A Systematic Scoping Review and Conceptual Analysis of New-Onset Fibromyalgia Manifestations After Non-Hospitalized COVID-19: Empirics, Definitions, Methodologies, Pathophysiology, Mapping of Literature, and Knowledge Gaps

A Systematic Scoping Review and Conceptual Analysis of New-Onset Fibromyalgia Manifestations After Non-Hospitalized COVID-19: Empirics, Definitions, Methodologies, Pathophysiology, Mapping of Literature, and Knowledge Gaps | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search A Systematic Scoping Review and Conceptual Analysis of New-Onset Fibromyalgia Manifestations After Non-Hospitalized COVID-19: Empirics, Definitions, Methodologies, Pathophysiology, Mapping of Literature, and Knowledge Gaps Shiloh Plaut doi: https://doi.org/10.1101/2025.10.23.25338705 Shiloh Plaut 1 University of Nicosia medical school Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: shilowhale{at}gmail.com Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract The global coronavirus pandemic has led to a quiet wave of a chronic illness referred to as ‘Long/Post Covid-19 syndrome’ (LC) which bears a notable resemblance to functional somatic or ‘fibromyalgia-type’ syndromes, and whose pathophysiology is undetermined. The lack of effective therapies for LC is straining healthcare systems worldwide and causing widespread public health and socioeconomic concerns. “Fibromyalgia” is a controversial chronic pain condition of unknown etiology largely attributed to generalized sensory hypersensitivity due to dysregulated central pain processing pathways (i.e., central sensitization). Despite intense research and growing attention in the scientific community, the clinical overlap of fibromyalgia, somatic symptom disorder, and post-viral chronic fatigue, is a medical puzzle yet to be solved, especially when occurring in non-severe infections and previously healthy individuals. This systematic scoping review covers the empirical findings on new-onset fibromyalgia manifestations after non-hospitalized covid-19. MEDLINE, Web of Science, and APA PsycINFO were searched in a systematic scoping approach for empirical studies on new-onset fibromyalgia after non-severe non-hospitalized covid-19, charting study characteristics and outcome data. A total of 228 records were included. Various types of methods, tools, and study designs are being used for LC research, with inconsistency in key concepts and definitions. This leads to a fragmented understanding of the relationship between SARS-CoV-2 infection and LC. Prevalence studies of post-Covid fibromyalgia are ongoing and susceptible to bias. The empirical evidence supports an overlap between LC, chronic fatigue syndrome, and fibromyalgia but the molecular mechanisms still remain unclear. There are conflicting findings regarding presence of viral particles, central sensitization, autoantibodies, and more. This review highlights the need for standardized definitions and rigorous methodologies in research on LC. Future research should focus on epidemiological population-based studies with representative sampling and improving methodology, refining evolving definitions, harmonization of research, elucidating neurological mechanisms in hypothesis driven studies, and developing effective therapeutic strategies. The discussion synthesizes findings and offers an integrative mechanism for the pathophysiology of fibromyalgia and multisystem medically unexplained manifestations of LC as a non-autoimmune connective tissue disease and is used to make testable theory-based predictions for future investigations. 1. Introduction As the aftermath of the coronavirus pandemic continues to unravel, many convalescent patients have remained with long-term multi-symptom illness following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) ( 1 ). Terms such as ‘long COVID-19’ (LC), post-acute sequelae of COVID-19 (PASC), and post-COVID-19 condition (PCC) are used somewhat interchangeably in the literature to describe the persistent symptoms and sequelae that can last for weeks, months, and even years, following the acute phase of SARS-CoV-2 infection. Although it had initially received less attention, LC is lately becoming recognized as a global public health challenge ( 1 – 4 ), to such an extent that the National Institute of Health (NIH) allocated more than 1 billion dollars for LC research in the year 2021 ( 5 ). The incidence of “post-acute COVID-19 condition” is estimated to be approximately 10–35% of individuals positive for SARS-CoV-2 and is said to occur more frequently in COVID-19 cases that involved hospitalization ( 2 , 4 , 6 – 8 ) but these estimates vary with the timeframe of data collected since initial acute COVID-19 and the definitions used. Despite ongoing extensive investigations and lots of speculations, the pathophysiological mechanisms of the post-acute sequelae of COVID-19 are poorly understood, thus impeding the development of effective treatments. Interestingly, the medically unexplained multisite symptoms of LC have symptomatologic overlap and a surprising resemblance to functional psychosomatic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia and may even share a similar pathophysiology ( 9 – 14 ). Post-viral infection syndromes are already known to be characterized by persistent disabling fatigue, arthralgia/myalgia, neurocognitive difficulties, and mood disturbances ( 15 ). New-onset fibromyalgia syndrome is being identified as a prevalent condition in convalescent individuals following acute COVID-19 ( 16 , 17 ). According to a study in Sweden, many of convalescent COVID-19 patients who initially only had mild SARS-CoV-2 infection and were previously healthy that are affected by LC have generalized chronic pain and fatigue and fulfill the 2016 diagnostic criteria for “fibromyalgia” ( 16 ). What’s more, LC patients often fulfill the diagnostic criteria for ME/CFS ( 18 ). Many individuals who experience LC exhibit persistent pain despite having experienced mild initial infection, therefore effective pain management strategies in LC syndrome are needed ( 16 , 19 ). In this paper findings are presented from a systematic scoping review covering the empirical findings on new-onset fibromyalgia after non-hospitalized Covid-19, followed with a synthesis of data for offering a pathophysiological mechanism for the syndrome of fibromyalgia. “Fibromyalgia syndrome” ( 20 ) is a heterogenous chronic pain condition of unknown etiology characterized by widespread musculoskeletal pain, post-exertional malaise, fatigue, and cognitive difficulties, and considerably overlaps with ME/CFS whose predominant feature is relentless fatigue while musculoskeletal pain is implied in its name ( 21 ). Fibromyalgia, which lies within the spectrum of medically unexplained symptoms ( 22 , 23 ) (sometimes regarded as a “non-disease”) and whose chronic pain is frequently said to be unattributable to any identifiable organic pathology ( 24 ), has an estimated prevalence of ∼1-6 percent of the general population and leads to a significant burden on the healthcare system and considerably impacts patients’ quality of life and emotional health ( 20 , 25 – 27 ). Despite extensive research in the recent decades ( 28 ), the patho-mechanisms underlying fibromyalgia are still disputed and poorly elucidated ( 29 ) and the field remains in relative stagnation in terms of translation to therapeutic clinical impact, in what can be termed “a huge unmet medical need” ( 30 ). After having been regarded as a connective tissue disorder in the nineteenth and twentieth centuries ( 31 ), that idea has since then been abandoned and the most accepted and widely investigated theory nowadays for the pain of fibromyalgia is central sensitization (i.e., a dysfunction of ascending and descending somatosensory processing neural pathways in the spinal cord and brain, facilitated by structural and functional alterations in the central nervous system or a “nociplastic” malfunction) although, there are some authors who question this thesis ( 14 , 32 – 37 ). The international association for the study of pain (IASP) explains that it’s a pain disorder of its own, not a symptom of any other underlying organic disease ( 38 ). Remarkably, in a cross-sectional survey of Canadian Rheumatologists, 30 percent of them asserted that fibromyalgia was a psychosocial condition ( 39 ). Even though the pathophysiology of fibromyalgia is still under much dispute by researchers and practitioners in the field ( 16 , 40 ), the therapeutic strategy for fibromyalgia is usually derived from this theory of “central sensitization” ( 32 , 41 – 44 ) and is generally considered by clinicians to be ineffective ( 30 , 33 , 45 – 47 ). As with fibromyalgia, results in medical tests that are offered as standard care are often unremarkable in patients with LC ( 8 , 12 , 48 , 49 ) and some authors nowadays describe a subset of patients as having “functional long-COVID” or “ME/CFS subtype of long COVID” or a “central sensitization phenotype” in cases that present with subjective complaints and functional impairment yet no apparent organ damage ( 11 , 50 – 52 ). Some authors argue that LC is likely a disorder of the domain of psychology and psychosomatics ( 30 , 53 ). This manuscript is divided into two parts: Part 1 presents the findings from the systematic scoping literature review and the empirical evidence on new-onset fibromyalgia after non-hospitalized SARS-CoV-2 infection. The motivation behind this review was to find out what the evidence is on new-onset fibromyalgia manifestations post-Covid-19, and the goal was to clarify key concepts and definitions, map existing evidence, identify gaps in knowledge, and report on the extent and types of evidence, the methods being used to research it, and report on the methodological consistency or inconsistency across studies in this new emerging field of research. For this reason, a scoping-type review was conducted. In Part 2, building on a synthesis of data, a connective-tissue-based theoretical model is presented for the pathophysiology of fibromyalgia syndrome. The objective is to apply this model to fibromyalgia features of LC and reconcile the findings and anomalies encountered in part 1. The model depicts a neuromechanobiological disorder of the musculoskeletal system driven by the cascade of myofibroblast extracellular matrix remodeling and their natural tensile force generation in soft tissue, which drive peripheral and central pain mechanisms. Implications and predictions of this model are discussed. 2. Methods The review follows recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) ( 54 ). 2.1. Search strategy A systematic search was conducted using key phrases on fibromyalgia and covid-19 in Web of Science, MEDLINE, and PsycInfo, in all fields for all study types since inception until December 31, 2024. Detailed documentation of the search phrases that were used for each database can be found in the supplementary material. An example of the search phrase used in MEDLINE (via PubMed) is as follows: ((“fibromyalgi*” OR “myofascial pain*” OR “central sensitization*” OR “central sensitisation” OR “nociplastic pain”) OR (“Fibromyalgia”[Mesh] OR “Central Nervous System Sensitization”[Mesh] OR “Myofascial Pain Syndromes”[Mesh])) AND ((“covid*” OR “coronavirus” OR “sars-cov-2”) OR (“COVID-19”[Mesh] OR “Coronavirus”[Mesh] OR “SARS-CoV-2”[Mesh])). Inclusion criteria: A record was to be included if its full text was accessible for review, and related to new-onset fibromyalgia features after sars-cov-2 infection (confirmed, self-reported, or suspected), in individuals who did not have fibromyalgia prior to infection, in the absence of a reported clear pathology or well-defined organ damage to account for symptoms after non-severe non-hospitalized Covid-19. Specifically, this included primarily studies related (but not limited) to epidemiology, symptoms, pathophysiology, disease course, patient surveys and experiences, diagnostics, and interventions, as well as studies reporting empirical evidence in the context of a theoretical mechanistic link to the putative pathophysiology of fibromyalgia. “Fibromyalgia features” were defined for this purpose as either clinical diagnosis of fibromyalgia, fulfilling criteria for fibromyalgia, stated suspicion of fibromyalgia, positive screening for fibromyalgia, new onset widespread musculoskeletal or “non-specific”/myofascial pain in the absence of a clear pathology or well-defined organ damage to account for it after non-severe non-hospitalized Covid-19. Empirical studies (e.g., clinical trials, qualitative or quantitative observational studies, case reports, etc.) both basic/translational research and clinical, and reviews (topical, narrative, systematic, meta-analyses) to be eligible. Various terms are being used in literature to refer generally to long-lasting symptoms after COVID-19, e.g., long-haul COVID-19, chronic COVID, long COVID, post COVID, post-acute COVID-19, etc. The a-priori Long COVID-19 definition for the review’s purpose is described in the supplementary material, taking a similar approach to Phillips & Williams (2021) ( 8 ) that assert that “long covid is not a condition for which there are currently accepted objective diagnostic tests or biomarkers, i.e., it is not blood clots, myocarditis, multisystem inflammatory disease, pneumonia, or any number of well-characterized conditions caused by covid-19.” Exclusion criteria: Studies published in journals whose highest ranking was Q4 in their specialty field(s) in the year of the record’s publication according to the journal citation reports (JCR) (using the Journal Citation Indicator ranking) were excluded. For papers published during the year 2024 whose ranking was unavailable in JCR, the quartile given in the previous year was taken. Studies published in journals not listed in JCR were excluded from the systematic part. Non-English language records were excluded. After title and abstract read, items deemed either “relevant” or “possibly relevant” (i.e., not irrelevant or off-topic) based on title and abstract underwent a full text inspection for final inclusion or exclusion based on the abovementioned criteria. During the full text read of an included paper, the reference list was also inspected to identify additional records on post-Covid fibromyalgia that were potentially eligible for inclusion. 2.2. Data charting For the included records, data abstracting and charting was conducted on a charting form for the documentation of essential information from each record (title, first author, publication date, journal, type of study, aims of the study, summary of study design and methods, population characteristic if relevant, main findings, main theme(s), JCR quartile for peer-reviewed publications). Each article was tagged by its focus according to its main theme(s) developed during the review of the literature. 2.3. Additional non-systematic searches for subtopics and preprints Additional literature was added as part of the scoping search from pubmed and web of science and from the preprint database medRxiv. This part was not done systematically and included subtopics such as post-covid, myofascial tissue in long covid, fascia, myofibroblasts and fibrosis in post-covid-19, acupuncture in long covid, lifestyle and fibromyalgia-type syndromes, medically unexplained symptoms after covid-19, long/post covid treatment, chronic fatigue syndrome in LC (due to the significant clinical overlap with fibromyalgia), and acupuncture in chronic fatigue syndrome, and other subtopics identified during the review process such as joint hypermobility syndrome. The literature from this non-systematic narrative part will be presented separately in the findings section. Figure 1 shows a diagram summarizing the scoping review process. Download figure Open in new tab Figure 1: Schematic outline of the systematic scoping review process. 3. Part one-findings from the systematic scoping review After removal of duplicates, 307 records were initially screened, afterwards 198 were excluded based on title/abstract or full text read (of them three records were excluded because of no access to their full text). 42 records were added from the cited reference list of included records. 150 records were included in the systematic literature review, and an additional 78 from non-systematic searches, for a total of 228 records finally included in the scoping review. Records whose main topic was ME/CFS even without involving fibromyalgia were included due to the close symptomatologic overlap ( 55 ) between the two syndromes. Whenever there was ambiguity whether the sampled population in a study was hospitalized or not, the record was included in the review. If both hospitalized and non-hospitalized patients were recruited in a study, the record was included. Also, non-empirical studies on fibromyalgia and covid (such as opinion, viewpoints, speculations and hypotheses, etc.) were included. Few older studies on sars-cov-1 were found but none fit the inclusion criteria. Common themes were (a single record may be allocated to more than one theme): Chronic fatigue or chronic fatigue syndrome after viral infection ( 49 , 55 – 71 ) Putative LC relevant patho-mechanisms ( 11 , 13 , 14 , 21 , 24 , 36 , 43 , 51 , 55 , 58 , 61 , 67 , 72 – 101 ) Chronic pain after sars-cov-2 infection or during the covid pandemic ( 30 , 49 , 68 , 102 – 124 ) Observational studies of fibromyalgia syndrome after COVID-19 ( 10 , 16 , 48 , 52 , 104 , 114 , 125 – 134 ) Overlap between fibromyalgia and/or chronic fatigue syndrome and/or LC ( 13 , 21 , 43 , 51 , 53 , 55 , 64 , 66 , 71 , 86 , 123 , 124 , 128 , 132 , 135 – 141 ) Speculation on emotional/psychosocial stress as a trigger of fibromyalgia post-COVID-19 ( 21 , 53 , 102 , 105 , 124 , 142 , 143 ). Speculations or empirical investigations on possible central sensitization in LC ( 52 , 53 , 72 , 77 , 92 , 103 , 104 , 110 – 112 , 117 , 137 , 139 , 142 – 148 ) Hypothetical and speculative papers on potential treatments for LC ( 14 , 56 , 58 , 109 , 124 , 147 , 149 , 150 ) Interventions in LC or post-viral infection fatigue ( 68 , 137 , 151 – 161 ) SARS-CoV-2 and myofascial-type pain ( 19 , 121 , 127 , 145 , 162 , 163 ) Other (e.g., study protocols, post-COVID manifestations, LC phenotyping, rheumatoid arthritis, hypermobility syndrome) ( 2 , 8 , 65 , 68 , 87 , 126 , 135 , 136 , 138 , 140 , 141 , 164 – 186 ). The distribution of publication ranking according to JCR quartile (ranging from Q1 to Q3) was as follows: Q1-80/148 (54%), Q2-54/148 (36%), Q3-14/148 (9%). Two additional records were included: a clinical guideline ( 186 ) and the full paper of a study that was presented as a meeting abstract ( 183 ). The records were of the following types: Observational human studies (excluding case series, case reports, and conference abstracts) (n=60) ( 2 , 10 , 16 , 48 , 49 , 52 , 61 , 64 , 65 , 67 – 69 , 75 , 77 , 81 , 85 , 88 , 91 , 93 , 99 – 101 , 104 , 105 , 108 , 111 – 115 , 118 , 121 , 127 – 130 , 132 – 137 , 140 , 141 , 144 – 146 , 148 , 154 , 155 , 163 , 167 , 170 , 173 , 177 – 179 , 182 , 183 , 185 ) Case reports or case series (n=6) ( 19 , 126 , 160 – 162 , 171 ) Interventional studies (n=8) ( 89 , 150 – 153 , 156 , 157 , 159 ) Non-systematic reviews (including narrative reviews, speculative reviews, and topical articles) (n=37) ( 11 , 13 , 14 , 21 , 36 , 51 , 55 – 58 , 72 – 74 , 76 , 79 , 80 , 82 – 84 , 90 , 92 , 95 , 96 , 102 , 103 , 109 , 110 , 117 , 138 , 142 , 147 , 149 , 166 , 176 , 180 , 181 , 184 ) Systematic reviews (with or without meta-analysis) (n=12) ( 24 , 59 , 60 , 62 , 70 , 94 , 106 , 107 , 116 , 124 , 143 , 158 ) Comments, editorials, viewpoints, and letters (n=14) ( 8 , 30 , 43 , 53 , 66 , 78 , 86 , 87 , 97 , 98 , 119 , 139 , 169 , 174 ) Congress/meeting abstracts (n=8) ( 63 , 71 , 120 , 122 , 123 , 125 , 131 , 175 ) Official clinical guidelines (n=1) ( 186 ) Other (descriptive papers, study protocols) (n=4) ( 164 , 165 , 168 , 172 ) Figure 2 shows the distribution of record types included in the systematic part. Download figure Open in new tab Figure 2: Distribution of records according to types of publications. A brief description of types of records excluded e.g., ( 17 , 187 – 206 ), is provided in the supplementary material. The following sections present the main findings of the review. 3.1. Definitions, Research Inclusion/Exclusion Criteria in LC studies, and Measurement Tools 3.1.1. Definitions & Research Inclusion/Exclusion Criteria An analysis of the methodologies employed in LC studies reveals significant heterogeneity in LC definitions and the inclusion and exclusion criteria for LC research including LC patients, individuals with a prior SARS-CoV-2 infection, and control subjects. This variability underscores the evolving understanding of LC and the challenges that stem from studying such a novel and complex condition. Various approaches to inclusion and exclusion criteria were found in studies as follows: COVID-19 individuals : COVID-19 or SARS-CoV-2 infected individuals were seen defined differently across studies and involved different inclusion and exclusion criteria. A “COVID-19” individual was established either by self-report of the participant (e.g., based on symptoms consistent with COVID-19, a self-reported physician diagnosis of COVID-19, or self reported positive COVID-19 test), positive immunoglobulin response, a documented positive test in healthcare databases or COVID registries (e.g., PCR test), or by logical combinations of these conditions, for example. To give a specific example, in a study by Peterson et al. ( 75 ), symptomatic COVID-19 individuals were those who self-reported the symptoms that they had experienced during active COVID-19 infection from a list modified from the CDC and provided evidence of a previous positive PCR or antibody ELISA test indicating infection. On the other hand, the asymptomatic COVID-19 group consisted of those participants who self-reported no symptoms and had a previous positive PCR and/or positive antibody test (or self-reported that they had no symptoms but had a positive antibody test). In case of a non-LC (i.e., recovered COVID-19) infected individual, absence of persistent symptoms beyond a certain timeframe or the absence of symptoms altogether defined the convalescent group ( 91 , 185 ). Such participants may have undergone a brief verbal screening to confirm no active symptomatology. Severity of acute illness: few studies stratified the COVID-19 group based on the severity of their acute COVID-19 illness (e.g., hospitalized vs. non-hospitalized). Additionally, unclear onset of symptoms was sometimes used as an exclusion criteria for self-reported COVID-19 ( 153 ). Controls and Healthy controls: were also seen defined differently across studies, depending on the study ( 81 , 91 , 104 , 115 ). The heterogeneity in defining these crucial comparator groups has significant implications for interpreting research findings and understanding the true impact of SARS-CoV-2 infection. Healthy uninfected controls were often defined as individuals who have no prior history of COVID-19 infection, often confirmed through PCR and antibody testing, while other studies defined control groups as those with no active symptomatology or implementing both conditions ( 91 ). Naturally, the longer the duration into the pandemic the more difficult it would have been for investigators to find non-infected individuals. Damasceno et al. (2023) ( 115 ) chose adults who had COVID-19 for at least 3 months prior to the data collection and without a chronic pain syndrome. Examples of inclusion criteria are (i) individuals that reported they did not have a confirmed objective COVID-19 test (e.g., PCR or home kit) ( 127 ), (ii) individuals that do not have a previous history of medical conditions as self-reported, (iii) no previous symptoms self-reportedly and negative result on the PCR and antibody test ( 75 , 118 ), and (iv) based on (absence of) diagnoses in medical records or healthcare registries. The non-infection healthy control group in Peterson et al., for example, were those who self-reported no previous symptoms and were negative on the PCR and antibody test administered immediately prior to carrying out the study’s investigation ( 75 ). Long COVID, Post-COVID condition, Persistent COVID symptoms, and other parallelterms: A fundamental aspect of LC research is the definition used to identify affected individuals. Various studies employ different criteria, often aligning with guidelines from organizations like NICE and WHO, or developing their own definitions. A consistent inclusion criterion across many studies was, naturally, the persistence of symptoms for a defined duration following the acute phase of SARS-CoV-2 infection (e.g., 4, 6, 12 weeks). Another additional inclusion condition often used for LC was confirmation of prior SARS-CoV-2 infection (by positive PCR, serology, self-reportedly, independent clinician, rapid antigen test with documentary proof from a health authority ( 159 ), or documentation in electronic health records). Some LC studies included only previously healthy individuals. Self-reported history of confirmed or probable COVID-19 infection according to WHO guidelines was also seen integrated into the inclusion criteria ( 91 ). Certain studies focused on individuals experiencing a particular set of new persistent symptoms after acute COVID-19 ( 133 ), such as musculoskeletal pain ( 114 ) or neurological symptoms ( 182 ) whereas others focused on evident reduction in the level of functioning and activity or participation in daily life compared to before the infection ( 16 ). Exclusion of alternative etiologies: some studies incorporated a process to rule out alternative medical etiologies for persistent symptoms, such as medical evaluations by physicians, or self-reportedly. Pre-existing chronic pain prior to COVID-19 infection, pre-existing chronic fatigue syndrome or fibromyalgia were sometimes part of the exclusion criteria ( 155 ). Examples of inclusion criteria for Post COVID/Long COVID/Chronic COVID/Subacute COVID/“persistent symptoms” or “non-recovery from COVID”: (i) participant self-reporting not to have been fully recovered after COVID-19 ( 146 ), (ii) participant self-reported physician-made diagnosis of LC ( 150 ), (iii) self-reported physician made diagnosis combined with a previous positive COVID-19 test ( 128 ), (iv) persistent symptoms beyond a specified interval of time (e.g., 12 weeks) ( 141 , 165 ), (v) presence of any persistent symptom since SARS-CoV-2 infection (or any persistent symptom among a predetermined list of symptoms) ( 93 , 99 , 185 ), (vi) persistent symptoms and negative Covid test for excluding active infection ( 75 , 154 ), (vii) based on the world health organization’s consensus definition ( 101 ), (viii) Bierle et al.’s (2021) criteria ( 144 ), (ix) fulfilling the official 2015 diagnostic criteria for ME/CFS ( 155 ), (x) persistent post-exertional malaise for 3 or more months verified by the DePaul Symptom Questionnaire ( 89 ), (xi) referral to-or diagnosis by-a post-Covid clinic, and more ( 137 , 156 ). A reader would notice correctly that some of the above examples can conflate “LC syndrome” and “persistent COVID symptoms,” which are not necessarily the same. Noteworthy, as opposed to simply including persistent symptoms, in case a syndrome is what investigators are aiming to investigate, defining LC for the purpose of a study as at least one persistent symptom, any symptom, even hyposmia, does not necessarily reflect a syndrome, in agreement with Phillips and Williams ( 8 ). Lau et al. (2024) ( 159 ), for example, included individuals fulfilling the Centers for Disease Control and Prevention criteria for post-acute COVID condition and at least one of 14 symptoms included in their post-acute COVID-19 syndrome 14-item improvement questionnaire (PACSQ-14) for four weeks or more after SARS-CoV-2 infection. Matta et al. (2022) ( 185 ), in their widely cited publication of whether belief in having had COVID-19 and actually having had the infection (when verified by SARS-CoV-2 serology testing) were associated with persistent physical symptoms after COVID-19, in the context of LC, included individuals with at least one persistent symptom among a list of symptoms present for the past 4 weeks and lasting more than 8 weeks. That list consisted of headache, back pain, joint pain, muscular pain, sore muscles, sleep problems, fatigue, sensory symptoms such as pins and needles, tingling or burning sensation, skin problems, poor attention or concentration, hearing impairment, stomach pain, constipation, breathing difficulties, palpitations, chest pain, dizziness, cough, diarrhea, anosmia, and other symptoms. Eccles et al. (2024) ( 170 ) determined non-recovery from COVID-19 from a dichotomous self-reported response to the question “Thinking about the last or only episode of COVID-19 you have had, have you now recovered and are back to normal?” while Amsterdam et al. (2024) ( 133 ) recruited outpatients from a post-COVID clinic who, subsequent to non-hospitalized COVID-19, developed a prolonged illness, leading to a diagnosis of LC syndrome characterized by the persistence of one or more symptoms for over a month: dyspnea, cough, cognitive decline, brain fog, or fatigue, going by reference to the 2020 published NICE guidelines. Azcue et al. ( 141 ) took a similar approach and explicitly excluded respiratory symptoms persisting for 12 weeks post-infection, severe bilateral pneumonia, admission to an intensive care unit, or other manifestations necessitating hospitalization. The Centers for Disease Control and the National Academies of Sciences, Engineering and Medicine offer their definitions for LC terminologies ( 80 ). Table 1 summarizes, in a non-exhaustive list, official definitions according to several national and international health bodies. View this table: View inline View popup Table 1: Selective example of definitions and terminologies used for persisting COVID symptoms. Overall, there is inconsistency in LC definitions and research criteria across studies, the formal international bodies vary in their exact definitions which aren’t necessarily operative and applicable for a research study, and empirical studies don’t always employ or refer to an official LC definition. 3.1.2. Assessment and Measurement Tools Methodological consistency in the field could be beneficial, and is important for generalizability and for better coherence in future research and meta-analyses. Recurring instruments used for assessments and measurements in empirical studies as found in the reviewed literature are as follows. Questionnaires and scores such as: The visual analogue scale: for multiple measures such as pain and fatigue. The brief pain inventory (BPI) ( 128 ) and verbal numeric pain rating scale: for assessing pain ( 148 ). Fatigue Severity Scale ( 128 ): for assessing fatigue. Insomnia Severity Index: for the evaluation of insomnia ( 16 ). Fibromyalgia Symptom Scale (FSS) including the widespread pain index (WPI) and symptom severity scale (SSS) based on the ACR fibromyalgia diagnostic criteria and/or modified for self-administration ( 10 , 128 ), Fibromyalgia Rapid Screening (FIRST) questionnaire ( 135 ), and the central sensitization inventory (CSI) ( 146 ): for assessment of fibromyalgia-type features, screening, or diagnosis. It is worth noting here that the CSI has not been validated to assess or measure central sensitization or neural activity ( 29 ), despite several studies using it for this purpose. Fibromyalgia Impact Questionnaire (or revised version) and its counterpart Symptom Impact Questionnaire (SIQ or SIQ-revised) for assessing psychosomatic disease burden ( 136 , 137 ). More data regarding fibromyalgia questionnaires can be found in a systematic review by Carrasco-Vega et al. (2023) ( 218 ). Post-COVID-19 Functional Status (PCFS) self-reporting version: for assessing functional status post-COVID-19 infection. Yorkshire Rehabilitation Scale (C19-YRS) questionnaire: for assessing LC impact and need for rehabilitation in LC patients. The European Quality of Life Instrument versions ( 16 , 146 ) and Short Form 36 ( 16 ): for evaluating health-related quality of life. Versions of the Patient Health Questionnaire (PHQ-2, 8, 9): for depression assessment. Patient Health Questionnaire 15 (PHQ-15) for assessing somatic symptoms. Hospital Anxiety and Depression Scale ( 16 ) and Generalised Anxiety Disorder-7 scale: for anxiety assessment. Other measurement tools and methods more commonly used were: Quantitative sensory testing ( 88 ). Algometer for pressure pain threshold ( 75 , 148 ). Cold pressure test for conditioned pain modulation ( 75 ). Diagnostic codes of the international classification of diseases when using data from medical records. Table 2 provides a comprehensive summary of the instruments and methods used in studies. View this table: View inline View popup Table 2: Summary of tools and methods that were used in the reviewed studies. Some of these were used more often than others, and some only in one study. The studies cited for each tool are a selected example for reference. The tools are not listed by order of their frequency used in studies. 3.2. Long COVID-19 mechanisms Elucidating the mechanism of LC is still a matter of ongoing research. To give a brief overview, putative LC patho-mechanisms, as found in the literature, included: immune dysregulation and/or autoimmunity ( 73 , 78 , 86 , 95 , 99 , 140 ), stress-induced small fiber neuropathy ( 21 ), mitochondrial dysfunction ( 81 ), metabolic abnormalities ( 81 ), infection induced genetic or epigenetic changes ( 83 ), impaired hemopoiesis ( 81 ), blood-brain barrier damage, endothelial dysfunction ( 80 ), direct viral invasion and cytotoxicity, cytokine storm ( 142 ), persistence of viral particles in peripheral tissue ( 55 , 86 ), re-activation of latent pathogens ( 55 , 140 ), dysbiosis ( 159 ) and/or disruption of the gut-brain axis ( 86 , 159 ), dysautonomia, hormonal imbalance ( 55 ), amyloid-containing deposit accumulation in blood vessels causing local hypoxia ( 67 ), reduced cellular aerobic capacity, skeletal muscle injury and inflammatory myopathy ( 88 ), deconditioning or skeletal muscle atrophy ( 88 ), coagulation abnormalities or microthrombi, cerebral vasculopathy ( 90 ), psychosomatics ( 30 , 68 , 98 ), central sensitization, neuroinflammation, glial-cell reactivity, brainstem dysfunction or other central neurological pathology ( 24 , 51 , 72 , 86 , 90 , 139 , 142 ), each of these which may plausibly overlap with another in a multifaceted pathophysiology. Correspondences in the field of rheumatology regarding the parallels between LC and fibromyalgia, and discussions on LC being regarded as psychosomatic or non-physiological, were also found ( 8 , 30 , 53 ), as well as criticism of the dualistic psychological-physiological medical thinking of physical versus mental illness ( 97 , 98 ). An integrative framework of interaction of biological, social, experiential, and psychological factors in LC functional somatic symptoms was advocated ( 97 ). There are some authors who suggest that all chronic pain must be considered in the context of the biopsychosocial model, although the evidence for this is still mixed ( 102 ). Other authors seem more inclined to suggest that emotional stress associated with COVID-19 could trigger the onset of post-COVID fibromyalgia ( 53 , 92 ). Several authors discuss the idea of coronavirus inducing central sensitization through neuroinflammation ( 51 , 77 , 79 , 112 , 114 , 146 ). Goldenberg (2024) ( 55 ) gives an overview of the overlap between LC and fibromyalgia-type syndromes, covering the latest empirics in relation to current theories, and argues for a refined definition of LC that’s limited to persistent multisystem symptoms in the absence of well-defined organ damage. Calabrese and Mease (2024) ( 43 ) note that emotional dysregulation is often attributed to fibromyalgia pathogenesis in theory but argue against it being the primary pathogenic cause, pointing out a lack of strong evidence that psychological stress causes fibromyalgia, and there being few, if any, prospective longitudinal studies that show this to be the case. Instead, they suggest a two-way relationship where pain treatment can improve emotional issues, as was shown in empirical studies ( 43 ), implying pain itself significantly contributes to emotional dysregulation. Even if some commonality among mechanisms exists, fibromyalgia after COVID-19, they argue, shouldn’t be regarded as a synonym for LC but seen as a part of a more complex post-acute illness. Meanwhile, in a study by Appelman et al. (2024) that investigated skeletal muscle biopsies of 25 LC adult patients after inducing post-exertional malaise by maximal exercise test, several abnormalities were found including extracellular amyloid deposits, metabolic dysfunctions, and more, compared to non-LC individuals ( 67 ). These findings are suggestive of a muscle tissue involvement in LC. Contrary to the mainstream literature on the subject, Shoenfeld and colleagues reiterate the possibility of expression of functionally active autoantibodies against epitopes belonging to the autonomic nervous system as a possible pathobiology to explain LC ( 14 , 74 , 76 , 78 ), seen by them as a syndrome of autonomic imbalance that overlaps with fibromyalgia and related syndromes. Empirical studies indeed found several distinct functionally active autoantibodies in LC patients ( 100 ), at least some of which seem to be associated with COVID-19 severity ( 14 ). Yet, the adequacy of such a theory, however appealing it may be, to mild and asymptomatic infection of coronavirus leading to LC, remains an open question ( 51 , 81 , 91 , 93 ). The authors also emphasized, rightfully so, that there is substantial controversy with regards to the etiology and pathophysiology of fibromyalgia syndrome ( 14 ). Recently, Yin et al. (2024) published compelling evidence underscoring immune dysregulation in LC ( 99 ) pointing towards improper crosstalk between cellular and humoral adaptive immunity. A comprehensive essay on LC’s putative pathophysiology, which wasn’t the purpose of this scoping review, can be found in publications dedicated to this subject ( 1 , 51 , 90 , 95 , 221 ). In summary, there are plenty of ongoing speculations on LC pathobiology and mechanism, some of which are substantiated more by empirical studies and some less, but a comprehensive theoretical explanation for LC, let alone for post-COVID-19 fibromyalgia, and a rational organic mechanism that offers an effective treatment and enables a-priori successful theory-based predictions are still lacking as research is ongoing. 3.3. Observational studies on widespread musculoskeletal pain and fibromyalgia after sars-cov-2 infection 3.3.1. Cross-sectional and cohort studies on post-Covid fibromyalgia prevalence and incidence Accumulating evidence indicates that persistent fibromyalgia-type symptoms, including widespread pain, fatigue, and cognitive impairments, can develop following COVID-19 infection as part of a post-viral infection syndrome. Early investigations on fibromyalgia post-COVID-19 are somewhat informative about epidemiology and prevalences. Studies used various methodologies and study designs, measurement tools, outcome measures, inclusion criteria, and, when relevant, control groups. Several of the studies that were found used online surveys and questionnaires inquiring into manifestations of chronic pain and fibromyalgia-type features (e.g., low mood, anxiety, myofascial-type pain, stress, fatigue, sleep impairment, functional impairment and decreased quality of life) after COVID-19, and multiple studies implemented a fibromyalgia self-reported questionnaire or used the ACR criteria as part of the outcome measures ( 10 , 16 , 81 , 85 , 104 , 111 , 114 , 115 , 118 , 125 , 131 , 132 , 146 , 148 ). Large population-based observational studies utilizing data from healthcare databases were also found. A few studies are described in more detail in this section to demonstrate the variety of methods and the finding that stem from them. The remaining observational studies on the subject of fibromyalgia post-COVID-19 that were included in this review are summarized in Table 3 below: A nationwide exploratory cross-sectional study out of Denmark and Spain by Ebbesen and colleagues (2024) ( 105 ) investigated the prevalence and risk factors of de novo widespread musculoskeletal pain after COVID-19 in non-hospitalized COVID-19 survivors. Demographic and medical data were collected through an online questionnaire from Danish adults with a confirmed SARS-CoV-2 infection that occurred at least 6 months prior to the study, between March 2020 and December 2021, a period mostly consisting of the first SARS-CoV-2 strains. Among 130,443 non-hospitalized respondents (58.2% women, mean age was 50.2 years), 5.3 percent of non-hospitalized COVID-19 survivors had new-onset widespread musculoskeletal pain at approximately 14 ± 6.0 months after infection, which was rated as moderate to severe in its intensity in 75.6% of cases. In a multivariate analysis, female sex, age, higher body-mass index (BMI), and previous history of migraine, whiplash, stress, type-2 diabetes, and comorbid chronic neurological disorders, were found as risk factors for de novo widespread post-COVID pain, with adjusted odds ratio of 1.549, 1.003, 1.043, 1.554, 1.562, 1.47, 1.56, and 1.532, respectively. View this table: View inline View popup Table 3: Summary of observational studies on new-onset fibromyalgia-type or myofascial-pain manifestations after COVID-19 in the systematic scoping review. Goudman et al. (2021) ( 146 ) from Belgium conducted a cross-sectional study by online survey distributed through social media to investigate the possibility of “central sensitization symptoms” (i.e., fibromyalgia-type features) following COVID-19 infection. They used three validated questionnaires and assessed the impact of chronic pain, health-related quality of life, and functional status. Among approximately 500 respondents who self-reported a “post-COVID infection state” (86% females, mean age 46.5±11.4, mean time since COVID-19 was 287±150 days), 70 percent had a score consistent with fibromyalgia features (central sensitization inventory score ≥40), and more than 90 percent were classified as medium to high level of “central sensitization-related” symptom severity. A positive correlation was found with both BMI and the time elapsed since infection. The authors also found a significant correlation between central sensitization inventory scores and post COVID-19 functional status scores (F = 46.17, p < 0.001) in a one-way ANOVA test among 486 individuals. However, this finding is expected because the items of both these questionnaires inquire into overlapping manifestations of chronic pain/fibromyalgia-type clinical impact, and do not necessarily reflect two separate variables, which seems to raise an intrinsic problem in the study’s analysis stage. Bierle and colleagues (2021) from the Mayo Clinic in Minnesota developed clinical criteria to diagnose patients with “post-COVID syndrome” as a syndrome consistent with central sensitization, through a modified Delphi process ( 144 ). Using their new developed diagnostic/screening method, they identified new-onset “central sensitization characteristics” (i.e., persistent new-onset fibromyalgia features) in 9% of patients that scheduled an appointment in the general context of a coronavirus infection, from November 2019 to early May 2020. These patients, if after a comprehensive evaluation, are shown to have no objective evidence of organ dysfunction, would be suitable to be diagnosed with LC, according to Bierle et al. Jennifer et al. (2023) analysed data from a large healthcare database (∼2.5 million patients) in a retrospective cohort study and compared COVID-19-positive patients to matched COVID-19-negative individuals based on medical records and healthcare utilization history. The incidence of several medical conditions was the outcome measured between date of recuperation from COVID-19 and end of study period (May 2021). Fibromyalgia incidence was found to be slightly higher after COVID-19 (0.28% new cases compared to 0.24% in controls, p=0.034 in non-hospitalized cases) ( 129 ). However, considering that delayed diagnosis of fibromyalgia is extremely common ( 30 ), reaching 6.4 years or even longer since the initial onset of symptoms according to a 2018 study ( 222 ), the above findings likely do not reflect the actual true state of fibromyalgia incidence after COVID-19. Next, Shani et al. (2024) ( 134 ) conducted a retrospective cohort analysis using a large database of electronic medical records to investigate relationships between the BNT162b2 vaccine, SARS-CoV-2 infection, and the onset of immune-mediated diseases. Follow-up periods ranged from 4 to 12 months for vaccinated individuals and up to 16 months for those infected with SARS-CoV-2. The study defined its outcomes as the first diagnosis of an immune-mediated disease, identified through ICD-9 codes and diagnostic descriptions. According to their results, vaccination did not affect new diagnosis of fibromyalgia in any age group. On the other hand, patients aged 45–64 years or older who were infected with SARS-CoV-2 had a significantly increased risk for new diagnosis of fibromyalgia within the timeframe of the study. Specifically, the incidence rate of fibromyalgia in those infected with SARS-CoV-2 aged 45-64 was 587.9 per 100,000 person-years, compared to 313.2 in those not infected. In those aged 18-44, the incidence was 259.7 per 100,000 person-years, compared to 157.7 per 100,000 person-years in individuals not infected. These findings are translated to hazard ratios (HR) of 1.71 (95 % CI: 1.31–2.22) in the 45-64 age range, and HR of 1.72 (95 % CI: 1.36–2.19) for individuals in the age group of 18-44. Nevertheless, Sørensen et al. (2022) ( 65 ) in their nationwide questionnaire study found conflicting results: the risk for fibromyalgia was not found to be significantly different between infected and uninfected individuals, amounting at 1% in COVID positive compared to 1.1% in COVID negatives (risk difference 0.02 95% CI: −0.09-0.14). Studies that specifically recruited LC populations provide some more insight. Bileviciute-Ljungar et al. (2022) ( 16 ) and Scherlinger et al. (2021) ( 118 ) found high rates of positive fibromyalgia diagnosis/screening (using the ACR criteria or the FiRST questionnaire) among LC individuals. In both these studies, fibromyalgia rates were as high as 40% and 56.7%, respectively. Remarkably, of the 40% of those who fulfilled criteria for fibromyalgia in Bileviciute-Ljungar et al.’s study, 55% indicated being healthy before their infection. In a widely cited study by Ursini et al. (2021) from Italy, which collected data via an online survey distributed among adult individuals (≥18 years) who developed COVID-19 three or more months before the survey publication (a total of 616 eligible individuals completed the survey, 77.4% women), 30.7% fulfilled the ACR survey criteria for classifying fibromyalgia 6 month on average after contracting COVID-19. Only 23 of 616 had a pre-Covid diagnosis of FM. Fibromyalgia was associated with a more severe acute infection (hospitalization), obesity, and with males. The survey was distributed on social network and was therefore subject to self-selection bias. Given these methodological constraints, there is restricted generalizability from the findings. Miladi et al. (2023) report high rates (19%) of post-Covid fibromyalgia as well in their study in Australia using a fibromyalgia screening questionnaire ( 131 ). Myofascial-pain-focused studies: case reports indicate the development or worsening of myofascial pain and localized trigger points following COVID-19, and responding to interventions like trigger point injections and dry needling ( 19 , 162 ). Few population-based studies are found ( 163 , 223 ), but considering that gross changes in health system capacity and resources, and individuals’ behavior had also changed during this time in relation to access to primary care, lifestyle, etc., drawing conclusions is limited. Di Stefano et al. (2023) ( 167 ) observed new-onset fibromyalgia-type features in 15 women after COVID-19 vaccination, eleven out of them met diagnostic criteria for fibromyalgia. Orthostatic intolerance was found in the majority. Nerve conduction studies were unremarkable, and most participants had normal quantitative sensory testing (QST). They were also found to have a normal skin biopsy post-vaccination. In summary, several studies evaluated fibromyalgia prevalence/incidence after COVID-19 or as part of LC by using patient self-reported surveys and/or electronic healthcare databases (for further elaboration see Table 3 ). Several of the online survey studies recruited patients by self-selection and involve crucial biases that limit the generalizability of the findings, as well as possible confounding factors. Studies using data from healthcare databases (e.g., confirmed diagnosis in medical records) should consider the effect of gross changes in health system capacity and resources, and individuals’ behavior change during the pandemic in relation to access to primary care, lifestyle, and more, and that some infected individuals did not necessarily undergo PCR testing. Based on the available evidence, and according to descriptions in the literature, fibromyalgia features seem to be more frequent after COVID-19 and are consist with the previously known clinical overlap between post-viral-infection syndrome, ME/CFS, and fibromyalgia, though the findings on incidence and prevalence rates differ significantly between studies. These discrepancies can be due to differing inclusion criteria, study population characteristics and comorbidities, hospitalization status, control group chosen, outcome measures, definition used for LC, period of the pandemic and sars-cov-2 variants, and more. Another topic receiving relatively more attention in the literature was fibromyalgia in rheumatoid arthritis patients after SARS-CoV-2 infection ( Table 3 ). It is well known that fibromyalgia syndrome often occurs concomitantly with inflammatory rheumatological disease - this has been termed by authors as “secondary fibromyalgia.” 3.3.2. Observational studies on LC, chronic fatigue syndrome, and overlapping fibromyalgia (molecular mechanisms, laboratory investigations, and others) Acknowledging the evident similarity between LC and fibromyalgia, Hackshaw et al. (2023) ( 135 ) from Texas, US, set up a pilot study to compare the low molecular weight fraction (aromatic amino acids and peptide backbones) in blood samples of fibromyalgia and LC patients using spectroscopic techniques. The fibromyalgia pattern was linked to the presence of side chains of glutamate at the bands centered at 1560 and 1579 cm −1 . Even though confounding factors were identified, such as the use of medications in the patient group and a difference in the populations characteristics, and the relatively small sample size questions the strength of their results, it shows a potential for the development of objective diagnosis-specific biomarkers in the future. The group’s research has since been carried further ( 136 ). Although not a study of LC per se, Das et al. (2022) undertook an impressive effort to try to uncover genetic components of chronic fatigue syndrome drawing on samples from the UK Biobank ( 61 ). By using a genome-wide association study and a combinatorial approach to analysis, they identified approximately 200 single nucleotides polymorphisms (SNPs) from 2,382 mostly European ME/CFS individuals (by self-reported diagnosis, most of them were in the age range of 61-80 years). When analysed, the total sampled population showed clustering into subgroups that seem to be associated with different phenotypes of ME/CFS. Biological processes suspected to be involved in the genome locations of the SNPs identified included, though aren’t limited to-metabolism, mitochondrial function, stress/infection, autoimmunity, sleep and the circadian rhythm, GABA synthesis, exocytosis, and synaptic vesicle cycle. Few of the SNPs had overlap or known association with other medical conditions including connective tissue diseases, fibromyalgia, multiple sclerosis, and post viral fatigue syndrome ( 61 ). Continuing with another discipline, a 2024 psychology-oriented study aimed to explore the possible association between personality profiles and LC in non-hospitalized non-severe cases, speculating that distinct patterns of coping mechanisms or traits could characterize individuals with LC or render them more susceptible to the syndrome. An association was found between more pronounced fibromyalgia features, a higher burden of depression and anxiety, diffuse pain, attention deficit, memory problems, headaches, perception of lower quality of life, and type D personality ( 133 ). Nevertheless, the directionality of such associations should be clarified in the future, since social withdrawal and new anxious and neurotic behaviour due to uncertainty regarding chronic disease and functional impairment might help explain the observed association between high scores on DS-14 questionnaire and new-onset chronic pain. 3.4. Central and peripheral nervous system abnormalities The neurological aspects of LC are another focus of research aiming to elucidate the persistent and often debilitating symptoms experienced by a substantial number of individuals who contracted COVID-19. Table 4 below summarizes the findings on this topic. Nerve conduction studies are being used for investigating neurological involvement in LC and, mostly did not reveal significant abnormalities in non-hospitalized LC. Corneal analysis revealed pathological findings (as elaborated in Table 4 ). Conditioned pain modulation (CPM), temporal summation, and other neurological abnormalities that may have relevance to the hypothesis of central nervous system sensitization in LC are another topic of ongoing investigations ( 75 , 148 ). View this table: View inline View popup Table 4: Summary of neurological studies of LC that were included in the systematic review. However, CPM might be altered after symptomatic COVID-19 even in the absence of long COVID-19, as reported by Peterson et al. (2022) ( 75 ). Overall, while some studies suggest the presence of peripheral nerve abnormalities in certain individuals, others, like the ones involving recuperating non-hospitalized patients with myopathic EMG findings, did not find a clear correlation with symptom severity. Azcue et al. (2025) ( 141 ) found that QST demonstrated significant differences in heat detection thresholds between LC patients and healthy controls, indicating impaired heat detection in the LC group. Cold detection showed a different trend. This variability highlights the need for researchers to employ a range of diagnostic techniques. So far, the findings appear to be heterogeneous, possibly reflecting the diverse range of neurological manifestations and the varied populations studied under the title of “Long COVID-19 syndrome.” 3.5. Generalized Joint Hypermobility Generalized Joint hypermobility (GJH) is known to be associated not only with fibromyalgia but functional psychosomatic syndromes in general, and a few authors reported a clinical pattern that they identified lately with regards to joint hypermobility and LC ( 126 , 171 ) based on clinical experiences, as well as a larger observational study. Gavrilova et al. ( 126 ) from Saint Petersburg of Russia described what they call a typical clinical observation of theirs, regarding post-COVID fibromyalgia syndrome. They describe a constellation of manifestations involving myalgia, a palpated fibrous cord or thickened/swollen tendons, positive antinuclear antibody test, postural orthostatic tachycardia (POT), and fibromyalgia features, in a hypermobile female patient, starting several months following discharge from hospital admission that was indicated for a non-severe COVID-19 ( 126 ). Eccles et al. (2024) ( 170 ) from the UK sought to explore whether GJH was a risk factor for non-recovery from COVID-19 infection. GJH was determined using the 5-part Hakim and Grahame self-report questionnaire by a cut-off score of ≥2 indicating GJH. According to their findings, the presence of GJH was not specifically associated with reported COVID-19 infection risk per se but was found to be significantly associated with self-reported non-recovery from COVID-19 (OR 1.43 (95% CI 1.20 to 1.70) in their study of 2,854 subjects. A 2024 multisite study by Grach et al. ( 140 ) from Mayo clinic compared patients diagnosed with LC and control subjects that had COVID-19 without LC diagnosis, using self-reported questionnaires. GJH was assessed according to the self-assessment 5-part hypermobility questionnaire. They found that 27 percent of LC patients screened positive for GJH compared to 10 percent of controls ( p = 0.026). Logarbo et al. (2024) ( 171 ) noticed a similar relation to hypermobility syndrome and reported findings that are in line with this issue, as further detailed in Table 5 which summarizes studies of GJH from the systematic review. View this table: View inline View popup Table 5: Findings regarding GJH as found in the systematic review. 3.6. Studies on Interventions For publications that are dedicated to the topic of LC treatment, the reader is referred to literature on LC interventions ( 51 , 80 , 186 , 224 – 226 ). Although the focus of the work was not to specifically review treatments for LC, and the Cochrane database was not used, a brief overview of treatments that were encountered during the review process is given as follows: Treatments that were either discussed or investigated in the context of LC or post-viral fatigue syndrome can be categorized into (i) non-pharmacological, (ii) pharmacological and nutritional, (iii) other interventional, (iv) and multimodal. These include: (i) mindfulness training ( 172 ), cognitive behavioral techniques ( 137 ), pain neuroscience education ( 110 ), balneotherapy ( 149 ), (ii) creatine ( 56 ), Ginseng ( 151 ), coenzyme Q10 and alpha lipoic acid supplements ( 155 ), L-arginine and vitamin C supplementation ( 80 ), synbiotics SIM01 or other supplement/probiotic complexes ( 159 ), melatonin ( 58 ), low-dose naltrexone ( 168 ), metformin ( 150 ), antivirals or other immune modulators ( 51 , 117 ), metabolic and other miscellaneous drugs such as colchicine and antihistamines ( 117 ), (iii) transcutaneous electrical nerve stimulation ( 156 ), pulsed electromagnetic field treatment or other electrophysiological method ( 161 ), plasmapheresis ( 51 ), hyperbaric oxygen therapy ( 157 , 165 ), (iv) L-acetyl-carnitine in combination with physical rehabilitation ( 154 ), multidisciplinary rehabilitation ( 153 , 186 ), multimodal ME/CFS-directed therapy ( 160 ), some of which were in non-blinded/non-randomized/non-controlled exploratory studies. While some of these publications reported overall positive results in the short term, others are more speculative. The following treatments were documented in a follow-up survey of patients attending the interdisciplinary post-COVID care clinic in Mayo clinic of Minnesota ( 48 ), which offers a multidisciplinary approach to the treatment of LC (combining use of off-label medications and nonpharmacologic rehabilitative approaches, many of which have previously been used for POT syndrome, ME/CFS, and fibromyalgia) for evaluating the response to different treatments. These treatments were either prescribed or self-used by patients: non-pharmacologic interventions (e.g., a “post COVID treatment program,” physical therapy, occupational therapy, biofeedback), off-label medications (low-dose naltrexone, propranolol, gabapentin, pregabalin, amitriptyline, guanfacine, N-acetyl cysteine, colchicine, midodrine, fludrocortisone, aripiprazole, pyridostigmine, etc. while additional therapies that physicians have been offering more recently, such as guanfacine, NAC, and L-arginine, were not captured in the survey), supplements (fisetin, coenzyme Q10, ginseng, ashwagandha, Reishi mushrooms, nattokinase, specialized pro-resolving mediators), and other interventions (plasmapheresis, transcranial magnetic stimulation, vagal nerve stimulator). These are mentioned here more as initial anecdotal evidence for investigators or stakeholders that may wish to study them further in the context of LC. Meanwhile, Blanchard et al. (2022) developed a mobile health application for fibromyalgia-type LC ( 164 , 173 , 177 ). Bileviciute-Ljungar et al. (2022) ( 16 ) from Sweden’s Karolinska Institute recruited individuals for their study of a multidisciplinary rehabilitation program, focusing on those with functional impairment and persistent symptoms after COVID-19. In their cohort of 100 individuals with post COVID-19 functional impairment, 40% met criteria appropriate for fibromyalgia diagnosis, while 68% reported being completely healthy before COVID-19. In their randomized controlled study of an eight-week telerehabilitation program, they report positive results for functional status, activity, pain, and health-related outcomes compared to the waiting list group after six months ( 152 , 153 ). Kjellberg et al. (2022) set up a double-blinded randomized controlled clinical trial to evaluate the therapeutic efficacy of hyperbaric oxygen therapy in LC patients who were healthy prior to COVID-19 ( 165 ). They have yet to publish their findings at the time or writing. Meanwhile, Zilberman-Itskovich et al. (2022) ( 157 ), in a randomized sham-controlled trial with 37 LC participants (of which only 10.8% were hospitalized during COVID-19) reported an improvement in clinical outcomes (sleep, memory, information processing, pain interference, anxiety, somatization, energy, total taste score, health-related quality of life) and brain perfusion, after hyperbaric oxygen therapy. Data were collected at 1-3 weeks after completion of 40 daily sessions, five sessions per week, with 100% oxygen by mask at a pressure of 2 ATA. Interestingly, turning to a study on prevention, in a 2024 multicenter randomized clinical trial by Bramante et al. ( 150 ), metformin, given to patients in the COVID-19 outpatient setting, was shown to reduce risk of developing LC when assessed at 300 days. The study included adults (30-85 years-old) with overweight or obesity and found a reduced incidence of LC diagnosis by approximately 40 percent (absolute reduction of 4.1 percent) compared with placeb. However, the HR did not appreciably change when adjusted for other a-priori baseline variables. In their study, LC was primarily ascertained by participant-reported receipt of a long COVID diagnosis from a medical provider. In summary, a wide range of potential treatments for LC are being investigated, encompassing non-pharmacological, pharmacological, interventional, and multimodal strategies, reflecting the syndrome’s complex and heterogeneous nature. While many treatments remain speculative or require further rigorous study, preliminary findings suggest some benefit from interventions such as multidisciplinary rehabilitation, probiotic supplements, and hyperbaric oxygen therapy, which seem to improve symptoms such as fatigue, cognitive and neurological symptoms, and quality of life, at least when examined in the short term, highlighting the need for continued research to establish efficacy and optimize management strategies. 3.7. Reviews (systematic reviews, meta-analyses, and narrative reviews) Table 6 summarizes the systematic reviews included in this scoping review. Particularly germane are the following: Fowler-Davis et al. (2021) conducted a systematic review of studies of interventions for post-viral fatigue ( 59 ). They found a range of treatment modalities that have been studied so far but conclude that more research involving heterogenous populations is needed to properly assess their effectiveness in the context of post-viral fatigue syndromes. Cohen and colleagues (2022) published a comprehensive review on the relationship between chronic pain and infections, elaborating on mechanisms that could be relevant to LC-associated pain ( 92 ). Rao et al. (2022) conducted a systematic review and meta-analysis (41 studies, 9,362 patients in total) to evaluate the prevalence and prognosis of post-COVID-19 fatigue ( 60 ). They found that fatigue prevalence was 44.9% (95% CI 0.329 - 0.575, I 2 = 70.57%) within the first 3 months post-recovery according to a small number of relevant studies, but substantial differences existed among studies. Female patients, inpatient setting, and individuals recruited through social media and in Europe had a higher prevalence of fatigue. A systematic review and meta-analysis by Kerzhner et al. (2024) ( 124 ) sought to evaluate rates of LC’s persistent pain manifestations, as well as the impairment to health-related quality of life and data on laboratory inflammatory markers in LC. In their analysis, a substantial level of heterogeneity was found and funnel plots demonstrated considerable asymmetry. The pooled proportion of individuals experiencing general body pain symptoms up to one year after COVID-19 acute phase resolution was found to be higher in the nonhospitalized compared to hospitalized individuals (0.306 vs. 0.089, respectively, I 2 = 95%, p (subgroup) = 0.009). They also discuss the increased associations related to young age, females, and less severe acute COVID-19, as well as a progressive temporal-proportional trend instead of the usual subsiding nature of most other symptoms ( 124 ). On that note, Ebbesen et al. witnessed a similar trend in their findings from a nationwide cross-sectional study ( 105 ). A systematic review and meta-analysis by Hwang et al. (2023) ( 62 ) appraised viral infections as an etiology of ME/CFS. View this table: View inline View popup Table 6: Overview of systematic reviews included in the scoping review. Narrative (non-systematic) reviews and topical articles were the most frequent type. Paroli et al. (2024) ( 79 ) detail the potential role of infection and inflammation in the etiopathogenesis of fibromyalgia and LC, and Choutka et al. (2022) ( 13 ) summarize the current understanding of unexplained post-acute infection syndromes, covering epidemiology, signs and symptoms, patho-mechanisms, and prognosis. A 2024 publication by Stefanou and colleagues ( 80 ) gives an updated overview of the neurological and psychiatric manifestations of LC, analysing recent advances in understanding its pathophysiology and the clinical presentation (including prevalence, risk factors, and temporal dynamics of neurological aspects), in addition to covering issues of prevention and vaccination, and exploring potential diagnostic and treatment implications. The authors also propose a standardized framework for the clinical approach and management of patients who have neurological manifestations of LC, plus recommendations for future research. They emphasize that in the absence of a standardized diagnostic framework, the development of comprehensive clinical practice guidelines is significantly impeded. They also stress that a thorough and interdisciplinary assessment of persistent symptoms after COVID-19 is imperative to exclude an underlying well-defined cause (e.g., endocrine, neurological, cardiovascular, autoimmunity, respiratory) ( 80 ) in order not to erroneously attribute such symptoms to LC. 3.8. Findings from preprints and the narrative literature search of subtopics As a part of the scoping review, subtopics were explored through a non-systematic search, supplemented by a targeted search of the medRxiv preprint database. Among the subtopics searched were small fibre pathology in LC, somatic symptoms, conditioned pain modulation, quantitative sensory testing, and more as elaborated in the methods section. The main findings are mentioned briefly in Table 7 which summarizes the studies found during the preprint and subtopic searches. As shown, more studies are found on GJH and LC. View this table: View inline View popup Table 7: Findings from subtopic searches and preprints. 4. Summary and conclusions The purpose of this systematic scoping review was to evaluate and map the body of scientific literature and evidence on new-onset fibromyalgia after non-severe non-hospitalized sars-cov-2 infection. It’s well-recognized that infectious agents such as Epstein Barr virus, cytomegalovirus, mycoplasma, Coxiella burnetii, and other pathogens can be triggers for post-infectious chronic fatigue or are associated with ME/CFS ( 73 , 86 , 92 ) but the pathobiology of such clinical manifestations is not well defined. In fibromyalgia syndrome, bacterial and viral infections, likewise, are recognized as a part of the aetiology ( 51 , 96 , 238 ). The overlap of fibromyalgia syndrome, post-viral functional somatic illness, and ME/CFS is an unsolved medical puzzle with increasing public and community health importance. Moreover, considering the empirical findings gathered in the review of literature regarding GJH, such as the results of Eccles et al. (2024) ( 170 ), hypermobility seems to be another piece in this puzzle. Research on fibromyalgia continues to primarily focus on pain, but fibromyalgia is a syndrome. Moving towards a wider view of fibromyalgia beyond pain is needed for the scientific community’s proper comprehension of this intriguing condition. The empirical evidence supports an overlap between LC, chronic fatigue syndrome, and fibromyalgia but the molecular mechanisms still remain unclear. Mechanisms such as neuroinflammation, immune dysregulation, viral persistence, glial cell reactivity, and central pain augmentation are studied, yet are under-researched, and with conflicting findings regarding the presence of viral particles, condition pain modulation, central sensitization, autoantibodies and more. The emergence of post-COVID-19 fibromyalgia presents a significant challenge, requiring a collaborative interdisciplinary approach that integrates evolving knowledge. Various types of methods, tools, and study designs are being used for LC research, with inconsistency in key concepts and definitions. This leads to a fragmented understanding of the relationship between SARS-CoV-2 infection and LC. Studies that recruit participants in open web-based surveys are subject to self-selection bias, therefore, many of these studies which were included in this scoping review do not allow a well-founded conclusion to be made regarding incidence or prevalence rates of new onset fibromyalgia after COVID-19. Such study designs limit the generalizability of the data greatly. Several significant biases were identified in the studies during the review, including recruitment, self-selection, and recall bias, and other methodological issues as stated in the previous sections. Based on the available evidence, there are indications that new-onset fibromyalgia occurs more frequently after COVID-19, but well-designed studies and meta-analyses are warranted to clarify this and to provide more accurate estimates of epidemiology and possible predisposing factors. The strongest evidence so far seems to be a large 2024 retrospective cohort study ( 134 ) that found hazard ratios of ∼1.7 for incidence of new clinically made diagnosis of fibromyalgia up to 16 months after COVID-19 compared to non-infected individuals in the age range of 18-64 years, regardless of vaccination status, but since diagnosis of fibromyalgia is a long process that can take several years in the community care setting, these values might conceivably be gross underestimations. Central sensitization: central sensitization is one of the areas of focus in LC research. While the observed associations between SARS-CoV-2 and chronic “nociplastic”-type pain syndromes highlight a potential pathogenic link, the precise underlying molecular pathways remain poorly understood and are under continuous debate across the literature. Neurocentric hypotheses such as diffuse pain augmentation in the central nervous system interestingly do not seem to align well with empirical evidence that was found during this systematic scoping literature review of LC, specifically in studies of pressure pain threshold, quantitative sensory testing ( 141 ), conditioned pain modulation ( 148 ), and temporal summation ( 148 ), nor do such notions seem to consolidate well with initial descriptions of plasmapheresis being reported as somewhat beneficial by nine out of nine LC patients ( 48 ). But with such a paucity of evidence found ( 75 , 88 , 89 , 101 , 112 , 113 , 141 , 148 , 203 , 206 , 220 ) it seems, however, still early to draw conclusions. Be that as it may, in well-designed studies the statistics paint the scientific picture. LC could indeed be a heterogenous condition with subtypes determined by multiple over- and under-represented molecular pathways in each subtype. But if the central sensitization paradigm ( 38 , 52 , 108 , 137 , 139 , 239 – 242 ) is as an axiom, there’s no need to adjust the theory ( 240 ) or spot out anomalies ( 68 , 69 , 91 , 101 , 148 , 203 , 243 – 250 ). The development of new onset musculoskeletal pain after COVID-19 is multifactorial, and can involve both direct viral causes, lifestyle and behavioral factors, other pre-existing and new comorbidities, psychological factors, and more. Having said that, simplistic hypotheses such as fatigue/pain catastrophizing, low psychological resilience, and physical deconditioning, might well explain fatiguability and exercise intolerance, but they do not seem to explain the broad symptomatology of the not-so-rare syndrome among mild non-hospitalized young and previously healthy female cases. Medicine, historically speaking, has had an unhealthy tendency to attribute that which it cannot comprehend to psychology, e.g., ( 251 ). An increased feeling of bodily stiffness, as seen in studies ( 189 ), doesn’t seem very intuitive when viewed from the standpoint of central sensitization. Problems in LC terminology inconsistencies : there is inconsistency across literature with regards to what LC basically is, besides the choice of nomenclature itself or the number of weeks duration. Using the term “post/long/chronic covid” to refer to any declined health including that due to well defined organ damage can lead to the conflation of “Long COVID syndrome” and other known medical diagnoses. Publications using this term without parsimony will make it difficult for future researchers attempting to review and analyze the body of literature, as well as to unnecessary confusion in the field. It is the author’s suggestion that if, after anamnesis, objective organ-relevant evidence in clinical investigations can explain the dominant new symptoms of a patient, this should not be referred to as LC or any of its synonyms. LC, indeed, may occur alongside other post severe-COVID-19 organ damage, but as a post-viral chronic fatigue-like syndrome it should be differentiated from such. Since the mechanisms are still ambiguous at this time, making an official distinction between persistent symptoms based on four or twelve weeks seems arbitrary and does not abstain from “multiplication of entities” with reference to the principle of Occam’s razor. If it is a syndrome, as with other syndromes, it should be recognized as a phenomenon and diagnosed clinically based on internationally accepted criteria. Chronic breathlessness ( 53 , 93 ), for example, is not a syndrome, it is a presenting complaint. ‘Suspicion of LC’ could be a more accurate term to consider in future studies in case the assessment was based on anamnesis alone without objective clinical testing. Finally, coherent terminology of a responsible international health body should be used with consistency. The term “post-covid” doesn’t seem like the best choice because it is not clear enough if the speaker refers to something happening any point in time after covid infection/pandemic or the syndrome. Author’s suggestion is: “Long COVID sequelae syndrome”-new-onset persistent medically unexplained multisymptom illness after sars-cov-2 infection, often presents clinically as ME/CFS or insidious fibromyalgia-type features. LC is a post-infection chronic condition that impairs one’s quality of life. Prospective studies will likely help formulate a comprehensive explanation, and uncover a causal link, if there is such, between infections and fibromyalgia. Ideas such as immune dysregulation, viral persistence, pure psychosomatics, neuroinflammation, glial reactivity, and central nervous system sensitization are, as noted, postulated, but remain to be further investigated in rigorous empirical studies that are designed according to theory-based hypotheses and with reproducible data. Hence, before announcing the discovery of well documented “central pain augmentation” in LC ( 137 , 139 ), studies that can clearly show this, and, preferably, can clearly link the disease with underlying pathogenic mechanisms, are needed. Further research is required to elucidate the relevant neurobiological (or psychobiological) pathways and inform targeted sensible effective therapeutic strategies. Multimodal rehabilitative approaches, as well as other approaches, are being studied in these relatively early stages of LC research, some of which seem to point in a positive direction. Knowledge gaps: The main knowledge gaps in understanding post-COVID-19 fibromyalgia that were identified from the above literature review are: Etiopathogenesis and theoretical framework: unraveling the underlying pathobiology and disease mechanisms. These crucial knowledge gaps revolve around the fundamental mechanisms that drive fibromyalgia-type clinical features, the role of viral triggering, contribution of dysregulated immune pathways, genetic and epigenetic predisposition, environmental and lifestyle factors, neural mechanisms and their temporal dynamics, and the supposed role of emotional stress. Also, the current evidence concerning the impact of hospitalization history on the incidence of post-COVID fibromyalgia is inconclusive. This ambiguity is likely attributable to methodological inconsistencies, disparate definitions of fibromyalgia and LC, and variations in the selection criteria of study populations. A comprehensive theoretical framework for fibromyalgia (and LC) is needed that goes beyond explanations focused solely on pain and hyperalgesia or fatigue. It should enable robust theory-based predictions and potentially lead to the development of disease-modifying treatments. Common symptoms that are documented as associated with LC include fatigue, low mood, shortness of breath, persistent cough, autonomic symptoms such as postural orthostatic intolerance, cognitive dysfunction, brain fog, sleep difficulties, low grade fever, and joint pain ( 212 , 226 , 252 – 254 ). Additional multiorgan manifestations as described in literature are myalgia, headache, chest pain or chest tightness, poor appetite, sicca, diarrhea, dizziness, sweating, alopecia, insomnia, restless legs, nightmares, and lucid dreams ( 252 , 255 – 257 ). An online survey conducted across multiple countries found that approximately 85% of respondents with persistent illness reported relapses, primarily due to exercise, physical or mental activity, and stress ( 252 ). Besides chronic pain, other manifestations of fibromyalgia include easy bruising ( 27 , 258 ), urinary urgency ( 259 ), functional gastrointestinal disturbances, sleep disturbances, autonomic symptoms, wheezing, brain fog ( 27 ), a reportedly distinct brain pattern on functional magnetic resonance imaging ( 28 , 139 , 260 ), tingling, creeping or crawling sensations ( 259 ), reduced skin innervation ( 261 ), close association with gastroesophageal reflux disease ( 262 ), various autoantibodies among subgroups of patients ( 263 , 264 ), dry mouth, dry eyes, blurred vision, restless legs, multiple chemical sensitivity, fluid retention, and more ( 27 , 44 , 265 ). In a 2023 meta-analysis that included 188,751 patients, an increased standardized mortality (SMR) ratio in fibromyalgia was found for mortality from infections (SMR 1.66, 95% CI 1.15 to 2.38), accidents (SMR 1.95, 95% CI 0.97 to 3.92), and suicide (SMR 3.37, 95% CI 1.52 to 7.50) ( 266 ). Diagnosis and assessment: bridging the gap to objective measures. This includes the need for biomarkers, the standardization of diagnostic criteria, phenotyping, correlation between objective findings and symptom severity, and addressing symptomatic overlap of the related syndromes. Phenotyping: can help clarify the varied underlying biological mechanisms and facilitate the development of subtype-specific therapies. Patient experience and coping. This includes, among other things, the consequences of clinician dismissal of symptoms ( 8 ), factors associated with late diagnosis, addressing the problem of medical stigma, and factors associated with over/under-diagnosis. Treatment/rehabilitation and interventions: moving towards effective strategies for treatment, including treatments for addressing specific symptoms (neurological, fatigue, musculoskeletal pain, mood, etc.), non-pharmacological treatments, personalized medicine approaches, understanding mechanisms of treatments and how they relate to the pathophysiology, integration of digital therapeutics, and striving for more patient education. Future research into LC interventions shouldn’t neglect the role of a rehabilitative approach for treating LC and fibromyalgia. Prevention: Need for better knowledge on evidence-based prevention strategies besides the obvious effort of avoiding infection. Prognosis: Need for better knowledge regarding fibromyalgia and post-COVID fibromyalgia-type syndrome prognosis. Methodological synchronization and harmonization in the field. As an evolving relatively amorphous field of research there is heterogeneity and inconsistency in fundamental aspects such as definitions, methods, and instruments used. Also, there are still limited systematic reviews, and there is a need for longitudinal studies. Bridging basic science and clinical research. Another significant knowledge gap concerns the extent to which clinicians are equipped with contemporary evidence-based knowledge regarding the evolving understanding of LC. 5. Recommendations for future research LC research is an evolving field whose fundamentals are still being articulated. Future research should focus on epidemiological population-based studies with representative sampling and improving methodology, refining definitions, elucidating mechanisms in hypothesis driven studies, and developing effective therapeutic strategies. As some of the studies did not explicitly delineate their inclusion and exclusion criteria, and in studies incorporating a control group the criteria for control subject selection were not always clearly described, nor was there given a justification for the sample size taken, adhering to checklists such as STROBE and CONSORT recommendations for reporting observational studies and trials can add to more rigor in this new developing field. Important methodological issues besides those mentioned above for consideration in the field based on the review are as follows: First, accurate assessment of post-COVID symptom trajectories necessitates future research that stratifies analyses by acute phase severity and hospitalization status. An analysis of all patients without making a distinction between severities of COVID-19 can add confounding factors related to hospitalization, antibiotic use, intensive care admission, and cases with well-defined organ damage, which could make it difficult to draw meaning from their results in terms of “LC.” The number of infection episodes, immunization status, behaviour and environmental factors during the initial recovery from the acute phase, and variant type, are also variables that could potentially be relevant to further investigate in the future. During the review process, patient surveys were found that did not corroborate the presence of the outcome being measured prior to acute covid-19, which makes it difficult to infer anything about new-onset or worsening of symptoms, or other self-reported measures. Also, hypermobility syndrome appears to be another confounding factor that should be taken into account in future epidemiological studies of LC, as this seems to be an important variable for the phenomenon. It is important to emphasize that undiagnosed fibromyalgia and/or GJH may contribute to the development of LC but are frequently overlooked in the clinical setting. This can add confounding to studies that make use of official diagnostic codes and criteria for fibromyalgia. Due to the high cut-off set by the ACR criteria, the absence of fibromyalgia diagnosis, taken as an indicator for absence of fibromyalgia syndrome, may not suffice for choosing controls. For example, an individual with chronic widespread pain and somatic symptom severity score of 4 (that is, not eligible for official fibromyalgia diagnosis) in the control group could confound the results, as the cut-off chosen for fibromyalgia diagnosis by the ACR seems to be biologically arbitrary. Secondly, in studies using diagnostic criteria or diagnostic codes that distinguish functional psychosomatic syndromes, the investigator should recognize that making a distinction between chronic widespread pain and fibromyalgia diagnosis (and even ME/CFS), or ignoring their overlap, may confound results if the mechanism is shared, as has been suggested by some authors ( 43 , 64 ). Moreover, researchers conducting a correlation analysis between variables or outcome measures that represent overlapping constructs such as stress and fibromyalgia diagnosis or chronic widespread pain and fibromyalgia-type symptoms, or CSI score and depression ( 108 , 120 , 243 , 267 ), will end up with results that seem redundant unless that is what the study was designed to do. Third, it’s worth noting that studies that recognize central sensitization as a phenomenon simply based on hypersensitivity in the palmar side of the participants’ dominant hand, for example ( 112 ), do not necessarily relate to a mechanism of nociplastic generalized central pain augmentation and sensory hypersensitivity. If the authors of a study conclude that generalized central hypersensitivity and allodynia were found, then they might like to demonstrate that it is, indeed, both central and generalized. A methodological issue ( 29 )was evident in literature in relation to the “central sensitization inventory” questionnaire, which tries to capture the impact of chronic pain conditions such as fibromyalgia ( 268 ) or “fibromyalgia-type features.” Authors have mistaken the CSI for central sensitization ( 111 , 115 , 117 , 139 , 184 ). The following offers a mechanistic explanation for new-onset medically unexplained fibromyalgia-chronic-fatigue-and-somatoform-type manifestations after COVID-19, while attempting to reconcile the main findings from the systematic scoping review regarding fibromyalgia and LC, primarily including: A multifaceted etiology. Overlap between LC, chronic fatigue syndrome, related functional somatic syndromes and fibromyalgia symptomatology (including multiple medically unexplained multisystemic refractory symptoms, widespread myofascial discomfort and myofascial pain, hyperalgesia, itching, fatigue, post-exertional malaise, POT syndrome and autonomic symptoms, morning stiffness, spasms, irritable bowel, multiple chemical sensitivity, and more) Multisystem non-specific clinical findings (subclinical inflammation and immune dysregulation, metabolic abnormalities, low-grade hypoxia, muscle histopathological abnormalities, intraepidermal small fibre pathology, etc.) Unremarkable results on routine medical tests. The risk factors. Significant association with both hypermobility syndrome and low vitamin D. A relatively high prevalence of LC in mild and subclinical acute disease cases among previously healthy individuals. Insidious and heterogenous nature of the condition. Pain varying in anatomical location, and neuroanatomically illogical distributions. Other anomalies and counterinstances such as discrepancies between empirical findings and expected findings in nerve conduction studies and pressure pain threshold measurements, dissociation between measures of sensitization and subjective burden ( 249 ), low correlations between disease burden and conditioned pain modulation ( 269 ), autoantibodies and inconsistent findings regarding them ( 263 , 270 ), evidence of peripheral neuropathy in subgroups, disappointing and poor response to theory-based pharmacotherapies, symptomatic response to weather change ( 271 ), discordance between autonomic small fiber pathology and autonomic symptoms ( 272 ), and more ( 248 – 250 ). There are many theories for fibromyalgia (e.g., autoimmunity, the gut-brain axis, nociplastic pain, etc.) ( 14 , 32 – 37 , 139 , 244 , 273 – 282 ), each of them leads to specific hypotheses, study designs, and study methods, and each can lead to different conclusions from the same findings. Any suggested theory should explain the broad symptomatology and manifestations of the syndrome besides merely pain and hyperalgesia. 6. Part two– synthesis of data and formulating a mechanism for “fibromyalgia syndrome” pathophysiology Part 1 of this work presented findings from the scoping review which covered empirical evidence of new-onset fibromyalgia-type symptomatology after COVID-19. An in-depth review of the putative pathophysiology of LC was not the purpose of the review and can be found elsewhere (see section 3.2 ). Part 2 is a synthesis of data and conceptual analysis based on the scoping review, for reconciling the findings and anomalies from part 1. The following sections offer a conceptual framework for fibromyalgia pathogenesis, for the purpose of discussing this mechanism in the context of LC. 6.1. Fascial Armouring: a conceptual framework for the etiopathogenesis and cellular pathway of ‘primary fibromyalgia syndrome’ Fibromyalgia-type syndromes (or “functional somatic syndromes”, also called “chronic overlapping pain conditions” or “central sensitization syndromes”) and myofascial pain syndromes are suggested to be overlapping manifestations of a common medical entity with shared molecular pathways ( 74 , 139 , 265 , 280 , 283 – 289 ), or “two sides of the same coin” ( 283 ). The conceptual framework of ‘Fascial Armouring’ offers a non-autoimmune connective-tissue-based mechanism for fibromyalgia-type psychosomatic syndromes that’s based on the cascade of inflammatory myofibroblast force generation in soft tissue and dysregulated extracellular matrix remodeling, which may drive peripheral and central pain mechanisms ( 290 ). In its severe form, this suggested mechanism is anticipated to physiologically manifest as a mild-to-moderate global chronic exertional compartment-like syndrome ( 87 , 290 ), which might help explain “central sensitization symptoms” and propel fibromyalgia multiorgan and multisystem manifestations such as: pain, hyperalgesia, mechanical hypersensitivity, tender spots/trigger points, allodynia, general bodily discomfort, itching, muscle spasms, chronic fatigue, cognitive symptoms, autonomic abnormalities, cardiovascular and metabolic alterations, morning stiffness, small fiber pathology, intramuscular collagen organization abnormalities, metabolic abnormalities, various psychosomatic symptoms, overlap with other chronic psychosomatic-functional pain conditions, close association with hypermobility syndrome, various autoantibodies and close association with systemic autoimmune connective tissue diseases, atypical profile of inflammatory biomarkers, low efficacy of central neuroactive pharmacological agents (e.g., tricyclics and gabapentenoids), mostly silent routine medical investigations, signs of longstanding subclinical chronic ischemia and oxidative stress, and more ( 290 ). The term ‘psychosomatic syndromes’ within the context of this paper refers to disorders that are usually attributed to mental, emotional, or psychological disorders manifesting somatically in the body top-down (e.g., via neuroendocrine pathways) without tissue histopathological abnormalities, typically regarded in medicine as disorders of organ functionality, not organic diseases, i.e., disorders of function, not of tissue integrity, composition, architecture, or structure. In terms of nosology, what distinguishes primary fibromyalgia syndrome from other functional (psycho)somatic syndromes is simply a matter of clinical consensus of definition, a fashion, since the “diagnosis” is not biologically attached to a specific measurable mechanism. Thus, from the standpoint of molecular biology, what truly distinguishes between these clinical syndromes is still not entirely understood. Fibromyalgia is one of the psychosomatic syndromes. The suggested mechanism is concisely outlined as follows, formulated by integrating five fundamental building blocks (this section presents the conceptual framework and theoretical model for the pathogenesis of fibromyalgia, and, afterwards, the clinical implications will be discussed): (i) Normal mechanobiology of myofibroblasts Myofibroblasts are contractile mechano-sensitive cells that can promote long-term contracture in tissue, and they have a complex mechanobiology often compared to smooth muscle cells. By synthesizing alpha-smooth muscle actin (α-SMA) fibres and focal adhesion complexes that grant them the ability to sustain mechanical tension in the surrounding extracellular matrix (ECM), myofibroblasts use a lockstep type mechanism to generate force ( 291 ). Myofibroblasts are induced by various signals and are part of the inflammatory and healing process, most known for in scar formation, but are also relevant, though somewhat overlooked, in other conditions including asthma ( 292 ), cardiac arrythmias ( 293 ), and during infection and events of systemic inflammation ( 294 ). A positive feedback loop is established as myo/fibroblast cell contractility and ECM matrix remodeling stress-shields local mechano-active cells from external force while sustaining surrounding tissue contracture and is largely facilitated by transforming growth factor β1 (TGF-β1) ( 291 ). After TGF-β is secreted in a latent form and then activated through interaction with integrins, it binds TGF receptors on the cell membrane which in turn activates a signaling pathway and transcriptional elements that are responsible for α-SMA expression - one of the key players in this mechano-active festivity ( 291 ). Mechanical force that is generated by contractile myofibroblast cells expressing α-SMA, is mediated by, and also stimulates, integrins and focal adhesion complexes. This provides further input into the positive feedback of mechano-sensitivity, which leads to more α-SMA synthesis as well as ED-A fibronectin and allows for more force generation in a vicious cycle ( 291 ). A distinct cytokine-mediated pathway, the type-2 cytokine axis, may promote fibrosis independently of TGF-β, and involves the alarmin cytokines IL-25, IL-35, and IL-5 and IL-13 ( 295 ). Connective tissue growth factor (CTGF) is also a main actor in the signaling pathway of TGF-β-dependent myofibroblast stimulation ( 296 ). Nonetheless, clinically relevant factors that can attenuate or inhibit myofibroblasts are estrogen, vitamin D (via vitamin D receptor signaling), resveratrol, and more ( 297 – 300 ). Gut microbe-derived metabolites can influence fibroblast-to-myofibroblast differentiation and induce organ fibrosis ( 301 ). The delicate process of myofibroblast de-differentiation/senescence/apoptosis is important for the health of tissue and is influenced by factors such as fibroblast growth factors, prostaglandins, cellular communication network factor 1 (CCN1), metformin, and more ( 296 , 302 ). Myofascial tissue of normal healthy individuals contains myofibroblasts that are likely to contribute to the development of pain and the manifestation of “myofascial pain syndrome” due to their natural biological activity ( 303 , 304 ). Empirical investigations have demonstrated that myofibroblasts are normally present in fascia and interstitial ECM and contribute to the pre-stress and basal tone of the tissue ( 303 , 305 ). Some authors suggest that abnormal mechanical tension in myofascial tissue can serve as a source of pain and myofascial trigger point-related nociception ( 306 ). Schleip and colleagues estimate that forces generated by soft tissue myofibroblasts may reach ∼2 Newtons and generate 1 cm per month of contracture that’s sustained by matrix remodeling, which is not at all negligible ( 303 , 307 ). Myofibroblasts are a phenotype of mechano-active smooth-muscle-like cell which generally have a similar behavior and mechanobiology irrespective of the anatomical location or the tissue ( 308 ). Fibroblasts function as a large network ( 309 ). They form an extensive intricate cellular network in soft tissue that may have significant and underestimated physiological and functional importance ( 310 ). Fibroblasts can be arranged in nodules and cords and express altered contractile behavior and tensional homeostasis ( 311 , 312 ). Langevin et al. (2004) have shown, using confocal microscopy, histochemistry, immunohistochemistry, and electron microscopy, that fibroblasts form many cell processes and many points of cell-to-cell contact with each other when studied in vitro ( 310 ). About 30% of fibroblasts processes were shown to extend continuously from one cell to another using confocal microscopy. Other scholars have reported findings consistent with this when investigating human fibroblasts in vivo ( 313 , 314 ). When fibroblasts experience mechanical stimuli, they initiate a range of cellular responses such as changes in intracellular calcium and adenosine triphosphate release, activation of intracellular signaling, actin polymerization, and gene expression. It is possible that oscillations of calcium waves are a main facilitator of intercellular communication of fibroblasts, through fluctuations in the levels of cytosolic calcium and its effect on downstream cell signaling pathways ( 310 ). The nature of these oscillations likely depends, among several different factors, on substrate rigidity ( 315 ). (ii) Tensegrity qualities when superimposed on the interconnectedness of the fascio-musculo-skeletal system Fascia and the extracellular matrix constitute a complex dynamic interconnected extensive fiber-cellular network of connective tissue that undergoes a process of continuous remodeling and transmits and absorbs loads while it exhibits tensegrity-type qualities ( 290 , 304 , 316 ). ‘Tensegrity’ (the words ‘tension’ and ‘integrity’ merged) is a concept that describes the homeostasis of a complex pre-stressed structure that is stabilized under forces of compression and tension and functions as one connected spatial system ( 316 – 318 ). ‘Bio-tensegrity’ ( 319 ) is a biophysical conceptual framework under continuum biomechanics that incorporates the principles of tensegrity for a better understanding of human physiology and kinematics ( 304 , 320 , 321 ). It is a theoretical concept of biomechanics integrated into our discussion as a simplification. The theory suggested here also stands without the idea of organismal “bio-tensegrity,” though, as with most models, its aim is to simplify. In living tissues there is an ongoing dynamic balance of forces of cell traction and points of resistance within the ECM, with a state of reciprocal isometric mechanical tension ( 316 ). The dynamic bio-tensegral system and mechano-transducing signaling enable cells to mechanically sense changes, modify their microenvironment, and promote ECM remodeling in homeostasis and in disease states ( 316 ). Figure 3A-D displays tensegrity structures as an illustration of this concept of a pre-stressed structural system in a steady-state that is maintained in a balanced equilibrium of compressive and tensional forces – as an allegory for the human body. Its aim is to illustrate an anatomical situation of mechanical imbalance in the (fascio)musculoskeletal system. The purpose is to demonstrate tensegrity as a pillar in the model, not a specific clinical syndrome. Download figure Open in new tab Figure 3. An illustration of the concept of tensegrity. Floating compression elements transmit force through the tension elements. Changes to one node affect mechanical homeostasis of the structure and other nodes as well. In the setting of continuum biomechanics this principle can be called ‘bio-tensegrity’. Kenneth Snelson’s Audrey I 1966 (top right), eight up 1967 (top left), triple crown 1991 kansas city, MO (bottom left). 60.5 degrees 1992 stainless steel tensegrity structure (bottom right). Images from http://kennethsnelson.net . Observational studies highlighted the relevance of bio-tensegrity mechanotransduction on tumor cells by mediating the cellular response to ECM stiffness ( 316 , 319 ). In addition, existing empirical investigations of ECM (and fascia) in humans in vivo support the tensegrity properties of fascia by demonstrating its role in a continuous myofascial system where tension is balanced across different segments. For example, studies have shown that sustained manual pressure on the lateral raphe in patients with chronic low back pain resulted in an anterior shift of the transversus abdominis musculofascial corset system, suggesting the release of pre-existing tightness or adhesion in the posterior fascia and a change in its elastic properties ( 322 ). Manual intervention has also been shown to lead to increased sliding and thickness changes of the transversus abdominis, indicating a redistribution of tension within the myofascial system. Furthermore, research on isometric plantar-flexion demonstrated a strong correlation in stiffness changes between the lower limb muscles (gastrocnemius) and lumbar tissues (thoracolumbar fascia and erector spinae), highlighting a long-distance interaction within the myofascial tensegrity network ( 323 ). These findings collectively reinforce the concept of fascia as a force transduction network rather than merely local passive structures, supporting its tensegrity role in maintaining body stability and function. Virtually all organs and tissues are organized as prestressed structural hierarchies that exhibit immediate mechanical responsiveness and increase their stiffness in direct proportion to the applied mechanical stress ( 324 ). Molecules, cells, tissues, organs, and our entire bodies use “tensegrity” architecture to mechanically stabilize their shape, and to harmonize structure and function at all size scales ( 325 , 326 ). Like any other model, the tensegrity model described here is a simplification of the theory. Because tensegrities are composed of discrete networks of support elements, rather than a uniform medium like a chunk of metal or a rubber band, they provide a way to transmit mechanical forces along specific paths and to focus or concentrate stresses on distant sites and at different size scales. These are all features observed at the level of whole organs as well as tissues, cells, membranes, cytoskeletal networks, subcellular organelles, nuclei, mitotic spindles, transport vesicles, viruses, and proteins ( 325 ). (iii) Myofascial chains Fascia constitutes a most ubiquitous tissue that permeates the human body and is capable of transmitting and dispersing mechanical forces to a distance because of the structural connectivity of the (fascio)musculoskeletal system ( 304 , 327 , 328 ). On a more macroscopic level, as part of normal physiology, internal mechanical forces are transmitted within myofascial tissue along mechanical links called myofascial chains ( 304 , 307 , 321 , 327 , 329 ). In this way, for instance, force in the lower limb can be transmitted to the trunk and affect the lumbar musculature ( 327 ). Stretching of the upper limbs can lead to an increased maximal range of motion in the lower limbs, and vice versa ( 327 , 330 ). Cadaveric studies investigating force transfer in the human body indicate that anatomic structures normally described as leg, hip, and pelvis muscles interact with muscles of the spine and arm through the thoracolumbar fascia, thus forming an integrated functional system that allows for load transfer between the spine, pelvis, legs and arms ( 331 ). For example, the posterior layer of the thoracolumbar fascia was found to be continuous with the fascia of the gluteus maximus, and some of the superficial lamina fibers were found to cross the midline and fuse with both the lateral raphe and fibers derived from the fascia of the latissimus dorsi ( 331 ). Muscle and fascial tissue do not exist in isolation, but rather they function together in synergy to facilitate the body’s movements through mutual connections thus forming a myofascial tensional network that connects all parts of the body as a whole ( 323 ). Most skeletal muscles in humans are connected through connective tissue ( 327 ). (iv) Innervation and sensory functions of fascia Fascia contains a densely interwoven network of sensory nerve endings that are involved in the perception of pain ( 304 , 332 – 334 ), although the relationship between the nervous system and fascia is a relatively neglected field of research. Free and encapsulated nerve endings are located within myofascial tissue ( 335 ), including interoceptive receptors and Ruffini and Pacini corpuscles ( 304 ). Superficial fascial tissue is associated with skin mechanoreceptors and thermoreceptors, while the deep fasciae are known to affect proprioception ( 305 ). Fede & Stecco et al. (2021) showed that in fascia an impressive network of sympathetic nerve fibers is found, as was demonstrated in samples from mice ( 336 ). Nociceptor free nerve endings terminate in muscle interstitium. Non-myelinated C fibre receptors in muscle tissue are polymodal and respond to high mechanical pressure and chemical stimuli ( 337 – 339 ), as do A-delta fibres which are related to stretch receptors ( 337 ). The biochemical milieu can therefore affect nociception when nociceptive substances accumulate in muscle interstitium ( 340 ). Fascial dysfunction, overuse, strain injury, trauma, and inflammatory changes, are postulated to lead to pain due to pathological ECM remodeling accompanied by chemical and mechanical alterations ( 341 ). Pathological changes in fascia are characterized by increased tissue stiffness and changes in the ECM, including changes in both collagens and matrix metalloproteinases levels as well as alteration in myofibroblast activity ( 332 ). Abnormal mechanical forces and nociceptive mediators that are secreted by myofibroblasts and local cells (e.g., interleukin 1-beta, tumor necrosis factor-alpha, neuropeptide Y, substance P) may trigger pain via activation of peripheral sensory receptors ( 304 ). The transient receptor potential ankyrin cation channel TRPA1, which is widely expressed in sensory neurons, is known to respond to mechanical and chemical stimuli and is involved in acute and chronic pain, as well as in the sensation of itching (pruritus) ( 342 ). Among its natural endogenous agonists are products of oxidative stress. Lack of TRPA1 may attenuate the expression of transforming growth factor beta 1, interleukin 6, and α-SMA ( 342 ). Transient Receptor Potential vanilloid 4 ion channel TRPV4 is known to be responsive to mechanical stimuli and is likely to be relevant in musculoskeletal pain ( 343 , 344 ). (v) Substrate stiffness & rigidity of ECM ECM stiffness seems to be a crucial factor in the behavior and function of nerve cells ( 345 ). Researchers have investigated the effect of matrix rigidity on neuronal cells in vitro, and found a marked difference in growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks when comparing cultures grown in substrates with 100-fold differences of young modulus ( 346 ). Matrix stiffness may be a significant factor to modulate Schwann cell function and behavior ( 347 ). Specialized Schwann cells form a mesh-like network in the subepidermal border of the skin and are intimately associated with unmyelinated nociceptive nerves. This cell type is inherently mechanosensitive and capable of conveying nociceptive information to the nerve. As was shown using transmission electron microscopy, a distinct thick layer of fibrillar collagen is found to envelope their cell processes ( 348 ). The above findings, integrated mechanistically, provide the five main elements for forming the theoretical model of Fascial Armouring. Essentially, it can be summarized as: myofibroblast-mediated bio-tensegrity tension, compression, and ECM stiffness on a background of interrelated myofascial tissue and myofascial chains. Basically, it is a myofibroblast-driven disease of the fasciomusculoskeletal system, whose severe manifestations would be comparable to a mild-to-moderate global chronic exertional compartment-like syndrome (or a “myofascial pain syndrome of the whole body”) ( 290 ). Empirical findings that, when taken together, may support this mechanism for fibromyalgia can be found in several studies and are listed in Table 8 below. A more elaborate analysis of this model in relation to fibromyalgia and LC can be found in a recent study ( 87 , 290 ). A myofascial-based mechanism might help explain several manifestations of LC and fibromyalgia (and the overlap of both), particularly when initial infection was mild or asymptomatic and when medical evaluation reveals no prominent organic abnormalities such as pulmonary fibrosis or other organ damage. View this table: View inline View popup Table 8: Summarizes empirical findings that may support a tensegrity connective tissue-based mechanism for fibromyalgia. 6.2. “Fascial armoring” as a fascio-musculoskeletal medical entity of continuum biomechanics Let us now analyze this theoretical mechanism as a medical entity with clinical reasoning, for instance: one may infer from the mechanism that if myofibroblast-mediated “bio-tensegrity” tension and fascial stiffness develops in the temporal fascia, it is expected to manifest as a tension-like “primary headache disorder” ( 87 ). If tensegrity imbalance and compression transfer to thoracolumbar fascia, the expected manifestation would be a chronic “none-specific” low back pain ( 290 ). If it affects the palms and hands, it is expected to predispose to a Raynaud-like phenomena and/or carpal tunnel syndrome. Tension transferred to the spinal denticulate ligaments or dura-spinal-cord-associated abnormalities. Prevertebral fascia-spinal stiffness. If in the pelvic fascia-urinary urgency. Chest and torso-chest tightness, shallow breathing, and if severe, non-cardiac chest pain. Diaphragm and abdomen-predisposition to gastroesophageal reflux. Neck and pretracheal fascia-muscle tension dysphonia and dysphagia. Cervical fascia, parotid fascia, and superior cervical ganglion-dry mouth. Baroreceptors and stellate ganglion-autonomic imbalance. Neurovascular bundle and perivascular nerve plexus or nervi nervorum-sensory and vascular irregularities. Jaw-temporomandibular tension, dysfunction, and pain. Tympanic membrane and inner ear-hearing abnormalities. Proprioceptors-impaired coordination, impaired balance, microsomatognosia, and new onset clumsiness. Joint capsule or tendons-decreased joint range of motion, and if myotatic reflex is involved-muscle spasms. Muscle spindles-increased resting tone and activation of the stretch reflex, and sustained tonic muscles during sleep. Epimysium-compression of striated muscle. Increased rigidity of subcutaneous fascia - activation of TRPA1 channels and itching sensation, and substrate stiffness dependent neurite alterations. Celiac plexus, mesentery, visceral fascia, abdominal muscles and/or the gut wall-disrupted peristalsis, subsequent bloating, distension, and stretching of the gut wall, alterations in gut microbiota, and so forth. Abnormal pendulousness affects gait and kinesthetics (e.g., robotic gait). Altered absorption and dissipation of kinetic energy throughout the fascio-musculoskeletal system would lead to a subclinical “functional” movement impairment without classic neurological signs (e.g., upper or lower motoneuron pathology or cerebellar dysfunction). Increased intra-abdominal pressure has the potential to compromise blood flow in the gonadal arteries/veins. Sleep impairment is a non-specific complaint easy to disregard as a psychological issue. Morning stiffness, a general feeling of heaviness, hypervigilance, mild pallor, low mood, and constant exhaustion, are naturally deduced if the abnormality is widespread. Recall that the guiding theme when clinically interpretating this entity is: myofascial tension, compression, and high ECM substrate stiffness. Worth noting, the mechanobiological cascade of myofibroblasts is not necessarily propagated as a classic inflammatory leukocyte-driven disease in its nature, therefore, it can be mostly silent when examined in routine medical investigations. Systemic subclinical chronic oxidative stress is achieved by this theoretical model as it portrays a global chronic exertional compartment-like syndrome. Unmyelinated muscle nociceptors are activated by hypoxia of muscle tissue which is exacerbated by muscle contraction ( 354 , 391 ). Sugawara et al. (1996) ( 392 ) report that mechanical compression of the dorsal root ganglion by a stimulus decreases the threshold needed to trigger a neuronal response, leading to the generation of action potentials. The same (in vitro) study also suggests that these action potentials can continue after the stimulus is removed, indicating increased mechanical sensitivity ( 392 ). Results from another (in vivo) study seem to be in line with these findings, revealing an ectopic spontaneous discharge generated within chronically compressed ganglia ( 393 ). It is interesting to note that dysfunction of the thoracolumbar fascia has been described as a chronic compartment syndrome of the paraspinal muscles ( 394 ). Some of the variability of this mechanism relates to fibroblasts being a diverse cell family. They secrete cytokines, growth factors, and various inflammatory mediators ( 295 ), neurotrophins ( 395 ), and matrix metalloproteinases, and can uptake cellular signaling molecules and serotonin which affect molecular biological pathways and metabolism ( 291 , 295 , 396 ). In certain conditions myo/fibroblasts can express major histocompatibility complex class II and CD74 and stimulate CD4+ T-cells in an antigen-dependent manner via T-cell receptor ligation ( 397 ). Also, substrate stiffness affects the function of monocytes/macrophages, dendritic cells, B-cells, and other immune cells ( 398 ). Low-grade inflammation is implicated in this mechanism. To the best of the author’s knowledge, no study has examined fascial myofibroblast concentration or blood CTGF levels in fibromyalgia. Box 1 summarizes T-cell dysregulation and its relevance to this framework. Box 1: T helper 17 cells and T regulatory cells and their relevance to the pathophysiological model T helper 17 (TH17) and regulatory T cells (Treg) are two distinct CD4+ T cell subtypes with opposing functions in the immune system. TH17 cells, regarded as proinflammatory, produce IL-21 and IL-22, as well as signature cytokines IL-17A and IL-17F, and are implicated in the pathogenesis of various autoimmune and inflammatory diseases ( 399 ). TH17 cells not only trigger B-cell proliferation but also promote the formation of germinal centers together with isotype switching ( 399 ). In contrast, Treg cells are known for their immunosuppressive properties, mediated by the expression of FoxP3 and the production of TGF-β, and play a crucial role in maintaining immune homeostasis and preventing autoimmunity ( 400 ). The differentiation of naive CD4+ T cells into TH17 or Treg cells is critically influenced by the cytokine milieu present during T cell activation. In addition to these effector T-cell subsets, a specialized T helper cell subset, called follicular B helper T cells has been identified, which plays an important role in B cell induction of induction of germinal centers and isotype class switching. The development of TH17 cells is driven by a combination of pro-inflammatory cytokines, including IL-1β, IL-6, and TGF-β. These cytokines activate the transcription factor RORγt, which is essential for TH17 cell differentiation and the production of IL-17 family cytokines ( 400 ). IL-23, while not required for the initial differentiation, is crucial for the survival and expansion of TH17 cells ( 400 ). Treg cell differentiation is primarily induced by TGF-β and mediated by the transcription factor FoxP3 ( 400 ). A delicate balance between TH17 and Treg cells is tightly regulated by the interplay of cytokines. While TGF-β together with the inflammatory cytokine IL-6 can induce the differentiation of naive T cells into the Th17 phenotype, TGF-β, favors Treg induction ( 400 ). The dysregulation of the Th17/Treg balance has been implicated in various autoimmune and inflammatory diseases ( 401 ). Interestingly, TH17 cells, known for their pro-inflammatory cytokine production, can promote myofibroblast activation and collagen deposition, contributing to fibrosis ( 402 ). IL-17A increases and stabilizes TGF-βRII expression on fibroblast, and the TH17-associated cytokine IL-22 similarly enhances TGF-β signaling in fibroblasts ( 295 ). It was shown that TGF-β in turn induces the expression of IL-17A when produced concurrently with the pro-inflammatory cytokines IL-1, IL-6, or TNF ( 295 ). Some of the abovementioned cytokines known to be produced and secreted by myofibroblasts (e.g., IL-6) ( 401 ), can influence TH17/Treg balance ( 399 , 400 ). Since LC is a newly recognized syndrome, empirical studies have yet to fully investigate whether similar abnormalities occur in post-acute cases of sars-cov-2 infection. Myofascial tissue in LC is a relatively neglected field of research. When searching MEDLINE for the term “COVID myofascial” only 20 items were found, mostly in the field of physiotherapy. Figure 4 outlines fascial armouring as a medical entity of rheumato-psycho-neurology for explaining fibromyalgia-type syndromes. The main motif to keep in mind is substrate rigidity of ECM, myofascial tension, mechanical compression, and tensegrity imbalance. The clinical presentation would depend on multiple factors and does not necessarily depend strictly on the occurrence of pain. Pain in this framework is a manifestation of the entity, but it isn’t the actual entity itself. The suggested theoretical model, intrinsically, has variations. Download figure Open in new tab Figure 4. An outline of Fascial Armouring as a multifactorial rheumopsychoneurological medical entity. The clinical manifestation de facto depends on several factors (environmental, genetic and epigenetic, behavioral, psychological, co-morbidities, the specific cytokine profile, etc.) as well as the severity and location of the armouring and anatomical structures involved, and compensatory mechanisms. Involvement of the abdominal fascia, enteric nervous system, psoas muscle, and intestines navigates the abnormality more towards an irritable bowel-like syndrome. Involvement of the pelvic fascia navigates more towards genitourinary symptoms. Tensegrity forces affecting the lower back area will manifest as a tension-like “non-specific” low back pain, and so forth. A widespread disorder would manifest initially as multiorgan medically unexplained symptoms or a “somatic symptom-like disorder” (later in severe cases- “fibromyalgia syndrome” or a “myofascial pain syndrome of the whole body”). Some susceptible individuals might be more prone to neurophysiological dysfunction and mood disorders in chronic cases. The boundary of a medical entity goes as far as the boundary of the biological process which underlies it. An unhealthy lifestyle is an important contributing factor to this entity, as seen in the top right rectangle representing the etiology. Sedentary individuals would have a larger component contributed by immobilization stress especially during lockdowns. Pain leads to the release of neuropeptides, cytokines, and chemokines, and neurogenic inflammation. It is accepted by neurobiology that peripheral sensitization may lead to central sensitization, a process mediated by neurotransmitters such as glutamate. Many factors lead to sleep disruption. The gut-brain axis is likely involved as well. Persistent cough, as often seen following COVID-19, would likely be related to pulmonary injury during the acute phase. Olfactory/gustatory disfunction would be related to injury of olfactory/gustatory system during COVID-19. Pancreatic injury could lead to metabolic abnormalities, and so forth. This scheme focuses on the psychosomatic subtype of long COVID-19, where no well-defined abnormality is found following a mild or asymptomatic infection, and symptoms and complaints seem out of proportion and don’t make much sense clinically. Any mechanism suggested for this entity must be able to explain its broad symptomatology besides merely pain. Dashed lines and arrows have no unique significance in this schematic and are simply meant for visual clarity. Not all links and relationships are depicted in this scheme. ECM-extracellular matrix, IBS-irritable bowel syndrome, MMP-matrix metalloproteinase, POTS-postural orthostatic tachycardia syndrome. 6.3. Soft tissue myofibroblasts in the context of Covid-19 Figure 5 outlines the positive feedback loop of myofibroblast force generation in ECM alongside various factors that may provide enhancing or suppressing input to regulate the pathway. For simplicity, latent TGF-β and the proto-myofibroblast phenotype are not shown. Worth note, lifestyle is one of several etiological factors in this framework. A cytokine storm that may occur during infectious diseases is expected to fuel this pathway, leaving behind a remodelled and less healthy fascia. During infection with SARS-CoV-2, as with other infections, pro-inflammatory and pro-fibrotic processes are activated and involve various inflammatory mediators including TGF-β ( 403 ). TGF-β was mentioned as a main cytokine that fosters the differentiation and cellular activity of myofibroblasts ( 404 ). After SARS-CoV-2 infection, fibrotic changes facilitated by myo/fibroblast are seen in several tissues and organs (including lungs, heart, kidney, liver, intestines, and more) ( 254 , 405 – 414 ). Muscle biopsies in post-COVID-19 patients with persistent complaints of fatigue, myalgia, and/or weakness lasting for up to 14 months revealed myopathic changes, including muscle fiber atrophy, mitochondrial abnormalities, subsarcolemmal accumulation, inflammation, and capillary alterations, suggesting skeletal muscle as a target of SARS-CoV-2 ( 178 , 179 ). The angiotensin converting enzyme 2 (ACE2) and TMPRSS2, which are the key mediators that allow viral invasion by SARS-CoV-2 ( 415 ), are found in extrapulmonary and musculoskeletal tissue including muscle cells, smooth muscle cells, pericytes, endothelial cells, macrophages, chondrocytes, synovium cells, osteoblasts, and osteoclasts ( 416 – 423 ). Mast cell-mediated activation of fibroblasts can contribute to fibrotic changes seen in LC ( 11 ). Download figure Open in new tab Figure 5. The vicious cycle of myofibroblasts transforms the osteomyofascial tensegrity-like system into a high pre-stress biomechanical system: This is suggested to be the core cellular pathway of primary fibromyalgia syndrome. Various factors provide input into the cycle of myofibroblast contractility and matrix remodeling. Insofar as COVID-19 involves systemic cytokines, pro-inflammatory, and pro-fibrotic signals including TGF-β1, and stimulates fibroblast-to-myofibroblast differentiation in various tissues, it is part of the etiology. Studies have shown that estrogen inhibits TGF-β1 and myofibroblasts and is associated with lower fascial stiffness ( 404 , 424 , 425 ), therefore, estrogen is expected to be a protective factor whereas low estrogen states are anticipated to be a risk factor ( 87 ). Myofibroblasts secrete cytokines such as IL-11, IL-8, and IL-6 ( 295 , 401 ), some of which are crucial to the balance of TH17 Treg cells ( 400 , 402 ). IL-17A has been implicated in pathways of fibrosis in fibroblasts ( 295 ). IL-11 acts both in paracrine and autocrine signaling and has downstream effects on nearby cells. The proto-myofibroblast phenotype is not shown for the purpose of simplicity. Open arrows signify stimulation/enhancement while closed arrows signify suppression. IL-interleukin, TGF-β1 – transforming growth factor beta-1, α-SMA-alpha smooth muscle actin. Figure created with BioRender.com . While this paper presents a conceptual framework for elucidating fibromyalgia-type manifestations of LC, it has not been empirically tested. Figure 6 below illustrates how several mechanisms may possibly contribute to persistent symptoms - functional and non-functional - after SARS-CoV-2 infection, and its infection-associated organ damage, e.g., pulmonary fibrosis, renal injury, myocardial injury, neuroinflammation, etc. The plausible contributing mechanisms may include immune cell dysregulation and autoimmunity, persistence of viral particle shedding in peripheral tissue, latent neurotropic pathogen reactivation, vagus nerve dysfunction or autonomic nervous system neuroinflammation, endothelial damage, hypercoagulability, muscle atrophy, immune-mediated myopathy, vascular disruption in the blood–brain barrier, and other abnormalities ( 1 , 7 , 12 , 426 , 427 ) including, possibly, a connective tissue abnormality that involves the myofascioskeletal bio-tensegrity-like system. These abovementioned suggested mechanisms are not necessarily mutually exclusive. Download figure Open in new tab Figure 6. Persistent symptoms after COVID-19 have a multifaceted pathogenesis that may result from multiple cellular processes and organ systems involving various abnormalities. Even though lung fibrosis is noted, the term “long COVID-19 syndrome” should be reserved to multisystem medically unexplained symptoms after COVID-19 with no demonstrated well-defined organic damage to explain them, with no alternative organic diagnosis for them and no comorbidity to account for them, of the kind that is typically dismissed or labeled medically as “psychosomatic”. This syndrome should not be conflated with persistent symptoms after hospitalization or known lung or cardiac damage nor with post-intensive care syndrome, which are not the focus of this paper. For practical purposes, individuals who have pulmonary fibrosis after COVID-19 should be labeled as having “pulmonary fibrosis” (which can be covid-19 induced and which has its etiopathogenesis) rather than “LC syndrome”. Myocarditis induced cardiomyopathy, likewise, should be designated as “myocarditis induced cardiomyopathy.” Figure created with BioRender.com. 7. Interpreting LC manifestations and drawing theory-based predictions In 2020 the World Health Organization declared covid-19, caused by sars-cov-2, a global pandemic ( 428 ). Approximately 10-30 percent of individuals who had covid-19 experience persistent bothersome symptoms after recovery from the acute phase ( 2 , 7 , 226 , 429 ) in what is officially termed “long covid” or post-acute covid-syndrome. While the social and economic burden of LC is a matter still being figured ( 430 ), many individuals with LC experience heavy symptom burden and a persistent medically unexplained multisymptom illness, termed by some scholars as “functional long covid” as opposed to an “organic long covid” ( 50 ). The observed similarity between LC and psychosomatic syndromes such as fibromyalgia and ME/CFS has led researchers to suspect a shared underlying mechanism ( 9 , 10 , 16 , 21 , 51 , 55 , 139 , 146 ). Some experts agree that LC should be defined as a psychosomatic disorder ( 30 ). Nevertheless, attributing the condition to deconditioning or labeling patients with normal results on medical investigations as “functional long COVID-19”, as opposed to an “organic long COVID”, is problematic. Although it is true that improving respiratory muscle function can alleviate symptoms in cases where muscle atrophy and deconditioning are contributing to LC symptoms ( 431 ), attributing the condition solely to deconditioning and psychological factors fails to comprehensively address its complexity ( 432 ). Enck & Mazurak (2018) ( 433 ) emphasize that biopsychosocial models should not neglect organic biological aspects, even when applying them to somatoform-type disorders. To date, controlled trials and large-scale cohort studies have not shown that current pharmaceutical therapies effectively reduce symptoms or improve radiological and biomarker profiles in LC ( 432 ), and there is an urgent need for effective treatments ( 226 , 434 ). While existing theories offer some insights, they often fall short in fully explaining the broad symptomatology of fibromyalgia. This underscores the imperative to explore novel mechanistic frameworks that can provide a more integrated explanation. Understanding the patho-mechanisms involved in LC may potentially lead to the development of better treatments. The following sections explain predictions that are derived from the mechanism suggested here for the pathogenesis of fibromyalgia syndrome. 7.1. Mechanistic Predictions of ‘Long COVID-19’ Manifestations Based on the Suggested Biomechanical Model From the suggested mechanism of myofibroblast-generated tensegrity tension and ECM alterations in myofascial tissue, predictions regarding LC may be drawn, based on a mechanistic analysis. Any factor that enhances the cycle of myofibroblast mechanobiology and contributes to myofibroblast activity, theoretically leads to more cell contractility (and inherent reactive feedback regulation), and may advance the disorder, while factors that inhibit this cycle are generally expected to be protective factors. Based on the model, predictions can be made, explained as follows: Risk/protective factors and relieving factors: Hypermobility syndrome/Ehlers-Danlos syndrome: Collagen microarchitecture affects mechanosensitive signaling in cells followed by an induction of myofibroblasts and secretion of proangiogenic factors (vascular endothelial growth factor and IL-8) when studied in human adipose-derived stem cell culture ( 435 ). Hypermobile Ehlers-Danlos syndrome is associated with ECM disarray and increased myofibroblast phenotype when studied in vitro ( 436 ). Hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders are probably not separate entities but rather appear to be both on a continuum characterized by altered ECM homeostasis and a chronic inflammatory state ( 436 ). If ECM microarchitecture augments myofibroblast activity in patients with hypermobility syndrome, it is mainly for this reason that GJH is expected to increase their risk for fibromyalgia-type symptoms, a relationship that should be weakly explained statistically by psychological stress levels alone ( 290 ). Mechanical tension on the skin has been shown to enhance myofibroblast activity ( 437 ). The application of mechanical forces such as by use of splints further corroborates this finding ( 438 ). The development of myofascial pain is linked to tight-fitting clothes ( 290 , 439 , 440 ). Tight-fitting clothes and accessories are expected to predispose individuals to fibromyalgia due to input into the integrin-mediated yes-associated protein cascade of myofibroblast mechano-activity. Lifestyle and exercise (movement): Though not performed on myofascial tissue in vivo, a study showed that cyclical mechanical stretch reduces myofibroblast differentiation of primary lung fibroblasts ( 441 ). Tissue stretch reduces TGF-β1 and type-1 procollagen in mouse subcutaneous connective tissue ( 442 ). Immobility leads to fibrosis and an increase in myofibroblasts in knee joint capsule when studied in vivo ( 443 ). Immobility allows for the development of abnormal cross linking between connective tissue fibres ( 444 ). These findings provide, in general, the biological rationales for the role of exercise (movement) versus sedentarism according to the suggested myofascial-based mechanism. It is interesting in this respect that yoga involves cyclical stretching of almost all body parts as an integral aspect of the practice. The effect of taking hot showers during the acute induction phase of myofibroblasts following infection, and the long-term effect of a possible activation of heat shock proteins in a subcutaneous population of myofibroblast requires further investigation. It is not necessarily expected to be inert. The effect of weather changes on symptoms will be facilitated by the biophysical effects of temperature, electromagnetics and humidity on myofascial tissue and hyaluronic acid. If factors such as tattoo ink or smoking induce subcutaneous myofibroblasts, sedentary people with whole-body tattoos and smokers are expected to have worse and more prolonged psychosomatic symptoms after covid-19. A similar link is expected for those using cosmetics and topical creams containing substances that upregulate pathways of subcutaneous fibroblast-to-myofibroblast differentiation. Environmental factors such as pollutants, chemicals, and microbes can trigger or protect from fibrosis ( 295 , 445 ). Diet and the gut brain axis ( 446 ) fit in the mechanism of LC from multiple angles and not only in relation to connective tissue. Obesity: in obesity, connective-tissue fibrosis is induced and mediated by mechano-transducing signaling pathways ( 447 ). Fibrotic processes mediated by myofibroblasts can transform the mechanical properties of subcutaneous tissue, increasing its rigidity and connective tissue stiffness ( 447 ). For this reason, obesity is predicted to be a significant risk factor for LC. Other manifestations based on the model Hair loss: adipocyte to myofibroblast transition is a possible cause of alopecia ( 448 ). The connective tissue sheath and follicular papilla can use gap junctions to form a communicating network. During hair cycling, this network plays a part in the control of hair follicle dynamic structural changes ( 449 ). Hair loss is therefore expected to occur and be weakly explained by psychological stress levels. Pallor : might be an overlooked manifestation, reflecting impaired peripheral perfusion due to autonomic and non-autonomic or hydrostatic causes. Explaining Morning stiffness : Tomasek et al. (2002) ( 291 ) describe the dynamics of fibroblast populations in three-dimensional collagen lattices and the process of generating traction and tension in their surrounding matrix of collagen fibrils. Over several hours the forces increase until a plateau is reached. If a similar process occurs in fascia in vivo, then a period of immobility would be comparable to this process of allowing the cells to reach the plateau of a higher tension state uninterrupted. (Fascio)Musculoskeletal : altered pendulousness of the legs. If the physician is searching for an objective mechanism-based sign of the disease to test bedside, this might be a relatively good one. Cardiovascular : A mild chronic compartment-like syndrome affecting multiple muscles should, by a chronic contraction of skeletal muscles, impair perfusion and lymph flow and alter starling forces which could exacerbate pre-existing subclinical cardiovascular issues. The typical presentation would, by reasoning, include changes in blood pressure regulation, fatigue on exertion or after a heavy meal, palpitations, higher resting heart rate, cold feet and palms, sub/clinical impairment of sexual function, and absence/impairment of morning erection in males, due to impaired blood flow to various organs. Chronic compressive forces in the periorbital fascia would lead to subclinical reduced optic disc perfusion. Idiopathic fluid retention might also be derived mechanistically. Active loci : possibly due to mechanical stress on the muscle spindles as well as sympathetic overactivity. Tonic slow adapting receptors in nuclear chain fibers of the muscle spindle would activate gamma motoneurons via the stretch reflex in prestressed myofascial tissue. Also, afferent input from gastrocnemius-soleus muscle C-fibres produces long-lasting excitability of the biceps femoris/semitendinosus α-motoneuron efferent fibers through the flexion reflex in an animal model ( 450 ). A mechanistic discussion of myofascial pain syndrome and active loci in the context of this framework is available in a recent study ( 290 ). Immune system: based on a finding that substrate stiffness affects immune cell function ( 398 ). Fibroblasts and inflammatory myofibroblasts secrete cytokines as part of their natural activity ( 295 ). An overactive (or “irritable”) state of immune cells due to paracrine proinflammatory cytokine secretion, chronic low-grade inflammation, and increased substrate rigidity of the ECM would likely predispose the immune system to over-reacting in intolerance to “irritant” antigens. Such immune hyperirritability could be evident in the form of predisposition to gluten intolerance, multiple chemical sensitivity, association with autoinflammatory reactions, or other clinical or subclinical immune dysregulation. Fibromyalgia and LC are associated with mast cell dysregulation ( 451 ). A mechanistic explanation, among several, can be related to findings ( 452 ) that tissue stiffness affects mast cell behavior and function. Metabolism: Myofibroblasts secrete IL-6, IL-8, and IL-11 ( 295 , 401 ). The cytokine IL-6, besides its effect on CD4+ T lymphocytes, can activate indoleamine 2,3-dioxygenase, as shown in different cell types ( 84 , 453 , 454 ), and therefore is potentially intimately related to the metabolic balance of the tryptophan-indoleamine 2,3-dioxygenase 1-kynurenine and serotonin pathway. Metabolites of this pathway (e.g., the neurotoxic metabolite quinolinic acid) ( 455 ), some of which can cross the blood brain barrier ( 456 ), were observed in altered systemic levels in fibromyalgia ( 457 , 458 ), and are linked to cognitive impairment and depression ( 84 ). Besides cytokines, the gut microbiome has the capacity to modulate indoleamine 2,3-dioxygenase 1 too, for example via butyrate production ( 84 , 459 ). Mood and psychosomatic disorders: post-traumatic stress disorder, anxiety, and depression are known manifestations of ‘long COVID-19’ ( 460 ). “Post-traumatic stress disorder” in this framework (not only in the context of LC) is expected to have a bio-mechanical aspect involving the (fascio)musculoskeletal system. Any acute sympathetic or inflammatory reaction which leads to a simultaneous abrupt contraction of multiple muscles and of the osteomyofascial tensegrity structure would cause a sudden shift in its biomechanical and energetic elastic state. The energetic shift and the mechanical tension locked in the ECM by contracting cells would lead to an increase in widespread tension in the body irrespective of alpha motoneurons. Sympathetic nerve fibers embedded in fascia would also be affected, which is a relevant interface with emotion and cognition. If the musculoskeletal tension is not released after this acute event, overtime fascia and ECM will be remodeled in this higher-tension state which initially was supposed to be a temporary sympathetic defensive reaction. This is followed by myo/fibroblasts remodeling the ECM and stress shielding themselves to mask the tension while, importantly, they form “supermature” focal adhesions and upregulated expression of α-SMA. In their resolution phase, the balance of proliferative and apoptotic signals is crucial for the outcome of myofibroblast cells ( 296 ). They can either undergo apoptosis (mediated by fibroblast growth factor 1, prostaglandin E2, and IL-1beta), evade apoptosis and persist in the tissue, or enter senescence (mediated by CCN1 with upregulated intracellular p16 and p21, and characterized by the acquisition of a senescence-associated secretory phenotype, specifically the secretion of TGF-β1 and pro-inflammatory cytokines and chemokines such as IL-6, CCL2, IL-1α, IL-1β, IL-8, PDGF, and ECM proteins), or other possible fates ( 296 ). Myofibroblasts become much more active above a certain threshold of matrix rigidity ( 461 ). Higher ECM pre-stress in the tensegrity-like structure crosses the threshold for myofibroblast activity and propels their cascade of mechanobiology and stress shielding, but once fascia is remodeled this way, it is much more difficult to resolve. Fibromyalgia does not typically erupt in patients overnight. The systemic implications aren’t limited to myofascial tissue, and include changes in metabolism and secretory profile of myofascial cells, changes in vasculature, effects on the immune system, and more. Interestingly, circulating systemic fibroblast growth factors can deeply affect brain physiology ( 462 ). Also, the intracranial ECM is suggested to be implicated in the pathophysiology of stress-induced depression ( 463 ). Overlap with “myofascial pain syndromes” : The clinical overlap of myofascial pain and associated psychosomatic and “non-specific” pain conditions (or “central sensitizations symptoms”) is likely to be evident in relation to LC. Figure 7 illustrates in general the clinical overlap reflected by the mechanistic overlap, as suggested by this conceptual framework (not all relationships are depicted in this scheme). 7.2. Predictions of results on investigations and means for testing the hypotheses The myofibroblast-based model can be tested by several different methods. A preliminary non-invasive straightforward approach would be to measure muscle damping ( 350 ) which should reflect increased muscle tension. Pendulousness of the legs or arms of fibromyalgia-type LC patients compared to controls could be a relatively simple clinical test to start with, after controlling for age, sex, and body mass index. The inclusion of subjects would focus more on persistent “fibromyalgia-ness” patients who had mild acute infection, rather than dyspneic patients who had severe acute pulmonary covid-19. Shear wave elastography/strain elastography or magnetic resonance elastography can help measure the stiffness of tissue for comparing fibromyalgia-like LC patients and healthy controls. Again-focusing on those with multiple multiorgan psychosomatic complaints after mild/asymptomatic infection and excluding subjects who were hospitalized during the acute phases. The resonance of tissue and its response to internal organ oscillations might also be found to be altered. Sub/clinical decreased joint range of motion should be seen on careful examination when taking into consideration hypermobility syndrome. Demonstrating an inappropriately normal joint range of motion in a hypermobile individual is false-normal and pathological. Biopsies can be used to measure myofibroblast density, or to examine if fascial cells express elevated levels of α-SMA. But since myofibroblast can de-differentiate and leave behind a remodeled dysfunctional fascia, testing only by this method might actually be deceptive. Needle biopsy may be sufficient for this ( 464 ). Smokers are expected to have a higher density of myofibroblasts in myofascial tissue compared to non-smokers. Overall, pharmacological agents that enhance myofascial fibroblast-to-myofibroblast transdifferentiating are expected to predispose to LC and fibromyalgia. Microdialysis of muscle, for example of the trapezius muscle ( 368 ) or vastus lateralis ( 340 )-not all patients necessarily have increased concentrations of algesic substances and signs of anerobic metabolism in the same muscles because not all patients necessarily have the trapezius (or vastus lateralis) deeply affected. The clinical variability is derived from a mechanistic variability regarding which anatomical structures and layers are more involved. Laser doppler fluxmetry and isotope washout methods can also be used ( 465 ). Quality of radial pulse on palpation could be a fairly useful clinical sign for the condition. Severe cases might have abnormally elevated serum and urinary creatine as a result of muscle breakdown and oxidative stress, if muscle cells fail to compensate. Increased physiological response to the Valsalva maneuver and exertional dizziness would be characteristic of a mild-to-moderate global chronic compartment-like syndrome. Activation of the stretch reflex due to diffuse involvement of the muscle spindles or tendon would manifest as increased muscle tone not mediated by alpha motoneurons. Biophysical tests-strain elastography, atomic force microscopy, optical coherence elastography, dynamic mechanical analysis, etc., of fascial/myofascial tissue might be insightful, although these would have to take into account the complexity of the model and possible confounding factors. Age, sex, pH, temperature, hydration, hyaluronic acid composition, elastin and collagen polymorphisms, adipocytes, cell phenotype and density, are all variables that may affect the properties of fascia in vivo. Heterogenous clinical complaints are derived from the mechanistic variability. When the transformation of fascial ECM reinforces the cycle of myofibroblast force generation, myofascial degree of stiffness increases and muscles are then subjected to low-grade chronic ischaemia. Over time, in the absence of full muscle relaxation and due to insufficient nutrients and oxygen, muscle mass and muscle cells experiencing longstanding low-grade hypoxia will undergo long term structural, metabolic, and genetic/epigenetic level adaptations and compensations, while the immune system is continuously drawn into the process due to ongoing tissue injury. Sedentarism reinforces atrophy of skeletal muscle. Afterwards, matrix material such as collagen replaces atrophic skeletal muscle mass and at this stage fatigue and weakness become more prominent. Meanwhile, fascia can either continue in its positive feedback, or break the cycle and proceed to a stress-relaxation failure stage, where it experiences mechanical creep and has lower shear modulus. A higher myofascial Young’s modulus is expected if pain, tension, and stiffness are the main complaint, and lower fascial stiffness is expected if fatigue, weakness, and pain are the predominant complaint. Download figure Open in new tab Figure 7. Overlaps of psychosomatic fibromyalgia-type conditions. The syndrome of long covid-19 refers here to ME/CFS-fibromyalgia-type persistent clinically unexplained symptoms. The clinical manifestation de facto depends on multiple factors including environmental, genetic, behavioral, psychological, iatrogenic, and which anatomical structures are more involved etc. Individuals with known organ damage after severe hospitalized covid-19 or those with lung parenchymal scarring after infection or those hospitalized with hypoxia are not the focus of this illustration. Involvement of the abdominal fascia and intestines navigates the abnormality more towards a functional gut disorder or irritable bowel-like syndrome. Involvement of the pelvic fascia navigates more towards genitourinary symptoms. Masseter and temporalis muscle fatigue during mastication would be associated with temporomandibular involvement. Involvement of the lumbar and abdominal region navigates more towards “non-specific” low back pain, and so forth. In clinical terms, “SSD” and “CWP” can be said to be a prodrome of fibromyalgia. Not all relationships are depicted in this diagram. Colors are for visual clarity and have no special meaning. The term “healthy individual” is subject to the reader’s interpretation. CWP-chronic widespread pain. LC-long covid-19. ME/CFS-myalgic encephalomyelitis/chronic fatigue syndrome. MPS-myofascial pain syndrome. SSD-somatic symptom disorder. Cadaveric studies might not be the best choice to investigate the tensegrity dynamics. Mathematical computer models might be more useful in this case. 8. Conclusions Long COVID-19 is increasingly becoming a public health concern and, similarly to fibromyalgia, still lacks a comprehensive biology-based definition, diagnosis, staging, epidemiology, pathophysiology, prognosis, prevention, and treatment. The term “LC syndrome” and its synonyms should be reserved for patients with a persistent clinical picture that does not fit other known organic diseases, when no well-defined organ damage is found to account for the patient’s clinical picture. Several plausible mechanisms have been hypothesized in literature so far to explain LC such as direct viral toxicity, dysregulation of the immune system, persistence of viral particles in peripheral tissue, latent viral reactivation, neuroinflammation, microbiome alterations, an imbalance of serotonin in the brain, vascular disruption in the blood–brain barrier, brainstem dysfunction, dysregulated circadian rhythms, microvascular endothelial damage, vascular thrombosis, deranged endocrine functions, tissue infiltration of amyloid-containing deposits, epigenetic changes, exercise-induced myopathy, sarcopenia and physical deconditioning, and more ( 1 , 7 , 12 , 426 , 427 , 429 , 466 ). Here, a different perspective is proposed for the pathophysiology of LC as a disorder of immuno-rheumo-psycho-neurology involving the (fascio)musculoskeletal system and the cascade of myofibroblast force generation and ECM remodeling in soft tissue. The suggested neuro-mechanobiological physiological model predicts a link between LC and myofascial proto/myofibroblast phenotype cells and is also used to make testable experimental predictions on investigations, and it predicts risk and relieving factors in LC, as well as effectiveness of treatment options. Still, this pathophysiological model clearly needs to be adjusted according to empirical studies. Physicians should be careful not to assume by default that a patient presenting with unexplained chronic pain and multiorgan medically unexplained symptoms is malingering or over exaggerating as this is a major barrier to treatment for fibromyalgia patients in many clinical settings and can easily become a similar obstacle for long covid patients. The conceptual framework of “fascial armouring” links between unhealthy lifestyle and pain and suffering. As with many other medical scenarios, it is multifactorial. An unbalanced body will hold an unbalanced mind. Holistic therapies targeting both body and mind are under-utilized in the treatment of chronic psychosomatic pain conditions. Biology does not separate or segregate itself into distinct medical specialties as we do in our profession, and the “body” and the “mind” are one being, one flesh. Further research is needed to better understand the post-acute sequala of covid-19 and how to best manage new onset psychosomatic symptoms in patients recovering from coronavirus infection. 9. Limitations The main limitation of this scoping review is that a sole researcher evaluated the studies. Being a new field, the review aimed to report the extent and range of studies on the subject. Much less was the focus to appraise the quality of the studies (in agreement with Peters et al., (2015) ( 467 )), which when done by a sole author can introduce biases. The exclusion of studies published in journals ranked Q4 according to JCR aimed to give a fair balance between quality and quantity, implementing an objective criterion. As a consequence, some literature was not covered. Another drawback could be that the H-index and other parameters weren’t taken into consideration. A rounded average of the quartile in the three years adjacent to the publication time might be a more reflective marker of a journal’s quality. Two major databases, Web of Science and Medline, were searched systematically, and the search was limited to the period of inception to end of the year 2024. Cochrane library was not used, which is another weakness. Keywords focused on fibromyalgia and covid, not chronic fatigue syndrome despite a notable overlap between the two syndromes. As stated, the review focused on investigating fibromyalgia-type symptomatology, and the issue of fatigue was not expressed in the systematic search. Fatigue after covid can occur due to several reasons (physical deconditioning, muscle atrophy and sarcopenia, lung scarring, endothelial damage, genetic, metabolic, and mitochondrial level alterations, etc.). The terms “conditioned pain modulation” or “quantitative sensory testing” were not used in the systematic search phrases, and the term “medically unexplained” or “somatic symptoms” was not used either. To understand the mechanisms involved in LC better, future scoping reviews on this topic should have a broader scope and include terms related to somatic symptom disorder sand the general phenomenology of functional somatic syndromes. These are possibly phenotypes of a medical entity which putatively share a pathogenesis linking them mechanistically, as some researchers have suggested. Focusing this current review on pain narrowed the reviewed literature to primarily pain-related studies, though, being a scoping review, a specific narrow question was not asked. Rather the question of “what is the evidence on fibromyalgia manifestations post-covid as a phenomenon” was the aim of the review as a precursory step for future empirical research and systematic reviews. Excluding studies that recruited patients with a history of hospitalized covid-19 could be a disadvantage, but it was meant for minimizing confounding by organ damage-related symptoms or post-intensive care syndrome. Fibromyalgia-type manifestations were the focus, which are typically described as non-organic, functional, medically unexplained, or non-physiologic. Also, as the field is relatively new, valuable studies might have been missed if not published yet, and the preprint database search was not systematic and included only one preprint database (medRxiv). This is a drawback especially when reviewing a subject which is still new and emerging. Congress abstracts or proceedings have been likewise not purposefully searched. “Fibromyalgia features” were a criterion for inclusion of a study in the review but the validity of the definition as provided in the methods section is debatable. Also, the exclusion of studies investigating the effects of the covid pandemic on fibromyalgia symptoms in patients that were already diagnosed with fibromyalgia prior to the pandemic, likely omitted potentially relevant data. The mechanism of exacerbation of fibromyalgia might reasonably be linked to the pathogenesis of the disease, especially when considering contemporary medical community’s common belief that emotional stress triggers fibromyalgia. Due to the overlap between myofascial pain syndrome and fibromyalgia (in terms of trigger points and tender spots etc.) the term myofascial pain was part of the search, but not the term “musculoskeletal pain” (or “pain” in general). This was due to time and resource constraints. Consequently, relevant studies likely have been missed, though some were included because they were identified in the cited references of included studies. As central sensitization is the most accepted theory for the mechanism of fibromyalgia, this term was integrated into the search strategy but other putative theories for fibromyalgia were not. Several theories, all of which are still under dispute, have been suggested for fibromyalgia pathophysiology, though none of them are currently considered good enough to attribute the pathophysiology to entirely. Future research should take this into consideration. Data Availability All data produced in the present study are available upon reasonable request to the authors Footnotes Abbreviations: ACR-American College of Rheumatology, BMI-body-mass index, CSI-Central sensitization inventory, COVID-19-coronavirus disease, CPM-conditioned pain modulation, ECM-extracellular matrix, EIH-exercise induced hypoalgesia, EMG-electromyography, GJH-generalized joint hypermobility, IL-interleukin, LC-long COVID-19, ME/CFS-myalgic encephalomyelitis/chronic fatigue syndrome, PCC-post covid condition, PCR-polymerase chain reaction, POT-postural orthostatic tachycardia, PPT-pressure pain threshold, RA-rheumatoid arthritis, SARS-CoV-2-severe acute respiratory syndrome coronavirus 2, SMA-smooth muscle actin, SMR-standardized mortality ratio, SSS-symptom severity scale, TGF-transforming growth factor, TH17-T helper 17, TNF-tumor necrosis factor, TRPA-transient receptor potential ankyrin, Treg-regulatory T, VAS-visual analogue scale, WHO-world health organization, WPI-widespread pain index References 1. ↵ Crook H , Raza S , Nowell J , Young M , Edison P . 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