Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2

Abstract:

This study aimed to assess pulmonary and muscle dysfunction by analyzing the slow component of oxygen uptake (VO2SC), and mechanical and ventilatory efficiency in adult women recovered from the severe acute respiratory syndrome coronavirus type II (SARS-CoV-2) during a constant load test. 32 women (N = 17 patients with SARS-CoV-2; N = 15 control group) performed two cardiopulmonary exercise tests (CPX) on a cycle ergometer.

In the first test, the participants performed incremental CPX until extenuation. In the second test the participants performed a 10-min CPX at a constant load intensity (watts) corresponding to the first ventilatory threshold. There was a 48-72 h rest period between the two tests. There was a significant increase in the VO2SC in the patients recovered from SARS-CoV-2 (160.4 ± 60 mL min-1) in comparison with the healthy participants (59.6 ± 65 mL min-1) (P < 0.001).

Mechanical efficiency significantly decreased in patients recovered from SARS-CoV-2 compared to the control group (P = 0.04). Ventilatory inefficiency significantly increased in the patients recovered from SARS-CoV-2 compared with the control group (P < 0.001). Adult women recovered from SARS-CoV-2 infection have important pulmonary and muscular dysfunction and fatigue which contributes to increasing the VO2SC and reducing mechanical and ventilatory efficiency during mild-moderate exercise at a constant load.

Source: Pleguezuelos E, Del Carmen A, Moreno E, Ortega P, Robles A, Serra-Prat M, Miravitlles M, Yebenes JC, Garnacho-Castaño MV. Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2. Sci Rep. 2022 Dec 4;12(1):20943. doi: 10.1038/s41598-022-24941-9. PMID: 36464697.  https://www.nature.com/articles/s41598-022-24941-9 (Full text)

Tissue specific signature of HHV-6 infection in ME/CFS

Abstract:

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development.

HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome.

Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls.

Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

Source: Prusty, Bhupesh K.; Kasimir, Francesca; Toomey, Danny; Liu, Zheng; Agnes Kaiping and Ariza, Maria Eugenia. Tissue specific signature of HHV-6 infection in ME/CFS. Front. Mol. Biosci. Sec. Molecular Diagnostics and Therapeutics. doi: 10.3389/fmolb.2022.1044964 https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract

Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals

Abstract:

Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer’s disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. ‘

Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.

Source: Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, Pasinetti GM. Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals. bioRxiv [Preprint]. 2022 Nov 23:2022.11.23.517706. doi: 10.1101/2022.11.23.517706. PMID: 36451886; PMCID: PMC9709800. https://www.biorxiv.org/content/10.1101/2022.11.23.517706v1.full (Full text)

Persistent alveolar type 2 dysfunction and lung structural derangement in post-acute COVID-19

Abstract:

SARS-CoV-2 infection can manifest as a wide range of respiratory and systemic symptoms well after the acute phase of infection in over 50% of patients. Key questions remain on the long-term effects of infection on tissue pathology in recovered COVID-19 patients. To address these questions we performed multiplexed imaging of post-mortem lung tissue from 12 individuals who died post-acute COVID-19 (PC) and compare them to lung tissue from patients who died during the acute phase of COVID-19, or patients who died with idiopathic pulmonary fibrosis (IPF), and otherwise healthy lung tissue.

We find evidence of viral presence in the lung up to 359 days after the acute phase of disease, including in patients with negative nasopharyngeal swab tests. The lung of PC patients are characterized by the accumulation of senescent alveolar type 2 cells, fibrosis with hypervascularization of peribronchial areas and alveolar septa, as the most pronounced pathophysiological features. At the cellular level, lung disease of PC patients, while distinct, shares pathological features with the chronic pulmonary disease of IPF. which may help rationalize interventions for PC patients.

Altogether, this study provides an important foundation for the understanding of the long-term effects of SARS-CoV-2 pulmonary infection at the microanatomical, cellular, and molecular level.

Source: André F. Rendeiro, Hiranmayi Ravichandran, Junbum Kim, Alain C. Borczuk, Olivier Elemento, Robert E. Schwartz. Persistent alveolar type 2 dysfunction and lung structural derangement in post-acute COVID-19. medRxiv 2022.11.28.22282811; doi: https://doi.org/10.1101/2022.11.28.22282811 https://www.medrxiv.org/content/10.1101/2022.11.28.22282811v1.full-text  (Full text)

Identifying Profiles and Symptoms of Patients With Long COVID in France: Data Mining Infodemiology Study Based on Social Media

Abstract:

Background: Long COVID-a condition with persistent symptoms post COVID-19 infection-is the first illness arising from social media. In France, the French hashtag #ApresJ20 described symptoms persisting longer than 20 days after contracting COVID-19. Faced with a lack of recognition from medical and official entities, patients formed communities on social media and described their symptoms as long-lasting, fluctuating, and multisystemic. While many studies on long COVID relied on traditional research methods with lengthy processes, social media offers a foundation for large-scale studies with a fast-flowing outburst of data.

Objective: We aimed to identify and analyze Long Haulers’ main reported symptoms, symptom co-occurrences, topics of discussion, difficulties encountered, and patient profiles.

Methods: Data were extracted based on a list of pertinent keywords from public sites (eg, Twitter) and health-related forums (eg, Doctissimo). Reported symptoms were identified via the MedDRA dictionary, displayed per the volume of posts mentioning them, and aggregated at the user level. Associations were assessed by computing co-occurrences in users’ messages, as pairs of preferred terms. Discussion topics were analyzed using the Biterm Topic Modeling; difficulties and unmet needs were explored manually. To identify patient profiles in relation to their symptoms, each preferred term’s total was used to create user-level hierarchal clusters.

Results: Between January 1, 2020, and August 10, 2021, overall, 15,364 messages were identified as originating from 6494 patients of long COVID or their caregivers. Our analyses revealed 3 major symptom co-occurrences: asthenia-dyspnea (102/289, 35.3%), asthenia-anxiety (65/289, 22.5%), and asthenia-headaches (50/289, 17.3%). The main reported difficulties were symptom management (150/424, 35.4% of messages), psychological impact (64/424,15.1%), significant pain (51/424, 12.0%), deterioration in general well-being (52/424, 12.3%), and impact on daily and professional life (40/424, 9.4% and 34/424, 8.0% of messages, respectively). We identified 3 profiles of patients in relation to their symptoms: profile A (n=406 patients) reported exclusively an asthenia symptom; profile B (n=129) expressed anxiety (n=129, 100%), asthenia (n=28, 21.7%), dyspnea (n=15, 11.6%), and ageusia (n=3, 2.3%); and profile C (n=141) described dyspnea (n=141, 100%), and asthenia (n=45, 31.9%). Approximately 49.1% of users (79/161) continued expressing symptoms after more than 3 months post infection, and 20.5% (33/161) after 1 year.

Conclusions: Long COVID is a lingering condition that affects people worldwide, physically and psychologically. It impacts Long Haulers’ quality of life, everyday tasks, and professional activities. Social media played an undeniable role in raising and delivering Long Haulers’ voices and can potentially rapidly provide large volumes of valuable patient-reported information. Since long COVID was a self-titled condition by patients themselves via social media, it is imperative to continuously include their perspectives in related research. Our results can help design patient-centric instruments to be further used in clinical practice to better capture meaningful dimensions of long COVID.

Source: Déguilhem A, Malaab J, Talmatkadi M, Renner S, Foulquié P, Fagherazzi G, Loussikian P, Marty T, Mebarki A, Texier N, Schuck S. Identifying Profiles and Symptoms of Patients With Long COVID in France: Data Mining Infodemiology Study Based on Social Media. JMIR Infodemiology. 2022 Nov 22;2(2):e39849. doi: 10.2196/39849. PMID: 36447795; PMCID: PMC9685517.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685517/ (Full text)

Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis

Abstract:

Background: The COVID-19 pandemic has become a huge threat to human health, infecting millions of people worldwide and causing enormous economic losses. Many novel small molecule drugs have been developed to treat patients with COVID-19, including Paxlovid, which block the synthesis of virus-related proteins and replication of viral RNA, respectively. Despite satisfactory clinical trial results, attention is now being paid to the long-term side effects of these antiviral drugs on the musculoskeletal system. To date, no study has reported the possible side effects, such as osteoarthritis, of Paxlovid. This study explored the effects of antiviral drug, Paxlovid, on chondrocyte proliferation and differentiation.

Methods: In this study, both in vitro and in vivo studies were performed to determine the effect of Paxlovid on chondrocyte degeneration and senescence. Furthermore, we explored the possible mechanism behind Paxlovid-induced acceleration of cartilage degeneration using transcriptome sequencing and related inhibitors were adopted to verify the downstream pathways behind such phenomenon.

Results: Paxlovid significantly inhibited chondrocyte extracellular matrix protein secretion. Additionally, Paxlovid significantly induced endoplasmic reticulum stress, oxidative stress, and downstream ferroptosis, thus accelerating the senescence and degeneration of chondrocytes. In vivo experiments showed that intraperitoneal injection of Paxlovid for 1 week exacerbated cartilage abrasion and accelerated the development of osteoarthritis in a mouse model.

Conclusions: Paxlovid accelerated cartilage degeneration and osteoarthritis development, potentially by inducing endoplasmic reticulum stress and oxidative stress. Long-term follow-up is needed with special attention to the occurrence and development of osteoarthritis in patients treated with Paxlovid.

Source: Kong K, Chang Y, Qiao H, Zhao C, Chen X, Rong K, Zhang P, Jin M, Zhang J, Li H, Zhai Z. Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis. J Transl Med. 2022 Nov 26;20(1):549. doi: 10.1186/s12967-022-03770-4. PMID: 36435786; PMCID: PMC9701426. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701426/ (Full text)

Mid-term Follow-Up chest CT findings in recovered COVID-19 patients with residual symptoms

Abstract:

Objectives: More than a year has passed since the initial outbreak of SARS-CoV-2, which caused many hospitalizations worldwide due to COVID-19 pneumonia and its complications. However, there is still a lack of information detailing short- and long-term outcomes of previously hospitalized patients. The purpose of this study is to analyze the most frequent lung CT findings in recovered COVID-19 patients at mid-term follow-ups.

Methods: A total of 407 consecutive COVID-19 patients who were admitted to the XXXX and discharged between February 27, 2020, and June 26, 2020 were recruited into this study. Out of these patients, a subset of 108 patients who presented with residual asthenia and dyspnea at discharge, altered spirometric data, positive lung ultrasound and positive chest X-ray was subsequently selected, and was scheduled to undergo a mid-term chest computer tomography study, which was evaluated for specific lung alterations and morphological patterns.

Results: The most frequently observed lung CT alterations, in order of frequency, were ground glass opacities (81%), linear opacities (74%), bronchiolectases (64,81%), and reticular opacities (63,88%). The most common morphological pattern was the nonspecific interstitial pneumonia pattern (63,88%). Features consistent with pulmonary fibrosis were observed in 32 patients (29,62%).

Conclusions: Our work showed that recovered COVID-19 patients that were hospitalized and that exhibited residual symptoms after discharge had a slow radiological recovery with persistent residual lung alterations.

Advances in knowledge: This slow recovery process should be kept in mind when determining the follow-up phases in order to improve the long-term management of patients affected by COVID-19.

Source: Marchetti F, Izzi N, Donatelli A, Valentini A, Muzic SI, Dore R, Di Sabatino A, Perrone T, Falaschi F, Sabatini U, Ballesio A, Meloni F, Lettieri S, Mojoli F, Perlini S, Novati S, Pagani E, Klersy C, Bruno R, Preda L. Mid-term Follow-Up chest CT findings in recovered COVID-19 patients with residual symptoms. Br J Radiol. 2022 Nov 25:20220012. doi: 10.1259/bjr.20220012. Epub ahead of print. PMID: 36427055.  https://pubmed.ncbi.nlm.nih.gov/36427055/

Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research

Abstract:

The COVID-19 pandemic accelerated the use of remote patient monitoring in clinical practice or research for safety and emergency reasons, justifying the need for innovative digital health solutions to monitor key parameters or symptoms related to COVID-19 or Long COVID. The use of voice-based technologies, and in particular vocal biomarkers, is a promising approach, voice being a rich, easy-to-collect medium with numerous potential applications for health care, from diagnosis to monitoring.

In this viewpoint, we provide an overview of the potential benefits and limitations of using voice to monitor COVID-19, Long COVID, and related symptoms. We then describe an optimal pipeline to bring a vocal biomarker candidate from research to clinical practice and discuss recommendations to achieve such a clinical implementation successfully.

Source: Fischer A, Elbeji A, Aguayo G, Fagherazzi G. Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research. Interact J Med Res. 2022 Nov 15;11(2):e40655. doi: 10.2196/40655. PMID: 36378504; PMCID: PMC9668331. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668331/ (Full text)

The Long-COVID Experience Changed People’s Vaccine Hesitancy but Not Their Vaccination Fear

Abstract:

Starting in early 2020, the COVID-19 pandemic has been responsible, worldwide, for millions of deaths and patients with long-COVID syndrome. In an attempt to stop the spread of the virus, the blanket administration of COVID-19 vaccines proved to be the most effective measure, yet the existence and availability of functional vaccines did not and, still, do not ensure the willingness and intent of people to be vaccinated.

This study assessed the similarities and differences in vaccine fears and vaccine hesitancy through between clusters of subjects: people that were not infected with COVID-19, people that had COVID but did not develop long-lasting symptoms, and people that were infected with COVID and developed long-COVID syndrome. From the sample of 1111 Italian people, it was found that individuals who experienced mild symptoms showed higher vaccine hesitancy (confidence, complacency, and collective responsibility) than those who did not contract COVID-19. People affected by long-COVID showed a lower overall hesitancy than individuals who had COVID-19 without incurring long-lasting symptoms and, thus, essentially resembled people who had no experience of COVID-19 infection in terms of the vaccine hesitancy scores. Vaccine fear remained unchanged across all three of the examined clusters.

Source: Duradoni M, Gursesli MC, Materassi L, Serritella E, Guazzini A. The Long-COVID Experience Changed People’s Vaccine Hesitancy but Not Their Vaccination Fear. Int J Environ Res Public Health. 2022 Nov 5;19(21):14550. doi: 10.3390/ijerph192114550. PMID: 36361430; PMCID: PMC9654193. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654193/ (Full text)

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Abstract:

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC.

To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record.

Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients.

In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Source: Guntur VP, Nemkov T, de Boer E, Mohning MP, Baraghoshi D, Cendali FI, San-Millán I, Petrache I, D’Alessandro A. Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC). Metabolites. 2022 Oct 26;12(11):1026. doi: 10.3390/metabo12111026. PMID: 36355108; PMCID: PMC9699059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699059/ (Full text)