Chronic limb ischemia manifestation in COVID-19 infection: awareness and treatment in primary care

Main Article Content

Sidhi Laksono
Reynaldo Halomoan Siregar
Hillary Kusharsamita


Chronic limb ischemia (CLI) is a type of peripheral arterial disease (PAD) that is still underdiagnosed and undertreated despite the increasing incidence, thus becoming a global health burden. And CLI reflects the local manifestations of a lethal systemic disease — atherosclerosis. If left untreated, chronic limb ischemia can result in major limb loss. In this pandemic era, limb ischemia has become one of several clinical manifestations that occur in patients with COVID-19 infection. Systemic inflammation in COVID-19 infection, direct viral infection, hypercoagulable state, and hyperinflammatory response are responsible for damage to the arterial system, causing endothelial dysfunction. Diagnosing PAD has become a challenge especially in the early stage and in the asymptomatic phase. The untreated condition could lead to the development of CLI. The primary physicians in the primary health facilities hold an important role in the early diagnosis and management of patients with CLI symptoms or with risk factors of CLI, especially in patients who have experienced COVID-19 infection. Due to the limitation of diagnostic testing modalities at primary health facilities, the physician can assess the ankle-brachial index (ABI) to determine the presence of CLI. Management of the disease is different for every patient and is customized based on the other comorbidities. Risk factors should be controlled in order to achieve a better outcome. A good management strategy will improve the quality of life of the patient. This review will discuss the occurrence of CLI in COVID-19 infection.

Article Details

How to Cite
Laksono, S. ., Siregar, R. H., & Kusharsamita, H. (2021). Chronic limb ischemia manifestation in COVID-19 infection: awareness and treatment in primary care. Universa Medicina, 40(2). Retrieved from
Review Article
Author Biographies

Sidhi Laksono, Faculty of Medicine, Universitas Muhammadiyah Prof. DR. Hamka, Tangerang

Dept Kardiologi dan Kedokteran Vaskuler FK UHAMKA

Reynaldo Halomoan Siregar, Faculty of Medicine of Universitas Katolik Indonesia Atma Jaya

Faculty of Medicine of Universitas Katolik Indonesia Atma Jaya

Hillary Kusharsamita, Faculty of Medicine, Universitas Diponegoro, Semarang

Faculty of Medicine, Universitas Diponegoro, Semarang


Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382:1329-40. doi: 10.1016/S0140-6736(13)61249-0.

Olinic DM, Spinu M, Olinic M, et al. Epidemiology of peripheral artery disease in Europe: VAS educational paper. Int Angiol 2018;37:327-34. doi: 10.23736/S0392-9590.18.03996-2.

Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation 2012;125:1449-72. doi: 10.1161/CIR.0b013e31824c39ba.

Tummala S, Scherbel D. Clinical assessment of peripheral arterial disease in the office: what do the guidelines say? Semin Intervent Radiol 2018;35:365-77. doi: 10.1055/s-0038-1676453.

Cimminiello C, Kownator S, Wautrecht JC, et al. The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk. Intern Emerg Med 2011;6:509-19. doi: 10.1007/s11739-011-0511-0.

Street TK. What the primary care provider needs to know for limb salvage. Methodist DeBakey Cardiovasc J 2012;8:57-9. doi:10.14797/mdcj-8-4-57

Simon F, Oberhuber A, Floros N, Düppers P, Schelzig H, Duran M. Pathophysiology of chronic limb ischemia. Gefasschirurgie 2018;23 (Suppl 1):13-8. doi: 10.1007/s00772-018-0380-1.

Kinlay S. Management of critical limb ischemia. Circ Cardiovasc Interv 2016;9:e001946. DOI: 10.1161/CIRCINTERVENTIONS.115.001946.

Thukkani AK, Kinlay S. Endovascular intervention for peripheral artery disease. Circ Res 2015;116:1599-613. doi: 10.1161/CIRCRESAHA.116.303503.

Davies MG. Criticial limb ischemia: epidemiology. Methodist DeBakey Cardiovasc J 2012;8:10-4. doi: 10.14797/mdcj-8-4-10.

Putko RM, Bedrin MD, Clark DM, et al. SARS-CoV-2 and limb ischemia: a systematic review. J Clin Orthop Trauma 2021;12:194-9. doi:10.1016/j.jcot.2020.11.018.

Soares RA, Vedovello RS, Medeiros SCG, et al. COVID-19 diagnosis in a patient with critical limb ischemia: complications and clinical outcomes. J Vasc Bras 2020;19:e20200071.

Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 2017;135:e726-79. doi: 10.1161/CIR.0000000000000 471.

ESC Scientific Document Group. 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2018;55:305-68. doi: 10.1016/j.ejvs.2017.07.018.

Nehler MR, Duval S, Diao L, et al. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg 2014;60:686-95.e2. doi: 10.1016/j.jvs.2014.03. 290.

Piazza G, Morrow DA. Diagnosis, management, and pathophysiology of arterial and venous thrombosis in COVID-19. JAMA 2020;324:2548-9. doi: 10.1001/jama.2020.23422.

Zhang Y, Cao W, Jiang W, et al. Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients. J Thromb Thrombolysis 2020;50:580-6. doi: 10.1007/s11239-020-02182-9.

Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. doi: 10.1016/S0140-6736(20)30628-0.

Hasan SA, Haque A, Nazir F. Acute limb ischemia: a rare complication of COVID-19. Cureus 2020;12:e11488. doi:10.7759/cureus.11488.

Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8. doi: 10.1016/S0140-6736(20)30937-5.

Jin Y, Ji W, Yang H, et al. Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Sig Transduct Target Ther 2020;5:293

Sturtzel C. Endothelial cells. Adv Exp Med Biol 2017;1003:71-91. doi: 10.1007/978-3-319-57613-8_4.

Godo S, Shimokawa H. Endothelial functions. Arterioscler Thromb Vasc Biol 2017;37:e108-e114. doi: 10.1161/ATVBAHA.117.309813.

Signorelli SS, Vanella L, Abraham NG, et al. Pathophysiology of chronic peripheral ischemia: new perspectives. Ther Adv Chronic Dis 2020;11: 2040622319894466. doi: 10.1177/204062231989 4466.

Rajendran P, Rengarajan T, Thangavel J, et al. The vascular endothelium and human diseases. Int J Biol Sci 2013;9:1057-69. doi: 10.7150/ijbs.7502.

Green SJ. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect.2020;22:149-50. doi: 10.1016/j.micinf.2020. 05.006.

Zhao Y, Vanhoutte PM, Leung SW. Vascular nitric oxide: Beyond eNOS. J Pharmacol Sci 2015;129:83-94. doi: 10.1016/j.jphs.2015.09.002.

Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA 2012;308:1660-7. doi: 10.1001/jama.2012.13415.

Lee YH, Shin MH, Kweon SS, et al. Cumulative smoking exposure, duration of smoking cessation, and peripheral arterial disease in middle-aged and older Korean men. BMC Public Health 2011;11:94. doi:10.1186/1471-2458-11-94

Lu L, Mackay DF, Pell JP. Association between level of exposure to secondhand smoke and peripheral arterial disease: cross-sectional study of 5,686 never smokers. Atherosclerosis 2013;229:273-6. doi: 10.1016/j.atherosclerosis.2013.05.015.

Lu L, Mackay DF, Pell JP. Second hand smoke exposure and intermittent claudication: a Scotland-wide study of 4231 non-smokers. Heart 2013;99:1342-5. doi: 10.1136/heartjnl-2013-304226.

Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;116:1509-26. doi: 10.1161/CIRCRESAHA.116.303849.

Quilici MT, Del Fiol Fde S, Vieira AE, et al. Risk factors for foot amputation in patients hospitalized for diabetic foot infection. J Diabetes Res 2016;2016:8931508. doi:10.1155/2016/8931508

Itoga NK, Tawfik DS, Lee CK, Maruyama S, Leeper NJ, Chang TI. Association of blood pressure measurements with peripheral artery disease events. Circulation 2018;138:1805-14. doi:10.1161/CIRCULATIONAHA.118.033348.

Emdin CA, Anderson SG, Callender T, et al. Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ 2015;351:h4865. doi: 10.1136/bmj.h4865.

Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014;383:1899-911. doi: 10.1016/S0140-6736(14)60685-1.

Aday AW, Everett BM. Dyslipidemia profiles in patients with peripheral artery disease. Curr Cardiol Rep 2019;21:42. doi:10.1007/s11886-019-1129-5.

Abola M, Golledge J, Miyata T, et al. Asia-Pacific consensus statement on the management of peripheral artery disease pocket guide for doctor: a report from the Asian Pacific Society of atherosclerosis and vascular disease Asia-Pacific peripheral artery disease consensus statement project committee. J Atheroscler Thromb 2020;27: 809-907.

Walker CM, Bunch FT, Cavros NG, Dippel EJ. Multidisciplinary approach to the diagnosis and management of patients with peripheral arterial disease. Clin Interv Aging 2015;10:1147-53. doi: 10.2147/CIA.S79355.

Deºer SB, Yucel SM, Demirag MK, et al. Relationship of inter-arm systolic blood pressure difference with subclavian artery stenosis and vertebral artery stenosis in patients undergoing carotid endarterectomy. Braz J Cardiovasc Surg 2019;34:136-41. doi: 10.21470/1678-9741-2018-0257.

Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis. Lancet 2012;379:905-14. doi: 10.1016/S0140-6736(11)61710-8.

Aboyans V, Criqui MH, Abraham P, et al. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation 2012; 126:2890-909. doi: 10.1161/CIR.0b013e318276fbcb.

Arain FA, Ye Z, Bailey KR, et al. Survival in patients with poorly compressible leg arteries. J Am Coll Cardiol 2012;59:400-7. doi: 10.1016/j.jacc.2011.09.055.

Shu J, Santulli G. Update on peripheral artery disease: epidemiology and evidence-based facts. Atherosclerosis 2018;275:379-81. doi: 10.1016/j.atherosclerosis.2018.05.033.

Aronow WS. Peripheral arterial disease of the lower extremities. Arch Med Sci 2012;8:375-88. doi: 10.5114/aoms.2012.28568.

Abouhamda A, Alturkstani M, Jan Y. Lower sensitivity of ankle-brachial index measurements among people suffering with diabetes-associated vascular disorders: A systematic review. SAGE Open Med 2019;7:2050312119835038. doi: 10.1177/2050312119835038.

Uccioli L, Meloni M, Izzo V, et al. Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag 2018;14:63-74. doi: 10.2147/VHRM.S125065.

Schmit K, Dolor RJ, Jones WS, et al. Comparative effectiveness review of antiplatelet agents in peripheral artery disease. J Am Heart Assoc 2014; 3:e001330. doi: 10.1161/JAHA.113.001330.

Katsanos K, Spiliopoulos S, Saha P, et al. Comparative efficacy and safety of different antiplatelet agents for prevention of major cardiovascular events and leg amputations in patients with peripheral arterial disease: a systematic review and network meta-analysis. PLoS One 2015;10:e0135692. doi: 10.1371/journal. pone.0135692.

Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J 2014;35:2864-72. doi: 10.1093/eurheartj/ehu080.

Ramos R, García-Gil M, Comas-Cufí M, et al. Statins for prevention of cardiovascular events in a low-risk population with low ankle brachial index. J Am Coll Cardiol 2016;67:630-40. doi: 10.1016/j.jacc.2015.11.052.

Giurato L, Vainieri E, Meloni M, et al. Limb salvage in patients with diabetes is not a temporary solution but a life-changing procedure. Diabetes Care 2015;38:e156-7. doi: 10.2337/dc15-0989.

Atturu G, Homer-Vanniasinkam S, Russell DA. Pharmacology in peripheral arterial disease: what the interventional radiologist needs to know. Semin Intervent Radiol 2014;31:330-7. doi: 10.1055/s-0034-1393969.

Zhao-Fleming H, Hand A, Zhang K, et al. Effect of non-steroidal anti-inflammatory drugs on post-surgical complications against the backdrop of the opioid crisis. Burns Trauma 2018;6:25. doi: 10.1186/s41038-018-0128-x.

Anderson K, Hamm RL. Factors that impair wound healing. J Am Coll Clin Wound Spec 2014; 4:84-91. doi:10.1016/j.jccw.2014.03.001.

Conen D, Everett BM, Kurth T, et al. Smoking, smoking cessation, and risk for symptomatic peripheral artery disease in women: a cohort study Ann Intern Med 2011;154:719-26. doi:10.7326/0003-4819-154-11-201106070-00003.

Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J Vasc Surg 2014;60:1565-71. doi: 10.1016/j.jvs.2014.08.064.

Fakhry F, Rouwet EV, den Hoed PT, et al. Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial. Br J Surg 2013;100:1164-71. doi: 10.1002/bjs.9207.

Murphy TP, Cutlip DE, Regensteiner JG, et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol 2015;65:999-1009. doi: 10.1016/j.jacc.2014.12.043.

Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg 2015;62:1642-51.e3. doi: 10.1016/j.jvs.2015.07.065.

Kobayashi N, Hirano K, Nakano M, et al. Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy. J Vasc Surg 2015;61:951-9. doi: 10.1016/j.jvs.2014.11.065.

Chung J, Modrall JG, Ahn C, et al. Multidisciplinary care improves amputation-free survival in patients with chronic critical limb ischemia. J Vasc Surg 2015;61:162-9. doi: 10.1016/j.jvs.2014.05.101.

Sandoval DL. Critical limb threatening ischemia: The time has come for a multidisciplinary approach. J Vasc Endovasc Therapy 2019;4:9.

Schiattarella GG, Perrino C, Magliulo F, et al. Physical activity in the prevention of peripheral artery disease in the elderly. Front Physiol 2014;5:12. doi:10.3389/fphys.2014.00012.

Aggarwal S, Loomba RS, Arora R. Preventive aspects in peripheral artery disease. Ther Adv Cardiovasc Dis 2012;6:53-70. doi: 10.1177/1753944712437359.