Addressing Lower Extremity Manifestations In Patients With Suspected COVID-19

By Kazu Suzuki, DPM, CWS, Albert Elhiani, DPM, Aasin Tareen, DPM, TIffany Chin, DPM, and Ulyana Kulish, DPM

The coronavirus pandemic, COVID-19 caused by the SARS-CoV-2 virus, has 5.9 million confirmed cases and 360,000 deaths worldwide at the time of this writing.¹ Common symptoms for an increased index of suspicion of COVID-19 include cough, fever, chills and shortness of breath. Aside from these symptoms, there are a few reported cases of peripheral extremity ischemia and chilblain-like lesions to the toes that have been deemed “COVID toes” in general. 

With this in mind, we would like to present three cases of foot and ankle complications that we have seen in patients with confirmed COVID-19 infection. Interestingly, two of the three patients had two negative COVID-19 tests prior to being discharged from the hospital and then presented within a week of discharge with distinct pedal complaints. 

While in our recent experience, the incidence of these pedal skin lesions appears to be increasing in prevalence, little is known about the underlying pathophysiology and cause. There is speculation that certain patients have a genetic predisposition to hypercoagulability when they are exposed to SARS-COV2, thereby triggering microvascular complications such as thrombosis and other embolic events.²

Another theory is that the virus may upregulate certain metabolic pathways to trigger vasculitis to medium and small blood vessels. Furthermore, the increased use of vasoactive medications for the treatment of the sequelae associated with COVID-19 may be linked to drug-related hypercoagulable or ischemic states.²

In a retrospective analysis of laboratory and clinical data of seven critically ill COVID-19 patients in Wuhan, China who had manifestations to the toes, Zhang and colleagues noted that patients exhibited digital cyanosis, blood blisters and dry gangrene.² Of note, all seven of these patients had an increased D-dimer laboratory value upon admission to the intensive care unit (ICU). Of the seven patient, six patients had elevated fibrinogen and fibrin degradation products while four had an increased prothrombin time. Upon receiving low molecular weight heparin, the four patients with an increased prothrombin time went on to meet the criteria of disseminated intravascular coagulation (DIC). This study elucidated that physicians need to take peripheral manifestations of COVID-19 seriously as these patients may have high mortality rates when they have advanced stages of the disease.²

Additionally, there is some evidence that the COVID-19 viral infection induces an antiphospholipid antibody syndrome (APS).² Antiphospholipid antibody syndrome manifests as an endothelial injury with platelet activation and antibodies mediated via a cascade of thrombotic events. Researchers have described lower extremity manifestations in the setting of anti-phospholipid antibody syndrome with regard to the H1N1 virus in a 2013 study.³ Furthermore, the study authors elucidated that these lower extremity manifestations were a response to autoantibodies generated via anti-phospholipid antibody syndrome and the virus triggering this catastrophic immune response. This proposed theory implies that the virus triggers a destructive autoimmune response.

Unwanted lower extremity manifestations can also be drug-related. In our institution, which is a level 1 trauma center, it is not uncommon for patients to be placed on vasopressors for extended periods of time and subsequently develop unwanted peripheral manifestations such as dry gangrene of the toes and fingers. Given the high volume of organ transplants at our facility, there are often patients who remain on vasopressors for extended periods of time and later require podiatric surgical intervention for pedal complications. 

Various drugs induce hypoxemic states that make it difficult for peripheral extremity tissue to thrive. Hypoxia and reperfusion to the extremities cause damage to tissues that may often be irreversible. With the increased use of mechanical ventilators in combination with vasopressors to maintain a hemodynamic state, one might expect to see more peripheral gangrene and peripheral ischemic manifestations in the population of critically ill patients with COVID-19.

When A 90-Year-Old Patient Has A Forefoot Rash And Digital Cyanosis After Two Negative Tests For COVID-19 

Case 1. The first patient is a 90-year-old female who presented to our clinic with mild pain and bruising of the toes of one week duration. Her past medical history included hypertension, gout and osteoarthritis. She was also admitted to a different hospital in March for pneumonia with confirmed COVID-19 but was never intubated. Her physicians discharged her after two negative tests for COVID-19, deeming her recovered from the infection.

Upon the physical exam, she appeared to have an erythematous rash to the forefoot and cyanosis of the fourth toe (see first photo to right). Due to the mild nature of her symptoms, we prescribed Tylenol 1000 mg three times a day for pain control as needed. After following the patient for six weeks, the cyanosis and pain completely resolved without any intervention, and appeared to be self-limiting (see second photo to right). We did refer the patient back to her vascular surgeon to screen for a possible abdominal aneurysm, which may cause these types of skin lesions. 

Case Study: When An Ex-Smoker with Diabetes And PAD Has Painful Skin Lesions Weeks After Prior ‘COVID19 Pneumonia’ Hospital Admission

Case 2. The second patient is a 67-year-old male and ex-smoker who had diabetes mellitus and peripheral arterial disease (PAD). He had a below-knee amputation on his right leg a decade ago and had a left hallux amputation a year ago due to PAD. In mid-March, the patient was admitted to a different hospital for COVID-19 pneumonia for two weeks. He was not intubated but “had a rough two weeks (and was not) able to breathe well.” 

Discharged from the hospital after two negative tests for COVID-19, the patient presented to our clinic in late April with very painful skin lesions that appeared as small disseminated papules to his toes and forefoot (see third photo to right). After performing local wound care with sharp debridement of necrotic skin tissue, we utilized a non-adherent wound dressing and mild compressive bandages. After two weeks of local wound care, the patient’s skin lesions and pain improved clinically (see fourth photo to right). On May 26, 4 weeks after the initial presentation, the patient achieved almost complete resolution of the skin lesions but they were still quite tender to touch despite the patient’s diabetic neuropathy. We gave the patient a higher dose of gabapentin for pain control. As of the date of publication, the patient continues to improve (see fifth photo to right.) 

In this case, we believe the thromboinflammation due to the virus caused a microembolic event, leading to painful violaceous and erythematous open lesions to the foot.

Case Study: When A Patient Experiences Severe Midfoot And Ankle Pain Days After Admission For Acute Respiratory Distress

Case 3. The third patient, an otherwise healthy 38-year-old male with no past medical history, was admitted to our institution on an emergent basis due to acute respiratory distress, while testing positive to COVID-19. The patient was immediately intubated in the emergency room and sent to the ICU. The patient was subsequently on vasopressors for three days. During his ICU stay, staff frequently repositioned him in a prone position for better oxygenation throughout the day. 

After seven days, the treating physicians extubated the patient and he was then transferred to the regular hospital floor for recovery. 

A podiatry consultation took place on the patient’s 11th hospital day after he complained of severe midfoot and ankle pain. Upon examination, ecchymosis was evident to the right great toe as well as the fifth toe with tenderness to palpation to the midfoot and lateral ankle region (see sixth photo to right). As there were no notable fractures on his radiographs, we suspected ligamentous sprain injury from repositioning the patient in the prone position. We prescribed leg elevation and a short-leg CAM walker boot, which improved his symptoms after four days. 

During severe cases of coronavirus infection, per our hospital protocol, patients may be placed in a prone position, which reduces the ventral-dorsal transpulmonary pressure difference. While this is a simple maneuver, it immediately benefits oxygenation as it allows for increased lung expansion. Patients undergoing repositioning while they are paralyzed and intubated may be susceptible to injuries of the lower extremity. In our institution, intubated patients who are positive for COVID-19 are kept in the prone position daily for up to 16 hours in a 24-hour period. With non-intubated patients, prescribed prone positioning is often for three hours twice a day or as much as the patient can tolerate.  

Reassessing Deep Vein Thrombosis Prophylaxis Protocols For Patients With Confirmed And Suspected COVID-19  

One critical aspect of the COVID-19 infection is that individuals are at a higher risk of blood clots, especially in severe cases.⁴ A significant amount of research is currently underway to evaluate the relationship between the severe inflammatory response and subsequent states of hypercoagulability. Current studies are investigating an enzyme called CD39, which researchers have shown to circulate “danger” signals and inflammatory cytokines in blood during thrombosis.⁵ This could mean that patients exhibiting this marker may be at higher risk of increased hypercoagulability. 

Due to the potentially fatal complications associated with a hypercoagulable state, early recognition and anticoagulation are imperative to improve clinical outcomes in the appropriate high-risk patients.

In a retrospective study of 449 patients with severe COVID-19 from Wuhan, China, Tang and colleagues noted that 99 patients mainly received low-weight molecular heparin (LMWH) for seven days or longer.⁶ The researchers noted no significant difference in 28-day mortality between heparin users (30.3 percent) and non-users (29.7 percent). However, the study authors did document a lower 28-day mortality rate for patients using low-weight molecular heparin with a sepsis-induced coagulopathy score of greater than or equal to 4.0 (40.0 percent versus 64.2 percent) or a D-dimer level greater than sixfold of the upper limit of normal in comparison to non-users of heparin.⁶   

It is recommended that all hospital inpatients positive for or suspected of having COVID-19 should receive VTE prophylaxis.⁷ The treating physician would base the choice of dose/pharmacological agent on thrombosis/bleeding risk and at the prescriber’s discretion. According to protocol at our institution, patients admitted on warfarin or a direct oral anticoagulant such as apixaban (Eliquis®, Bristol-Meyers Squibb), rivaroxaban (Xarelto®, Janssen), dabigatran (Pradaxa®, Boehringer Ingelheim), betrixaban (Bevyxxa®, Portola Pharmaceuticals) or edoxaban for a therapeutic indication should transition to therapeutic enoxaparin (Lovenox®, Sanofi-Aventis) if possible. 

One should consider unfractionated heparin (5000 units subcutaneously twice or three times daily) or mechanical prophylaxis if patients exhibit bleeding diathesis, active bleeding, or thrombocytopenia. Exclusion criteria for Heparin includes individuals who are currently on concomitant anticoagulation therapy, those who are on a trauma venous thromboembolism prophylaxis protocol, patients with intracranial pressure monitoring devices as well as a history of heparin-induced thrombocytopenia, pregnancy with delivery anticipated in 24 hours and hemodialysis.⁷      

Currently at Cedars Sinai Medical Center, all patients who are positive for COVID-19 receive 40 mg of enoxaparin daily on and throughout hospital admission for seven to 14 days. In addition, patients receive heparin (two units/mL), 1000 units in 0.9% NaCl 500 mL (six units/hour) to prevent arterial and central lines from clotting. Previously, treating physicians in the ICU at our facility addressed venous thromboembolism on a case by case basis, utilizing multiple risk stratification measures. COVID-19 appears to be particularly prothrombotic. Therefore, one should consider anticoagulation in nearly all cases of COVID-19 for prophylaxis as it may combat the morbid prothrombotic state. 

Dr. Suzuki is a staff physician of the Apex Wound Care Clinic in Los Angeles CA. He is a staff physician of the Department of Surgery at Cedars-Sinai Medical Center in Los Angeles. He can be reached at Kazu.Suzuki@cshs.org 

Dr. Elhiani is the Chief Podiatric Surgical Resident at Cedars Sinai Medical Center in Los Angeles.

Dr. Tareen is a second-year podiatric surgery resident at Cedars-Sinai Medical Center in Los Angeles.

Dr. Chin is a first-year podiatric surgery resident at Cedars-Sinai Medical Center in Los Angeles.

Dr. Kulish is a first-year podiatric surgery resident at Cedars-Sinai Medical Center in Los Angeles.

References 

1. World COVID-19 Stats. Available at: nCoV2019.live . Accessed May 29, 2020.

2. Zhang Y, Cao W, Xiao M, et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020;41(0):E006. doi: 10.3760/cma.j.issn.0253-2727.2020.0006. [Epub ahead of print]  

3. Durkin ML, Marchese D, Robinson MD, Ramgopal M. Catastrophic antiphospholipid syndrome (CAPS) induced by influenza A virus subtype H1N1. BMJ Case Rep. 2013;2013:bcr2013200474. Available at: https://dx.doi.org/10.1136/bcr-2013-200474 . Accessed May 27, 2020.

4. Columbia University. Thrombosis emerges as a significant risk for COVID-19 patients. Available at: https://www.cuimc.columbia.edu/news/thrombosis-emerges-significant-risk-covid-19-patients . Published April 30, 2020. Accessed May 29, 2020. 

5. Yadav V, Chi L, Kanthi Y, et al. ENTPD-1 disrupts inflammasome IL-1B-driven venous thrombosis. J Clin Invest. 2019;129(7):2872-2877.

6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. 

7. American Society of Hematology. COVID-19 and Coagulopathy: Frequently Asked Questions. Available at: https://www.hematology.org/covid-19/covid-19-and-coagulopathy. Updated May 18, 2020. Accessed May 27, 2020.