Introduction. Calciphylaxis is a rare, highly morbid pathological syndrome of vascular calcification and tissue necrosis. It is predominantly seen in patients with end-stage renal disease (ESRD) on chronic dialysis. There is no definitive standard of care for calciphylaxis, and the overall prognosis for patients, particularly those with ulcerated lesions, is bleak. One important role of wound care clinicians during the COVID-19 pandemic is to ensure that the continuity of care of an at-risk population is maintained while limiting the patient’s potential exposure to the virus. Innovative therapies paired with alternative treatment sites of service are one such method. Case Report. A 56-year-old female with ESRD on at-home peritoneal dialysis (PD) presented to the outpatient wound clinic with a punch biopsy-proven calciphylaxis lesion. Within days, state-wide “shelter-at-home” orders due to the COVID-19 pandemic went into effect. To prevent disruption in care and to minimize risk to the patient, the lesion was treated with bi-weekly self-application of a continuous topical oxygen therapy (cTOT) device paired with weekly telemedicine visits. The wound completely resolved after 9 weeks of topical oxygen therapy with no complications or device malfunctions. Conclusions. This case, to the authors’ knowledge, is the first to document healing in a calciphylaxis wound with the use of cTOT. Topical oxygen therapy may be a beneficial adjunctive therapy in the treatment of wounds caused by calciphylaxis. Finding creative ways to navigate this current health care crisis is essential to help mitigate risk for vulnerable patients with advanced comorbidities.

Most modern-day health care professionals in the United States practice medicine in ideal conditions, with the assumption that resources and supplies are ample and readily available. The COVID-19 viral pandemic challenges this assumption not just in the United States but around the world. Patients with chronic illnesses (eg, diabetes, hypertension, and obesity) are at an increased risk of morbidity and mortality from COVID-19.^1-4 The implication of this increased risk for patients with hard-to-heal wounds who frequently suffer from such comorbidities is dire.

The important role of wound care clinicians during this pandemic is to ensure that the continuity of care of an at-risk population is maintained while limiting the patient’s potential exposure to SARS-CoV-19—the virus that causes COVID-19. Vigilance in keeping wound care patients free from hospital admissions permits hospital beds to remain open for severely ill patients with COVID-19. In doing so, determining who needs to be seen in person, and who can safely remain at home for treatment, has implications for the patient, the health of medical workers, and the public.

Herein, the authors present a case of a biopsy-proven calciphylaxis lesion in a patient with end-stage renal disease (ESRD) that was successfully treated with a self-application of a continuous topical oxygen therapy (cTOT) device paired with telemedicine visits. This regimen allowed for continued care and uncomplicated healing while mitigating the potential exposure to SARS-CoV-19 that the patient may have experienced had she attended weekly outpatient clinic visits. This case, to the authors’ knowledge, is the first to document healing in a calciphylaxis wound with the use of cTOT. 

A 56-year-old female with ESRD presented to the outpatient wound clinic following an in-patient hospital stay, with a punch biopsy-proven calciphylaxis lesion. The patient was on at-home peritoneal dialysis (PD) for 3 months, subsequent to 9 months of hemodialysis. The calciphylaxis diagnosis rendered the patient ineligible for kidney transplant and removed her from the kidney transplant list. 

Upon presentation to the outpatient clinic, the patient reported a painful, discolored lesion of the left lateral calf of 3 weeks’ duration with no history of trauma or other inciting incident. The lesion measured 3.6 cm x 2.2 cm and was covered by necrotic tissue (Figure 1). The periwound tissue was inflamed and exhibited violaceus mottling without evidence of infection. Past medical history included type 2 diabetes mellitus, amyloidosis, anemia, atrial fibrillation, calcinosis cutis, coronary artery disease, congestive heart failure, hyperlipidemia, hypertension, insomnia, restless leg syndrome, tachycardia, and vitamin D deficiency. Home medications consisted of amlodipine, bisacodyl, ferric citrate, furosemide, losartan, metoprolol, ropinirole, rosuvastatin, sevelamer carbonate, and zolpidem. A comprehensive lab workup demonstrated the following abnormal values: glucose 199 mg/dL, potassium 5.4 mmol/L, blood urea nitrogen (BUN) 74 mg/dL, creatinine 13.43 mg/dL, phosphorus 8.4 mg/dL, parathyroid hormone 341.1 pg/mL, magnesium 2.99 mg/dL. The patient’s calcium score was within normal limits at 9.1 mg/dL.

Shortly after the patient’s initial outpatient visit, the state of Ohio activated a shelter-in-place order due to the COVID-19 pandemic. Taking into account that the patient’s comorbidities placed her at an increased risk of mortality and morbidity if exposed to SARS-CoV-19, a multidisciplinary discussion was held to formulate a treatment regimen that would minimize her need to leave her home and limit her potential exposure to the virus. 

Nephrology directed the patient to continue her nightly PD at home with 1 extra dwell for better phosphorus clearance. However, the patient did visit the infusion center 3 times a week for 4 weeks of intravenous sodium thiosulfate (STS) infusions. Medication adjustments included a switch from warfarin to apixaban, as well as prescriptions for sevelamer and ferric citrate. She also was started on a low phosphorus, low potassium, and 2-g sodium diet. 

With access to the outpatient wound center limited to emergent cases, and considering the patient’s known risk factors, the primary author opted to begin a wound care regimen consisting of home application of cTOT via the NATROX Oxygen Delivery System (ODS; Inotec AMD), covered by exudate-absorbing secondary dressings. Patient progress was tracked through weekly telemedicine visits. 

The ODS generates oxygen through electrolysis of water drawn from the atmosphere. The 98% pure humidified oxygen is delivered directly to the wound at a rate of approximately 15 mL per hour. A long, thin, flexible tube connects directly to the cellphone-sized portable oxygen generator at one end, and to a flexible ODS or diffuser that sits on the wound at the other (Figure 2). The web-like wound interface of the ODS permits wound exudate to pass through to the secondary dressing while allowing the diffusion of oxygen across the wound bed. A set of 2 rechargeable batteries powers the system.⁵

The patient changed the ODS 2 times weekly using a bordered foam as a secondary dressing to maintain a proper, moist wound environment. By employing weekly telemedicine visits, the primary author was able to monitor wound progress and ensure the patient did not encounter any treatment complications while also limiting potential patient exposure to SARS-CoV-19. The wound completely resolved with 9 weeks of therapy without complications or device malfunctions (Figure 3). The patient was reinstated to the kidney transplant list. 

Calciphylaxis, also referred to as calcific uremic arteriolopathy (CUA), is a rare, highly morbid pathological syndrome of vascular calcification and tissue necrosis. Primary lesions appear as painful violaceous skin lesions that develop secondary to extensive small vessel calcification.⁶ Clinically, patients may present with areas of tissue necrosis and nonhealing wounds.⁷ Vascular calcification of the dermis is a consistent finding in cases of calciphylaxis, but calcifications of the muscle, brain, lungs, intestine, and mesentery also have been reported.^8-12 Although the disease process in humans has been documented in the medical literature since 1898,^13,14 the condition is still poorly understood and continues to be a treatment challenge for clinicians.

Definitive diagnosis of calciphylaxis requires a tissue biopsy. Histologic findings typically consist of calcification within the media and intima of both the small and medium arterioles with considerable hyperplasia, fibrosis, and inflammatory infiltrate.^15,16 Subcutaneous calcium deposits, fat necrosis, and vascular microthrombi are also common.^15,16 Pathologic examination may reveal tissue calcification and ischemic epidermolysis, while radiographic studies often reveal calcification of median and small vessels.^7,17 

Calciphylaxis is predominantly seen in patients with ESRD on chronic dialysis. Between 1% to 4% of patients with ESRD may show signs of calciphylaxis.^7,18 The overall prognosis is bleak—complications such as amputation, infection, or death occur in 60% to 80% of patients affected, and the disease has a 1-year mortality rate of 45% to 80%.^18-20 Patients with ulcerated lesions have a greater mortality rate than those with nonulcerated lesions, with sepsis being the leading cause of death.^13,19,20 The majority of calciphylaxis lesions occur on the lower extremity.^13,20 

Additional implicated risk factors for calciphylaxis include hyperphosphatemia, hypercalcemia, diabetes mellitus, secondary hyperparathyroidism, elevated calcium-phosphorus product, female sex, warfarin use, corticosteroid use, protein C or S deficiency, malnutrition, liver disease, hypokalemia, and vitamin D therapy.^18,20-24 Thus, in patients with suspected CUA, it is essential to conduct laboratory evaluations of renal function, mineral bone parameters, liver function, infection, coagulation, inflammation, autoimmune disease, and malignancy.²⁵ 

There is no set standard of care for the treatment of calciphylaxis. A comprehensive treatment plan requires a multidisciplinary approach. In 2010, Sowers and Hayden suggested various therapeutic approaches to treat and prevent CUA²⁴; among these were the attempt to normalize metabolic parameters via medication and dialysis, adjust calcium and phosphorus ratios by replacing all calcium phosphate binders with noncalcium phosphate binders, use the antioxidant STS, improve wound hypoxia, and provide proper wound care.  

With the present patient, nephrology adjusted dialysis and medication, but improving wound hypoxia and providing proper wound care fell to the primary author and her team. Given the restrictions imposed by COVID-19, this challenge was even greater than usual. With the need to “think outside the hospital” in order to provide care in the lowest-risk environment possible to a high-risk patient while minimizing the use of resources, the primary author determined that at-home treatment was the best course of action.

With no consensus on effective wound care management for CUA, and limited data regarding successful therapies, the use of adjunctive wound therapies and dressings often varies widely based on the clinician’s experience. Although the etiology of chronic wounds is multifactorial, hypoxia is a common component in a vast majority of cases. However, oxygen is essential for wound healing;  numerous biochemical and cellular processes requisite for wound healing are highly dependent on a sufficient supply of oxygen.^26-28 Thus, supplementing oxygen to chronic wounds may help promote healing.^26,29 

Hyperbaric oxygen therapy (HBOT) has been proposed as a treatment modality in calciphylaxis with some success.^24,30-33 While HBOT has been used therapeutically since the 1600s, it was not until the 1960s that this modality was used for wound healing.³⁴ Around the same time, topical oxygen therapy (TOT) also was introduced for the treatment of chronic wounds, but it was only in more recent decades that TOT has truly garnered interest in the wound care space.^27,31 Growing evidence shows TOT has a positive effect on chronic wound healing outcomes by facilitating the oxidative killing of bacteria, regulating growth factors, aiding in collagen synthesis and deposition, influencing angiogenesis, and decreasing wound infection rates.^26,29,35,36

Topical oxygen therapy has shown promising results with treating arterial, diabetic, venous stasis, and other chronic ulcerations. In a 2015 article, Dissemond et al reviewed the effectiveness of TOTs for wound healing. They concluded that although no single TOT approach is widely used universally throughout the wound healing community, there is increasing evidence that suggests its effectiveness as an adjunctive therapy to speed wound healing outcomes.²⁶ In 2019, Nataraj et al conducted a systematic review of the use of TOT in healing diabetic foot ulcers, concluding that TOT may be an important adjunct modality in the management of chronic ulcers as it facilitates chronic wound healing, particularly in lower grade ulcers.³⁷

A recent study by Hunter et al demonstrated potential antibiotic properties for TOT as the microbiome of healed wounds shifted to a predominantly aerobic population vs the microbiome of the 1 unhealed wound that retained anaerobic flora.³⁸ Both Hayes and Silvestrini observed autolytic debridement properties of TOT within days of initial placement in which the wounds began to appear healthier, with decreased signs of infection and increased signs of granulation.^5,29 

When formulating the treatment plan for this patient, the primary author recalled an article by Ng and Peng, which stated that combination therapy is more effective than single-agent therapy if the therapies act synergistically.¹⁶ In their report, Ng and Peng¹⁶ referenced work by Rogers and Coates,³⁰ which recommended using HBOT as an adjunctive with STS in the treatment of CUA. Considering the high-risk status of the patient, shelter-in-place order, potential for cross contamination, limitations in medical personnel staffing, restricted clinic hours, and personal protection equipment shortages, the primary author determined that HBOT was not a viable treatment option. At this point, the primary author’s thoughts shifted toward cTOT with TOT paired with telemedicine. 

As discussed previously, the use of innovative remote therapies is essential during a pandemic. For this patient, TOT permitted at-home treatment, was easy to use, was portable, and had minimal risks of complications. This patient was well-suited for self-application of TOT as she was fully independent, accustomed to self-procedures such as PD, and compliant with her medical care.

This is a single case report and the findings cannot be used to draw a definitive conclusion. A prospective, controlled study is needed to investigate the efficacy of TOT for calciphylaxis. It cannot be said definitively that TOT is why this wound healed, but this case lends credence to the idea of using cTOT as an adjunct to CUA treatment.  

This case report suggests that TOT may be a beneficial adjunctive therapy in the treatment of wounds caused by calciphylaxis. It also demonstrates a successful patient outcome utilizing a remote therapeutic wound care modality in conjunction with telemedicine to decrease exposure of at-risk patients during a pandemic.

Note: The authors are grateful to Jane Clark for her technical support.Authors:

Affiliations: ¹Kent State University College of Podiatric Medicine (KSUCPM), Independence, OH; and ²University Hospitals Podiatric Residency, Richmond Heights, OH

Correspondence: Windy Cole, DPM, CWSP, KSUCPM Wound Care Research Department, Cleveland Foot and Ankle Clinic, 7000 Euclid Avenue Suite #101, Cleveland, OH 44103; Wcole4@kent.edu 

Disclosure: This case was supported in part by Inotec AMD through the donation of the NATROX Topical Oxygen Device.