The Journal of Arthroplasty Vol. 24 No. 5 2009

Case Report

Metal Hypersensitivity

Can It Mimic Infection?

Ashish Anand, MD,* Fred McGlynn, MD,y and William Jiranek, MD*

Abstract: Metal hypersensitivity leading onto hardware rejection is reported as arare phenomenon. If not suspected, it can be a harrowing experience for the patientbecause it can lead to a seemingly never-ending cycle of tests and procedures. Thiscase highlights the fact that although metal hypersensitivity is rare, it should beincluded in the differential once infection has been excluded. Key words:replacement, hypersensitivity, infection.© 2009 Elsevier Inc. All rights reserved.

Metal sensitivity is not a new problem for orthopedicsurgeons. The first case was reported in 1966 byFoussereau and Laugier [1], who reported eczema-tous dermatitis with nickel. The severity of reactionvaries form mild dermatitis to severe eczematousdermatitis, urticaria, or vasculitis. These externalchanges are associated with internal metallosis andother inflammatory changes in the surrounding softtissues [2]. The literature is dominated by hyper-sensitivity to stainless steel implants and cobalt alloyimplants, although there have been a few reports ofhypersensitivity to titanium implants [2-4]. Our casehighlights the fact that delay in suspecting metalhypersensitivity can increase the morbidity of thepatient as well prove to be very expensive in thelong run.

From the *Deparment of Orthopedics, VCUMedical centre, Richmond,Virginia; and yFellowship Faculty, Tuckahoe Orthopedics, Richmond,Virginia.

Submitted January 28, 2008; accepted May 2, 2008.No benefits or funds were received in support of this study.Reprint requests: Ashish Anand, MD, Primus Ortho and Spine

Hospital, Chanakya Puri, Delhi 21, India.© 2009 Elsevier Inc. All rights reserved.0883-5403/08/2405-0032$36.00/0doi:10.1016/j.arth.2008.05.002

826.e2

Case Description

A 70-year-old healthy white male presented toour clinic as a self-referral for long-standing kneeswelling after knee arthroplasty done 20 monthsbefore his appointment at our clinic.

At the time of his knee arthroplasty surgery,genesis implant (Zimmer) was used. The patient'simmediate postoperative course was complicated bypulmonary embolism for which he was successfullytreated. However, 2 months later, the patientpresented with swelling around the knee joint. Aknee aspirate revealed a turbid fluid that had a whiteblood cell count of 56000 but no bacteria on Gramstain. His erythrocyte sedimentation rate and C-reac-tive protein (CRP) were elevated, and the x-rayswere normal. Subsequent cultures (aerobic bacter-ial/anaerobic bacterial/fungal and mycobacterial)were negative. In addition, polymerase chain reac-tion (PCR) for bacterial nucleic acid (Gram-positivebacteria, Gram-negative bacteria, and fastidiousbacteria) was negative. The patient's case was stilltreated as an acute infection, and he underwentdebridement with liner exchange and was placed onintravenous vancomycin for 6 weeks and oralciprofloxacin for 6 months. Cultures at the time ofsurgery as well as PCR analysis of the synovial fluidwere negative for infection.

5

Fig. 1. X-ray at 20 months showing evidence of lysis onthe medial tibial plateau.

Fig. 2. X-ray at last follow-up showing well-alignedcomponents with no evidence of loosening.

826.e26 The Journal of Arthroplasty Vol. 24 No. 5 August 2009

At 6-month follow-up, the patient had minimalswelling around the suprapatellar pouch. X-rays atthis time were normal. The blood work revealednormal sedimentation rate and CRP values. As forthe patient, his swelling had never subsided after thesecond procedure, and he continued to have painoff and on. The patient had a good range of motionat 6 months follow-up.At 1 year follow-up, the swelling persisted, and

the aspirate again did not reveal any evidence ofinfection on culture as well as PCR. The bloodworkup and the x-rays were normal at that time.Approximately 18months after the index surgery,

the patient noticed further increase in the size of theswelling associated with a limp. X-rays done at thistime revealed lysis around the tibia, but the aspiratewas negative for infection on cultures and PCR.Physical examination revealed synovial hypertro-phy and a catch in midflexion. The knee wasclinically stable with no evidence of any midflexioninstability. An arthroscopic synovectomy was per-formed, and biopsy revealed nonspecific chronicinflammatory changes. Because the patient hadbeen having persistent negative cultures, an alter-native etiology was looked into, and metal allergywas suspected. The patient denied any history ofhaving rashes or eruptions in the last 18 months.The surgeon at this point referred the patient to adermatologist. Allergen Patch test (T.R.U.E—ThinLayer rapid use epicutaneous test) was performedby the dermatologist, and it revealed the patient hadhypersensitivity to nickel and cobalt. Subsequently,the treating surgeon contacted the Zimmer Com-pany for samples of Tivanium (Ti-6A1-4V alloy) andZimaloy (cobalt-chromium-molybdenum alloy).Patch testing with these samples did not reveal anelement of hypersensitivity.

The patient presented to us 20 months after theindex surgery for a second opinion, at this time, hehad swelling around the left knee and a limp. Therewere no systemic signs of infection, and theerythrocyte sedimentation rate, CRP, and interleu-kin-1 were normal. On examination, the left kneerevealed marked atrophy of the quadriceps andboggy synovial thickening. Range of motion was 0°to 100° with the terminal part being painful. X-raysrevealed evidence of loosening on the tibial side(Fig. 1). There was no periosteal reaction. Aspirationof the joint revealed a hemorrhagic fluid and wasnegative for infection on cultures and PCR. Metalhypersensitivity was suspected, and a single stagereimplantation with alternate bearing surfaces(titanium implant; Biomet) was performed. Intrao-perative frozen sections and cultures were negativefor any evidence of infection. Biopsy specimen sentat the time of surgery revealed essentially a mono-nuclear infiltrate composed of lymphocytes, plasmacells, and macrophages, which was consistent withmetal sensitivity.

The postoperative course was uneventful, and at14 months follow-up, the patient did not have anysystemic signs of infection or swelling around theknee joint. He had a range of motion of 0° to 120°that was painless. X-rays done at 14 monthsrevealed well-aligned components with no evidenceof loosening (Fig. 2).

Metal Hypersensitivity � Anand et al 826.e27

Discussion

A well-done joint arthroplasty results in pain-free functioning joint and an improvement inquality of life. If patient presents with recurrenceof the preoperative symptoms and rapid manifes-tation of x-ray signs (osteolysis), infection has tobe excluded.The gold standard [5] for the diagnosis of

infection is intraoperative cultures. Although jointaspiration is commonly used for preoperativeinvestigation, inaccuracies occur with a dry tapand a false-negative culture is not uncommon [6].Once infection has been excluded, metal hyper-sensitivity must enter in the differential diagnosis,especially if there is a rapid occurrence of osteolysisand appearance of radiolucent lines on x-rays.Recent studies by Willert et al [7] have shown thathistological analysis in a case of metal hypersensi-tivity will reveal evidence of an immunologicalresponse. This manifests as a diffuse collection ofperivascular lymphocytes, plasma cells–localizedbleeding, fibrin exudation, necrosis, and presenceof macrophages with drop-like inclusions, whereasin infection, neutrophils predominate and areresponsible for the production of various enzymesand inflammatory mediators [8], which degradethe tissues thereby producing radiolucent lines.Study by Davies et al [9] has shown that thepattern and type of inflammation seen in peripros-thetic tissues obtained from hips with metal-on-metal and metal-on-polyethylene implants arevery different (lymphocytic in metal-on-metaland histiocytic in metal-on-polyethylene hips).According to the authors, this response mightrepresent a mode of failure for metal-on-metaljoint arthroplasties.In the present case, the patient had rapid onset of

symptoms, althoughx-rays signswere lagging behind.The patient had persistently negative cultures; it

was only when 18 months had elapsed that analternative etiology was looked into as the patientcontinued to be symptomatic. Although the patienthad a positive patch test, he did not show anyevidence of hypersensitivity when a sample speci-men provided by the company was used, therebyfurther adding to the confusion. Our findings areconcordant with the findings of Granchi et al [10],which showed that in patients with a total kneearthroplasty, the frequency of positive patch testingis higher than in the normal population. However,no predictive value is attributable to the sensitizationbecause patch testing was not able to discriminatebetween stable and loose implants.

Similarly, Hallab et al [8] have shown an inci-dence of 14% on patch testing for nickel in thegeneral population. The most likely explanation fornegative patch test results with company-providedsamples is individual variation in patch sensitivity, ashas been reported before by Hindsen et al [11]. Theyreported variation in nickel reactivity in the samepatients when tested on different occasions. Theexact etiology for this variation has been attributedto multifactorial causes such as drugs, hormones,ultraviolet radiation, and so on.

The ancillary test that has been reported useful indiagnosing metal hypersensitivity is the lymphocyteblast transformation test [8,12,13]. This could not bedone because this test has a limited availability atselected centers and was not available at our facility.

With the recent trend toward metal-on-metalbearings, we should be ready to see more cases ofmetal hypersensitivity, which will always challengethe orthopedic surgeon because such case has avaried presentation [14].

The key to preventing morbidity lies in suspect-ing hypersensitivity when infection has been ex-cluded and symptoms cannot be explained by anyother etiology.

References

1. Foussereau J, Laugier P. Allergic eczemas frommetallic foreign bodies. Trans St Johns Dermatol Soc1966;52:220.

2. Halpins DS. An unusual reaction in muscle inassociation with a vitallium plate; a report of possiblemetal hypersensitivity. J Bone Joint Surg Br 1975;57:451.

3. Merritt K, Rodrigo JJ. Immune response to syntheticmaterials. Sensitization of patients receiving orthope-dic implants. Clin Orthop Relat Res 1996:71.

4. Thomas RH, Rademaker M, Goddard NJ, et al. Severeeczema of the hands due to an orthopedic plate madeof vitallium. Br Med J 1987;294:106.

5. Spangehl MJ, Younger AS, Masri BA, et al. Diagnosisof infection following total hip arthroplasty (review).Instr Course Lect 1988;47:285.

6. Roberts P, Walters AJ, McMinn DJ. Diagnosinginfection in hip replacements; the use of fine needleaspiration and radiometric culture's. Bone Joint SurgBr 1992;74:265.

7. Willert HG, Buchhorn GH, Fayyazi A, et al. Metal onmetal bearings and hypersensitivity in patients withartificial hip joints. A clinical and histomorphologicalstudy. J Bone Joint Surg 2005:28.

8. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity inpatients with orthopedic implants. J Bone Joint SurgAm 2001;83-A:428.

826.e28 The Journal of Arthroplasty Vol. 24 No. 5 August 2009

9. Davies AP,Willert HG, Campbell PA, et al. An unusuallymphocytic perivascular infiltration in tissues aroundcontemporary metal-on-metal joint replacements.J Bone Joint Surg Am 2005;87:18.

10. Granchi D, Cenni E, Tigani D, et al. Sensitivity toimplant materials in patients with total knee arthro-plasties. Biomaterials 2008;29:1494.

11. Hindsen M, Bruze M, Christensen OB. Individualvariation in nickel patch test reactivity. Am J ContactDermat 1999;10:62.

12. Hallab NJ. Lymphocyte transformation testing forquantifying metal-implant–related hypersensitivityresponses. Dermatitis 2004;15:82.

13. Hallab NJ, Anderson S, Stafford T, et al. Lymphocyteresponses in patients with total hip arthroplasty.J Orthop Res 2005;23:384.

14. Gawkrodger DJ. Metal sensitivities and orthopedicimplants revisited: the potential for metal allergy withthenewmetal-on-metal joint prostheses. Br JDermatol2003;148:1089.