Category: Overlapping Illnesses

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic

Summary:

Background The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well defined.

Methods We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the ME/CFS phenotype.

Findings The median age was 47 years, 59·0% were female; 49·3% White, 17·2% Hispanic, 14·9% Asian, and 6·7% Black. Only 12·7% required hospitalization. Seventy-two (53·5%) patients had no known comorbid conditions. Forty-five (33·9%) were significantly debilitated. The median duration of symptoms was 285·5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86·5%), post-exertional malaise (82·8%), brain fog (81·2%), unrefreshing sleep (76·7%), and lethargy (74·6%). Forty-three percent fit the criteria for ME/CFS.

Interpretations Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

Source:  H Bonilla, TC Quach, A Tiwari, AE Bonilla, M Miglis, P Yang, L Eggert, H Sharifi, A Horomanski, A Subramanian, L Smirnoff, N Simpson, H Halawi, O Sum-Ping, A Kalinowski, Z Patel, R Shafer, L. Geng. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. medRxiv 2022.08.03.22278363; doi: https://doi.org/10.1101/2022.08.03.22278363

Persistent capillary rarefication in long COVID syndrome

Abstract:

Background: Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection.

Methods: This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4-25 µm.

Measurements and main results: Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: – 45.16%; D6: – 35.60%; D7: – 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).

Conclusions: Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

Source: Osiaevi I, Schulze A, Evers G, Harmening K, Vink H, Kümpers P, Mohr M, Rovas A. Persistent capillary rarefication in long COVID syndrome. Angiogenesis. 2022 Aug 11:1–9. doi: 10.1007/s10456-022-09850-9. Epub ahead of print. PMID: 35951203; PMCID: PMC9366128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366128/ (Full text)

Distinguishing features of Long COVID identified through immune profiling

Abstract:

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID.

Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus.

Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

Source: Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeffrey R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Pena-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki. Distinguishing features of Long COVID identified through immune profiling. medRxiv 2022.08.09.22278592; doi: https://doi.org/10.1101/2022.08.09.22278592

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity

Abstract:

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).

Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome.

Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Source: Maes M, Andrés-Rodríguez L, Vojdani A, Sirivichayakul S, Barbosa DS, Kanchanatawan B. In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity. CNS Neurol Disord Drug Targets. 2022 Aug 6. doi: 10.2174/1871527321666220806100600. Epub ahead of print. PMID: 35946099.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms

Abstract:

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms.

The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines.

These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Source: Abdullah L, Ferguson S, Niedospial D, Patterson D, Oberlin S, Nkiliza A, Bartenfelder G, Hahn-Townsend C, Parks M, Crawford F, Reich A, Keegan A, Kirkpatrick B, Mullan M. Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms. Harmful Algae. 2022 Aug;117:102286. doi: 10.1016/j.hal.2022.102286. Epub 2022 Jul 12. PMID: 35944953. https://pubmed.ncbi.nlm.nih.gov/35944953/

Post-acute COVID-19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance

We recently published in Gut to show that gut dysbiosis persisted for at least 6 months in patients with post-acute COVID-19 syndrome (PACS).1 Murine and human studies have also reported microbial alterations associated with different PACS symptoms.2 3 With the pandemic entering its third year, PACS could potentially affect recovered individuals for over 1 year.4 It remains unknown whether PACS-associated gut dysbiosis would also linger for such a long time.

Here, we conducted a prospective study to determine long-term alterations in the gut microbiome of patients with COVID-19 using shotgun metagenomic sequencing (online supplemental materials). A total of 155 patients with COVID-19 in Hong Kong were followed up for an average of 14 months after SARS-CoV-2 viral clearance, and 155 age-matched, sex-matched and body mass index-matched subjects without COVID-19 were recruited as controls. Patients with COVID-19 were infected with the original or earlier variants of SARS-CoV-2 from January 2020 to February 2021. Consistent with previous finding that 76.4% of patients had PACS 6 months after recovery from acute COVID-19,1 we found that the prevalence of PACS was 78.7% at an average of 14-month (IQR 11–18 months) follow-up. The three most common symptoms were fatigue (50.9%), memory problems (44.5%) and difficulty in sleeping (35.5%, figure 1A). Gut dysbiosis in these patients did not fully recover. Both bacteria diversity (p=0.0036, figure 1B) and richness (p=0.00032, figure 1C) of patients with COVID-19 were still significantly lower than that of controls. Principal coordinates analysis of beta diversity also showed distinct separation of patients with COVID-19 from controls (F=8.3822, p<0.001, figure 1D). These observations suggest persistent gut dysbiosis beyond 1 year in patients with PACS

Read the rest of this article HERE.

Source: Su Q, Lau RI, Liu Q, Chan FKL, Ng SC. Post-acute COVID-19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance. Gut. 2022 Aug 8:gutjnl-2022-328319. doi: 10.1136/gutjnl-2022-328319. Epub ahead of print. PMID: 35940857. https://gut.bmj.com/content/early/2022/08/08/gutjnl-2022-328319 (Full text)

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study

Abstract:

Background: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.

Methods: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician’s diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls.

Findings: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint.

Interpretation: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.

Funding: ZonMw; Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; Provinces of Drenthe, Friesland, and Groningen.

Source: Ballering AV, van Zon SKR, Olde Hartman TC, Rosmalen JGM; Lifelines Corona Research Initiative. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet. 2022 Aug 6;400(10350):452-461. doi: 10.1016/S0140-6736(22)01214-4. PMID: 35934007. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01214-4/fulltext (Full text)

Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

in English, German

Background: A sizable part of post-COVID syndrome meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A doubling of cases of ME/CFS within the next years is therefore projected.

Objectives: Presentation of the current state of knowledge on ME/CFS.

Materials and methods: Unsystematic review of the literature and of own contributions in research and patient care.

Results and conclusions: ME/CFS is a neuroimmunological disease, mostly infection-induced, usually persisting throughout life. Clinically it is characterized by fatigue lasting at least 6 months and the defining core feature of exercise intolerance (post-exertional malaise, PEM). Exercise intolerance is defined as a worsening of symptoms after (even mild) everyday exertion, which usually begins after several hours or on the following day, is still noticeable at least 14 h after exertion, and often lasts for several days (up to weeks or longer). Furthermore, ME/CFS is characterized by pain, disturbances of sleep, thinking and memory, and dysregulation of the circulatory, endocrine, and immune systems.

As a separate clinical entity, ME/CFS should be distinguished from chronic fatigue, which occurs as a symptom of a range of very different diseases. The diagnosis of ME/CFS is made clinically using established international diagnostic criteria and requires careful stepwise diagnosis to exclude other diagnoses. A causal therapy for ME/CFS has not been established; the focus is on symptoms relief, treatment of the often accompanying orthostatic intolerance, and assistance with anticipatory energy management (pacing).

Source: Renz-Polster H, Scheibenbogen C. Post-COVID-Syndrom mit Fatigue und Belastungsintoleranz: Myalgische Enzephalomyelitis bzw. Chronisches Fatigue-Syndrom [Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome]. Inn Med (Heidelb). 2022 Aug;63(8):830-839. German. doi: 10.1007/s00108-022-01369-x. Epub 2022 Jul 13. PMID: 35925074. https://pubmed.ncbi.nlm.nih.gov/35925074/  https://link.springer.com/article/10.1007/s00108-022-01369-x (Full text in German)

Serum of Post-COVID-19 Syndrome patients with or without ME/CFS differentially affects endothelial cell function in vitro

Abstract:

A proportion of COVID-19 reconvalescent patients develop post-COVID-19 syndrome (PCS) including a subgroup fulfilling diagnostic criteria of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (PCS/CFS). Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive. Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro.
PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay.
While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients. Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers. PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups. Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation.
Overall, PCS and PCS/CFS patients′ sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients.
Source: Flaskamp L, Roubal C, Uddin S, Sotzny F, Kedor C, Bauer S, Scheibenbogen C, Seifert M. Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro. Cells. 2022; 11(15):2376. https://doi.org/10.3390/cells11152376  https://www.mdpi.com/2073-4409/11/15/2376/htm (Full text)