Dermatologic Changes in Experimental Model of Long-COVID

Abstract:

The COVID-19 pandemic, declared in early 2020, is an unprecedented global health crisis, causing over 7.0 million deaths and ongoing challenges. While the pharmaceutical industry expedited vaccine development, mutant SARS-CoV-2 strains remain a major fear. Moreover, concerns regarding the long-term health repercussions of COVID-19-affected individuals persist since individuals affected by mild and moderate to severe SARS-CoV-2 infection experience long-term cardiovascular complications, liver dysfunction, pulmonary afflictions, kidney impairments, and most importantly neurocognitive deficits.
In recent studies, we documented pathophysiological changes in various organs following the post-acute infection of mice with murine hepatitis virus-1 (MHV-1), a coronavirus, at both 7 days and 12 months after infection. One part of the body that can be drastically affected by SARS-CoV-2 is the skin. Studies have shown major changes in the skin post-acute SARS CoV-2 infection in humans. However, long-term dermatologic changes post-COVID have never been explored.
For the first time, we show several cutaneous findings both at the acute stages and long-term post-infection of mice with MHV-1 coronavirus (a promising experimental model to study acute and long-COVID). Precisely, we found destruction of the epidermal layer, an increase in the number of hair follicles, extensive collagen deposition in the dermal layer, and hyperplasticity of the sebaceous glands at the acute stages, along with thinning of the panniculus carnosus, as well as the adventitial layer, which corresponds well with studies in humans.
In contrast, the cutaneous investigation in the long-COVID phase shows the absence of hair follicles from both the epidermal and dermal layers, the destruction of adipose tissues, and the devastation of the epidermal layer. Further, treatment of these mice with a 15 amino acid synthetic peptide, SPIKENET (SPK), which was effective in preventing Spike glycoprotein-1 binding with host receptors, as well as has a potent anti-inflammatory response to severe inflammatory stimulus) restored the loss of hair follicles and re-architected the epidermal and dermal layers.
Additionally, destruction in fatty tissue in the infected mice was successfully restored post-treatment with SPK. These findings suggest that SARS-CoV-2 initiates the changes early post-infection, leading to devastating skin alterations in the long term which can be prevented by our newly identified peptide drug SPK.
Source: Hussain, H.; Paidas, M.J.; Rajalakshmi, R.; Fadel, A.; Ali, M.; Chen, P.; Jayakumar, A.R. Dermatologic Changes in Experimental Model of Long-COVID. Preprints 2023, 2023122339. https://doi.org/10.20944/preprints202312.2339.v1 https://www.preprints.org/manuscript/202312.2339/v1 (Full text available as PDF file)

Cannabinoids and the Endocannabinoid System in Early SARS-CoV-2 Infection and Long COVID-19—A Scoping Review

Abstract:

Coronavirus disease-19 (COVID-19) is a highly contagious illness caused by the SARS-CoV-2 virus. The clinical presentation of COVID-19 is variable, often including symptoms such as fever, cough, headache, fatigue, and an altered sense of smell and taste. Recently, post-acute “long” COVID-19 has emerged as a concern, with symptoms persisting beyond the acute infection. Vaccinations remain one of the most effective preventative methods against severe COVID-19 outcomes and the development of long-term COVID-19. However, individuals with underlying health conditions may not mount an adequate protective response to COVID-19 vaccines, increasing the likelihood of severe symptoms, hospitalization, and the development of long-term COVID-19 in high-risk populations.
This review explores the potential therapeutic role of cannabinoids in limiting the susceptibility and severity of infection, both pre- and post-SARS-CoV-19 infection. Early in the SARS-CoV-19 infection, cannabinoids have been shown to prevent viral entry, mitigate oxidative stress, and alleviate the associated cytokine storm. Post-SARS-CoV-2 infection, cannabinoids have shown promise in treating symptoms associated with post-acute long COVID-19, including depression, anxiety, post-traumatic stress injury, insomnia, pain, and decreased appetite. While current research primarily focuses on potential treatments for the acute phase of COVID-19, there is a gap in research addressing therapeutics for the early and post-infectious phases. This review highlights the potential for future research to bridge this gap by investigating cannabinoids and the endocannabinoid system as a potential treatment strategy for both early and post-SARS-CoV-19 infection.
Source: Scott C, Hall S, Zhou J, Lehmann C. Cannabinoids and the Endocannabinoid System in Early SARS-CoV-2 Infection and Long COVID-19—A Scoping Review. Journal of Clinical Medicine. 2024; 13(1):227. https://doi.org/10.3390/jcm13010227 https://www.mdpi.com/2077-0383/13/1/227 (Full text)

Long COVID: Molecular Mechanisms and Detection Techniques

Abstract:

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a significant health concern following the COVID-19 pandemic. Molecular mechanisms underlying the occurrence and progression of long COVID include viral persistence, immune dysregulation, endothelial dysfunction, and neurological involvement, and highlight the need for further research to develop targeted therapies for this condition. While a clearer picture of the clinical symptomatology is shaping, many molecular mechanisms are yet to be unraveled, given their complexity and high level of interaction with other metabolic pathways.
This review summarizes some of the most important symptoms and associated molecular mechanisms that occur in long COVID, as well as the most relevant molecular techniques that can be used in understanding the viral pathogen, its affinity towards the host, and the possible outcomes of host-pathogen interaction.
Source: Constantinescu-Bercu A, Lobiuc A, Căliman-Sturdza OA, Oiţă RC, Iavorschi M, Pavăl N-E, Șoldănescu I, Dimian M, Covasa M. Long COVID: Molecular Mechanisms and Detection Techniques. International Journal of Molecular Sciences. 2024; 25(1):408. https://doi.org/10.3390/ijms25010408 https://www.mdpi.com/1422-0067/25/1/408 (Full text)

Arterial Stiffness and Oxidized LDL Independently Associated With Post-Acute Sequalae of SARS-CoV-2

Abstract:

Objective: COVID-19 survivors can experience lingering symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) that appear in different phenotypes, and its etiology remains elusive. We assessed the relationship of endothelial dysfunction with having COVID and PASC.

Methods: Data was collected from a prospectively enrolled cohort (n=379) of COVID-negative and COVID-positive participants with and without PASC. Primary outcomes, endothelial function (measured by reactive hyperemic index [RHI]), and arterial elasticity (measured by augmentation index standardized at 75 bpm [AI]), were measured using the FDA approved EndoPAT. Patient characteristics, labs, metabolic measures, markers of inflammation, and oxidized LDL (ox-LDL) were collected at each study visit, and PASC symptoms were categorized into 3 non-exclusive phenotypes: cardiopulmonary, neurocognitive, and general. COVID-negative controls were propensity score matched to COVID-negative-infected cases using the greedy nearest neighbor method.

Results: There were 14.3% of participants who were fully recovered COVID positive and 28.5% who were COVID positive with PASC, averaging 8.64 ± 6.26 total number of symptoms. The mean RHI was similar across the cohort and having COVID or PASC was not associated with endothelial function (P=0.33). Age (P<0.0001), female sex (P<0.0001), and CRP P=0.04) were positively associated with arterial stiffness, and COVID positive PASC positive with neurological and/or cardiopulmonary phenotypes had the worst arterial elasticity (highest AI). Values for AI (P=0.002) and ox-LDL (P<0.0001) were independently and positively associated with an increased likelihood of having PASC.

Conclusion: There is evidence of an independent association between PASC, ox-LDL, and arterial stiffness with neurological and/or cardiopulmonary phenotypes having the worst arterial elasticity. Future studies should continue investigating the role of oxidative stress in the pathophysiology of PASC.

Source: Zisis SN, Durieux JC, Mouchati C, Funderburg N, Ailstock K, Chong M, Labbato D, McComsey GA. Arterial Stiffness and Oxidized LDL Independently Associated With Post-Acute Sequalae of SARS-CoV-2. Pathog Immun. 2023 Dec 20;8(2):1-15. doi: 10.20411/pai.v8i2.634. PMID: 38156116; PMCID: PMC10753933. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10753933/ (Full text)

What do infectious disease specialists think about managing long COVID?

Abstract:

This survey of infectious disease providers on long COVID care revealed a lack of familiarity with existing resources, a sentiment of missing guidelines, and scarcity of dedicated care centers. The low response rate suggests that infectious disease specialists do not consider themselves as the primary providers of long COVID care.

Long COVID (or post-acute sequelae of COVID-19, PASC) complicates an estimated 10–30% of non-hospitalized cases and 50–70% of hospitalized cases of acute SARS-CoV-2 infection.(Reference Davis, McCorkell, Vogel and Topol1) The work-up often requires multiple disciplines to collaborate, both for diagnostic evaluation and for offering symptomatic treatment.(Reference Parker, Brigham and Connolly2) For this purpose, an infrastructure of so-called long COVID clinics has been developing,(Reference Vanichkachorn, Newcomb and Cowl3) oftentimes under the supervision of a single medical specialty. Given that long COVID is a complication of an infection, the medical subspecialty of infectious diseases (ID) has frequently been involved in devising and running such clinics. Here, we intended to survey ID providers in North America regarding their role in managing long COVID and their perspective on the availability of resources. For this purpose, we used the Emerging Infections Network (EIN), which is a provider-based sentinel network funded by the Infectious Diseases Society of America and the Centers for Disease Control and Prevention (http://ein.idsociety.org/). Our implicit hypothesis was that ID providers are insufficiently equipped to provide long COVID care because neither infection work-up nor antiviral treatment play a role in current management.

We designed a questionnaire, tested it among peers, and sent it out to all 2,978 EIN listserv subscribers on 3 occasions between February 7 and February 26, 2023. The survey contained 8 questions, 7 of which were structured questions. There was an option to make additional open-text field comments.

The response rate was very low, with 117 of 2,978 providers who filled out the survey (3.9%). Of these 117, 46 stated that they did not care for long COVID patients, and we analyzed the responses of the remaining 71 providers (2.4% of 2,978). Most of these would see long COVID patients once a month or less often (50/71). Thirteen indicated they were specifically seeing long COVID patients. Only 15 out of 71 (21%) felt “very comfortable” in making a diagnosis of long COVID, and most thought the resources available to clinicians involved in long COVID care were inadequate (55%) or were unaware of such resources (18%). The management consists mostly of a case-by-case-based approach without standardization (55%), followed by behavioral education for energy conservation (44%). Access to a long COVID clinic was considered easy by only 17%, while 48% stated there was no dedicated clinic located nearby, and 35% highlighted that locally available clinics were not easily accessible.

The open-text field answers were notable for showing that long COVID is a “complicated syndrome, currently without a specialty home” and that it is not easy to provide “holistic care to patients in our existing system.” Also, the absence of straightforward definitions, national guidelines, and dedicated research was pointed out. Lastly, one provider argued that “this is a primary care issue with collaboration with any needed specialists.”

The low response rate, the small percentage of ID providers heavily involved in long COVID care, and some free text statements can be seen as key findings of our survey. Our interpretation is that long COVID—although originating from an acute infection—is not perceived to be in the wheelhouse of the infectious diseases subspecialty. Infectious disease providers may not consider themselves as well-equipped as a generalist such as primary care providers.(Reference Berger, Altiery, Assoumou and Greenhalgh4) Long COVID patients, however, are likely to benefit from designated points of generalist care, with access to pertinent medical specialties and rehabilitative services (physical therapy, occupational health, and mental health), in order to receive comprehensive management for their signs and symptoms. In addition, widespread healthcare worker burnout in the wake of the pandemic may contribute to a subjective saturation with COVID-19-related topics and have reduced survey participation.

A minority of responders considered themselves very comfortable in diagnosing long COVID, the resources for appropriate clinical care were mostly felt to be inadequate, and management seems to happen on a case-by-case base (i.e., non-standardized). This points to the general unease about what constitutes best practice in long COVID care. We speculate that similar findings would be encountered in other medical specialties. Also, there is a considerable need for more research in the field, as evidenced by a recent award by the Agency for Healthcare Research and Quality to study new models of delivery of long COVID care (https://www.ahrq.gov/coronavirus/long-covid-grant-awards.html).

In conclusion, our survey of infectious disease providers and their perspective on long COVID care suggested a lack of familiarity with existing resources, a sentiment of missing guidelines, and scarcity of dedicated care centers. In addition, the low response rate to this survey can be interpreted as ID providers not regarding their specialty as the primary point of contact for delivering long COVID care.

Source: Lyons MD, Beekmann SE, Polgreen PM, Marschall J. What do infectious disease specialists think about managing long COVID? Antimicrobial Stewardship & Healthcare Epidemiology. 2023;3(1):e236. doi:10.1017/ash.2023.519 https://www.cambridge.org/core/journals/antimicrobial-stewardship-and-healthcare-epidemiology/article/what-do-infectious-disease-specialists-think-about-managing-long-covid/E89D7EA86E873D517D24FBB20D304A8D (Full text)

 

Smartphone-based evaluation of static balance and mobility in long-lasting COVID-19 patients

Abstract:

Background: SARS-CoV-2 infection can lead to a variety of persistent sequelae, collectively known as long COVID-19. Deficits in postural balance have been reported in patients several months after COVID-19 infection. The purpose of this study was to evaluate the static balance and balance of individuals with long COVID-19 using inertial sensors in smartphones.

Methods: A total of 73 participants were included in this study, of which 41 had long COVID-19 and 32 served as controls. All participants in the long COVID-19 group reported physical complaints for at least 7 months after SARS-CoV-2 infection. Participants were evaluated using a built-in inertial sensor of a smartphone attached to the low back, which recorded inertial signals during a static balance and mobility task (timed up and go test). The parameters of static balance and mobility obtained from both groups were compared.

Results: The groups were matched for age and BMI. Of the 41 participants in the long COVID-19 group, 22 reported balance impairment and 33 had impaired balance in the Sharpened Romberg test. Static balance assessment revealed that the long COVID-19 group had greater postural instability with both eyes open and closed than the control group. In the TUG test, the long COVID-19 group showed greater acceleration during the sit-to-stand transition compared to the control group.

Conclusion: The smartphone was feasible to identify losses in the balance motor control and mobility of patients with long-lasting symptomatic COVID-19 even after several months or years. Attention to the balance impairment experienced by these patients could help prevent falls and improve their quality of life, and the use of the smartphone can expand this monitoring for a broader population.

Source: Corrêa BDC, Santos EGR, Belgamo A, Pinto GHL, Xavier SS, Silva CC, Dias ÁRN, Paranhos ACM, Cabral ADS, Callegari B, Costa E Silva AA, Quaresma JAS, Falcão LFM, Souza GS. Smartphone-based evaluation of static balance and mobility in long-lasting COVID-19 patients. Front Neurol. 2023 Dec 11;14:1277408. doi: 10.3389/fneur.2023.1277408. PMID: 38148981; PMCID: PMC10750373. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10750373/ (Full text)

Analysis of post-COVID symptoms and predisposing factors for chronic post-COVID syndrome

Abstract:

Introduction: While there is sufficient information about acute COVID-19, which can cause a multisystemic and fatal disease, post-COVID syndrome and risk factors for this condition remain poorly known. We aimed to identify postCOVID symptoms and risk factors for chronic post-COVID syndrome through this study.

Materials and methods: This prospective cross-sectional study was conducted on 254 out of 384 COVID-19 patients admitted to our COVID-19 polyclinic between February and April 2021. The patients were questioned with a list of 37 symptoms at the fifth and twelfth weeks after disease onset via phone review, and their acute post-COVID (APC) and chronic post-COVID (CPC) symptoms were recorded. Data on risk factors were collected from the hospital’s medical records system. Associations between symptom count in the CPC phase and age, sex, hospitalization, RT-PCR result, specific radiological findings, comorbidities, and long-term medications were evaluated.

Result: Two hundred twenty-one patients had APC symptoms, and 138 patients had CPC symptoms. While the most common symptom was fatigue at week five, it was hair loss at week 12. Symptoms were observed significantly less in the CPC phase than in the APC phase (Z= -12.301, p= 0.00). Female sex and the presence of specific radiological findings were significantly associated with the occurrence of CPC symptoms (p= 0.03, p= 0.00, respectively). Long-term use of angiotensin-2 receptor blockers (ARBs) was correlated with a low symptom count in the CPC phase (p= 0.00).

Conclusions: Female sex and the presence of specific radiological findings were risk factors for developing CPC. Long-term use of ARBs was associated with a low chronic post-COVID symptom burden. A substantial cluster of multisystemic symptoms was observed in both phases, and this condition highlights the requirement for customized outpatient management that includes long-term follow-up and treatment of COVID-19 patients. Identifying the high-risk patients that will develop persistent symptoms can guide this management.

Source: Abalı H, Demir D, Gül Ş, Şimşek Veske N, Tural Onur S. Analysis of post-COVID symptoms and predisposing factors for chronic post-COVID syndrome. Tuberk Toraks. 2023 Dec;71(4):378-389. English. doi: 10.5578/tt.20239606. PMID: 38152008. https://pubmed.ncbi.nlm.nih.gov/38152008/ (Full text available as PDF file)

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Abstract:

The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin.

This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

Source: Chambers, P.W.; Chambers, S.E. Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach. Preprints 2023, 2023121881. https://doi.org/10.20944/preprints202312.1881.v2 https://www.preprints.org/manuscript/202312.1881/v2 (Full text available as PDF file)

How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms

Our study involves collaboration/participation in order to develop culturally sensitive multinational tools for assessing post viral symptoms.

We discuss the creation of questionnaires using patient participation, and the translation of these questionnaires using international collaboration.

Patient engagement in collaboration on the creation and use of these types of instruments is of particular importance for patients who historically have not been true partners in collaborative efforts to understand diseases.

This has occurred for those with the post-viral illness called Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which has generated considerable resentment and estrangement among the patient community.

Our article reviews:

1) why participation of diverse groups/patients is important in the development of instruments to measure key symptoms of ME/CFS,

2) why the ME/CFS group of patients needs to be included specifically (as an example),

and

3) why structured health questionnaires are important/useful.

Our article also has an overall aim of demonstrating collaborative efforts with patients and others on creating multinational scales.

We provide examples of participatory processes used in developing and translating patient-driven instruments so that they can be used in non-English speaking countries.

Our article illustrates how patients and international researchers can be involved in efforts to develop and translate international assessment instruments to validly capture domains of unexplained illness like ME/CFS.

With the onset of another post-viral illness, Long COVID, there is a world-wide need to create valid and culturally sensitive assessment instruments to measure critical symptoms, many of which are similar to ME/CFS.

Source: Leonard A. Jason and Joseph A. Dorri. How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms. The Australian Community Psychologist., Volume 32 No 1  https://psychology.org.au/getmedia/c300a432-c7fd-4f97-9322-ce16429067e4/ac-vol-32(1)-2023-final-draft.pdf#page=63 (Full text)

Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue, and cognitive dysfunction suggesting a key role for the central nervous system, in the pathophysiology of this disease. Several studies have reported altered functional connectivity (FC) related to motor and cognitive deficits in ME/CFS patients. In this study, we compared functional connectivity differences between 31 ME/CFS and 15 healthy controls (HC) using 7 Tesla MRI. Functional scans were acquired during a cognitive Stroop color-word task and blood oxygen level-dependent (BOLD) time-series were computed for 27 regions of interest (ROIs) in the cerebellum, brainstem, and salience and default mode networks.

Region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (p=0.027) for ME/CFS patients compared to HC. Our ROI-to-voxel analysis found significant impairment of FC within ponto-cerebellar regions in ME/CFS. Correlation analyses of connectivity with clinical scores in ME/CFS patients detected associations of FC with ‘duration of illness’ and ‘memory scores’ in salience network hubs and cerebellum vermis, and with ‘respiratory rate’ within medulla and the default mode network FC.

This novel investigation is the first to report extensive involvement of aberrant ponto-cerebellar connections consistent with ME/CFS symptomatology. This highlights the involvement of the brainstem and the cerebellum in the pathomechanism of ME/CFS.

Source: Maira INDERYAS, Kiran Thapaliya, Sonya Marshall-Gradisnik, Markus Barth, Leighton Barnden. Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurosci. Sec. Brain Imaging Methods. Volume 17 – 2023 | doi: 10.3389/fnins.2023.1318094 https://www.frontiersin.org/articles/10.3389/fnins.2023.1318094/full (Full text)