Manifestations of COVID-19 in an Orthopedic Practice

COVID-19 has had a profound impact on our society, classified by the World Health Organization as a global pandemic.¹ In addition to impacting the way we practice, the pandemic placed unparalleled pressures on the health care field. Anecdotally, as practitioners, we have seen a wide array of clinical manifestations of this virus, that at times seem unexplainable beyond the pandemic itself. There are several documented dermatological manifestations of COVID-19, as well as a myriad of systemic related illnesses and musculoskeletal symptoms. 

We felt prompted to write this review after seeing several patients with idiopathic thrombotic events that occurred in the period post-COVID-19 vaccination and/or booster. The aim of this article is to review the literature regarding COVID-19, the vaccination/booster shots, and thrombotic adverse events relevant to orthopedic and podiatric practitioners. Lastly, we will present 3 unique case reports from our practice.

Understanding the Mechanism of Action of COVID-19

COVID-19 induces high levels of inflammation, hypoxia, and endothelial tissue damage that predispose patients to elevated rates of thrombus formation.² The viral infections trigger an inflammatory immune response, resulting in activation of the coagulation system. Negative feedback controls upregulation of these coagulation factors, and physiological anticoagulants such as tissue factor pathway inhibitor, anti-thrombin, and protein C.³ Due to upregulation in the coagulation system, utilization of these physiological anticoagulants eventually leads to disruption in the hemostatic mechanism and relationship of the procoagulant and anticoagulant systems. This effectively results in an increase of D-dimer and the development of micro-thrombosis with potential scattered intravascular coagulation.³

Additionally, during early infection, there is an upregulation of interferon (INF-1) which mutes early viral replication. Increased expression of INF-1 with sudden spikes of an inflammatory response, increased viscosity and changes to small vessel vasculature cause changes that can lead to microangiopathy.⁴ Established early in the pandemic, there is a strong link between elevated D-dimer and fibrinogen degradation products with an increase in mortality.² Anticoagulant therapy became a calculated treatment to decrease the risk of thrombosis and improve the clinical management of patients with COVID-19 patients.³

A Closer Look at COVID-19-Related Ailments

Throughout the course of the pandemic, reports emerged of skin manifestations described as erythematous, widespread urticaria, chickenpox-like vesicles, and rashes, which include petechial, purpuric changes, transient livedo reticularis, and acro-ischemic lesions.⁵ These skin lesions can also cause blisters, itching, and/or pain, and be associated with swelling and discoloration. COVID-19 has become responsible for producing chilblain lupus erythematosus like eruptions that have become known as “COVID toes.”⁴ Some discussions contend that pustular morphology and dusky lesions are suggestive of drug etiology, while a petechial or vesicular pattern, involvement of buttocks or acral sites, suggest an infectious etiology.⁵ 

In addition to skin manifestations, there are reports of thromboembolic events of the lower extremity possibly related to COVID-19. In one study of 184 Dutch patients with COVID-19 admitted to the ICU, 31 percent experienced a thromboembolism, despite receiving standard venous thromboembolism prophylaxis with low molecular weight heparin.² The documented cases of COVID toes and lower extremity thromboembolism are relatively well-cited up to this point, however with the emergence of the vaccinations for COVID-19 and later booster shots, we have observed personally and in the literature, several unexplained foot and ankle manifestations. 

What Do We Know About Adverse Reactions to the COVID-19 Vaccine?

Thrombotic thrombocytopenia after vaccination has been seen throughout the history of vaccinations with these adverse events being cited with vaccinations for influenza, H1N1, rabies, and pneumococcal vaccinations.⁶ Thrombosis with thrombocytopenia syndrome (TTS) or vaccine-induced immune thrombotic thrombocytopenia (VITT), associated with venous and arterial thromboembolism are also documented.^6,7 TTS is characterized by exposure 4 to 30 days prior to presentation, followed by thrombosis, mild-to-severe thrombocytopenia, and a positive PF4-heparin ELISA. The most common areas affected include the cerebral and splanchnic veins.⁷ 

VITT clinically resembles spontaneous autoimmune heparin-induced thrombocytopenia (HIT). HIT results from platelet-activating immunoglobulin G (IgG) antibodies against platelet factor 4 (PF4) complexed with heparin.⁶ This complex then binds to the platelet FcRγIIA receptors and causes activation and formation of platelet microparticles. These microparticles initiate blood clot formation and induce a prothrombotic cascade, which consequently decreases platelet count and causes thrombocytopenia.⁶ 

Oxford–AstraZeneca or Vaxzevria Vaccine. Although not authorized for use in the U.S., the FDA has cleared the vaccine for exportation, and therefore we feel it pertinent to discuss. In March 2021, many countries suspended this specific vaccine due to reports of severe coagulation disorders after its administration.² Patients studied developed one or more thrombotic events, mainly cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis, pulmonary embolism, deep vein thrombosis (DVT) and ischemic stroke, some of which resulted in death.^2,3 Most of the patients were women under 60 years of age, a third of whom had predisposing factors for thrombosis.^2,3 

Johnson & Johnson (Janssen) Vaccine. In April 2021, the Centers for Disease Control and Prevention (CDC) and the FDA (US Food and Drug Administration), recommended a halt in the use of the Janssen vaccine.⁸ This was a precautionary measure after several reported cases of severe types of blood clots. These cases occurred mostly in women and those under the age of 60.⁸

COMIRNATY/Pfizer-BioNTech Vaccine. The first case of DVT after vaccination with COMIRNATY was reported in February 2021. Forty other thrombotic cases were later reported for both mRNA vaccines.⁸

Moderna Vaccine. A report of a case of purpuric rash and thrombocytopenia in a 60-year-old male patient after vaccination with the Moderna COVID-19 vaccine also exists.⁸

Results indicate that VITT is a side effect, albeit somewhat rare, of Vaxzevria and the Janssen COVID-19 vaccines, and these thrombotic events can be fatal. Literature is unclear why or how this becomes fatal. Most commonly, patients affected will develop CSVT, splanchnic vein thrombosis, or other arterial or venous blood clots.⁹ In addition to the side effects above, immune thrombocytopenia is a point of investigation as a potential side effect for all approved COVID-19 vaccines worldwide. Red flags include persistent and severe headaches, focal neurological symptoms (including new-onset blurred vision), shortness of breath, abdominal or chest pain, swelling and redness in a limb, or pallor and coldness in a limb, typically occurring within 4 to 26 days post-vaccination.^8,9 In summary, systematic safety of COVID-19 vaccines is essential to ensure that benefits are superior to the risks. In most cases, we feel, and the literature supports that, the benefits of the vaccine supercede the risks.

When Cases of Lower Extremity Pathology Present After COVID-19 Vaccination 

Case 1. A 61-year-old male with a history of bilateral neuropathy secondary to a rare reaction to allopurinol presented with no other significant comorbidities. He is a non-smoker, non-drinker, works in sales, and is a restoration mechanic of classic cars in his spare time. The patient presented to our office, accompanied by his wife, for a left fifth metatarsal fracture following a slip in a grocery store parking lot. We placed him in a surgical shoe for 4 weeks, and the fracture was healing unremarkably. At his 4-week follow-up for X-ray examination, he noted he had a “bluish-purple” appearing right second digit. Full workup revealed a non-viable digit with wet gangrene. There was no history of trauma and no known etiology. The only pertinent change in the patient’s medical history at that time was the booster dose of the Moderna COVID-19 vaccine 2 weeks prior to his visit with us. Based on the clinical presentation and assessment, the patient required amputation of the affected digit, from which he healed uneventfully.

Case 2. A 37-year-old female nurse with no comorbidities underwent fifth toe arthroplasty with a total tourniquet time of 17 minutes and utilization of a contralateral venous compression pump pre-, intra- and postoperatively. The patient was ambulatory throughout the postoperative period in a surgical shoe. She received her second dose of the Pfizer-BioNTech vaccine 2 weeks postoperatively, within a day of removal of 4 sutures from the fifth toe. At 6 weeks postop, she returned to regular shoe gear and developed shortness of breath and began feeling overly anxious. She went to a local ER, resulting in diagnosis with a DVT and a pulmonary embolism (PE) and was admitted for 72 hours for thrombolytic therapy and observation. One physician at the facility agreed it was likely related to the vaccination, as they had seen and were aware of similar cases. However, another physician discredited that completely and attributed it to the surgery or family history.

Case 3. An 85-year-old male well-known to our practice for bilateral end-stage ankle DJD has a past medical history significant for hypertension and DJD of the hip, knee, and ankles B/L. He is a social drinker, non-smoker, and avid competitive softball player. He originally presented for preoperative total ankle arthroplasty planning and CT follow-up. However, on exam, he demonstrated significant edema to the left thigh and leg. The patient related awareness of the swelling for 2 weeks prior to his office visit. He had no known history of long trips, no period of immobilization, and had actually played in a softball game the night before. The patient did note a Pfizer-BioNTech booster 3 weeks prior to this new onset pain and swelling. A STAT venous duplex ultrasound in the local ER, revealed an acute deep vein thrombosis (DVT) of the popliteal vein. Patient has been on Apixaban since the diagnosis. 

In a similar report by Mahgoub and colleagues, a 79-year-old man suddenly developed right lower extremity DVT a few days after receiving his first dose of the mRNA-1273 COVID-19 vaccine. He went on to receive the second dose, and later experienced an extensive acute deep venous thrombosis and a concurrent acute pulmonary embolism.⁹ There are multiple well-known risk factors that can lead to venous thromboembolism, which include recent trauma, surgeries, periods of immobilization or prolonged immobility, family history of thrombosis, hormonal contraception or substitution therapy, Hashimoto thyroiditis, hypertension, and recent pregnancy.^8,9 None of our patients in this case study presented with any of these risk factors. There is a paucity of discussion of such events in the literature, and thus we felt compelled to address our findings in this blog. 

In Conclusion

Fever, muscle pain, fatigue, and headache very common adverse effects of receiving the COVID-19 vaccines.³ We note increasingly more reports of skin manifestations, thrombotic, and embolic events with these vaccines and the virus as well. It is always plausible that these patients’ foot issues begin before or exist at the time they receive the COVID-19 vaccine or test positive for the virus by coincidence. In general, when considering a patient with similar foot issues to those described above it may be advisable to consider other viral diseases, idiopathic chilblains, chilblains lupus erythematosus, vasculitis, pernio, Aicardi–Goutières syndrome, a connective tissue disorder, underlying osseous abnormalities, or even the effects of recent exposure to cold temperature or the possibility of ill-fitting footwear creating pressure points or sores.¹⁰ If nothing else, we hope this article serves orthopedic and podiatric practitioners with a differential diagnosis for some unknown pathologies that may arise post COVID-19 vaccinations. We feel it important, and have made it a part of our practice, to dedicate time in the past medical history portion of our examination to discuss COVID-19 related symptoms, vaccine, and booster history to aid in some of these differential diagnoses. 

Dr. Miller is a Fellow of the American College of Foot and Ankle Surgeons. He is the Director of the Pennsylvania Intensive Lower Extremity Fellowship in Malvern, PA, and the Podiatric Residency Program at Phoenixville Hospital in Phoenixville, PA.

Dr. Capuzzi is a current Fellow of the Pennsylvania Intensive Lower Extremity Fellowship in Malvern, PA.

Dr. Tonucci is a second-year podiatric surgical resident at Tower Health/Phoenixville Hospital in PA.

References

1. WHO Announces Covid-19 Outbreak a Pandemic. World Health Organization, World Health Organization. Available at: https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic. Published March 12, 2020. Accessed March 23, 2022.
2. Miller JD, Atves JN, Steinberg JS. COVID-19 coagulopathy and limb salvage: what you should know. Podiatry Today. Available at: https://www.hmpgloballearningnetwork.com/site/podiatry/covid-19-coagulopathy-and-limb-salvage-what-you-should-know. Published February 2021. Accessed April 21, 2022.
3. Abdel-Bakky MS, Amin E, Ewees MG, et al. Coagulation System Activation for Targeting of COVID-19: Insights into Anticoagulants, Vaccine-Loaded Nanoparticles, and Hypercoagulability in COVID-19 Vaccines. Viruses. 2022;14(2):228.
4. Shishak M, Shishak S, Rajput S. Differentials of red toes in dermatology–Are COVID toes real?. Ind J Med Sci. 2020;72(2):112.
5. Jimenez-Cauhe J, Ortega-Quijano D, de Perosanz-Lobo D, et al.  Enanthem in patients with COVID-19 and skin rash. JAMA Dermatology. 2020;156(10):1134-1136.
6. Sharifian-Dorche M, et al. Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review. J Neurol Sci. 2021;428:117607.
7. Long B, Bridwell R, Gottlieb M. Thrombosis with thrombocytopenia syndrome associated with COVID-19 vaccines. Am J Emerg Med. 2021;49, 58-61.
8. Brazete C, Aguiar A, Furtado I, Duarte R. Thrombotic events and COVID-19 vaccines. Int J Tuberculosis Lung Dis. 2021;25(9):701-707.
9. Mahgoub A, Awuah D, Hussain MS, Deliwala S, Bachuwa G, Younas M. Development of venous thromboembolism after COVID-19 mRNA-1273 vaccine inoculation. Cureus. 2022;14(2). Available at: https://www.cureus.com/articles/84228-development-of-venous-thromboembolism-after-covid-19-mrna-1273-vaccine-inoculation .
10. Nirenberg MS, del Mar Ruiz Herrera, M. Foot manifestations in a COVID-19 positive patient: a case study. J Am Podiatr Med Assoc. 2020. doi: 10.7547/20-088. Online ahead of print.