Delayed Hypersensitivity to Endocardial Device: An Under‐Recognised Cause of Systemic Symptoms

Device syndrome is a poorly characterised and debated entity caused by allergic reactions to metallic components of patent foramen ovale (PFO) closure devices [1, 2]. We describe the case of a patient who developed systemic symptoms with oedema following endocardial prosthesis implantation. A 37-year-old woman presented to the allergy clinic with swelling of the eyelids, cheeks and hands evolving over 3 days. She initially reported periorbital and cheek swelling during the very first days of symptom onset; however, these resolved rapidly and were never clinically observed. The only persistent oedema was subtle and located on the hands, primarily manifesting as rapid fluctuations in body weight. She also reported new-onset palpitations, chest pain, migraine with ophthalmic aura, nausea and vomiting. Ten days earlier, she had undergone percutaneous closure of an ostium secundum atrial septal defect using an Occlutech device made of nitinol (nickel−titanium alloy). A prior reaction to costume jewellery had been documented 2 years earlier. The patient was taking no medications known to induce oedema. Cardiac evaluation revealed atrial fibrillation and elevated NT-proBNP levels (700 pg/mL), with preserved cardiac function and correct device positioning on transesophageal echocardiography. Transthoracic echocardiography showed no pulmonary hypertension or left-sided volume overload, with improvement in right heart function, thereby excluding mechanical complications and a cardiac cause of the oedema. An internal medicine evaluation further excluded alternative non-cardiac causes. The patient was initially treated for atrial fibrillation with flecainide and a beta-blocker, followed by amiodarone; all antiarrhythmic therapies were discontinued due to lack of efficacy and secondary hyperthyroidism. Antithrombotic therapy for the prosthetic valve included aspirin and clopidogrel, later switched to apixaban. Ultimately, all treatments were stopped except for aspirin. Patch testing using a standard metal-ion series was performed using Finn Chambers (SmartPractice, Phoenix, AZ). Readings done at Day (D) 2 and D3 revealed positivity to nickel (II) sulphate hexahydrate 5% pet. (++) and titanium oxalate (+++). Direct patch testing of the device itself under occlusion also yielded a strong positive (+++) reaction (Figure 1), according to the International Contact Dermatitis Research Group scoring system. A diagnosis of device syndrome was established. Systemic corticosteroids led to transient symptom resolution, but symptoms recurred after tapering. A therapeutic trial combining dupilumab with tapering oral corticosteroids induced marked improvement, though mild oedema persisted. Dupilumab was discontinued due to articular side effects, followed by relapse 2 months later. Based on a review reporting successful nickel desensitisation cases [3], oral desensitisation to nickel and titanium was proposed. Nickel desensitisation was not initiated because it requires prior regulatory approval from the Belgian Federal Agency for Medicines and Health Products (AFMPS), a process associated with substantial financial constraints. The patient therefore opted to proceed only with titanium desensitisation. Following the first doses of titanium desensitisation, the patient experienced a reproduction of her systemic symptoms—palpitations, migraines with aura, nausea and diffuse oedema. In this context, the desensitisation procedure effectively acted as a controlled provocation test, reinforcing the involvement of titanium. After dose adjustment and gradual exposure, symptoms progressively improved. Titanium desensitisation was finally discontinued early at the patient's request, given the significant improvement of her symptoms during the treatment. No relapse has occurred since, and the patient remains under close follow-up to confirm long-term stability. Device syndrome was first described in 2005 [1]. It encompasses systemic manifestations—primarily migraine with aura, palpitations and atrial fibrillation—occurring as a delayed type IV hypersensitivity reaction to metallic components, most commonly nickel. The oedema and fluctuations in body weight responded promptly to diuretics and consistently improved with systemic corticosteroids. This pattern was not compatible with classic drug-induced oedema and instead strongly supported an immunologically mediated mechanism. The recent randomised trial by Apostolos et al. [2] provided major confirmation of the link between device syndrome and nickel sensitisation. In patients undergoing percutaneous PFO closure, those with nickel hypersensitivity developed significantly more systemic symptoms (71% vs. 21%), corresponding to a tenfold increase in risk. Conducted in a cardiology setting, this study objectively established nickel as a trigger for systemic post-implantation reactions while noting the absence of severe events. Our observation extends these findings by providing an allergologic perspective, documenting a mixed delayed hypersensitivity to both nickel and titanium, thereby broadening the spectrum of metals potentially involved. The manufacturer later confirmed that the implanted device consists of a titanium external coating over an internal nitinol structure. Although nickel is not intended to be in direct contact with tissues, local inflammation may facilitate nickel ion release into surrounding tissues or circulation. Allergy testing for all constituent metals should be systematically performed in patients presenting with unexplained systemic symptoms after prosthesis implantation. Although titanium patch testing is debated due to its irritant potential, several elements in this case support true sensitisation: intense (+++) reaction, extension beyond chamber limits and persistence across readings. These characteristics are atypical for irritant reactions. The patient's clinical evolution further supported this interpretation: reproduction of symptoms during titanium exposure, followed by remission upon cessation of desensitisation. While oral nickel desensitisation has been primarily investigated in systemic nickel allergy syndrome, several studies have shown its ability to induce long-term immune tolerance and improve quality of life. In the study by Rizzi et al. [3], mean quality-of-life scores improved by 20% after 1 year of treatment, confirming the potential of this approach for systemic nickel hypersensitivity. This immunotherapy may represent a promising option when allergen avoidance is impossible, such as in implanted metallic devices. In our patient, desensitisation to nickel and titanium was therefore proposed as an experimental therapeutic strategy to modulate delayed immune responses and reduce persistent symptoms associated with the endocardial prosthesis. Device syndrome should be systematically considered in patients presenting with systemic symptoms after metallic prosthesis implantation. This case highlights the importance of a comprehensive allergologic workup—including patch testing of the device's metallic components—to guide therapeutic management and expand the range of known allergens beyond nickel, notably to titanium. D. Lahrichi: writing – original draft, investigation. G. Pintea Bentea: writing – review and editing. G. Dupire: writing – review and editing, supervision, validation. This research did not receive any specific grant from public, commercial or not-for-profit funding agencies. Written informed consent was obtained from the patient for publication of this case and the accompanying clinical data. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.