Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome.

Introduction: A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed. Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC). Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores. Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld's syndrome): A new flame.

In the present review, recent findings regarding autoimmune/inflammatory syndrome by adjuvants (ASIA) are described. Patients with ASIA present with complaints such as fatigue, cognitive impairment, arthralgias, myalgias, pyrexia, dry eyes and dry mouth. During the last few years, it has been postulated that these symptoms in patients with foreign body implants are due to a chronic inflammatory process and an adjuvant effect of the implanted biomaterial. Ultimately, these inflammatory reactions result in (an increase of) allergies, autoimmune diseases, immune deficiency and/or lymphomas. Pre-existent allergic disease has been found to be an important risk factor for the development of ASIA after foreign body implantation. Explantation of the foreign body results in the majority of patients in an amelioration of the symptoms. There is an urgent need to start adequately adjusted epidemiological studies to obtain better evidence which percentage of patients does develop symptoms and/or diseases such as ASIA, immune deficiency, and/or autoimmune diseases after implant surgery.

Silicone breast implants and autoimmune rheumatic diseases: myth or reality.

PURPOSE OF REVIEW: In the present review, recent findings regarding silicone breast implants (SBIs) complicated by rheumatic autoimmune diseases are described. RECENT FINDINGS: Despite changes in the principal constituents of the silicone implants during the past 50 years, silicone remained an adjuvant that may 'bleed' and subsequently may be a chronic stimulus to the immune system resulting in similar clinical manifestations as 50 years ago. Silicones are spread throughout the body and can be detected in tissues and the central nervous system. Autoimmune/inflammatory syndrome by adjuvants (ASIA), allergies, autoimmune diseases, immune deficiencies and lymphomas occur in patients with SBIs. There is a need for adequately adjusted epidemiological studies to ascertain the frequency of these diseases. Explantation of the breast implants, however, should be advised to patients with complaints, as 60-80% of patients show an amelioration of the signs and symptoms after explantation. SUMMARY: SBIs are associated in a proportion of patients with complaints such as fatigue, cognitive impairment, arthralgias, myalgias, pyrexia, dry eyes and dry mouth. Silicones can migrate from the implant through the body and can induce a chronic inflammatory process. Explantation of SBI results in the majority of patients in an amelioration of the symptoms.

Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature.

In this study, we compared one hundred patients with autoimmune/inflammatory syndrome induced by adjuvants (ASIA) due to silicone implant incompatibility syndrome diagnosed in 2014 in Maastricht, the Netherlands, with one hundred historical patients with adjuvant breast disease diagnosed in the Baylor College of Medicine, Houston, USA, between 1985 and 1992. Similarities and differences between these two cohorts were identified to determine whether the spectrum of silicone-related disease changed during the last 30 years. Patients with complaints possibly due to silicone-filled breast implants were prospectively examined in the Reinaert Clinic, Maastricht, the Netherlands between January 2014 and October 2014. All patients were evaluated for the fulfilment of ASIA criteria. Results were compared to results of the Baylor College cohort and 18 other reviewed historical cohorts. Clinical manifestations between the Maastricht and Baylor College cohorts were comparable. Fatigue was observed in 98 current patients and in 95 historical patients. Arthralgia was observed in 91 versus 81 historical patients. Myalgia was observed in 54 versus 91 patients. Cognitive impairment was observed in 78 versus 81 patients, pyrexia was observed in 64 versus 52 patients, sicca complaints in 73 versus 72 patients and severe neurological manifestations in 20 versus 32 patients. From the 54 patients who underwent removal of their silicone breast implant, 50 % (n = 27) of the patients experienced improvement of complaints after explantation of the implant. Also, in the 18 reviewed historical cohorts, similar clinical manifestations were described. Our findings suggest that no major changes were present in the observed clinical manifestations between the Maastricht and Baylor College cohorts. Also, despite changes in the principal constituents of the silicone implants during the past fifty years, silicone remained an adjuvant that may 'bleed' and subsequently may be a chronic stimulus to the immune system resulting in similar clinical manifestations as observed in the Maastricht cohort, the Baylor College cohort and 18 other large cohorts of patients. We therefore conclude that silicone-related disease has not changed during the last 30 years.

Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis.

BACKGROUND: A poor vitamin D status has been associated with a high disease activity of multiple sclerosis (MS). Recently, we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS (RRMS) patients. In the present study, we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures. METHODOLOGY/PRINCIPAL FINDINGS: Fifteen RRMS patients were supplemented with 20,000 IU/d vitamin D3 for 12 weeks. Vitamin D and calcium metabolism were carefully monitored, and T cell characteristics were studied by flowcytometry. All patients finished the protocol without side-effects, hypercalcaemia, or hypercalciuria. The median vitamin D status increased from 50 nmol/L (31-175) at week 0 to 380 nmol/L (151-535) at week 12 (P<0.001). During the study, 1 patient experienced an exacerbation of MS and was censored from the T cell analysis. The proportions of (naïve and memory) CD4+ Tregs remained unaffected. Although Treg suppressive function improved in several subjects, this effect was not significant in the total cohort (P=0.143). An increased proportion of IL-10+ CD4+ T cells was found after supplementation (P=0.021). Additionally, a decrease of the ratio between IFN-γ+ and IL-4+ CD4+ T cells was observed (P=0.035). CONCLUSION/SIGNIFICANCE: Twelve week supplementation of high dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism. The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator, and may be used as outcome measure for upcoming randomized placebo-controlled trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT00940719.