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based tests like MELISA are better suited for diagnosing implant-related metals sensitivity than patch testing as the relationship between skin hypersensitivity and systemic hypersensitivity (Ständer, et al., 2017) is ill-defined. Performing the LTT under optimised stimulating conditions might be a useful additional tool for the diagnosis of hypersensitivity (Ständer, et al., 2017) (FDA, 2019). To test whether patients with symptoms attributed to dental amalgam differed from healthy controls, a study compared 23 amalgam patients, 30 subjects who considered themselves healthy with amalgams and 10 subjects without amalgam using MELISA and other tests. The researchers found that a high frequency of positive results was obtained among healthy subjects with or without dental amalgam, and concluded that the test cannot be used as an objective test for mercury allergy (Cederbrant, et al., 1999).
166:). After consultation with a dentist, a subgroup of 111 patients who showed allergy to their dental metals replaced their restorations with non-metallic materials. Nickel was the most common sensitizer, followed by inorganic mercury, gold, phenylmercury, cadmium and palladium. As compared to lymphocyte responses in healthy subjects, the CFS group had significantly increased responses to several metals, especially to inorganic mercury, phenylmercury and gold.
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118:, H-thymidine, by dividing lymphocytes (proliferation); the other by cell staining and microscopy evaluation. The level of reactivity is measured as a Stimulation Index (SI), against the naïve lymphocytes from the unexposed sample (negative control). Viability and reactivity are determined by cell count as well as reaction to the positive control.
114:, to serve as a positive control. Finally, the blood is exposed to the suspected allergen/s in several different concentrations, to ensure that the conditions in vitro are as similar as possible to those in vivo. The lymphocyte reaction to each allergen is measured by two separate technologies: one based on the uptake of a radioactive
275:
Another study by the same critical author used 34 patients to test the sensitivity and specificity if the MELISA test, and concluded that it is not useful for diagnosis of contact allergy to the metals gold, palladium and nickel, since many false-positive results will be obtained (Cederbrant, et al.,
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and environmental health. It has been used to screen workers exposed to metals, chemicals or other allergens in their workplace. This is what the test was developed for originally, at Astra’s (now Astra-Zeneca) laboratories in Södertälje, Sweden. In the U.S., a similar technique (BeLT) is routinely
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inducing fatigue-like symptoms. A study (Stejskal, et al., 1999) of 930 patients with CFS-like symptoms showed 62% testing MELISA-positive to metal allergy. Of those who removed the offending metals, 76% improved, but there was no placebo control. Metal hypersensitivity is not widely recognized by
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Type IV hypersensitivity to metals is common, particularly to nickel, however hypersensitivity related complications associated with metal implants are less frequently reported. Potential hypersensitivity complications include skin rashes, chronic joint pain, swelling, aseptic loosening, and joint
271:
The developers of the MELISA test argue that the critical articles calculated the sensitivity and specificity of in vitro lymphocyte proliferation tests using patch testing as its reference. It is well-known that patch testing can cause irritative local reactions. It is generally agreed that LTT
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In spinal surgery, microscopic titanium particles are present in the tissues surrounding the implant. These particles activate macrophages that increase bone absorption and inflammatory reactions. Released nanoparticles will circulate in the body fluids, eventually accumulating in remote organs.
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Titanium and its main alloy (Ti6Al4V) are generally seen as hypoallergenic options for arthroplasty and for dental implants. Although uncommon, with a prevalence estimated at between 0.6-6.3%, titanium hypersensitivity has been reported post-implantation with symptoms including impaired fracture
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Titanium has been shown to induce clinically relevant hypersensitivity which can be detected with MELISA testing. The accuracy of patch testing for titanium allergy, in particular, seems to be variable; the Mayo clinic failed to find any positive reactions to titanium in over a decade, despite
157:
The frequency of metal-induced lymphocyte responses was examined in 3,162 dental patients in three
European laboratories using the MELISA test. The patients suffered from local and systemic symptoms attributed to their dental restorations. The effect of dental metal removal was studied in 111
267:
Whilst two articles have concluded that the MELISA test may give false positive (Cederbrant, et al., 1999) (Cederbrant, et al., 1997) reactions, a subsequent study concluded the MELISA test is "reproducible, sensitive, specific, and reliable for detecting metal sensitivity in metal-sensitive
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is a cell culture and requires live memory lymphocytes. Lymphocytes are isolated from a blood sample and cultured in an incubator for five days. A portion of the blood is kept intact (unexposed to allergens) to serve as a negative control. A second portion is exposed to a universal allergen,
192:
Many authors conclude that LTT-based blood tests like MELISA may be a better option for detecting systemic allergies from implants, while patch testing is better suited to detecting dermal hypersensitivity. They add that LTT based testing may also be a good option in cases of indeterminate
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1997). The clinical relevance of the test has been shown by the decrease of patient-reported metal-specific responses following the removal of the allergy-causing metals (however the trial did not have a placebo control). (Stejskal, et al., 2006) (Valentine-Thon, et al., 2006)
121:
MELISA is an optimised, standardised version of the lymphocyte transformation test (LTT) which was developed in the early 1960s to help identify allergies to drugs, metabolites and metals. The LTT for beryllium is now accepted as the gold standard for diagnosing
153:
MELISA was further developed to help to assess the impact of hypersensitivity to metals used in dentistry. Hypersensitivity to dental metals may be associated with local oral reactions including oral lichen planus, stomatitis and ulceration.
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Thomas, P. et al., 2006. Hypersensitivity to titanium osteosynthesis with impaired fracture healing, eczema, and T-cell hyperresponsiveness in vitro: case report and review of the literature. Contact
Dermatitis, p. 55:
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Davis, M., Wang, M., Yiannias, K. & Keeling, K., 2011. Patch testing with a large series of metal allergens: findings from more than 1,000 patients in one decade at Mayo Clinic. Dermatitis, pp. 22(5):256-71.
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Niki Y, Matsumoto H, Otani T, Yatabe T, Kondo M, Yoshimine F, Toyama Y. Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty. Biomaterials 2005; 26:
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MELISA uses morphological screening to provide an additional level of accuracy. This ensures that non-hypersensitivity related cells (eg. macrophages) are not included in the radioactively positive counts
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healing, local eczema, pain, swelling, systemic dermatitis, implant loosening, and failure, all of which have been reported to resolve with implant removal and replacement with a non-titanium implant
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Willert H, Buchhorn G, Fayyazi A. Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints: a clinical and histomorphological study. J Bone Joint Surg Am. 2005; 87(1):28-36.
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Hosoki, M. et al., 2018. Cross-sectional observational study exploring the clinical risk of titanium allergy caused by dental implants. Journal of
Prosthodontic Research, Vol 62(4), pp. 426-431.
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Granchi D, Cenni E, Giunti A, Baldini N. Metal hypersensitivity testing in patients undergoing joint replacement. J Bone Joint Surg Br 2012; 94(8): 1126-1134. doi: 10.1302/0301-620X.94B8.28135.
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Issa Y, Brunton P, Glenny A, Duxbury A. Healing of oral lichenoid lesions after replacing amalgam restorations: a systemic review. Oral Surg Med Oral Pathol Oral Radiol Endod 2004; 98: 553-565.
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Lionberger D, Samorajski J, Wilson C, Rivera A. What role does metal allergy sensitization play in total knee arthroplasty revision? J Exp Orthop 2018; 5(1):30. doi: 10.1186/s40634-018-0146-4.
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MELISA utilizes a greater number of lymphocytes than other LTTs (1 x 10 cells). As memory cells are relatively rare this higher concentration of lymphocytes ensures improved sensitivity.
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Dodd M, Begley A. 2019. The utility of MELISA testing for metal allergy in patients requiring TMJ replacement. Br J Oral
Maxillofac Surg 2019; 57(10). doi: 10.1016/j.bjoms.2019.10.254.
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Opstal, N. F., 2011. Revision of a tibial baseplate using a customized oxinium component in a case of suspected metal allergy: a case report. Acta Orthop Belg., pp. 77:691-695.
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to metals, chemicals, environmental toxins and molds. Type IV hypersensitivity reactions, particularly to nickel, are well established and may affect 20% of the population.
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Sicilia A., e. a., 2008. Titanium allergy in dental implant patients: a clinical study on 1500 consecutive patients. Clinical Oral
Implants Research, pp. Aug;19(8):823-35.
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Carossino A, Carulli C, Ciuffi S. Hypersensitivity reactions to metal implants: laboratory options. BMC Musculoskelet Disord 2016; 17: 486. doi: 10.1186/s12891-016-1342-y.
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Ramachandran, R. e. a., 2006. The effects of titanium and polymethylmethacrylate particles on osteoblast phenotypic stability. J Biomed Mater Res A. p. 77:512–517.
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Stejskal V, Danersund A, Lindvall A, Hudecek R. Metal-specific lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology
Letters 1999; 20: 289-298.
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Stejskal V, Forsbeck M, Nilsson R. Lymphocyte transformation test for diagnosis of isothiazolinone allergy in man. J Invest
Dermatol 1990; 94: 798–802.
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Silverberg N, Pelletier J, Jacob S, Schneider L. Nickel allergic contact dermatitis: identification, treatment, and prevention. Pediatrics 2020; 145.
229:. The authors hypothesize that if the immune system is constantly displaying an allergic reaction to a metal present in the body, this will alert the
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Stejskal V, Cederbrant K, Lindvall A, Forsbeck M. MELISA – an in vitro tool for the study of metal allergy. Toxicol in Vitro 1994; 8: 991–1000.
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Müller, K. & Valentine-Thon, E., 2006. Hypersensitivity to titanium: clinical and laboratory evidence. Neuro
Endocrinol Lett, pp. 1:31-5.
94:(or memory lymphocytes) that have had prior contact with a given allergen. This is in contrast to a type-I allergy, which is mediated by IgE
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Evrard, L., Waroquier, D. & Parent, D., 2010. Allergies to dental metals. Titanium: a new allergen. Rev Med Brux, pp. 31(1):44-49.
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Newman L. Significance of the blood beryllium lymphocyte proliferation test. Environ Health
Perspect 1996; 104(Suppl 5): 953-956.
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The test is also used to determine whether metal allergy is a contributing factor in the development of chronic diseases such as
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Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopedic implants. J Bone Joint Surg Am 2001; 83: 428-436.
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Wood, M. & Warshaw, E., 2015. Hypersensitivity reactions to titanium: diagnosis and management. Dermatitis, pp. 26:7-25.
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Valentine-Thon E, Schiawara H. Validity of MELISA for metal sensitivity testing. Neuro
Endocrinol Lett 2003;24(1–2): 57–64.
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Some surgeons and researchers suggest LTT testing prior to surgery in patients with suspected/self-reported metal allergy
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hypersensitivity or in patients with joint failure of an unknown cause since it has higher sensitivity than patch testing
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Goto, M., Mitsui, Y., Tanesue, R. & Okawa, T., 2013. Hypersensitivity to Suture Anchors. Case reports in Orthopedics.
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test. In genetically predisposed individuals, an ongoing exposure to allergens can induce type-IV hypersensitivity.
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Hallab, N., 2009. A review of the biologic effects of spine implant debris: fact from fiction. SAS J, p. 3:143–160.
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Richardson, T. e. a., 2008. Serum titanium levels after instrumented spinal arthrodesis. Spine, p. 33:792–796.
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Bruce G, Hall W. Nickel hypersensitivity-related periodontitis. Compend Contin Educ Dent 1995; 178: 180-184.
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Tosti A, Piraccini BM, Peluso AM. Contact and irritant stomatitis. Semin Cutan Med Surg 1997; 16: 314-319.
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The MELISA test measures type-IV delayed hypersensitivity reaction. Type-IV reactions are mediated by
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Laiendecker R, Van Joost T. Oral manifestation of gold allergy. J Am Acad Dermatol 1994; 30: 205-209.
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allergy in asymptomatic workers exposed to beryllium dust (Mroz, et al., 1991) (Newman LS, 1996).
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MELISA uses partially depleted monocytes to replicate the lymphocyte/monocyte balance in vivo
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may have been created or edited in return for undisclosed payments
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patients with metal hypersensitivity and symptoms resembling
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McMinn D, Zaiee H. 2013. The Ceramic BMHR. Available at:
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This article is about the blood test. For other uses, see
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129:MELISA differs from standard LTTs in several ways:
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213:several published cases of titanium allergy.
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173:76% reported long-term health improvement
76:Memory Lymphocyte Immunostimulation Assay
686:Enzyme multiplied immunoassay technique
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293:https://doi.org/10.1542/peds.2020-0628
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234:researchers as an accepted cause of
636:Ouchterlony double immunodiffusion
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179:2% reported worsening of symptoms
169:Following dental metal removal:
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78:) is a blood test that detects
16:Blood test for hypersensitivity
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626:Chromatin immunoprecipitation
176:22% reported unchanged health
98:and is often tested using an
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671:Chemiluminescent immunoassay
651:Counterimmunoelectrophoresis
781:Direct fluorescent antibody
250:The MELISA test is used in
225:(Sterzl, et al., 1999) and
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803:Total complement activity
200:Titanium hypersensitivity
766:Complement fixation test
184:Orthopaedics and surgery
160:chronic fatigue syndrome
80:type IV hypersensitivity
21:Melisa (disambiguation)
641:Radial immunodiffusion
756:Diagnostic immunology
646:Immunoelectrophoresis
252:occupational medicine
246:Occupational medicine
53:neutral point of view
776:Immunohistochemistry
771:Immunocytochemistry
740:Latex fixation test
618:Immunoprecipitation
255:used to screen for
706:Immunofluorescence
701:Radiobinding assay
240:multiple sclerosis
227:multiple sclerosis
844:Immunologic tests
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823:Categories
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605:immunology
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149:Dentistry
86:Mechanism
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749:Other
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