An adolescent female with acute limb ischemia tested positive for COVID-19 at the emergency room. Her history of present illness started 1 year and 8 months prior to admission when she presented with generalized erythematous skin patches that progressed to generalized hyper-and-hypopigmentation (salt-and-pepper pattern). She had intermittent arthralgia, weight loss, and cyanosis of the distal digits when exposed to cold temperatures. The cyanotic digits were tender but eventually became erythematous and painless. She also had persistent skin dryness, which prompted a consult with a dermatologist. Systemic sclerosis was initially suspected, and a skin biopsy revealed sclerosing dermatosis (Fig. 1). She was seen in a Rheumatology outpatient clinic for evaluation of systemic Scleroderma but was eventually lost to follow-up. In the interval, she was noted with Raynaud phenomenon, which, 1-week prior to admission, progressed to ischemia of the distal digits of the right hand and cyanosis of the fingers and toes of the other extremities. She consulted back to the rheumatology clinic, where she was started on Sildenafil 1 mg/kg/dose two times a day and Amlodipine 0.4 mg/kg/dose once a day. The medications were taken with good compliance; however, there was still progression of ischemia of the distal extremities. This prompted a consult at the emergency department. The review of systems revealed a 1-week history of non-productive cough with no associated dyspnea. She has no known co-morbidities, previous surgeries, or prior hospital admissions. There was no similar condition in their family. There was also no known case of COVID-19 in the household.
She was brought to a tertiary government university hospital and designated COVID-19 referral center in Manila, Philippines. At the emergency department, she was seen awake, not in distress, but non-ambulatory due to tender bilateral toes. Vital signs were as follows: BP 102/64 mmHg, heart rate 111 bpm, respiratory rate 20 cpm, peripheral Oxygen saturation 98%, and temperature 36.5 °C. Her cardiovascular, chest, abdominal, and genitourinary examinations were unremarkable, but notable in the systemic examination was the generalized hyper-and-hypopigmentation of the skin appearing in salt-and-pepper pattern (Fig. 2). She had multiple dental caries but had no feeding or oromotor deficits. She had violaceous discoloration and sensory deficits of the distal phalanges of bilateral hands and feet (Fig. 3). The patient did a subjective report of sensory function during the neurologic physical exam. She reported a 50% sensory deficit at the 3rd, 4th, and 5th distal phalanges of the left hand; 2nd distal phalanx of the right hand; 1st distal phalanx of the left foot; and all distal phalanges of the right foot. There was absent sensation over the 3rd and 4th distal phalanges of the right hand.
Routine COVID-19 point-of-care testing was done using SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR), and she tested positive. She was subsequently admitted for limb-salvaging interventions. Radiographic imaging of the bilateral hands and feet was negative for joint space or osseous abnormality. Doppler studies were done for the ischemic limbs and showed triphasic bilateral radial, ulnar, and brachial pulses. No surgical intervention was contemplated for the patient at the time of admission, and maximization of medical management was prioritized. Iloprost was the initial drug of choice for ischemic ulcers but was not started due to its unavailability in the institution. She was then started on Nifedipine 0.4 mg/kg/dose every 6 hours, Sildenafil 2 mg/kg/dose three times a day, and Nitroglycerin patch over the affected digits. Prednisone and Naproxen sodium were started for anti-inflammation and analgesia, respectively but were eventually discontinued.
The concurrence of COVID-19 with juvenile systemic Scleroderma was postulated to have triggered the limb ischemia. Additional tests done for this patient revealed normal PT-INR, elevated D-dimer levels, normal protein C, low protein S, and normal Fibrinogen levels. To date, there is no international protocol in the initiation of venous thromboembolism prophylaxis for patients with systemic Scleroderma with concomitant COVID-19. This patient, however, was started on Enoxaparin 0.5 mg/kg/dose subcutaneously every 12 hours and was carefully monitored for signs of bleeding and heparin-induced thrombocytopenia. While at the COVID ward, she had worsening sensory deficits on the 4th and 5th digits of the left hand but had no progression of the ischemia. She also had no new-onset pain or pallor in the uninvolved digits. While awaiting for the peripheral angiography, she underwent arterial doppler studies with digit-brachial index measurement. The examination revealed monophasic to biphasic signals at the distal bilateral radial and ulnar arteries and monophasic signals of the left anterior tibial artery and bilateral peroneal arteries; which suggest peripheral arterial disease of the bilateral upper and lower extremities.
After finishing 14 days of isolation at the COVID ward, she was subsequently transferred to the non-COVID ward for the continuation of management. She was started on Methotrexate 0.3 mg/kg/dose twice a day weekly and Folic acid 0.2 mg/kg/dose for the diffuse cutaneous disease. Because she had persistent and progressive skin involvement, she was started on Cyclophosphamide 500 mg per body surface area (BSA) and Uromitexan 40% of the cyclophosphamide dose. No hematuria was noted during the course of therapy. She was seen by the orthopedics service and was advised to undergo left small distal interphalangeal joint disarticulation; however, the parents did not consent to it. Medical management was then continued, and no untoward reactions were noted while she was on Methotrexate. Peripheral angiography was subsequently done, revealing complete occlusion of the proximal right dorsalis pedis artery, diminutive left ulnar and interosseous arteries, and diminutive left 4th and 5th digital arteries. Vasodilators were continued, and she was noted to have improvement of the distal extremities after 4 weeks. No progression of ischemia was noted in the interval, and she was discharged with regular follow-up for Cyclophosphamide infusion on outpatient basis.
Our patient was managed in a tertiary COVID-19 referral institution. She was classified as having mild COVID-19 because of a history of non-productive cough but with unremarkable chest radiograph. Immunologic work up for systemic Scleroderma was done, revealing positive Anti-nuclear antibody and elevated Anti-phospholipid antibodies. Detection of Systemic sclerosis-selective autoantibodies was not done due to its unavailability in the institution. The following adjunctive tests were also done: Protein C (80%, normal value: 70-130%), Protein S (37%, normal value: 72-106%), and Erythrocyte sedimentation rate (4 mm/hr., normal value: 0-15 mm/hr). D-dimer was elevated at 0.79 μg/mL (prolonged for age, normal value: 0.16-0.39 μg/mL). Low Protein S activity and elevated D-dimer were attributed to the pro-thrombotic state of the patient.
Investigations for vascular pathology using Arterial Doppler with segmental pressures and waveform studies revealed peripheral arterial disease. Four-extremity angiogram showed luminal narrowing of distal arteries only on the bilateral upper extremities.
To date, there is no established guideline for the initiation of anti-thromboembolic prophylaxis for patients with Scleroderma and concomitant COVID-19 infection. However, because of the predominantly hypercoagulable state of COVID-19 patients on top of the vascular pathology in Scleroderma, it was deemed prudent to start the patient on Enoxaparin. For the Scleroderma-related Raynaud phenomenon, the goals were to increase comfort and prevent secondary ischemic sequelae, which can be achieved using arteriolar vasodilators [7, 8]. The patient was maintained on Nifedipine 10 mg/tab every 8 hours, Sildenafil 25 mg/tab every 12 hours, and Nitroglycerin patch. Central to the management of Raynaud phenomenon is avoidance of the precipitating circumstances such as cold and stress, and this was emphasized to the patient [7, 8]. Severe digital ulcers are often addressed with Prostacyclin, but due to its unavailability, the patient was started on Bosentan instead [9, 10]. The standard therapy to address the diffuse skin involvement in systemic Scleroderma is Methotrexate, with which the patient had good compliance [7, 8]. Due to progressive skin thickening and persistence of cutaneous lesions, she was started on Cyclophosphamide with subsequent infusions done on outpatient basis.
On follow-up, the patient still experienced Raynaud phenomenon, but there was no progression of the digital ulcers. She has had a total of 5 cycles of Cyclophosphamide infusion, and her previously cyanotic but non-ischemic digits have significantly improved. The adolescent medicine, child psychiatry, rehabilitation medicine, and gastroenterology services were actively managing this patient to help her cope with the burden of chronic autoimmune disease. Adherence to treatment was ensured by providing regular online, and face-to-face clinic consults, providing free medicines and diagnostics through the medical social services, and involving the family in the patient’s care.
