Long COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: similarities and differences of two peas in a pod

Sr. Editor,

Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Prolonged recovery of COVID-19 symptoms, so-called Long COVID-19, has been described even in patients who have mild symptoms and did not required hospitalisation. Various studies showed that at least one out of ten COVID-19 symptomatic patients develop Long
COVID-19.

Although there is an absence of a evidence-based clinical practice guidelines neither a clear aetiopatogenesis, a clinical case definition of post-COVID-19 condition was proposed across the International Severe Respiratory and Emerging Infection Consortium (ISARIC) and the World Health Organization (WHO). Long COVID-19 occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.

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Source: Qanneta R, COVID-19 persistente y Encefalomielitis Mialgica /Sındrome de Fatiga Cronica: similitudes y diferencias,  Reumatologia Clinica (2022), doi: https://doi.org/10.1016/j.reuma.2022.05.003 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167847/pdf/main.pdf (Full text available in English as PDF file)

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long.

The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.

We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2.

We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

Source: Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022 May 25;13:877772. doi: 10.3389/fneur.2022.877772. PMID: 35693009; PMCID: PMC9174654.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174654/ (Full text)

ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects

Abstract:

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease.

We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.

Source: Shiers S, Ray PR, Wangzhou A, Sankaranarayanan I, Tatsui CE, Rhines LD, Li Y, Uhelski ML, Dougherty PM, Price TJ. ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects. Pain. 2020 Nov;161(11):2494-2501. doi: 10.1097/j.pain.0000000000002051. PMID: 32826754; PMCID: PMC7572821. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572821/ (Full text)

A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021

Abstract:

Importance: While much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID.

Objective: To estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery.

Design: We jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study.

Results: Analyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms.

Conclusions and relevance: The occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane.

Source: Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, Blyuss O, Bobkova P, Bonsel G, Borzakova S, Buonsenso D, Butnaru D, Carter A, Chu H, De Rose C, Diab MM, Ekbom E, El Tantawi M, Fomin V, Frithiof R, Gamirova A, Glybochko PV, Haagsma JA, Javanmard SH, Hamilton EB, Harris G, Heijenbrok-Kal MH, Helbok R, Hellemons ME, Hillus D, Huijts SM, Hultström M, Jassat W, Kurth F, Larsson IM, Lipcsey M, Liu C, Loflin CD, Malinovschi A, Mao W, Mazankova L, McCulloch D, Menges D, Mohammadifard N, Munblit D, Nekliudov NA, Ogbuoji O, Osmanov IM, Peñalvo JL, Petersen MS, Puhan MA, Rahman M, Rass V, Reinig N, Ribbers GM, Ricchiuto A, Rubertsson S, Samitova E, Sarrafzadegan N, Shikhaleva A, Simpson KE, Sinatti D, Soriano JB, Spiridonova E, Steinbeis F, Svistunov AA, Valentini P, van de Water BJ, van den Berg-Emons R, Wallin E, Witzenrath M, Wu Y, Xu H, Zoller T, Adolph C, Albright J, Amlag JO, Aravkin AY, Bang-Jensen BL, Bisignano C, Castellano R, Castro E, Chakrabarti S, Collins JK, Dai X, Daoud F, Dapper C, Deen A, Duncan BB, Erickson M, Ewald SB, Ferrari AJ, Flaxman AD, Fullman N, Gamkrelidze A, Giles JR, Guo G, Hay SI, He J, Helak M, Hulland EN, Kereselidze M, Krohn KJ, Lazzar-Atwood A, Lindstrom A, Lozano R, Magistro B, Malta DC, Månsson J, Mantilla Herrera AM, Mokdad AH, Monasta L, Nomura S, Pasovic M, Pigott DM, Reiner RC, Reinke G, Ribeiro ALP, Santomauro DF, Sholokhov A, Spurlock EE, Walcott R, Walker A, Wiysonge CS, Zheng P, Bettger JP, Murray CJ, Vos T. A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021. medRxiv [Preprint]. 2022 May 27:2022.05.26.22275532. doi: 10.1101/2022.05.26.22275532. PMID: 35664995; PMCID: PMC9164454.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164454/ (Full text)

Generalizable Long COVID Subtypes: Findings from the NIH N3C and RECOVER Programs

Abstract:

Accurate stratification of patients with Post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies and could enable more focused investigation of the molecular pathogenetic mechanisms of this disease. However, the natural history of long COVID is incompletely understood and characterized by an extremely wide range of manifestations that are difficult to analyze computationally. In addition, the generalizability of machine learning classification of COVID-19 clinical outcomes has rarely been tested.

We present a method for computationally modeling long COVID phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Using unsupervised machine learning (k-means clustering), we found six distinct clusters of long COVID patients, each with distinct profiles of phenotypic abnormalities with enrichments in pulmonary, cardiovascular, neuropsychiatric, and constitutional symptoms such as fatigue and fever.

There was a highly significant association of cluster membership with a range of pre-existing conditions and with measures of severity during acute COVID-19. We show that the clusters we identified in one hospital system were generalizable across different hospital systems. Semantic phenotypic clustering can provide a foundation for assigning patients to stratified subgroups for natural history or therapy studies on long COVID.

Source: Reese J, Blau H, Bergquist T, Loomba JJ, Callahan T, Laraway B, Antonescu C, Casiraghi E, Coleman B, Gargano M, Wilkins K, Cappelletti L, Fontana T, Ammar N, Antony B, Murali TM, Karlebach G, McMurry JA, Williams A, Moffitt R, Banerjee J, Solomonides AE, Davis H, Kostka K, Valentini G, Sahner D, Chute CG, Madlock-Brown C, Haendel MA, Robinson PN; and the RECOVER Consortium. Generalizable Long COVID Subtypes: Findings from the NIH N3C and RECOVER Programs. medRxiv [Preprint]. 2022 May 25:2022.05.24.22275398. doi: 10.1101/2022.05.24.22275398. PMID: 35665012; PMCID: PMC9164456. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164456/ (Full text)

Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19

Abstract:

Neurologic complications can be seen in mild to severe COVID-19 with a higher risk in patients with severe COVID-19. These can occur as a direct consequence of viral infection or consequences of treatments. The spectrum ranges from non-life-threatening, like headache, fatigue, malaise, anosmia, dysgeusia, to life-threatening complications, like stroke, encephalitis, coma, Guillain-Barre syndrome. A high index of suspicion can aid in early recognition and treatment. Outcomes depend on severity of underlying COVID-19, patient age, comorbidities, and severity of the complication. Postacute sequelae of COVID-19 range from fatigue, headache, dysosmia, brain fog, anxiety, depression to an overlap with postintensive care syndrome.

Source: Dangayach NS, Newcombe V, Sonnenville R. Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19. Crit Care Clin. 2022 Jul;38(3):553-570. doi: 10.1016/j.ccc.2022.03.002. Epub 2022 Mar 23. PMID: 35667743; PMCID: PMC8940578. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940578/ (Full text)

Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study

Abstract:

Importance Multi-organ impairment associated with Long COVID is a significant burden to individuals, populations and health systems, presenting challenges for diagnosis and care provision. Standardised assessment across multiple organs over time is lacking, particularly in non-hospitalised individuals.

Objective To determine the prevalence of organ impairment in Long COVID patients at 6 and at 12 months after initial symptoms and to explore links to clinical presentation.

Design This was a prospective, longitudinal study in individuals following recovery from acute COVID-19. We assessed symptoms, health status, and multi-organ tissue characterisation and function, using consensus definitions for single and multi-organ impairment. Physiological and biochemical investigations were performed at baseline on all individuals and those with organ impairment were reassessed, including multi-organ MRI, 6 months later.

Setting Two non-acute settings (Oxford and London).

Participants 536 individuals (mean 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post-COVID-19). 331 (62%) with organ impairment or incidental findings had follow up, with reduced symptom burden from baseline (median number of symptoms: 10 and 3, at 6 and 12 months).

Exposure SARS-CoV-2 infection 6 months prior to first assessment.

Main outcome Prevalence of single and multi-organ impairment at 6 and 12 months post-COVID-19.

Results Extreme breathlessness (36% and 30%), cognitive dysfunction (50% and 38%) and poor health-related quality of life (EQ-5D-5L<0.7; 55% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single organ impairment. At baseline, there was fibro-inflammation in the heart (9%), pancreas (9%), kidney (15%) and liver (11%); increased volume in liver (7%), spleen (8%) and kidney (9%); decreased capacity in lungs (2%); and excessive fat deposition in the liver (25%) and pancreas (15%). Single and multi-organ impairment were present in 59% and 23% at baseline, persisting in 59% and 27% at follow-up.

Conclusion and Relevance Organ impairment was present in 59% of individuals at 6 months post-COVID-19, persisting in 59% of those followed up at 1 year, with implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID.

Source: Andrea Dennis, Daniel J Cuthbertson, Dan Wootton, Michael Crooks, Mark Gabbay, Nicole Eichert, Sofia Mouchti, Michele Pansini, Adriana Roca-Fernandez, Helena Thomaides-Brears, Matt Kelly, Matthew Robson, Lyth Hishmeh, Emily Attree, Melissa Heightman, Rajarshi Banerjee, Amitava Banerjee. Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study. medRxiv 2022.03.18.22272607; doi: https://doi.org/10.1101/2022.03.18.22272607  https://www.medrxiv.org/content/10.1101/2022.03.18.22272607v1.full.pdf (Full text)

Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study

Abstract:

Objective: Non-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19.

Approach and results: We conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10-3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10-3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57- 0.75], p = 0.001 and AUC = 0.60, CI [0.51- 0.69], p = 0.03, respectively).

Conclusion: Sulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.

Source: Charfeddine S, Ibnhadjamor H, Jdidi J, Torjmen S, Kraiem S, Bahloul A, Makni A, Kallel N, Moussa N, Boudaya M, Touil I, Ghrab A, Elghoul J, Meddeb Z, Thabet Y, Ben Salem K, Addad F, Bouslama K, Milouchi S, Hammami R, Abdessalem S, Abid L. Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study. Front Cardiovasc Med. 2022 May 12;9:866113. doi: 10.3389/fcvm.2022.866113. PMID: 35647070; PMCID: PMC9133483. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133483/ (Full text)

Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study

Abstract:

Background: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database.

Methods: 6306 patients identified as having CFS during the 2000-2012 period and 6306 controls (with similar distributions of age and sex) were analyzed.

Result: The patients with CFS were predominantly female and aged 35-64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn’s disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group.

Conclusion: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.

Source: Leong KH, Yip HT, Kuo CF, Tsai SY. Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study. J Transl Med. 2022 Jun 11;20(1):268. doi: 10.1186/s12967-022-03461-0. PMID: 35690765. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03461-0  (Full study)

Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis

Abstract:

Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features. There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis. The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.

Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”. Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.

Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index. Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value. All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.

Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.

Source: Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M. Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis. Autoimmun Rev. 2022 Jun 8:103129. doi: 10.1016/j.autrev.2022.103129. Epub ahead of print. PMID: 35690247. https://pubmed.ncbi.nlm.nih.gov/35690247/