Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients with putative allergic reactions to devices or implants will present with a history of exposure to metals with prior sensitivity. This may take the form of an allergic reaction to a body piercing or watch/belt buckle and/or difficulties with a previous implant (dental, orthopedic, cardiac or vascular).
Orthopedic implants associated with cutaneous or systemic hypersensitivity reactions include all forms of prostheses, stabilizers, rods, Nuss bars (Figure 1), plates, and screws.
Cardiac devices of potential concern include bare metal coronary stents, drug eluting stents, patent foramen ovale disc occluders, pacemakers, sternal wiring, and defibrillators. Orthodontia, including brackets and wires for dental braces, coils used in aneurysm repair, copper or nickel-containing gynecologic devices, and neural stimulators for pain (Figure 2) are other sources of potential metal implant allergy.
Common allergens include nickel, cobalt, chrome, molybdenum, gold, palladium, or materials in bone cement (eg, methyl methacrylate and/or N,N-dimethyl-p-toluidine) and sterilizing procedures (eg, ethylene oxide). Localized and systemic reactions to orthopedic devices occur with both static and dynamic implants.
Characteristic findings on physical examination
Device or implant reactions are commonly eczematous but can range in severity and presentation. Cutaneous findings may take the form of urticaria, bullous eruptions, edema, vasculitis, pruritus, and/or DRESS (Drug Reaction (or Rash) with Eosinophilia and Systemic Symptoms) syndrome. Potential systemic findings include osteolysis, joint failure/loosening, pain, burning, arthralgias, myalgias, reticular telangiectatic erythema, eosinophilic cellulitis, granulomas, gross infection, or rarely aseptic lymphocytic vasculitis-associated lesions (ALVAL).
Dental metal allergy may present as a lichenoid type reaction resembling oral lichen planus or burning mouth.
Expected results of diagnostic studies
Allergy to implants is often a diagnosis of exclusion when infection and device failure have been excluded. Cutaneous histologic findings are consistent with delayed hypersensitivity reactions, including edema in the epidermis, and an influx of immune cells such as T-lymphocytes and macrophages.
ALVAL and pseudotumors have more typically been associated with newer metal-on-metal bearings and rarely encountered.
Diagnostic criteria that support a causative association between metal release from an orthopedic metal implant, metal allergy and allergic metal dermatitis overlaying the implant for metal-induced cutaneous reactions proposed by Merle et al and recently revised by Thyssen et al include the following:
Chronic eczema beginning weeks or months after the implant was placed
Eruption overlaying the implant
Morphology consistent with dermatitis (erythema, induration, papules and vesicles) in the absence of other contact allergens or systemic cause
In rare instances, systemic allergic dermatitis (disseminated dermatitis typically localized in body flexures)
Histology consistent with allergic contact dermatitis
Positive patch test reaction to a metal used in the device or implant (often a strong reaction)
Serial-dilution patch testing with positive reaction to low concentrations of the metal under suspicion
Positive in-vitro test to metals, eg, the lymphocyte transformation test for nickel, cobalt or chrome
Dermatitis is therapy resistant
Complete and rapid recovery after total removal of the offending implant
Patch testing, coupled with clinical history, is used to the make the diagnosis. Patch testing can be performed to determine if a type IV allergy exists to a specific allergen. We recommend patch testing in accordance with the guidelines established by the North American Contact Dermatitis Group (NACDG). Patch tests are applied to unaffected skin sites (usually on the back) using aluminum disks. Patch tests are removed after 48 hours and read on day 2 or 3, and read again on day 6 or 7.
An expanded standard baseline or screening series, such as that of the NACDG, should be considered for those with a history of clinical dermatitis. In most cases this will include nickel, cobalt, and chrome salts as well as other allergens that may or may not be associated wtih a device reaction, especially bacitracin, neomycin, N,N,-dimethyl-p-toludine and methylmethacrylate.
In all cases of putative device allergy a partial or complete prothesis patch testing series should be performed, to include metals and other potential device allergens such as titanium, vanadium, molybdenum, copper, aluminum, palladium, manganese, platinum, indium, gold, iron, tantalum, zirconium, tin, as well as chlorhexidine and bone cement components.
Obtaining device information including the list of biomaterials and sterilizing methods is crucial in order for all the components of the device, including any cements, antibiotics, and sterilizing materials, to be included in the patch test battery. Device manufacturers may distribute patch test kits, which include materials that may not be found on the standard screening patch test series. Patch testing with metal salts is generally preferred to testing with solid metal pieces. When available the manufacturer test kits should be obtained and used for testing.
While most patients with allergic dermatitis due to device or implant allergy are patch-test positive to a component of the device or materials used in the implant procedure, some patients may have negative patch-test results. In these instances other potentially useful tests include intra-dermal testing; in vitro lymphocyte transformation tests; RAST; or ELISA assays that measure cytokine activity.
Allergy to devices or implants caused by metals may be difficult to distinguish from a reaction that stems from other materials encountered during insertion of the device. For example, ethylene oxide gas, used to sterilize some medical equipment, can elicit an immune response that mimics delayed-type hypersensitivity reactions; although this is most frequently an IgE-mediated reaction reported in hemodiaylsis patients.
Allergies to latex, rubber, suture materials, antiseptic scrubs, wound dressings, adhesives, sterilizing agents, or topical antibiotics have all been reported and may mimic device or implant allergy. For this reason patch testing for prosthesis allergy should include components of orthopedic bone cement including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide and antiobiotics such as gentamicin, tobramycin, clindamycin, and erythromycin.
The differential diagnosis of post-implant erythema is broad and includes localized livedo reticularis, reticular telangiectatic erythema, reticulated erythematous mucinosis, erythema ab igne, intravascular reactive angioendotheliomatosis, pressure dermatitis, intralymphatic histiocytosis, and Wells syndrome.
Who is at Risk for Developing this Disease?
Nickel is the most frequent allergen found with diagnostic patch testing. The prevalence of metal allergy for nickel is reported to be as high as 17% for women and 3% for men. Nickel allergy is higher in women than in men, as women are more likely to have ear piercings.
Allergy to metals such as cobalt and chromium ranges from about 1% to 2% of the general population. Among patients with contact dermatitis the prevalence of cobalt and chromium allergy is 6% and 3.4% respectively.
Although the prevalence of allergy among the general population is significant, most individuals, even nickel-sensitized patients, will tolerate low levels of metals in prosthetic devices or implants without adverse reactions.
It has been speculated that patients who have previous exposure to metals are at increased risk for developing a reaction to a device or prosthesis; however, this has never been proven. Exposure to metal can take the form of body piercings, surgical clips or staples, mitral valve prostheses, nickel-plated parts (cannulae, retractors, skin closures), orthopedic implants (screws, joint prothesis, plates, rods), acupuncture needles and many more items. In recent years there has been concern for exposure to metals via cell phones, communication devices, and some alternative medications.
Additional putative risk factors include high frequency or prolonged exposure to the metal, occlusion, or impaired skin barrier function.
While there is no definite genetic predisposition to metal allergy, some research has linked mutations in the filaggrin gene complex with metal or jewelry allergy.
What is the Cause of the Disease?
Metal contact allergy stems from repeated or prolonged exposure to metals in high concentrations, often in the form of jewelry, piercings, cellular phones, other personal communication devices, leather and clothing fasteners.
Some may develop sensitization due to occupational exposure in the construction or metal industry. Metal exposure at levels sufficient to contribute to nickel sensitization has also been reported in hairdressers, retail clerks, domestic workers, locksmiths, carpenters and caterers. Those who are in work in metal plating operations or are in contact with curing cement, dyeing agents, pottery colorants, leather tanning agents and antirust agents in coolants are also at risk for occupational chromium exposure.
Alternatively, patients may be sensitized by a previous metal implant or device that has been subjected to mechanical wear or corrosion.
The induction phase occurs when the metal first contacts the skin and stimulates the immune system to produce antigen-specific T-lymphocytes.
Upon repeat exposure to the allergen the activation of these antigen-specific T-lymphocytes results in the cell-mediated immune response that manifests clinically as allergic contact dermatitis.
Local reactions are thought to be mediated by delayed cell-mediated hypersensitivity reactions (type IV). Metal ions may bind to proteins to activate the immune system and interact with endothelial cells to express intracellular adhesion molecule 1 (ICAM -1). ICAM-1 enhances the recruitment and activation of inflammatory cells. Metal debris may be phagocytosed by antigen-presenting cells that interact with T-lymphocytes to evoke a greater immune response. Recently, it was shown that nickel may activate the innate immune system by binding to Toll-like receptor 4.
Systemic Implications and Complications
Implant failure due to metal sensitivity is controversial. In one study 60% of patients with poorly functioning or failed hip arthroplastic implants had metal allergy. Another review of patients with failed metal-on-metal arthroplastic devices documented that over 80% had metal sensitivity. While retrospective studies of patients with failed implants show higher rates of metal sensitivity, it remains unclear if metal allergy predisposes to device failure, or if a poorly functioning device contributes to metal sensitization. Non-allergic causes of device failure such as infection, recurrent dislocation, fracture or aseptic osteolysis must be ruled out before a clinician attributes the implant failure to metal allergy.
In-stent restenosis (ISR) has been associated with metal allergy in some reports. Among those patients, the most frequent allergens were gold, nickel, chromate, manganese and molybdenum. It has been suggested that metallic ions from stents induce expression of ICAM-1 on endothelial cells, which signals inflammatory cells and leads to the development of neointimal hyperplasia. Over time this proliferation can lead to ISR. Nevertheless, this topic remains in question as some studies have failed to demonstrate a correlation between positive patch test results and ISR.
Rare systemic reactions with generalized eczema have been reported following the placement of dental materials, especially metals.
Patch testing for suspected device allergy and treatment of cutaneous reactions.
Removal of the device or implant to which the patient is allergic.
Replacing the device with one free of the patient’s allergens.
Optimal Therapeutic Approach for this Disease
Consider pre-procedural patch testing in patients with known or suspected metal allergy of a magnitude that concerns the patient or the treating physician, especially if alternative procedures or devices are available. For example, patients undergoing correction of pectus excavatum with the Nuss/pectus bar procedure can be fitted with titanium bars that have not been associated with adverse cutaneous reactions. Alternatively, the allergenic device may be modified or coated prior to insertion, such as polytetrafluoroethylene (PTFE) covered stents or PTFE sheet coverings that have been used with success in pacemaker contact dermatitis.
Consider post-procedural patch testing in patients with dermatitis, putative systemic allergic reactions including loosening or joint swelling, especially if the patient is so impaired that the prosthesis or device may need to be replaced.
Dermatitis can be managed temporarily with topical corticosteroids and systemic antihistamines, both of which have a relatively benign side effect profile and are cost-effective. Occasionally, a short-course of tapered systemic corticosteroids may be indicated.
In many cases the allergenic device or implant can be replaced with one that does not contain the offending allergen and which most patients will tolerate. For example titanium, oxidized zirconium (Oxinium) or ceramic-based orthopedic prostheses or customized silicone or gold-coated pacemakers may be used in nickel-, cobalt- and chrome-allergic individuals instead of routinely used first-line devices. In dentistry, titanium orthodontic wires are available to replace nickel metal braces. And lichenoid reactions have cleared by removing dental amalgams in the occasional mercury-allergic patient and replacing them with composites.
It is noteworthy that alternative device metals such as titanium or coated devices or devices created with alternative materials are often more costly than those containing first-line materials such as chrome, cobalt or stainless steel.
Removal of the implant is the most efficacious treatment option; however, this puts the patient at risk for complications associated with surgery and anesthesia and is not always indicated (see patient management). Additionally, some implants are generally not amenable to removal as in the case of endovascular stents.
Although contact allergy is considered to be a chronic condition, most patients report a resolution of symptoms within days to months once the allergen has been removed. Additionally, some may not display symptoms upon every exposure to the allergen as seen in patients with gold allergy who often tolerate gold crowns or restorations without any mucosal or systemic reactions.
HOW SHOULD THE PATIENT BE MONITORED AND FOLLOWED UP?
Patch testing or lymphocyte transformation testing for nickel, cobalt or chromium is generally unnecessary unless a year or more has passed and the clinical findings have changed, progressed or persisted.
With concern for secondary bacterial infection in areas of skin erosion or breakdown, appropriate cultures and antibiotics should be considered.
Patients should be instructed to avoid implants or jewelry containing the offending allergen(s) in the future. In cases where alternative device materials may not be available (eg, PFO occluders), selecting an alternative material with the least amount of the allergen may be the only alternative. In patients with metal allergy, the use of drug-eluting (coated) coronary stents may be considered in lieu of bare metal stents.
Patch testing with chemicals in standard generally accepted concentrations is safe and rarely induces sensitization.
Patch testing or in vitro lymphocyte proliferation testing results to metals may not always be predictive of the development of localized or systemic cutaneous reactions. In most cases a dynamic prosthesis such as a hip or knee that is perfectly functioning without evidence of loosening should not be removed, even if the patient has a positive patch test to a metal or other material contained in the device.
Unusual Clinical Scenarios to Consider in Patient Management
In some situations patients may present prior to device insertion with concerns of future cutaneous complications. Because only a minority of patients will present with metal allergy following device implantation, it is recommended that clinicians refrain from routine pre-operative patch testing, unless the patient has a history of metal allergy or previous cutaneous or systemic reaction to an implant or device of a magnitude that it concerns the patient or the treating physician.
In some cases it may be difficult to establish the direct clinical relevance of certain positive patch-test results. This may be due to cross-reactivity of the allergen with another substance. Alternatively, the patient may have been sensitized to an allergen but never have developed a reaction that warranted clinical evaluation.
Review disorders listed in the differential diagnosis (see Are You Confident of the Diagnosis?) of putative cutaneous and systemic allergic reactions to devices and implants; expert dermatologic review including skin biopsy and laboratory studies may be indicated in cases with atypical presentation.
What is the Evidence?
Honari , G, Ellis , SG, Wilkoff B , L, Aronica M , A, Svensson L , G, Taylor J , S. “Hypersensitivity reactions associated with endovascular devices”. Contact Dermatitis. vol. 59. 2008. pp. 7-22. (The authors review allergic reactions associated with endovascular and other implanted devices described in over 100 publications. The text summarizes the composition of some commonly used implanted devices and considers the potential immunotoxic effects of many of these biomaterials. Recommendations are made for evaluating patients with putative stent or cardiac device allergy, including a description of specific materials to include in patch testing.)
Koster , R, Vieluf , D, Kiehn , M, Sommerauer, M, Kähler, J, Baldus, S. “Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis”. Lancet. vol. 356. 2000. pp. 1895-7. (The authors evaluate the relationship between allergic reactions to stent components and the occurrence of in-stent restenosis. This study analyzed rates of stenosis, as determined by quantitative coronary angiography and epicutaneous patch test results. Patients with allergic patch-test reactions to nickel and molybdenum were reported to have a higher frequency of in-stent restenosis. The authors conclude that allergic reactions to nickel and molybdenum released from stents may be one of the triggering mechanisms for in-stent restenosis.)
Thyssen J , P, Menne , T, Schalock , PC, Taylor J , S, Maibach , HI. “Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopaedic implants before and after surgery”. Br J Dermatol . vol. 164. 2011. pp. 473-8. (The authors review evidence for patch testing prior to surgery and propose criteria for evaluating patients with putative allergic complications postoperatively. Because metal allergy increases the risk of complications in only a minority of patients, these authors recommend that clinicians refrain from routine patch-testing prior to surgery. Notable exceptions include patients who have already had implant surgery with complications suspected to be allergic or a history of clinical metal intolerance. Diagnostic criteria for allergic dermatitis reactions caused by metal implants are proposed.)
Kubba , R, Taylor , JS, Marks , KE. “Cutaneous complications of orthopedic implants. A two-year prospective study”. Arch Dermatol . vol. 117. 1981. pp. 554-60. (The authors conducted a 2-year prospective study of cutaneous eruptions in orthopedic implant recipients. The study found that in general allergic cutaneous complications of orthopedic implants were rare. In implant recipients who develop cutaneous reactions, the likelihood of the reaction to be attributed to allergy is greater if the implant is of the static type, if there is a history of metal sensitivity, if the eruption is in the area of the implant, and if the eruption is eczematous and persistent.)
Thyssen , JP, Menne , T. “Metal allergy – A review on exposures, penetration, genetics, prevalence, and clinical implications”. Chem Res Toxicol. vol. 23. 2010. pp. 309-18. (In this review the changing prevalence of metal allergy in the United States and Europe is discussed. The text includes comments on the genetic association between metal allergy and filaggrin gene complex mutations. Important information on the sources of environmental metal exposures and the most frequently encountered contact allergens is succinctly summarized.)
Warshaw , EM, Nelsen , DD, Sasseville , D, Belsito , DV, Maibach, H I, Zug, K A. “Positivity ratio and reaction index: patch-test quality-control metrics applied to the North American Contact Dermatitis Group database”. Dermatitis. vol. 21. 2010. pp. 91-7. (Positivity ratios and reaction indices were calculated for 79 North American Contact Dermatitis Group standard allergens tested over a 12-year period. The study includes relevant information on the patch-test preparations that are most accurate and those that are most problematic. Nickel sulfate was among the most accurate while chrome was in the problematic group. Preparations in the problematic group are associated with a greater proportion of weak, irritant, and questionable reactions.)
Svedman , C, Ekqvust , S, Moller , H, Bjork , J, Pripp , CM, Gruvberger , B. “A correlation found between contact allergy to stent material and restenosis of the coronary arteries”. Contact Dermatitis. vol. 60. 2009. pp. 158-64. (The authors considered if contact allergy to stent material is a risk factor for restenosis by comparing rates of restenosis in patients with stainless steel stents, with or without gold plating, who were epicutaneously tested for metal sensitivity. Relevant findings demonstrated a correlation between contact allergy to gold, gold stent, and restenosis and increased degree of chest pain in gold-allergic patients with gold-plated stents.)
Hallab , NJ, Merritt , K, Jacobs , JJ. “Metal sensitivity in patients with orthopaedic implants”. Curr Concepts Rev, J Bone Jt Surg. vol. 83-A. 2001. pp. 428-36. (Current challenges in the clinical determination of metal hypersensitivity to implanted devices are summarized along with the proposed mechanisms of immune responses to metallic implants. They reported that the prevalence of dermal sensitivity to metals in patients with a joint replacement device is substantially higher than that in the general population. They also reported that the relationship between metal sensitivity and implant failure remains unclear.)
Basko-Plluska , JL, Thyssen , JP, Schalock , PC. “Cutaneous and systemic hypersensitivity reactions to metallic implants”. Dermatitis. vol. 22. 2011. pp. 65-79. (This article reviews the current understanding of the association between metal sensitivity and cutaneous allergic reactions. The authors describe the nature of skin eruptions and systemic reactions observed from exposure to metal implants, including relevant information on the most common metals that elicit allergic reactions. Delayed-type hypersensitivity reactions secondary to intravascular stents, dental implants, cardiac pacemakers, and implanted gynecologic devices are also summarized.)
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