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Metals as a Common Trigger of Inflammation Resulting in Non-Specific Symptoms: Diagnosis and Treatment

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Background: The multiple symptoms of chronic fatigue syndrome (CFS) and fibromyalgia resemble those described in patients suffering from autoimmune/inflammatory syndrome induced by adjuvants (ASIA). It has been suggested that chronic metal-induced inflammation might play a role both in CFS and fibromyalgia as well as in ASIA. Humans are exposed to metals mainly through the release of metal ions from corroding dental restorations and orthopedic implants, food, vaccines and jewelry. Metals readily bind to sulphur and other groups in the mitochondria, enzymes and cell proteins. Metal-bound proteins are recognized by the immune system of susceptible subjects and might trigger an abnormal immune response, including allergy and autoimmunity. Objectives: To study three subjects with CFS and two with fibromyalgia, all of whom suspected metal exposure as a trigger for their ill health. Methods: We measured delayed-type hypersensitivity to metals (metal allergy) using a validated lymphocyte transformation test, LTT-MELISA. All patients except one were sensitized to metals present in their dental restorations. The remaining patient reacted to metals in his skull implant. The removal of sensitizing metals resulted in long-term health improvement. Nine healthy controls matched for gender and age showed only marginal reactivity to the metals tested. Conclusions: Patients with CFS and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery. This allergy to metals might initiate or aggravate non-specific symptoms in metal-sensitized patients.
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... SIR, Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently identified condition under debate [1,2]. The exposure to adjuvants such as silicone [3], vaccines [4] and others may lead to an aberrant immune response, with arthralgia, myalgia and chronic fatigue being its common symptoms [5]. Diagnostic criteria have been proposed for ASIA [5], and the most frequent autoimmune disease related to it is undifferentiated connective tissue disease (UCTD) [5,6]. ...
... The exposure to adjuvants such as silicone [3], vaccines [4] and others may lead to an aberrant immune response, with arthralgia, myalgia and chronic fatigue being its common symptoms [5]. Diagnostic criteria have been proposed for ASIA [5], and the most frequent autoimmune disease related to it is undifferentiated connective tissue disease (UCTD) [5,6]. Metal implants have been suggested in a few case reports as a trigger for ASIA [7,8]. ...
... The exposure to adjuvants such as silicone [3], vaccines [4] and others may lead to an aberrant immune response, with arthralgia, myalgia and chronic fatigue being its common symptoms [5]. Diagnostic criteria have been proposed for ASIA [5], and the most frequent autoimmune disease related to it is undifferentiated connective tissue disease (UCTD) [5,6]. Metal implants have been suggested in a few case reports as a trigger for ASIA [7,8]. ...
... Such assumptions are possible due to the compliance of the described cases with several ASIA criteria, e. g. exposure to an external stimulus before clinical manifestations, the appearance of 'typical' clinical manifestations, removal of inciting agent induces improvement, evolvement of an autoimmune disease and other clinical manifestations [17][18][19]. More recent studies confirm the connection between ASIA and metal implants, marking mercury, nickel, cobalt, chromium as the most reactogenic substances [20][21][22][23]. There are reports of an infrequent metal as an instigator of autoimmune response-titanium [21,24]. ...
... More recent studies confirm the connection between ASIA and metal implants, marking mercury, nickel, cobalt, chromium as the most reactogenic substances [20][21][22][23]. There are reports of an infrequent metal as an instigator of autoimmune response-titanium [21,24]. ...
... Rights reserved. [20][21][22][23]. In 2013 Loyo E. et al. presented a case report describing a clinical case of ASIA development after the installation of a nickel-titanium chin implant. ...
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Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is associated with a hyperergic response of the immune system. The spectrum of clinical changes in ASIA is extensive and difficult to diagnose. Panniculitis is a heterogeneous group of diseases characterized by lesions of the adipose tissue. Panniculitis may become one of the signs of ASIA progress. To describe the clinical signs and morphological changes in the subcutaneous fat as a manifestation of ASIA, developing after osteosynthesis with metal structures. In this case-based review, were searched for all articles published in PubMed and Scopus databases until March, 2021 using the following keywords “panniculitis”, “erythema nodosum”, “Weber-Christian Disease”, “idiopathic lobular panniculitis”, “Autoimmune/inflammatory syndrome induced by adjuvants”, “Shoenfeld’s syndrome”, “metal allergy” “metal implants”, “metal hypersensitivity” and reviewed them. Irrelevant items and duplicates were excluded. We report a case of an adult female patient presenting with a non-healing uninfected surgical wound following implantation of metal osteosynthesis construction and panniculitis developed after surgery. A comprehensive examination of the patient to check for ASIA was conducted. Considering the medical history of exposure to metals, tissue lesions, arthralgia, myalgia, low-grade fever, the disappearance of symptoms on the background of immunosuppressive therapy suggested the diagnosis of ASIA. Report affords clinicians and pathologists additional insight into the clinical and morphological picture of ASIA-associated panniculitis which, if remain unidentified, may cause severe complications. We recommend the removal of constructions with adjuvant activity in patients with suspected ASIA-associated manifestations.
... Immunologically, implant allergy results from autoimmunity/inflammatory reactions and type 4 delayed hypersensitivity reactions [15][16][17]. The triggering of these autoimmune reactions, hypersensitivity, or inflammatory reactions are attributed to metal-bound proteins recognized by the immune system or by free radical formations produced by metal binding to sulfur in mitochondria, enzymes, and cell proteins [15][16][17]. ...
... Immunologically, implant allergy results from autoimmunity/inflammatory reactions and type 4 delayed hypersensitivity reactions [15][16][17]. The triggering of these autoimmune reactions, hypersensitivity, or inflammatory reactions are attributed to metal-bound proteins recognized by the immune system or by free radical formations produced by metal binding to sulfur in mitochondria, enzymes, and cell proteins [15][16][17]. ...
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A 57-year-old woman underwent cervical implant surgery for a dislocated cervical spine fracture, and she complained of continuous intractable neck pain after surgery. Eight years later, she developed a plantar skin rash, subsequently diagnosed as a metal allergy, and metal dentures were replaced with ceramic ones. The skin rash, however, persisted for four more years after that and was eventually treated with cervical implant removal. Subsequently, her skin rash and her neck pain improved simultaneously. This synchronous improvement strongly suggested that the neck pain could have been caused by a cervical implant allergy. We discuss a case of posterior cervical implant allergy that presented with neck pain and plantar skin rash years after surgery.
... Recent research has found that endotoxin, a potent immunestimulatory component in the outer membrane of gram-negative bacteria, contributes a large proportion of the in vitro toxicity of urban PM 2.5 from China to human lung cells, beyond the well-known chemical toxicants, such as heavy metals and PAHs . Complete dissection of component-and source-specific contribution to PM-induced pulmonary toxicities would advance the further understanding of the chemical-microbial interplay on the LRI disease development ( Fig. 1) Galli et al., 2008;Lee et al., 2012;Stejskal, 2014). ...
... This also suggests that most of the particles had a high-water content during polluted days, which might favor the survival of microbes (Stanier et al., 2004). However, the viability or infectivity of these detected pathogen species, like (Aquilina et al., 2021;Armstrong et al., 2004;Cao et al., 2020;Conticini et al., 2020;Fernstrom & Goldblatt, 2013;Galli et al., 2008;Kim et al., 2015;Lee et al., 2012Lee et al., , 2015Liang et al., 2020;Moorthy et al., 2015;Pavia, 2011;Simoes et al., 20002006;Stejskal, 2014;Tchounwou et al., 2012;Wu et al., 2020;Zhong et al., ;Zhu et al., 2020;Zuo et al., 2020). COPD, chronic obstructive pulmonary disease; PAHs, polycyclic aromatic hydrocarbons; SARS, severe acute respiratory syndrome all other members of the microbial community, has not been well understood. ...
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Airborne particulate matter (PM) pollution, as a leading environmental health risk, causes millions of premature deaths globally every year. Lower respiratory infection (LRI) is a sensitive response to short-term exposure to outdoor PM pollution. The airborne transmission of etiological agents of LRI, as an important pathway for infection and morbidity, bridges the public health issues of air quality and pathogen infectivity, virulence, resistance, and others. Enormous efforts are underway to identify common pathogens and substances that are etiological agents for LRI and to understand the underlying toxicological and clinical basis of health effects by identifying mechanistic pathways. Seasonal variations and geographical disparities in the survival and infectivity of LRI pathogens are unsolved mysteries. Weather conditions in geographical areas may have a key effect, but also potentially connect LRI with short-term increases in ambient air PM pollution. Statistical associations show that short-term elevations in fine and coarse PM lead to increases in respiratory infections, but the causative agents could be chemical or microbiological and be present individually or in mixtures, and the interactions between chemical and microbiological agents remain undefined. Further investigations on high-resolution monitoring of airborne pathogens in relation to PM pollution for an integrated exposure–response assessment and mechanistic study are warranted. Improving our understanding of the spatiotemporal features of pathogenic bioaerosols and air pollutants and translating scientific evidence into effective policies is vital to reducing the health risks and devastating death toll from PM pollution. Graphical abstract
... In a previous study on ambient PM, the increase in IL-8 production by ne PM particles (PM1) was associated as a result of metal content, particularly Zn and As (Perrone et al., 2010). Heavy metals are generally known to induce in ammatory responses (Dong et al., 1998;Honda et al., 2015;Marth et al., 2001;Stejskal, 2014). Thus, increased expression of in ammatory factors in cells exposed to dust particles can be attributed with the higher content of heavy metals in this. ...
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Background: Contact allergy can manifest in a variety of ways clinically. Systemic contact allergy may occasionally present with pain in muscles and joints. Fibromyalgia is a chronic rheumatic disease characterized by pain and with virtually unknown aetiology. Objectives: The aim of this study was to investigate the contact allergy rates to the sensitisers in a baseline series and compare with corresponding rates in dermatitis patients and the general population. Methods: Patch testing with the Swedish baseline series was performed in 120 individuals with fibromyalgia. Fisher's exact test was used for pair-wise comparisons of contact allergy rates between the fibromyalgia group and two control groups, dermatitis patients and individuals in the general population. Results: Contact allergy was significantly more common in the fibromyalgia group compared to the general population concerning nickel and the fragrance markers Myroxolon pereirae and fragrance mix I. There were fewer allergic reactions to preservatives in the fibromyalgia group compared with the dermatitis group. Conclusions: Myroxolon pereirae and fragrance mix I represent besides fragrance allergy also allergy to flavoring substances which indicate that oral exposure to flavoring substances and hygiene products might be important for sensitisation and possibly elicitation of systemic contact allergy symptoms in fibromyalgia individuals.
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In 2011, Shoenfeld Y and Agmon-Levin described five medical conditions with similar complex of symptoms and signs and a common pathogenesis, namely siliconosis, the Gulf War syndrome, the macrophagic myofasciitis syndrome, postvaccination phenomena, and the sick building syndrome. The authors proposed to gather these five entities under a common syndrome denominated autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Genetically predisposed individuals, the exposure to environmental factors such as silicone, aluminum salts, adjuvant contained in vaccines, mineral oils, collagen, and hyaluronic acid and metal implants are a prerequisite to the appearance of ASIA. The epidemiology of ASIA is unknown; therefore, it is necessary to increase the international database. The immunogenetic, epigenetic, inflammatory mechanisms of each adjuvant and molecular mimicry should continue to be studied. The treatment of ASIA is in agreement with the clinical manifestations and in the identification of risk factors.
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