Recurrent rash over a cardiac implantable electronic device: A rare case of antibacterial envelope hypersensitivity

Key Teaching Points.

• •Differentiating infection from hypersensitivity reaction: Hypersensitivity reactions to the TYRX envelope can mimic cardiac implantable electronic device infections, making differentiation crucial to avoid unnecessary device removal and associated morbidity. A combination of clinical presentation, inflammatory markers, and patch testing can help distinguish between infection and allergic response, particularly in patients with an atopic history or drug sensitivities. The expected absorption timeline of the TYRX envelope (approximately 9 weeks) aligns with the resolution of symptoms in hypersensitivity cases, further supporting a time-limited immune response rather than an ongoing infection.
• •Treatment of hypersensitivity reaction: If hypersensitivity is suspected, symptomatic treatment with systemic steroids (in case of systemic rash and/or elevated liver enzymes), antihistamines, and topical corticosteroids may allow for symptom resolution without needing device removal.
• •Importance of personalized approach: Clinical decisions regarding the use of antibacterial envelopes should be tailored to each patient, considering their individual risk factors, potential benefits, and possible adverse reactions. Identifying patients with a history of drug allergies, eosinophilia, or atopic conditions may help predict those at an increased risk of hypersensitivity reactions.

Introduction

Cardiac implantable electronic device (CIED) infections can result in serious complications, including endocarditis, sepsis, and increased mortality, often necessitating complete removal of the CIED system.^1,2 The TYRX absorbable antibacterial envelope (Medtronic, Minneapolis, MN), impregnated with rifampin and minocycline, provides local antimicrobial activity for approximately 7–10 days after implantation. It is used to mitigate infection risks and stabilize the device, particularly in high-risk patients,3, 4, 5 such as those undergoing device replacement (eg, implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy defibrillator generator changes) or upgrades; individuals with diabetes or end-stage renal disease; immunocompromised patients; those with a history of CIED infections; and cases involving prolonged procedure times or complex implants.⁶ Clinical trials, including the WRAP-IT trial,⁷ have demonstrated that the TYRX envelope can reduce the incidence of major infections by up to 50% compared with standard practice.

However, inflammatory reactions to the TYRX envelope have been documented and can mimic device infections. Previously, we reported 3 cases of purulent, culture-negative discharge from device pockets after TYRX envelope use,⁸ suggesting a possible allergic or inflammatory response rather than infection. Distinguishing between hypersensitivity reactions and infections is critical to avoid unnecessary device removal. Although existing literature highlights that an inflammatory response to various components of the antibacterial envelope may manifest with wound dehiscence, herein, we present the first reported case of an allergic reaction to the TYRX envelope, characterized by recurrent localized rash over the CIED site and systemic allergic manifestations without wound dehiscence.

Case report

We report the case of a 63-year-old man with no previously known drug allergies and a medical history significant for nonobstructive hypertrophic cardiomyopathy complicated by paroxysmal atrial fibrillation for which he was started on amiodarone 200 mg daily. Cardiac magnetic resonance imaging demonstrated late gadolinium enhancement exceeding 30% of left ventricular mass and the presence of a left ventricular apical aneurysm. Given these high-risk features of sudden death, implantation of an ICD was recommended, as indicated by clinical practice guidelines. Given that he did not have any pacing indications, the decision was made to proceed with implantation of an extravascular (EV)-ICD system (Aurora EV-ICD, Medtronic).⁹ To minimize the risk of infection, the patient received 2 g of intravenous cefazolin immediately before the procedure. The implantation procedure was uncomplicated, but required 4 different substernal tunneling attempts to find an adequate lead position without P-wave oversensing. Final device interrogation revealed no P-wave sensing on the ventricular channel with a more lateral lead position, with R-wave amplitudes steadily exceeding 2 mV. Given the prolonged procedure time, a TYRX antimicrobial envelope was placed around the EV-ICD within the pocket to reduce the risk of infection. Routine chest radiograph (Supplemental Figure 1A and 1B) and device interrogation showed no abnormalities, and the patient was discharged in excellent condition with acetaminophen prescribed for pain management.

Two weeks later, the patient developed a generalized rash (Figure 1A), primarily affecting the upper extremities and limbs. The rash was initially suspected to be triggered by a viral infection or a drug reaction, with amiodarone as a possible culprit, given its potential to cause both immediate and delayed allergic reactions owing to its long half-life of several months. Three days later, laboratory tests revealed significantly elevated liver function tests (LFTs), including alanine aminotransferase at 424 U/L (normal <40), aspartate aminotransferase at 97 U/L (normal <37), and alkaline phosphatase at 199 U/L (normal <144), along with a mildly increased creatinine level of 1.14 mg/dL. Amiodarone was stopped, the rash resolved, and LFTs normalized within a few days after oral methylprednisolone and topical triamcinolone treatment. However, the patient continued to experience mild diffuse pruritus. Upon further questioning, the patient had a history of quiescent asthma, and he had experienced a generalized urticarial reaction a decade ago after unintended prolonged exposure to a neighbor’s cat, which resolved with corticosteroid and antihistamine treatment.

Figure 1.

A: Right arm with pruritic rash caused by an allergic reaction. B–C: Recurrent localized rash above the EV-ICD pocket resembling “bug bites.” The incision shows a well-healed scar. EV-ICD = extravascular implantable cardioverter-defibrillator.

Five weeks later, the patient successfully underwent pulmonary vein isolation. Periprocedural ICD interrogation showed normal lead parameters. The site of implantation in the left lateral chest and the subxiphoid site showed well-healed scars and were without ecchymosis, redness, drainage, or hematoma. The skin was mobile over the device. The patient denied pain or discomfort at the implantation site.

Six weeks after the EV-ICD implantation, the patient developed a pruritic rash resembling “bug bites” directly over the device pocket (Figure 1B). No fever or pain was reported, and the incision site appeared intact without signs of hematoma, purulent drainage, or device erosion. No additional rash was observed elsewhere on the body, although the patient continued to experience diffuse itching. The rash resolved with topical corticosteroids and clotrimazole. However, over the next 2 weeks, the patient experienced recurrent episodes of localized pruritic rash over the EV-ICD pocket (Figure 1C) along with persistent diffuse itching. Although the rash responded to antihistamines and topical corticosteroids, concerns arose regarding a potential device-related infection. The patient reported no fevers or chills. At no time was there wound dehiscence, drainage, or confluent erythema over the entire pocket. At this point, the differential diagnosis included CIED infection vs allergic reaction to a component of the ICD system itself or one of the components of the TYRX envelope. Blood tests were ordered to further investigate the patient’s condition. C-reactive protein, erythrocyte sedimentation rate, and white blood cell count were within normal ranges. However, a comprehensive metabolic panel showed a new rise in LFTs and creatinine, which subsequently decreased after corticosteroid treatment (Figure 2). In addition to the LFT abnormalities, elevated immunoglobulin E (IgE) levels (199 kU/L) and an increased eosinophil percentage (7.3%) were noted, raising concerns about a possible hypersensitivity reaction.

Figure 2.

Progression of ALT levels (U/L) over several months, showing declines after treatment with systemic corticosteroids and loratadine. Topical steroids were also used intermittently as needed. ALT = alanine aminotransferase.

Patch testing was performed using the NAC-80 North American Comprehensive Series (2024 edition), with all allergens testing negative (Figure 3A and 3B), except for propolis (a bee-/hive-derived allergen). However, this finding was deemed clinically irrelevant because the patient had no known exposure to propolis. Given the suspicion of a hypersensitivity reaction related to the EV-ICD or TYRX envelope, additional patch testing was conducted for titanium (the primary material of the EV-ICD) and rifampin and minocycline (antimicrobial agents in the TYRX envelope). Although no skin reaction was noted to titanium, the patient exhibited a positive reaction to rifampin (identification 1:1000 duplicates, 0.06 mg/mL) (Figure 3C), suggesting a potential allergic response to this component. A positron emission tomography scan was considered to evaluate for CIED infection, but ultimately deferred given the atypical features of infection and the likely diagnosis of a type I immunologic drug reaction mediated by IgE to rifampin. To manage symptoms, loratadine was prescribed, leading to effective symptom control.

Figure 3.

A–B: Patch testing (NAC-80 North American comprehensive series, 2024 edition) with negative results. C: Exposure to intradermal injection of rifampicin (“R”) (positive) and minocycline (“M”) (negative).

Twelve to 16 weeks after implantation, the rash had completely resolved, and the patient remained asymptomatic. A follow-up device interrogation confirmed stable lead impedances, with an R-wave amplitude of 8.2 mV, and no recorded episodes of ventricular arrhythmias (Supplemental Figure 1C).

Discussion

This case underscores the importance of considering hypersensitivity reactions in patients presenting with recurrent localized skin manifestations after CIED implantation with the TYRX envelope. Although the TYRX envelope significantly reduces infection risk,^5,7,10 its components, particularly rifampin and minocycline, may induce hypersensitivity responses in susceptible individuals. The patient’s clinical course, including the absence of wound dehiscence, normal inflammatory markers, fluctuating LFTs, eosinophilia, elevated IgE levels, and a positive patch test for rifampin, strongly suggests an IgE-mediated type I hypersensitivity reaction rather than a device infection.¹¹

The distinction between infection and hypersensitivity is critical, given that unnecessary explantation of the device can lead to significant morbidity. This case highlights the following key diagnostic considerations:

• (1)Preceding systemic manifestations: although a pocket infection may present with localized rash over the device site, it would not be expected to be preceded by a generalized rash and systemic signs such as transient elevation of liver enzymes and creatinine, nor would it be expected to cause pruritus or respond to systemic and topical corticosteroids.
• (2)Lack of systemic inflammatory response: the normal white blood cell count, C-reactive protein, and erythrocyte sedimentation rate levels argued against an infectious etiology.
• (3)Positive patch testing: the identification of rifampin sensitivity in patch testing provided further support for an allergic reaction.

Although the presentation several weeks after implantation could theoretically be consistent with a bacterial infection owing to coagulase-negative staphylococci,^12,13 the presence of a generalized rash before localized symptoms, transient systemic findings, and response to corticosteroids make a hypersensitivity reaction the more likely diagnosis. In addition, the TYRX envelope is designed to be fully absorbed within approximately 9–10 weeks,⁷ which closely mirrors the time course of the patient’s symptoms. The gradual resolution of symptoms 12 weeks after implantation further supports a time-limited immune response to the envelope rather than an ongoing infectious process. Given these findings, a positron emission tomography scan was ultimately deemed unnecessary. The patient’s symptoms resolved with antihistamine therapy, and no device-related complications were observed at 6-month follow-up. This case raises awareness about potential adverse immune responses to the TYRX envelope and underscores the need for heightened clinical suspicion when evaluating postimplantation complications. It also adds to the growing body of literature suggesting that device-related hypersensitivity reactions can masquerade as infections^8,14, 15, 16 and highlights the importance of individualized patient assessment to prevent unnecessary interventions.^2,17 Identifying patients with a history of drug allergies, eosinophilia, or atopic conditions may help predict those at an increased risk of hypersensitivity reactions. In patients with known antibiotic allergies, alternative antimicrobial strategies should be explored, including systemic prophylaxis with agents less likely to induce hypersensitivity. If hypersensitivity is suspected, symptomatic treatment with antihistamines and topical corticosteroids may allow symptom resolution without needing device removal.

Conclusion

This case highlights the potential for hypersensitivity reactions to the TYRX envelope and particularly its antibiotic components, emphasizing the importance of distinguishing between infection and allergic responses in patients with CIED. Awareness of the expected absorption timeline of the envelope, along with targeted diagnostic tools such as patch testing and inflammatory markers, can aid in accurate diagnosis and prevent unnecessary device removal. Clinicians should consider hypersensitivity reactions in patients presenting with delayed localized symptoms after CIED implantation and manage them with conservative treatment when appropriate.

Disclosures

The authors have no conflicts of interest to disclose.