A Case of Rapidly Progressive Unilateral Non-Nephrogenic Hemorrhagic Bullous Calciphylaxis Responding to Systemic Sodium Thiosulfate Therapy

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Calciphylaxis is a rare and life-threatening condition that presents as progressive cutaneous necrosis secondary to small- and medium-sized vessel calcification and subsequent thrombosis.¹ It commonly presents as bilateral, well-demarcated, painful, retiform purpura that evolves into necrotic gray-black eschars. More rarely, it can present as hemorrhagic or serous bullous lesions leading to ulceration.¹ Calciphylaxis is most often seen in patients with end-stage renal disease and secondary hyperparathyroidism. Other risk factors include obesity, diabetes, and warfarin use.¹

Less commonly, calciphylaxis is seen in patients without renal issues, in which case it is referred to as non-nephrogenic calciphylaxis. The most commonly affected areas include the thighs, buttocks, and abdomen.^2,3 Mortality from calciphylaxis is high, ranging from 33% if the patient presents with plaques only to above 80% at 6 months if ulceration develops.^4-6 Thus, increased recognition of this challenging-to-diagnose condition and its variable clinical presentation is essential to early treatment initiation. This case report describes an atypical presentation of non-nephrogenic unilateral bullous calciphylaxis in a 71-year-old female to highlight this rare presentation, emphasizing the importance of considering calciphylaxis in the differential diagnosis for bullous disorders, and demonstrating ways to effectively make this rare diagnosis.

A 71-year-old female with a pertinent medical history of hypertension, obesity, and poorly controlled type 2 diabetes presented for evaluation of multiple painful hemorrhagic bullae on her left leg. She first noticed a small red blister on her left Achilles tendon area with surrounding erythema and swelling approximately 1 week prior to hospital presentation for abdominal pain and an ulcer on her left hallux, which was treated with vancomycin, ampicillin-sulbactam, doxycycline, and ciprofloxacin. Because there was no improvement with antibiotics, the patient re-presented to the emergency department.

On physical examination, the patient had 4 coalescing erythematous hemorrhagic bullae 2 cm to 7 cm in size on a background of retiform purpura on the left lateral posterior leg, lateral ankle, and dorsal foot (Figure 1). The patient was not on warfarin. Her laboratory workup showed normal parathyroid hormone level 49 pg/mL, total vitamin D level 36 pg/mL, and creatinine level 0.91 mg/dL, and elevated blood urea nitrogen level 37 mg/dL. The differential diagnosis included pressure-induced bullae, bullous calciphylaxis, bullous diabeticorum, bullous pemphigoid, contact dermatitis, edema blisters, bullous cellulitis, and coma blisters. Radiographs of the patient's left leg were negative for osteomyelitis. A punch biopsy of a bulla on the left posterior leg revealed partial epidermal necrosis and detachment, neutrophilic inflammation, edema, and subcutaneous vascular microcalcifications highlighted by von Kossa staining, consistent with calciphylaxis (Figure 2). Period acid-Schiff and Gram stains were negative for fungal and bacterial forms, respectively. Based on the patient's clinical history, risk factors, physical examination showing bullae and retiform purpura, and biopsy findings, the diagnosis of bullous calciphylaxis was made.

The patient was started on thrice-weekly IV STS infusion and wound care. Over the next 3 weeks, the area of necrosis progressed to involve areas of prior purpura, reflecting progression of the calciphylaxis. The wound was cleaned with soap and water, after which it was patted dry and topical collagenase was applied on the dry eschar area (when present). The wound was then covered with a nonadherent dressing (Mepilex; Mölnlycke) and wrapped with an elastic bandage. The dressing was changed daily until the wound healed.

After 6 months of IV STS infusions and the wound care regimen detailed above, the patient exhibited significant improvement, with resolution of purpura and healing of her wounds (Figure 3). Given her underlying poorly controlled diabetes and persistent open wound, the patient developed gangrenous infection of the left foot requiring transmetatarsal amputation. Due to the risk of koebnerization (ie, the appearance of new skin lesions on previously unaffected skin secondary to trauma) into surgical sites from the amputation, IV STS infusion was continued while the surgical site was healing.

Diagnosis of non-nephrogenic calciphylaxis can be challenging, and making the diagnosis of hemorrhagic bullous calciphylaxis can be even more difficult. Typical cases of calciphylaxis are often misdiagnosed, most commonly as cellulitis,⁷ and it can be challenging to differentiate calciphylaxis from other mimickers, especially for non-dermatologists. In the case of hemorrhagic bullous calciphylaxis, an additional challenge is that the differential diagnosis is particularly broad, which includes neutrophilic dermatoses such as bullous pyoderma gangrenosum or Sweet syndrome, cholesterol emboli, bullous pemphigoid,³ pemphigus vulgaris, edema bullae, bullous diabeticorum, and linear immunoglobulin A bullous dermatosis. When considering the use of skin biopsy to help make the diagnosis, it is necessary to consider that the sensitivity of skin biopsy in the diagnosis of calciphylaxis is variable,⁸ and that there have been reports of calciphylaxis possibly exhibiting the Koebner phenomenon.^9,10 However, in the case in the current report, given the atypical presentation and broad differential diagnosis, skin biopsy findings were vital in narrowing down the disease possibilities and making the diagnosis of calciphylaxis.

In addition to severe pain and a propensity for secondary infections, calciphylaxis is a highly debilitating disease with an overall mortality rate at 12 months of 45%, with a twofold increase in mortality when/if ulcers develop.^4-6 Therefore, prompt diagnosis and early treatment intervention are essential. This case is described to illustrate that the clinical presentation of calciphylaxis can be variable. The authors of the current report recommend considering bullous calciphylaxis in a patient presenting with painful bullae on a background of retiform purpura.

As a single case report, this article has inherent limitations. Moreover, there is a scarcity of comparable cases, making it challenging to conduct a thorough investigation into the underlying causes and contributing factors of non-nephrogenic calciphylaxis.

The case reported highlights the importance of considering calciphylaxis in a patient presenting with painful bullae on a background of retiform purpura. It is also important to note that while skin biopsy does have risk in patients with calciphylaxis, in cases such as this one it can be used to exclude other pathologies of non-nephrogenic calciphylaxis with bullous presentation. Furthermore, systemic STS infusion can be used to manage unilateral calciphylaxis and may be better tolerated than intralesional STS infusion due to patient preference regarding pain. Ultimately, this case showcases the diagnostic challenges of calciphylaxis and stresses the significance of prompt identification and intervention of this rare disease to mitigate morbidity and mortality.

Author: Rachel Wetstone, MD, MPH^1-3; Rebecca Yim, MD, BA^1,4,5; Colleen Gabel, MD¹; Kaitlyn Yim, MD⁶; Patrick O’Donnell, MD⁶; and Fnu Nutan, MD¹

Affiliations: ¹UMass Chan Medical School, Department of Dermatology, Worcester, MA; ²University of Connecticut School of Medicine, Department of Medicine, Farmington, CT; ³Florida International University, Herbert Wertheim College of Medicine, Miami, FL; ⁴Tulane University School of Medicine, New Orleans, LA; ⁵Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA; ⁶UMass Chan Medical School, Department of Pathology, Worcester, MA

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Rachel Wetstone, MD, MPH; University of Connecticut Department of Internal Medicine, 100 Hospital Drive Farmington, CT, 06030; rwetstone@uchc.edu

Manuscript Accepted: July 31, 2024