Answer:
Evaluation of symptoms suspected to be dependent on immunologic responses to implanted metals is complicated by the limitations of testing. These reactions are T cell dependent and patch testing would be the preferred method if we had reagents for each metal and if all of the metals penetrated the epithelium equally. Alas, such is not the case. In vitro testing with metal ions in solution mixed with lymphocytes from affected subjects has been suggested as means to overcome the reduced reactivity of specific metals or the reduced penetration of the metal through the keratin layer of the skin. The commercially licensed, in vitro lymphocyte transformation test for detecting ‘sensitivity to metals (LTT-MELISA) is not FDA approved and generally is not covered by insurance (1,2). It is available from laboratories in this country. LTT-MELISA is touted as superior to other testing modalities, such as patch testing, particularly for titanium, possibly due to the reduced immunologic reactivity of titanium (4,5). However, there is no consensus for the utility of the test with critics arguing the test is overly sensitivity (5,6,7). The additional challenge is that the only option, to my knowledge, would be to surgically remove the implanted metal with the associated risks inherent in this surgery. Making this recommendation on a test that is not generally accepted is difficult, but you may wish to document a shared decision making discussion regarding this controversy.
If LTT-MELISA testing is to be considered, test kits, locations of laboratories offering this test and other information is available at FAQs for US Customers - MELISA. I emphasize that this testing is not FDA approved.
I have attached some archived Ask the Expert questions about metal allergy.
I suggest a shared decision making discussion be documented related to the uncertain negative predictive value of patch testing for titanium allergy and uncertain positive predictive value of MELISA-LTT testing. I would emphasize the lymphocyte testing is a challenge due to delivery of viable cells and lack of FDA approval and insurance coverage. The decision forward would be based upon this discussion.
1. Vaelentin-Thon E, Müller K, Guzzi G et al. LTT-MELISA is clinically relevant for detecting and monitoring metal sensitivity. Neuroendocrin Letters 2006;27:17-24.
2. Yoshihisa, Yoko, and Tadamichi Shimizu. "Metal allergy and systemic contact dermatitis: an overview." Dermatology research and practice 2012 (2012).
3. Stejskal, V. D. M., et al. "MELISA—an in vitro tool for the study of metal allergy." Toxicology in vitro 8.5 (1994): 991-1000.
4. Hallab N J, Mikecz K, Jacobs J J. 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: 480–489.
5. Fage, Simon W., et al. "Titanium: a review on exposure, release, penetration, allergy, epidemiology, and clinical reactivity." Contact Dermatitis 74.6 (2016): 323-345.
6. de Graaf, Niels PJ, et al. "A retrospective study on titanium sensitivity: Patch test materials and manifestations." Contact dermatitis 79.2 (2018): 85-90.
7. Schalock PC, Menné T, Johansen JD et al. Hypersensitivity reactions to metallic implants—diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis 2011;66:4-19.
Ask The Expert Archive Main Page
2/20/2020: Metal patch test positive with rash and knee replacement
Have 79 year-old man with left knee replacement two years ago. About 6-8 months ago began with eczematoid/psoriatic rash most prominent over left knee (not present over right knee). Referred to me to patch testing. Tested to NAC 80 panel and metal panel. Showed many positives at 72 and 96 hours including 14 metals and methacrylate glue. Present left knee joint contains several metals positive with patch testing. Suspect he will need joint revision but concerned about angry back syndrome with so many positives - orthopod may have great difficulty choosing a new joint. Would lymphocyte transformation testing help me determine more accurate picture of his metal contact allergy and help orthopod choose appropriate joint for revision?
Your question was shared with Dr. Luz Fonacier, chief of allergy/immunology at Winthrop University and chair of the work group that produced the practice parameter on contact dermatitis (1). I have summarized her observations and suggestions below.
I would have a few questions about this case
1. A positive to 14 metals is very unusual. You may be dealing with ‘angry back syndrome’ from the start. I usually suspect ‘angry back’ if you have more than 5 positive patch tests.
2. A quote from Fisher’s textbook on contact dermatitis is the following: “if metal salts were tested close to each other a strong positive to nickel would be accompanied by false positive patch test reactions to adjacent metal salts, particularly cobalt and copper” (2). Apparently, a strong positive reaction to nickel creates a nonspecific hypersensitivity of the surrounding skin and induces a false positive reaction. This may be the situation you are facing.
3. If all of the positive tests are metals, you may be dealing with irritant reactions, usually pustules and follicular lesions, more common to metals and more likely in atopic individuals, perhaps due to skin barrier issues. In most irritant reactions, intensity usually wanes between the time of patch removal and the final reading.
4. A 72- and 96-hour reading is provided. Was the patch test removed at 48 hours and what was the reading at that time? If the patches were removed and read at 72 hours, the response was most likely an irritant reaction
5. Responses at 7-10 days after removal may help distinguish a true from false positive result. True positive responses tend to persist for 7-10 days, false positives do not.
6. The lymphocyte transformation test has several issues:
a. viable lymphocytes are required therefore logistical issues of shipping often complicate testing;
b. in vitro testing is only available for a limited number of metals;
c. most 3rd party payers do not cover this testing which is not FDA approved and has limited validation data other than from a single European site (3);
d. most literature continue to recommend patch testing as the standard, possibly with the exception of titanium due to potential occurrence of false negative patch skin test results.
Fisher’s textbook on contact dermatitis provides a summary of the ‘state of the art’ for in vitro lymphocyte proliferation (2):
i. Even if a patient has a positive delayed type hypersensitivity skin test response, reactions to an orthopedic implant are rare and cannot be predicted
ii. The most likely adverse effect of an allergy to an orthopedic implant is dermatitis, often at the site of the implant but can become generalized and affect the hands;
iii. Failure of the implant and delayed or poor wound or surgical site healing hav occurred;
iv. Preoperative testing may identify preexisting sensitivity but does not predict likelihood of joint failure and may help with selection of type of implant;
v. Postoperative testing may help in determining if metal allergy is responsible;
vi. Documented titanium allergy is very rare, if other metals are test positive then titanium would be an alternative;
vii. In cases of documented delayed type metal hypersensitivity or when an individual has a strong belief related to this possibility, legal concerns may outweigh medical concerns;
viii. The additional cost of titanium implant may be judged reasonable in light of the financial and personal cost in a knee or hip implant.
ix. The criteria for postimplant metal hypersensitivity are:
a. Major
i. Dermatitis overlying the implant
ii. Positive patch test to metal used in the implant
iii. Complete recovery after removal of the offending implant
iv. Chronic dermatitis beginning weeks to months after the transplant
b. Minor
i. Therapy resistant dermatitis
ii. Morphology consistent with acute eczema
iii. Systemic allergic skin symptoms or signs
iv. Histology consistent with eczema
v. Positive in vitro test to metals
The criteria are a bit confusing as the recommendation is not to use the in vitro test but a minor criteria is a positive in vitro test.
In summary, there is no official recommendation to use in vitro methodology as the testing has not been validated by multiple investigators and the FDA has not approved the testing. The use of viable lymphocytes and the absence of 3rd payer coverage also limit the utility of the testing. I would repeat the patch tests with the chamber more than 6 inches apart, take pictures before and at 48 hours, 72 hour, and possibly 4, 5 and 6 days. I would share this information with the patient and the orthopedist and recommend a titanium implant without nickel unless the repeat tests do not show sensitivity. I would emphasize that the in vitro testing is an option but currently not recommended. I am skeptical that the in vitro testing would facilitate a better alloy than titanium. If a non-metal option is a consideration, then I would recommend if multiple patch tests are positive.
1. https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/Contact-dermatitis-2015.pdf
Fonacier L, Bernstein D, Pacheco K et al. Contact dermatitis: A practice update—Update 2015. J Allergy Clin Immunol Pract 2015;3:S1-S39.
2. Fowler, Joseph F., and Matthew J. Zirwas. Fisher's Contact Dermatitis. 2019. Chapter 8, Medical devices, implants and equipment.
3. Wood MW, Warshaw EM. Hypersensitivity to titanium: diagnosis and management. Dermatitis 26;2015:1-25.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI
Ask The Expert Archive Main Page
4/25/2017: Lymphocyte Transformation testing and Metal ion testing
Is there any validity to Lymphocyte Transformation testing (LTT) and/or Metal ION testing?
Thank you for submitting a question to Ask the Expert. A question about this was submitted on Jan 9, 2013. Dr Lieberman provided a response, which I have provided for you here:
The test you referred to is not actually a serum test, but a whole blood test which measures lymphocyte reactivity upon exposure to metal. The test itself, that is, the lymphocyte transformation test, is a validated means of testing for delayed hypersensitivity, the type of hypersensitivity that results in contact dermatitis. How effective this is in detecting contact dermatitis to metal still remains somewhat undecided, but there is evidence in the literature that the test can detect delayed hypersensitivity to metals. This is of course important in dealing with metal implants.
We have actually answered a very similar question submitted to our website recently. I have copied the question and our response below. In addition, I have updated it with a link to the website of the company that performs this test should you wish to investigate it further, and other abstracts dealing with this issue.
In summary, the lymphocyte transformation test itself is a validated test for delayed hypersensitivity. It appears as if it can detect delayed hypersensitivity to metals, but its exact role, compared to patch testing for example, in detection of metal allergy has not been established to my knowledge.
Thank you again for your inquiry and we hope this response is helpful to you.
Orthopedic Analysis
Abstract
How lymphocyte-mediated metal sensitivity affects orthopaedic implant performance remains poorly understood. Do patients with implants exhibit elevated lymphocyte reactivity to metals and is this reactivity more generalized or more implant-alloy specific? We investigated these questions by measuring lymphocyte responses to implant metals (Cr+3, Co+2, Ni+2 at 0.1 mM, and Ti+4 at 0.001 mM) in six subject groups: Group 1a = young controls, Group 1b = age matched controls, Group 2a = subjects with osteoarthritis (OA) and no history of metal sensitivity, Group 2b = OA subjects with history of metal sensitivity, Group 3a = total hip arthroplasty (THA) subjects with no to mild radiographic osteolysis, and Group 3b = THA subjects with moderate osteolysis. Lymphocyte proliferation, using Lymphocyte Transformation Testing (LTT), and cytokine release provided quantitative reactivity measurement, where a stimulation index of >2 indicated metal sensitivity. OA subjects with a history of metal sensitivity (Group 2b) were more metal reactive to Ni than any other group, as expected (66% incidence and Stimulation Index >20). However, THA subjects (Groups 3a & b) were >3 fold more reactive to Cr (p < 0.04), than were controls (Groups 1a & b) or OA subjects (Groups 2a & b). THA subjects with moderate vs mild osteolysis (Group 3b vs 3a) were more reactive to Co (43% vs 0% incidence). Only osteolytic THA subjects demonstrated increased cytokine responses with >two-fold (p <0.05) increases in soluble interferon-γ (IFN-γ) and interleukin-2 (IL-2) levels in response to Cr challenge. This elevated incidence and averaged level of lymphocyte reactivity supports a metal-specific adaptive immune response and suggests involvement in the pathogenesis of poor implant performance, e.g. aseptic osteolysis. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.(SOURCE Lymphocyte responses in patients with total hip arthroplasty, JOURNAL of ORTHOPEDIC RESEARCH 23(2), 384-391, 2005).
Contact Dermatitis. 2011 May;64(5):273-9. doi: 10.1111/j.1600-0536.2011.01886.x.
Metal sensitivity in patients with orthopaedic implants: a prospective study.
Frigerio E, Pigatto PD, Guzzi G, Altomare G.
Source
Department of Technology for Health, Dermatological Clinic, IRCCS Galeazzi Hospital, University of Milan, Milan 20161, Italy.
Abstract
Background: Sensitization to orthopaedic implant materials is an unpredictable event that might affect implant performance.
Objectives: In candidates for hip or knee joint prosthesis implantation, to evaluate preoperative assessments for identifying patients with metal sensitivity, to determine the percentage of patients who developed metal sensitivity at 1 year after prosthesis implantation, and to examine the clinical relevance of patch tests and lymphocyte transformation tests (LTT-MELISA®) for the evaluation of metal sensitization.
Patients and Methods: A total of 100 patients referred for total hip or total knee arthroplasty were assessed preoperatively and then at 1 year post-implantation by means of patch tests with the metals present in the implant alloys. In a pilot study, 20 patients also underwent both patch testing and a lymphocyte transformation test (LTT-MELISA®) for the same metals.
Results: Only 72 of 100 patients were patch tested both before and after surgery, and 12 of 20 also underwent LTT-MELISA® before and after surgery. Of 31/100 patients with an apparent history of nickel sensitivity determined during preoperative assessment of subjects, 12 tested negative on both tests, and 4 with a negative history of nickel sensitivity tested positive. One year post-implantation (72 patients), 5 patients who had initially tested negative for a metal allergy became positive for at least one or more metal constituents of the prosthesis on at least one or the other test.
Conclusions: Given the discrepancies between the information obtained while taking patient histories and test results, preoperative history-taking alone appears to be insufficient for identifying patients with metal sensitivity. Moreover, the increase in the percentage of patients who tested positive for metal sensitivity 1 year post-implantation suggests the possibility of prosthesis-induced sensitization. Therefore, objective determination of metal sensitivity at preoperative assessment should be considered in planning arthroplasty intervention, as it would help the surgeon in selecting the most appropriate prosthesis for the patient and could benefit implant performance.
Clin Exp Allergy. 2008 Sep;38(9):1468-75. doi: 10.1111/j.1365-2222.2008.02970.x. Epub 2008 Mar 31.
Detection of chromium allergy by cellular in vitro methods.
Lindemann M, Rietschel F, Zabel M, Grosse-Wilde H.
Source
Institut für Immunologie, Universitätsklinikum Essen, Essen, Germany.
Abstract
Background: The standard assay for the detection of chromium sensitization, the patch test, does not allow discrimination between patients with and without clinical symptoms of allergy.
Objective: The aim of this study was to prove whether cellular in vitro tests are predictive of chromium allergy.
Methods: Chromium-sensitized volunteers with and without clinically manifest allergy and non-sensitized healthy controls (n=37, 19, and 26, respectively) were analysed by cellular in vitro methods using tri- and hexavalent chromium (chromium chloride and potassium dichromate) as stimuli. The results were correlated with clinical and anamnestic data.
Results: Sensitized individuals with an allergy displayed significantly higher lymphocyte transformation test (LTT) responses than sensitized volunteers without allergy and controls (P<0.05 and P<0.01, respectively). 12.5 microg/mL of chromium chloride and 50 ng/mL of potassium dichromate were found to be optimal to discriminate between sensitized individuals with and without allergy. Combining the results of chromium chloride and potassium dichromate LTT, a positive reaction to at least one of the stimuli was highly predictive of allergy [sensitization with vs. without allergy: Odds ratio (OR)=6.4, P=0.004; sensitization with allergy vs. controls: OR=11.5, P<0.0001]. On the contrary, IFN-gamma, IL-2, IL-4, IL-10, and IL-12 production to the ELISpot, patch test results, sensitization against other metals, and atopy score did not significantly discriminate between sensitization with and without allergy. However, IFN-gamma responses towards chromium chloride were significantly correlated with the strength of patch test reactivity (r=0.49, P=0.002). By IFN-gamma ELISpot, the average precursor cell frequency reactive to trivalent chromium could be defined as 26, 15, and 11 : 10(6) in volunteers with sensitization and allergy, with sensitization without allergy, and controls, respectively.
Conclusions: In contrast to the patch test, the LTT appears to be a method that is predictive of chromium allergy.
Question posted to Ask the Expert website 4/25/2012:
Do you feel that Lympocyte Transformation Tests are reasonable diagnostic alternates to patch testing for metal allergy? e.g. MELISA Foundation, etc. I realize that the data is limited but at least one reference indicates possible value for these modalities.
Klinik und Poliklinik für Dermatologie und Allergologie der Ludwig-Maximilians-Universität,
München, Germany.
Abstract
There are very few reports on hypersensitivity reactions in association with titaniumbased materials so that the existence of allergy to titanium is still put in question. We report on a patient in whom impaired fracture healing and eczema localized to the perioperative area developed upon titanium-based osteosynthesis. Patch testing gave no reactions to titanium nor to nickel, chromium, or cobalt. However, in the lymphocyte transformation test, the patient's lymphocytes showed markedly enhanced proliferation in vitro totitanium. After removal of the titanium material, fracture healing was achieved and the eczema cleared. Parallel to this, in vitro hyperreactivity to titanium disappeared. Although contact allergic reactions to titanium have been very rarely reported, these findings support a diagnosis of titanium allergy in our patient.
Answer:
I think that there is credible evidence in the literature to indicate that delayed hypersensitivity testing to metals can be a useful test in detecting the presence of contact allergy. I am sending you a link (copied below) to a study employing delayed hypersensitivity testing to detect metal allergy. In addition, there is evidence in the dermatologic literature (1) indicating that lymphocyte transformation testing may be coming of age in terms of its usefulness to detect contact allergy not only to metals, but to other substances.
As with all tests, there are false-positives and false-negatives, and the diagnosis of contact allergy remains a clinical diagnosis in which tests are used to add additional evidence of its existence to a specific agent. Thus interpreting these tests is much like interpreting the immediate hypersensitivity skin tests and tests for serum-specific IgE. The reference to which I sent the link will give you some perspective on false-positive and false-negative tests using delayed hypersensitivity testing.
Reference:
1. Basketter D and Menne T. Lymphocyte transformation tests in patients with allergic contact dermatitis. Contact Dermatitis 2005; 53:1.
Sincerely,
Phil Lieberman, M.D.
Dr. Jacqueline A. Pongracic, FAAAAI