine A, Zeffiro TA. Effects of SARS-CoV-2 Infection on Attention, Memory, and Sensorimotor Performance. medRxiv [Preprint]. 2022 Sep 23:2022.09.22.22280222. doi: 10.1101/2022.09.22.22280222. PMID: 36172134; PMCID: PMC9516858. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516858/ (Full text)

COVID-19 immunopathology: From acute diseases to chronic sequelae

Abstract:

The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also a critical site of immune cell activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, recent reports also suggest the involvement of extrapulmonary tissues in COVID-19 pathology.

The interplay of both innate and adaptive immune responses is key to COVID-19 management. As a result, a robust innate immune response provides the first line of defense, concomitantly, adaptive immunity neutralizes the infection and builds memory for long-term protection. However, dysregulated immunity, both innate and adaptive, can skew towards immunopathology both in acute and chronic cases.

Here we have summarized some of the recent findings that provide critical insight into the immunopathology caused by SARS-CoV-2, in acute and post-acute cases. Finally, we further discuss some of the immunomodulatory drugs in preclinical and clinical trials for dampening the immunopathology caused by COVID-19.

Source: Arish M, Qian W, Narasimhan H, Sun J. COVID-19 immunopathology: From acute diseases to chronic sequelae. J Med Virol. 2022 Sep 3. doi: 10.1002/jmv.28122. Epub ahead of print. PMID: 36056655. https://onlinelibrary.wiley.com/doi/10.1002/jmv.28122 (Full text)

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system

Abstract:

Background: Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is a significant insoluble fibrin amyloid microclot load in the circulation of individuals with long COVID, and that these microclots entrap a substantial number of inflammatory molecules, including those that might prevent clot breakdown. Scientifically, the most challenging aspect of this debilitating condition is that traditional pathology tests such as a serum CRP (C-reactive protein) may not show any significant abnormal inflammatory markers, albeit these tests measure only the soluble inflammatory molecules. Elevated, or abnormal soluble biomarkers such as IL-6, D-Dimer or fibrinogen indicate an increased risk for thrombosis or a host immune response in COVID-19. The absence of biomarkers in standard pathology tests, result in a significant amount of confusion for patients and clinicians, as patients are extremely sick or even bed-ridden but with no regular identifiable reason for their disease. Biomarkers that are currently available cannot detect the molecules present in the microclots we identified and are therefore unable to confirm their presence or the mechanisms that drive their formation.

Methods: Here we analysed the protein content of double-digested microclots of 99 long COVID patients and 29 healthy controls. The patients suffering from long COVID reported their symptoms through a questionnaire completed by themselves or their attending physician.

Results: Our long COVID cohort’s symptoms were found to be in line with global findings, where the most prevalent symptoms were constant fatigue (74%,) cognitive impairment (71%) and depression and anxiety (30%). Our most noteworthy findings were a reduced level of plasma Kallikrein compared to our controls, an increased level of platelet factor 4 (PF4) von Willebrand factor (VWF), and a marginally increased level of α-2 antiplasmin (α-2-AP). We also found a significant presence of antibodies entrapped inside these microclots.

Conclusion: Our results confirm the presence of pro-inflammatory molecules that may also contribute to a failed fibrinolysis phenomenon, which could possibly explain why individuals with long COVID suffer from chronic fatigue, dyspnoea, or cognitive impairment. In addition, significant platelet hyperactivation was noted. Hyperactivation will result in the granular content of platelets being shed into the circulation, including PF4. Overall, our results provide further evidence of both a failed fibrinolytic system in long COVID/PASC and the entrapment of many proteins whose presence might otherwise go unrecorded. These findings might have significant implications for individuals with pre-existing comorbidities, including cardiovascular disease and type 2 diabetes.

Source: Kruger A, Vlok M, Turner S, Venter C, Laubscher GJ, Kell DB, Pretorius E. Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovasc Diabetol. 2022 Sep 21;21(1):190. doi: 10.1186/s12933-022-01623-4. PMID: 36131342; PMCID: PMC9491257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491257/ (Full text)