Extravascular implantable cardioverter-defibrillator implantation in a patient with nickel and cobalt allergies

Key Teaching Points.

• •Consider hypersensitivity reaction (HSR) in the differential diagnosis when patients with cardiac implantable electronic devices (CIEDs) experience local or systemic inflammation, particularly after ruling out infection.
• •It is important to obtain a history of HSR prior to CIED implantation to identify patients who may benefit from primary prevention of CIED-HSRs.
• •When planning for primary prevention of CIED-HSRs, consider which components are insulated vs noninsulated. Consider using newer CIEDs such as extravascular ICDs to reduce potential allergen exposure.

Introduction

As global implantation rates for cardiac implantable electronic devices (CIEDs) exceed 1 million a year,^1,2 the number of rare complications including device hypersensitivity has increased. CIED-hypersensitivity reactions (CIED-HSRs) to pacemakers and implantable cardioverter-defibrillators (ICDs) are difficult to diagnose because they share a similar presentation as CIED-infection and skin patch testing has low sensitivity.³ Primary and secondary prevention of device reactions involves the utilization of hypoallergenic device components or coatings such as gold, polytetrafluoroethylene, and silicone to protect against metal leach. Although allergic reactions to plastic resin have also been reported, they are extremely rare compared with metal allergies. Common biocompatible alloys used in CIEDs have been shown to leach nickel and metal ions during in vitro and in vivo studies.4, 5, 6 In this case report, we share the first implantation of an extravascular ICD (EV-ICD) for a patient with known nickel and cobalt allergies, which were addressed with thermoplastic insulation and alternative metal electrodes.

Case report

A 37-year-old man with a history of diabetes, hypertension, and smoking presented with progressive chest pressure and dyspnea and was found with electrocardiographic and echocardiographic features of hypertrophic cardiomyopathy. Cardiac magnetic resonance imaging confirmed the hypertrophic cardiomyopathy diagnosis, demonstrating asymmetric septal hypertrophy (maximum septal thickness of 2.1 cm at the mid-distal septum) and hyperdynamic left ventricular systolic function (72%) with near-systolic cavity obliteration of the mid-distal left ventricle. Extensive myocardial scar was seen throughout the epicardial and midmyocardial aspect of the basal-distal septum, as well as near transmural involvement of the distal left ventricle or the apex (18% late gadolinium enhancement). Given these findings and the report of sudden death of the patient’s maternal uncle at the age of approximately 50 years, the patient was referred for ICD implantation. The initial plan to implant a Boston Scientific subcutaneous ICD (S-ICD) was canceled owing to reported skin reactions to jewelry and possible nickel allergy. The patient subsequently underwent formal skin patch testing (T.R.U.E. test patch panels, Mekos Laboratories AS), which demonstrated reactivity to nickel and cobalt (Figure 1).

Figure 1.

Skin patch testing conducted with T.R.U.E. test patch panels (Mekos Laboratories AS) and interpreted according to the International Contact Dermatitis Research Group criteria per manufacturer guidelines. Panel 1 results are shown. Panel 2 and 3 are not shown given negative results.

After further discussion, the patient underwent implant of a newer EV-ICD (Aurora EV-ICD; Medtronic, Minneapolis, MN) (Figure 2). Appropriate lead parameters demonstrated signal amplitude of 5.7 mV, impedance of 59 Ω, and successful cardioversion during defibrillation threshold testing at 40 J output. One-month follow-up demonstrated a well-healed incision with no signs of HSR (Figure 3), and no issue has been reported now, approximately half a year after implant.

Figure 2.

Plain radiograph of posterior-anterior and lateral views after implantation.

Figure 3.

Incision site at 1 month after implantation.

Discussion

CIED-HSRs are increasing in number as annual rates of device implantation exceed 1 million worldwide per year. Although the true incidence is difficult to ascertain, investigators have estimated a rate as high as 1 in 500 cases.⁷

The diagnosis is made clinically: CIED-HSRs commonly feature local inflammatory skin reactions overlying the device pocket including erythema, edema, pruritus, eczematous rashes, scaly plaques, and skin erosion.³ Less frequently, systemic involvement including anaphylactoid reaction, asthma, eosinophilic myocarditis, erythroderma, systemic inflammatory response syndrome, device malfunction from excessive current drain, and remote site dermatitis has been reported.^3,8, 9, 10, 11, 12, 13 Reactions often occur weeks to months after implantation.¹⁴

The challenge is to differentiate HSRs from device infections, which are more prevalent and must be ruled out owing to high morbidity and mortality.^3,7 Other confounding diagnoses include pressure dermatitis and reticular telangiectatic erythema.¹⁵ An allergy history is associated with an increased risk of CIED infection, although no causal relationship has yet been demonstrated. HSRs potentially lead to cytokine production and oxidative stress that can affect the local tissue environment and create fluid pockets to increase the risk of superinfection.¹⁶ Therefore, it is important to include CIED-HSR on the differential for late complications of CIED implantation. CIED-HSR diagnosis is confirmed by explantation of the offending device followed by observation of symptom resolution without recurrence. Most tissue biopsy–proven cases reveal granulomatous dermatitis, consistent with a cell-mediated, type IV delayed HSR.³

A variety of materials have been implicated in CIED-HSRs including silicone,¹⁰ titanium,^{8,10,12,17,18} polyurethane,^10,12,14,19 nickel,^7,8,13,15,20, 21, 22 epoxy,²³ and cobalt.^11,22 Nickel is the most common allergen often implicated in contact dermatitis to jewelry, seen in up to 20% of the general population, with female patients more likely to be sensitive than men.^14,24 Antigens such as nickel have been shown to bind with Langerhans cells leading to inflammatory T-helper cell responses via programmed-death-ligand-1-dependent signaling.^25,26 Langerhans cells are distributed across all skin layers including subcutaneous tissues.²⁷ For implanted cardiac devices, distribution models created with in vitro and in vivo data demonstrated that nickel leaching occurs less in subcutaneous/connective tissue compartments compared with epidermis/dermis or blood compartments and showed that the amount of leaching is low compared with existing standards of safe serum levels.^28,29 This is indirectly corroborated at a population level. Although up to 20% of the general population experiences skin reactions to nickel, the incidence of HSR adverse events with implanted devices is very rare.¹⁴ In CIEDs, nickel is mainly found in the lead conductors, as part of nickel-cobalt-chromium-molybdenum alloy (MP35N), and is often covered with thermoplastic material that reduces contact with the blood pool.

Skin patch testing is widely used for the various materials present in CIED components such as pulse generators, leads, headers/connectors. However, such testing has low sensitivity, especially if a patient has been treated with topical corticosteroids.³ Allergy to titanium, which is used for most pulse generators, is difficult to diagnose on skin patch testing. Some investigators argue that the test does not replicate the actual physiologic milieu of the CIED pocket and advocate instead for lymphocyte transformation tests, which are reported to demonstrate increased sensitivity.^18,30

Explantation with device reimplantation is considered the preferred management pathway when a CIED-HSR is diagnosed. Topical steroids for local reactions have been tried with moderate efficacy (57% success), and systemic steroids for systemic reactions have not been as efficacious (33% successful).³ Previous cases have reported on patients who have undergone up to 5 explantation-reimplantation cycles during the workup of CIED-HSR, exposing patients to an increased risk of procedural complications.^19,31 Ideally, CIED-HSR should be identified quickly or prevented by preoperative testing. However, there are currently no guidelines on CIED-HSR diagnosis, management, or preoperative testing from cardiology associations.^32,33 Contact dermatitis guidelines jointly published by the American Academy of Allergy, Asthma, and Immunology; the American College of Allergy, Asthma, and Immunology; and the Joint Council of Allergy, Asthma, and Immunology give a moderate (grade C) recommendation for preoperative metal sensitization skin patch testing in patients reporting a significant history of metal allergy.³⁴ Some concern exists that positive patch tests may needlessly prevent patients from accessing necessary or lifesaving metal implants given that studies with orthopedic, gynecologic, and endovascular implants have not shown positive nickel patch tests to predict future development of allergic reactions to nickel-containing implants^35,36 or adverse outcomes in implants.³⁶ However, in our patient with a history of metal allergy whose ICD serves to protect against a rare possibility albeit potentially deadly event, we felt that it was important to address these issues in shared decision making before implantation and find alternatives that minimize the risk of allergic reaction that could lead to removal of the implant. The supporting evidence provided by skin patch testing justified exploring alternative CIED options to allow for the primary prevention of a CIED-HSR to nickel and cobalt.

We preferred an EV-ICD for our young patient for whom long-term transvenous lead failure is a concern. Furthermore, eliminating the possibility of transvenous lead failure also decreases the risk of systemic HSR from insulation breaches or other lead component breakdowns. By avoiding components located within the bloodstream, EV-CIEDs theoretically decrease the risk of systemic release of any potential allergens. Compared with the Boston S-ICD, the noninsulated components (ring and coil electrodes) of the Medtronic EV-ICD are not made of MP35N, an alloy containing nickel and cobalt (Table 1). The S-ICD parasternal lead features a shock coil adjacent to 2 sensing electrodes made of MP35N, which come in direct contact with the patient’s soft tissues and skin.³⁷ There have been reports implicating metallic allergies in HSRs associated with the S-ICD.47, 48, 49, 50 The EV-ICD electrodes and coils are made from platinum-iridium and tantalum, with the pacing and sensing electrodes further coated with titanium nitride, a biocompatible compound used to prevent corrosion and metal ion release of substrate material.51, 52, 53, 54

Table 1.

Material data obtained from manufacturer specification sheets37, 38, 39, 40, 41, 42, 43, 44, 45, 46

Component	EV-ICD leads		Transvenous ICD leads						Pacing leads
	Medtronic EV-ICD	Boston Scientific S-ICD	Abbott Durata ICD leads 7120Q, 7121Q, 7122Q, 7170, and 7171	Biotronik Pamira ProMRI S and SD ICD leads	Biotronik Plexa ProMRI ICD lead	Boston Scientific RELIANCE ICD dual- and single-coil leads	Medtronic Sprint Quattro ICD dual- and single-coil leads 6935, 6935M, and 6947M	Medtronic OmniaSecure ICD lead	Medtronic SelectSecure MRI SureScan pacing lead	Abbott Tendril MRI pacing leads	Boston Scientific INGEVITY MRI pacing lead	Biotronik Setrox S lead
Lead conductor	MP35N	MP35N	MP35N/MP35N DFT	MP35N, MP35N DFT	MP35N	MP35N LT, PTFE sleeve (pace/sense); MP35N DFT LT, ETFE coating (shocking)	MP35N	MP35N, silver cored MP35N	MP35N	MP35N	MP35N DFT LT	MP35N
Insulation	Polyurethane, ETFE	Polycarbonate polyurethane	Silicone, Optim, ETFE, and PTFE	Polyurethane and silicone with SilGlyde coating	Silicone with SilGlyde coating	Silicone, polyurethane	Silicone, PTFE, ETFE	ETFE, silicone, SI polyimide, 55D polyurethane	Silicone rubber, ETFE, polyurethane	Optim	Silicone, polyurethane	Silicone
Connector pin	MP35N	MP35N	MP35N and stainless steel	MP35N	MP35N for DF4, stainless steel for IS-1 and DF-1	MP35N	MP35N	Not listed	Not listed	Stainless steel	316L stainless steel	Stainless steel, silicone
Pacing/sensing electrodes	Titanium nitride–coated platinum-iridium	MP35N	Titanium nitride–coated platinum-iridium alloy	Platinum-iridium	Platinum-iridium	Iridium oxide–coated platinum-iridium	Titanium nitride–coated platinum alloys	Not listed	Titanium nitride–coated platinum alloys	Titanium nitride–coated platinum-iridium alloy	Iridium oxide–coated platinum-iridium	Platinum-iridium
Defibrillation/coil electrodes	Platinum-iridium, tantalum	MP35N	Platinum-iridium alloy	Platinum-iridium with tantalum core	Platinum-iridium with tantalum core	Platinum, tantalum, titanium, silicone backfill	Platinum-clad tantalum	Not listed	N/A	N/A	N/A	N/A

EV-ICD = extravascular implantable cardioverter-defibrillator; DFT = drawn filled tube; ETFE = ethylene tetrafluoroethylene; ICD = implantable cardioverter-defibrillator; LT = low titanium; MP35N = a nonmagnetic, nickel-cobalt-chromium-molybdenum alloy; MRI = magnetic resonance imaging; N/A = not available; Optim = Abbott Cardiovascular proprietary copolymer blend of polyurethane and silicone; PTFE = polytetrafluoroethylene; S-ICD = subcutaneous implantable cardioverter-defibrillator.

Although ICD generators are often made of titanium, purities for various manufacturers differ and small amounts of nickel contamination have been reported in CIEDs and other implants containing titanium.^15,16,55 In contrast, polytetrafluoroethylene wrapping of ICD generators has been reported to increase the coil-to-can vector’s shock impedance leading to decreased efficacy.⁵⁶ In certain gold-plated ICDs, manufacturers have stated they cannot guarantee the gold layer’s efficacy after an ICD shock.³¹ As a result, we chose to implant the EV-ICD without generator coating. There has been no HSR reported in our patient in the brief follow-up period although long-term success remains to be determined. This case highlights a patient population that may derive more benefit from EV-ICD implantation over other alternatives.