Titanium hypersensitivity as a partial cause of arm swelling after pacemaker implantation

Dear Editor,

We thank Dr. Naoya Kataoka and Dr. Teruhiko Imamura for their careful reading of our case report [1] and for their insightful comments in a recent letter [2] regarding diagnostic certainty and causal attribution. We agree that it is essential to clearly explain how alternative etiologies were evaluated, clarify the limitations of our diagnostic testing, and align the proposed mechanism with the observed clinical course and treatment response.

We acknowledge that lead-related venous obstruction and upper-extremity deep vein thrombosis are common alternative explanations for unilateral arm swelling in patients with transvenous pacemaker leads. Venous stenosis or occlusion occurs in a substantial proportion of device recipients, often asymptomatically, and approximately 5% develop symptomatic venous obstruction over time. These complications can present with limb swelling and may occur beyond the immediate post-implantation period [3]. In our case report, we noted that thrombosis or stenosis needed to be excluded, and ultrasonography performed at the time of symptoms showed no thrombus or significant venous narrowing, despite mildly elevated D-dimer levels and low-grade inflammatory markers. We recognize the limitations of our diagnostic evaluation. Although no thrombus was detected on the initial ultrasound, we could not definitively rule out intermittent venous obstruction, such as transient microthrombosis or dynamic venospasm, with more sensitive imaging including venography or contrast-enhanced computed tomography (CT) at that time because the patient's symptoms were mild and improved with antihistamine treatment. If a central venous lesion had remained a concern, escalation to venography or contrast-enhanced CT would have been a reasonable next step. In addition, the patient was taking a calcium channel blocker and a dipeptidyl peptidase-4 inhibitor, both of which may have contributed to or exacerbated the arm edema.

Regarding the potential mechanism of swelling, we acknowledge the correspondents' observation that the rapid improvement with antihistamines is more consistent with a histamine-mediated process than with a bradykinin-mediated one, as bradykinin-mediated angioedema typically does not respond to antihistamines. We also note that previously reported cases of device hypersensitivity often suggest a delayed-type (type IV) hypersensitivity reaction, which is typically mediated by T lymphocytes and macrophages and is generally treated with corticosteroids. Although it is difficult to identify the exact mechanism in our case because no biopsy was performed, the clinical response to antihistamines suggests that histamine may have been involved, at least in part.

Regarding the recurrence of swelling after pacemaker generator replacement, mechanical manipulation of the device pocket during generator exchange may have amplified local inflammation within the fibrous capsule. Macrophage-driven foreign-body responses and fibrotic remodeling are known to occur around chronically implanted biomaterials [4]. Surgical intervention itself may elicit an immunological response.

Taken together, although the precise mechanism remains uncertain, it is likely that multiple factors—including local foreign-body inflammatory responses, potential drug-related edema, and partial histamine-mediated hypersensitivity—contributed in a complex and multifactorial manner. Further accumulation of evidence, including studies incorporating tissue biopsy, will be needed to better elucidate the underlying mechanisms.

We appreciate the opportunity to clarify these important points.

Patient permission/consent statement

Written informed consent was obtained from the patient for publication.

Declaration of competing interest

The authors state that they have no conflict of interest.