Coverage Policy Manual
Policy #: 2011075
Category: Laboratory
Initiated: December 2011
Last Review: October 2018
  Allergy Testing, Metal

Description:
Metals used in orthopedic implants corrode over time and release wear debris (particles and metal ions) as a consequence of their contact with biological fluids. Hypersensitivity to wear debris particles could potentially lead to a chronic inflammatory reaction in the area of the orthopedic implant and might be associated with implant failure. However, the causal link between metal allergies and implant complications is unclear. Some patients do exhibit hypersensitivity to various metals, but data are lacking that metal sensitivity leads to greater implant failure. It is also possible that implant loosening could result in an increased risk of metal allergy through release of wear debris particles.
 
Cutaneous metal sensitivity refers to contact allergies to metal jewelry, and thus differs from hypersensitivity to metal implants. It is not known whether individuals with cutaneous metal sensitivity are at increased risk of hypersensitivity to metal implants. In addition, there is a lack of clinical studies prospectively evaluating the risk of complications in patients with metal sensitivities who receive implants. In response to these and other uncertainties about metal implant systems, the Food and Drug Administration (FDA) has required post-marketing studies of metal ion concentrations in
metal-on-metal joint replacements and their effects on long-term outcomes for implant systems.
 
At present, there is not a universally accepted method to test for metal hypersensitivity to orthopedic implants. The two general categories of testing for metal allergies are:
 
In Vivo Testing: This involves epicutaneous skin testing i.e., patch testing and is the most common method used to diagnose contact allergy to metal. The accuracy of this testing method for diagnosing deep-tissue hypersensitivity is not well documented in the literature. There is also the possibility that the process of patch testing can sensitize an individual to certain metals.
 
In Vitro Testing: In vitro tests are based on reactivity of lymphocytes to metal-protein complexes and are known as lymphocyte transformation tests (LTT). Several in vitro metal allergy tests are commercially available in the U.S. at selected laboratories. The laboratories generally offer testing for allergies to metals in jewelry, food and dental implants and some also offer testing for allergies to metals in orthopedic implants.
 
The procedure for in vitro testing involves taking a blood sample, isolating immune cells containing lymphocytes and dividing the collected fraction of immune cells into portions that are each exposed to a different metal. The lymphocytes are then cultured with the metals for 5-6 days and the proliferation responses of the lymphocytes are measured. Metal-specific sensitivity is assessed by comparing non-treated to treated lymphocytes from the same individual. Findings are reported according to the quantity of response in the exposed samples. Different reporting systems are used by different companies. In one system, 2 to 4-fold response by treated lymphocytes is categorized as mild reactivity, a 5 to 8-fold response as moderate reactivity and any larger response is considered high reactivity (Orthopedic Analysis, 2011). Another company offering a different LTT test states that they present results according to a “stimulation index” (SI) an SI value over 3 indicates a positive reaction to that allergen (Melisa Medica Foundation).
 

Policy/
Coverage:
Metal testing using in-vitro methods, whether done prior to, or after joint arthroplasty, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, metal testing using in-vitro methods, whether done prior to, or after joint arthroplasty, is considered to be investigational. Investigational services are specific exclusions in most member benefit certificates of coverage.
 
 

Rationale:
A search of the MEDLINE database in October 2011 did not identify any large studies that described the incidence of metal allergy, reported the accuracy of tests for diagnosing metal allergy, or evaluated the impact of in vitro metal allergy testing on patient management decisions or health outcomes. A few published studies on LTT tests have included data on small numbers of patients with metal implants. For example, in 2011, European researchers (Frigerio) prospectively enrolled 100 patients in a study in which they underwent patch testing before and one-year after joint
replacement surgery; 20 patients also underwent LTT testing. A total of 72 patients completed the study; 12 of these had LTT testing. Among the study completers, 5 patients (7%) who tested negative before surgery changed to testing positive one year later and only 1 of the 5 had undergone both types of testing. In this individual, the patch test and LTT were negative pre-surgery and postsurgery, the patch test was negative but the LTT showed positive reactions to several types of metals.
 
No national guidelines were identified that provide recommendations on metal allergy testing before or after surgery with metallic orthopedic implants. The American Academy of Orthopedic Surgeons, for example, does not have a position statement on metal allergy testing. In 2011, researchers in the U.S. and Denmark published an article on a pragmatic approach to the clinical work-up of patients with potential allergies to metallic orthopedic implants (Thyssen). Based
on the authors’ review of the literature, they concluded “it is difficult to make general principles for good clinical practice prior to surgery. Complications caused by delayed-type hypersensitivity reactions to metal ions are rare and at the same time nickel allergy remains frequent in the general population and nickel, cobalt and chromium allergy remains frequent in dermatitis patients. This obviously makes it difficult to identify the few allergic subjects at risk of developing implant failure.
 
Large scale routine screening for metal allergy prior to surgery is therefore not recommended…” In addition, the authors commented on post-surgical testing of patients with implant failure. “The clinical work-up of a patient suspected of having an allergic reaction to a metal implant should include patch testing and possibly in vitro testing…” They note that patch testing remains the standard diagnostic method and is more widely available than in vitro testing.
 
In summary, allergic reactions to metal implants can occur, but they are probably rare and the true incidence is unknown. An in vitro diagnostic test for metal allergy is available, however the accuracy of this test for diagnosing clinically relevant metal allergy has not been determined. There is no evidence that testing for metal allergies in patients receiving metal implants changes patient management decisions, or improves health outcomes.
 
2013 Update
A search of the MEDLINE database through September 2013 was conducted. There was no new published literature or clinical guidelines identified that would prompt a change in the coverage statement.
 
2014 Update
A search of the MEDLINE database through September 2014 was conducted. There was no new information identified that would prompt a change in the coverage statement.
 
2016 Update
A search of the MEDLINE database through September 2016 was conducted. There was no new information identified that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
86353Lymphocyte transformation, mitogen (phytomitogen) or antigen induced blastogenesis

References: Acta Orthop, 2009; 80:646-52.(2009) The association between metal allergy, total hip arhtroplasty, and revision. Thyssen JP, Jakobsen SS, et al.

Frigerio E, Pigatto PD, et al.(2011) Metal sensitivity in patients with orthopaedic implants: a prospective study. Contact Dermatitis, 2011; 64:273-9.

Hallab NJ, Anderson S, et al.(2004) Immune responsed correlate with serum-metal in metal-onmetal hip arthroplasty. J Arthroplasty, 2004; 19(8 Suppl 3):88-93.

Hallab NJ, Mielcz K, Jacobs JJ.(2000) A triple assay technique for the evaluation of metal-induced, delayed-type hypersensitivity responses in patients with or receiving total joint arthroplasty. J Biomed Mater Res, 2000; 53:480-9.

Orthop Res, 2005; 23:384-91. Hallab NJ, Anderson S, et al.(2005) Lymphocyte responses in patients with total hip arthroplasty. J Orthop Res, 2005; 23:384-91.

Orthopedic Analysis.(2009) General information about the metal-LTT assay. http://www.orthopedicanalysis.com/metal-allergy/index.html. Accessed Dec 2011.

Thyssen JP, Menne T(2010) Metal allergy - a review on exposures, penetration, genetics, prevalence, and clinical implications. Chem Res Toxicol, 2010; 23:209-18.

Thyssen JP, Menne T, et al.(2011) Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopedic implants before and after surgery. Br J Dermatol, 2011; 164:473-8.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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