Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID

Abstract:

STUDY OBJECTIVES: Preliminary evidence suggests that the risk of Long COVID is higher among people with pre-existing medical conditions. Based on its proven adjuvant role in immunity, habitual sleep duration may alter the risk for developing Long COVID. The objective of this study was to determine whether the odds of Long COVID are higher amongst those with pre-existing medical conditions, and whether the strength of this association varies by habitual sleep duration.

METHODS: Using data from 13,461 respondents from 16 countries who participated in the 2021 survey based International COVID Sleep Study II (ICOSS II), we studied the associations between habitual sleep duration, pre-existing medical conditions, and Long COVID.

RESULTS: Of 2,508 individuals who had COVID-19, 61% reported at least one Long COVID symptom. Multivariable logistic regression analysis showed that the risk of having Long COVID was 1.8-fold higher for average-length sleepers (6-9h/night) with pre-existing medical conditions compared to those without pre-existing medical conditions [aOR 1.84 (1.18-2.90), P=0.008]. The risk of Long COVID was 3-fold higher for short sleepers with pre-existing medical conditions [aOR 2.95 (1.04-8.4), P=0.043] and not significantly higher for long sleepers with pre-existing conditions [aOR 2.11 (0.93-4.77), P=0.073] compared to average-length sleepers without pre-existing conditions.

CONCLUSIONS: Habitual short nighttime sleep duration exacerbated the risk of Long COVID in individuals with pre-existing conditions. Restoring nighttime sleep to average duration represents a potentially modifiable behavioral factor to lower the odds of Long COVID for at-risk patients.

Source: Linor Berezin, MD, et al. Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID. Journal of Clinical Sleep Medicine, Articles in Advance. https://jcsm.aasm.org/doi/pdf/10.5664/jcsm.10818 (Full text)

Metabolic Fingerprinting for the Diagnosis of Clinically Similar Long COVID and Fibromyalgia Using a Portable FT-MIR Spectroscopic Combined with Chemometrics

Abstract:

Post Acute Sequelae of SARS-CoV-2 infection (PASC or Long COVID) is characterized by lingering symptomatology post-initial COVID-19 illness that is often debilitating. It is seen in up to 30–40% of individuals post-infection. Patients with Long COVID (LC) suffer from dysautonomia, malaise, fatigue, and pain, amongst a multitude of other symptoms.
Fibromyalgia (FM) is a chronic musculoskeletal pain disorder that often leads to functional disability and severe impairment of quality of life. LC and FM share several clinical features, including pain that often makes them indistinguishable. The aim of this study is to develop a metabolic fingerprinting approach using portable Fourier-transform mid-infrared (FT-MIR) spectroscopic techniques to diagnose clinically similar LC and FM.
Blood samples were obtained from LC (n = 50) and FM (n = 50) patients and stored on conventional bloodspot protein saver cards. A semi-permeable membrane filtration approach was used to extract the blood samples, and spectral data were collected using a portable FT-MIR spectrometer. Through the deconvolution analysis of the spectral data, a distinct spectral marker at 1565 cm−1 was identified based on a statistically significant analysis, only present in FM patients. This IR band has been linked to the presence of side chains of glutamate.
An OPLS-DA algorithm created using the spectral region 1500 to 1700 cm−1 enabled the classification of the spectra into their corresponding classes (Rcv > 0.96) with 100% accuracy and specificity. This high-throughput approach allows unique metabolic signatures associated with LC and FM to be identified, allowing these conditions to be distinguished and implemented for in-clinic diagnostics, which is crucial to guide future therapeutic approaches.
Source: Hackshaw KV, Yao S, Bao H, de Lamo Castellvi S, Aziz R, Nuguri SM, Yu L, Osuna-Diaz MM, Brode WM, Sebastian KR, et al. Metabolic Fingerprinting for the Diagnosis of Clinically Similar Long COVID and Fibromyalgia Using a Portable FT-MIR Spectroscopic Combined with Chemometrics. Biomedicines. 2023; 11(10):2704. https://doi.org/10.3390/biomedicines11102704 https://www.mdpi.com/2227-9059/11/10/2704 (Full text)

Pathophysiology and potential treatment of long COVID: A report of signal index cases and call for targeted research

Abstract:

Objective: Long COVID has afflicted tens of millions globally leaving many previously-healthy persons severely and indefinitely debilitated. The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications.

Design: Case histories of the first three index events (among others) are presented. Unaware of others with similar remissions, each subject independently completed personal narratives and standardized surveys regarding demographics/occupation, past history, and the presence and respective severity grading of 33 signs/symptoms associated with long COVID, comparing the presence/severity of those symptoms during the pre-COVID, long-COVID, post-vaccination, and post-MCA phases.

Setting: Patient interviews, e-mails and telephone conversations.

Subjects: Three previously healthy, middle-aged, highly-functioning persons, two women and one man (ages 60, 43, and 63 years respectively) who, post-acute COVID-19 infection, developed chronic, unrelenting fatigue and cognitive impairment along with other severe, disabling symptoms. Each then independently reported incidental and unanticipated complete remissions within days of MCA treatment.

Interventions: The casirivimab/imdevimab cocktail.

Measurements and main results: Irrespective of sex, age, vaccination status, or illness duration (18, 8 and 5 months, respectively), each subject experienced the same complete remission of their persistent disabling disease within a week of MCA infusion. Each rapidly returned to normal health and previous lifestyles/occupations with normalized exercise tolerance, still sustained to date nearly two years later.

Conclusions: These index cases provide compelling clinical signals that MCA infusions may be capable of treating long COVID in certain cases, including those with severe debilitation. While the complete and sustained remissions observed here may only apply to long COVID resulting from pre-Delta variants and the specific MCA infused, the striking rapid and complete remissions observed in these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions and long COVID from other variants.

Key points

  • •Question: Considering that long COVID-19 has been devastating for many millions worldwide, what is the proposed pathophysiology and are there any effective treatments?
  • Findings: Previously-healthy middle-aged persons who had developed persistent debilitating post-acute SARS-CoV-2 sequelae, each experienced complete remission their symptoms within days of receiving a specific monoclonal anti-body infusion despite relative differences in sex, age, vaccination status, and long COVID duration.
  • Meaning: Certain monoclonal antibody infusions may be capable of reversing severe long COVID. Beyond providing an effective potential treatment for long COVID, these findings have mechanistic implications for treating other post-viral chronic conditions, including future long COVID variants.

Source: Kenneth A. Scheppke, Paul E. Pepe, Jonathan Jui, Remle P. Crowe, Eric K. Scheppke, Nancy G. Klimas, Aileen M. Marty. Pathophysiology and potential treatment of long COVID: A report of signal index cases and call for targeted research, The American Journal of Emergency Medicine, 2023. ISSN 0735-6757. https://doi.org/10.1016/j.ajem.2023.09.051. https://www.sciencedirect.com/science/article/abs/pii/S073567572300534X

Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program

Abstract:

Background: Evolving mutations of the novel coronavirus continue to fuel up the pandemic. The virus affects the human respiratory system along with other body systems, causing several sequelae in the survivors of the disease, presented as post-COVID-19 syndrome or long-COVID-19. This protocol utilized Hope Biosciences’ autologous, adipose-derived mesenchymal stem cells (HB-adMSCs) to evaluate safety and efficacy of HB-adMSC therapy to improve signs and symptoms associated with post-COVID-19 syndrome.

Methods: Ten eligible subjects with post-COVID-19 syndrome were enrolled in the program for a duration of 40 weeks who received 5 intravenous infusions of 2 × 108 autologous HB-adMSCs each at week 0, 2, 6, 10 and 14 with a follow-up at week 18 and end of the study at week 40. Safety assessments included incidence of adverse and serious adverse events along with the laboratory measures of hematologic, hepatic, and renal function. Efficacy was examined by quality-of-life assessments, fatigue assessments, Visual analog scale (VAS) of symptoms and monitoring of respiration and oxygen saturation rates.

Results: VAS scores and Fatigue Assessment scores (FAS) showed significant improvements post-treatment (P = 0.0039, ES = 0.91) compared to baseline. Respiration rates and oxygen saturation levels that were within the normal range at the baseline remained unchanged at the end of the study (EOS). Paired comparison between baseline and EOS for short-form-36 health survey questionnaire (SF-36) scores also showed improved quality-of-life with significant improvements in individual SF-36 evaluations. Mostly mild AEs were reported during the study period with no incidence of serious AEs. Also, no detrimental effects in laboratory values were seen.

Conclusions: The results of the expanded access program indicated that treatment with autologous HB-adMSCs resulted in significant improvements in the signs and symptoms associated with post-COVID-19 syndrome as assessed by VAS and FAS scores. Additionally, improvements in the patients’ quality-of-life as demonstrated using SF-36 scores that also showed significant improvements in individual scaled scores. Overall, administration of multiple infusions of autologous HB-adMSCs is safe and efficacious for improvements in the quality-of life of patients with post-COVID-19 syndrome.

Trial registration: Clinical trial registration number: NCT04798066. Registered on March 15, 2021. ( https://clinicaltrials.gov/ct2/show/NCT04798066?term=hope+biosciences&cond=Post-COVID-19+Syndrome&draw=2&rank=2 ).

Source: Vij R, Kim H, Park H, Cheng T, Lotfi D, Chang D. Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program. Stem Cell Res Ther. 2023 Oct 5;14(1):287. doi: 10.1186/s13287-023-03522-1. PMID: 37798650; PMCID: PMC10557203. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557203/ (Full text)

Serotonin reduction in post-acute sequelae of viral infection

Highlights:

  • Long COVID is associated with reduced circulating serotonin levels
  • Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
  • IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
  • Peripheral serotonin deficiency impairs cognition via reduced vagal signaling

Summary:

Post-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction.
Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Source: Wong et al., Serotonin reduction in post-acute sequelae of viral infection, Cell (2023), https://doi.org/
10.1016/j.cell.2023.09.013 https://www.cell.com/cell/fulltext/S0092-8674(23)01034-6 (Full text)

Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model

Abstract:

Long COVID has become a significant global health and economic burden, yet there are currently no established methods or diagnostic tools to identify which patients might benefit from specific treatments. One of the major pathophysiological factors contributing to Long COVID is the presence of hypercoagulability; this results in insoluble amyloid microclots that are resistant to fibrinolysis. Our previous research using fluorescence microscopy has demonstrated a significant amyloid microclot load in Long COVID patients. However, this approach lacked the elements of statistical robustness, objectivity, and rapid throughput.

In the current study, we have used imaging flow cytometry for the first time to show a significantly increased concentration and size of these microclots. We identified notable variations in size and fluorescence between microclots in Long COVID and those of controls even using a 20× objective. By combining cell imaging and the high-event-rate and full-sample analysis nature of a conventional flow cytometer, imaging flow cytometry can eliminate erroneous results and increase accuracy in gating and analysis beyond what pure quantitative measurements from conventional flow cytometry can provide.

Although imaging flow cytometry was used in our study, our results suggest that the signals indicating the presence of microclots should be easily detectable using a conventional flow cytometer. Flow cytometry is a more widely available technique than fluorescence microscopy and has been used in pathology laboratories for decades, rendering it a potentially more suitable and accessible method for detecting microclots in individuals suffering from Long COVID or conditions with similar pathology, such as myalgic encephalomyelitis.

Source: Turner S, Laubscher GJ, Khan MA, Kell DB, Pretorius E. Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model. Heliyon. 2023 Aug 29;9(9):e19605. doi: 10.1016/j.heliyon.2023.e19605. PMID: 37809592; PMCID: PMC10558872. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558872/ (Full text)

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

Abstract:

Background: Following SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic.

Methods: The study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA.

Results: The frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD–CD27–) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups.

Conclusions: The antibody responses to the spike protein, but not the anti-RBD B cell responses diverge between convalescent males and females who develop PCC. Our findings also suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens.

Source: Limoges MA, Quenum AJI, Chowdhury MMH, Rexhepi F, Namvarpour M, Akbari SA, Rioux-Perreault C, Nandi M, Lucier JF, Lemaire-Paquette S, Premkumar L, Durocher Y, Cantin A, Lévesque S, Dionne IJ, Menendez A, Ilangumaran S, Allard-Chamard H, Piché A, Ramanathan S. SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition. Front Immunol. 2023 Sep 21;14:1223936. doi: 10.3389/fimmu.2023.1223936. PMID: 37809081; PMCID: PMC10551145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551145/ (Full text)

Fibrin microthrombi in bladder urothelium after SARS-CoV-2 infection: Case report

Abstract:

A 45-year-old male with diabetes, hypertension and hyperlipidemia was referred to urology due to persistent symptoms of urinary frequency, urgency, nocturia, erectile dysfunction, and constant pain localized to the bladder, pelvis, and perineal area, 3–4 months after SARS-CoV-2 infection. A bladder biopsy showed urothelial mucosa and submucosa with hemorrhage and fibrin microthrombi in blood vessels. Hydrodistention of the bladder and pelvic floor physical therapy resolved symptoms, though bladder and pain symptoms returned upon reinfection with SARS-CoV-2. Urinalysis revealed elevated urinary interleukin-8, which may indicate localized bladder inflammation.

Source: Hoang Roberts L, Zwaans BMM, Jabbar K, Bartolone SN, Padmanabhan P, Peters KM. Fibrin microthrombi in bladder urothelium after SARS-CoV-2 infection: Case report. Urol Case Rep. 2023 Sep 25;51:102575. doi: 10.1016/j.eucr.2023.102575. PMID: 37829494; PMCID: PMC10565678. https://www.sciencedirect.com/science/article/pii/S2214442023002619 (Full text)

Observational Study of Repeat Immunoadsorption (RIA) in Post-COVID ME/CFS Patients with Elevated ß2-Adrenergic Receptor Autoantibodies—An Interim Report

Abstract:

There is increasing evidence for an autoimmune aetiology in post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). SARS-CoV-2 has now become the main trigger for ME/CFS. We have already conducted two small proof-of-concept studies on IgG depletion by immunoadsorption (IA) in post-infectious ME/CFS, which showed efficacy in most patients.
This observational study aims to evaluate the efficacy of IA in patients with post-COVID-19 ME/CFS. The primary objective was to assess the improvement in functional ability. Due to the urgency of finding therapies for post-COVID-Syndrome (PCS), we report here the interim results of the first ten patients, with seven responders defined by an increase of between 10 and 35 points in the Short-Form 36 Physical Function (SF36-PF) at week four after IA. The results of this observational study will provide the basis for patient selection for a randomised controlled trial (RCT), including sham apheresis, and for an RCT combining IA with B-cell depletion therapy. Trial registration number: NCT05629988.
Source: Stein E, Heindrich C, Wittke K, Kedor C, Kim L, Freitag H, Krüger A, Tölle M, Scheibenbogen C. Observational Study of Repeat Immunoadsorption (RIA) in Post-COVID ME/CFS Patients with Elevated ß2-Adrenergic Receptor Autoantibodies—An Interim Report. Journal of Clinical Medicine. 2023; 12(19):6428. https://doi.org/10.3390/jcm12196428 https://www.mdpi.com/2077-0383/12/19/6428 (Full text)

Low-dose naltrexone use for the management of post-acute sequelae of COVID-19

Abstract:

The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In contrast, in the United States, the National Center for Health Statistics (NCHS) estimates that around 11 % of individuals who have been infected with SARS-CoV-2 go on to experience long COVID. The underlying causes of PASC remains under investigation, and there are no currently established FDA-approved therapies.

One of the leading hypotheses for the cause of PASC is the persistent activation of innate immune cells with increase systemic inflammation. Naltrexone is a medication with anti-inflammatory and immunomodulatory properties that has been used in other conditions that overlap with PASC.

We performed a retrospective review of a clinical cohort of 59 patients at a single academic center who received low-dose naltrexone (LDN) off-label as a potential therapeutic intervention for PASC. The use of LDN was associated with a fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and a better functional status. This observation warrants testing in rigorous, randomized, placebo-controlled clinical trials.

Source: Bonilla H, Tian L, Marconi VC, Shafer R, McComsey GA, Miglis M, Yang P, Bonilla A, Eggert L, Geng LN. Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. Int Immunopharmacol. 2023 Oct 5;124(Pt B):110966. doi: 10.1016/j.intimp.2023.110966. Epub ahead of print. PMID: 37804660. https://www.sciencedirect.com/science/article/pii/S1567576923012912 (Full text)