**4.5.4 Other tests available**

*In vitro* tests such as the macrophage migration test, the lymphocyte blastic transformation test and the lymphocyte transformation test have mostly been used in research projects (Rasanen and Tuomi 1992; Bordignon et al. 2008). None of these have become routine analyses in the clinical setting, even when 2 or 3 methods have been combined. The lymphocyte transformation test measures proliferation of lymphocytes from peripheral blood in the presence and absence of a potential allergen after incubation for 7 days. The result is reported as a stimulation index (SI) and is therefore quantitative. The little use of such *in vitro* test is mainly explained by an overall limited availability, a small number of allergens that can be tested, and the need for fast examination of lymphocytes after sampling since they rapidly become incapable of proliferating. Nevertheless, the lymphocyte proliferation test has been claimed to better reflect immune reactions within the body whereas the patch test mainly rather reflect cutaneous reactivity. Thus, a linear correlation was identified between serum metal ion levels and lymphocyte reactivity suggesting that *in vivo* metal release is directly associated with metal contact allergy (Hallab et al. 2004).

### **4.5.5 Clinical work-up**

It is difficult to make general principles for good clinical practice before and after surgery regarding delayed type hypersensitivity reactions to orthopaedic implants. Allergic reactions to metal ions released from implants are rare and at the same time metal allergy

(Wahlberg 2006). Albeit there is raising concern that the patch test mainly measures cutaneous metal allergy rather than allergic reactions caused and effectuated by systemic immune cells, the patch test has worked well to establish an association between metal ion concentrations in the blood and urine, metal allergy and loosening of 1st generation metalon-metal hip implants. It is clear that a system test, e.g. the lymphocyte transformation test that measures immune reactivity in bone near structures or the blood may have a higher sensitivity and it is therefore warranted. However, no such test system is currently available

Fig. 4. Patch test reactions following 48 hours of occluded 5% nickel sulphate exposure. Upper line from left to right: irritative reaction, doubtful reaction (+?), and doubtful reaction (+?). Lower line from left to right: weak positive (1+), moderate positive (2+), and strong

*In vitro* tests such as the macrophage migration test, the lymphocyte blastic transformation test and the lymphocyte transformation test have mostly been used in research projects (Rasanen and Tuomi 1992; Bordignon et al. 2008). None of these have become routine analyses in the clinical setting, even when 2 or 3 methods have been combined. The lymphocyte transformation test measures proliferation of lymphocytes from peripheral blood in the presence and absence of a potential allergen after incubation for 7 days. The result is reported as a stimulation index (SI) and is therefore quantitative. The little use of such *in vitro* test is mainly explained by an overall limited availability, a small number of allergens that can be tested, and the need for fast examination of lymphocytes after sampling since they rapidly become incapable of proliferating. Nevertheless, the lymphocyte proliferation test has been claimed to better reflect immune reactions within the body whereas the patch test mainly rather reflect cutaneous reactivity. Thus, a linear correlation was identified between serum metal ion levels and lymphocyte reactivity suggesting that *in vivo* metal release is directly associated with metal contact allergy (Hallab

It is difficult to make general principles for good clinical practice before and after surgery regarding delayed type hypersensitivity reactions to orthopaedic implants. Allergic reactions to metal ions released from implants are rare and at the same time metal allergy

for allergist and surgeons in most centres and countries.

positive (3+) allergic reactions.

**4.5.4 Other tests available** 

et al. 2004).

**4.5.5 Clinical work-up** 

remains very frequent. This obviously makes it difficult to identify the few allergic subjects at risk before developing implant failure. Although it is a matter of controversy, it seems sensible to refrain from routine patch testing/allergy testing prior to surgery unless the patient has already had implant surgery with complications suspected to be allergic or a history of clinical metal intolerance of sufficient magnitude to be of concern to the patient or a health provider (Thyssen et al. 2011a). If a patient is strongly allergic to e.g. nickel or cobalt, one should consider inserting titanium based alloys. To demonstrate causal relationship between delayed type of hypersensitivity and aseptic loosening strict criteria (Tab. 2) should be followed (Thyssen et al. 2011a).


Table 2. Objective criteria that support a causative association between metal release from the implant, metal allergy and delayed type hypersensitivity reactions such as implant loosening, malfunction, pain or chronic inflammation (from Thyssen et al. 2011a)
