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Cutaneous Manifestations in COVID-19 “Long Haulers”: Is This A Part of the Multisystem Inflammatory Syndrome?

Cameron Y. S. Lee
American Journal of Infectious Diseases and Microbiology. 2021, 9(2), 48-50. DOI: 10.12691/ajidm-9-2-3
Received April 21, 2021; Revised May 27, 2021; Accepted June 06, 2021

Abstract

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a multisystem inflammatory syndrome that affects many different organs of the body. Extrapulmonary cutaneous manifestations are now being reported in greater frequency as occurring before or after onset of clinical symptoms. To the authors knowledge, there are few, if any published study that has documented the persistent cutaneous manifestations in patients who have recovered from COVID-19. In this report, we describe some of the cutaneous manifestations in patients known as COVID-19 “long haulers”.

1. Introduction

“Long Haulers” has been coined to describe patients that continue to experience persistent symptoms weeks to months after they have recovered from Covid-19. 1 The prevalence of persistent symptoms remains unclear. 2 It is estimated that even after 12 weeks, patients continue to experience symptoms related to the coronavirus. 3, 4 The most reported post-COVID-19 symptoms include dyspnea and fatigue. Extrapulmonary symptoms reported include myalgia, arthralgia, chest pain, cognitive deficits, neurological symptoms, fever, diarrhea, and skin rashes. 5, 6, 7, 8, 9 Reports of decreased oxygen saturations as low as 88% have also been reported. 10

2. Cutaneous Manifestations

Whether cutaneous manifestations are part of the clinical spectrum of COVID-19 remains unclear as they are observed in other viral infections. But, as the number of COVID-19 cases increase reporting cutaneous symptoms, our understanding will continue in terms of how the coronavirus affects the skin. Six morphologic cutaneous findings have been described: urticarial rash, confluent erythematous/maculo-papular/morbilliform rash, papulovesicular eruptions, purpuric vasculitic rash; livedo reticularis and chilblain-like acral rash. 11, 12

The incidence of cutaneous manifestations in patients infected with the coronavirus is estimated between 0.2 to 20%. 13, 14 Although most skin lesions occurred simultaneously or after other COVID-19 symptoms, reports of skin lesions occurring before other COVID-19 symptoms have been reported. 9, 15, 16

Persistent dermatological manifestations have been reported with increasing frequency in patients that have recovered from COVID-19. Persistent cutaneous manifestations in long haulers can be defined as lasting more than 60 days. 5 Morbilliform, urticarial and macular-erythema type lesions were frequently observed with laboratory confirmed polymerase chain reaction (PCR) testing. Further, polymorphic skin lesions have been reported. 9, 17, 18

As COVID-19 is a multisystem disorder that can affect many different organ systems, we hypothesize that the cutaneous manifestations are part of the newly identified multisystem inflammatory syndrome. Although the pathogenesis for development of rashes in patients infected with the coronavirus is yet to be elucidated, one hypothesis is a direct effect of the virus on the skin due to high concentrations of lymphocytes, lymphohistiocytic infiltrates and papillary dermal edema. 19, 20 A second theory is activation of the complement system resulting in a diffuse microvascular vasculitis. 21 Vascular injury leads to increased circulating angiotensin 2 levels that result in vasoconstriction, thrombosis and endothelial dysfunction. 22

In one of our patients, edematous pruritic plaques occur at various times on the palmar surface of the hands and fingers (Figure 5). To the authors knowledge, there is only one case report documenting cutaneous manifestations on the surface of the hand. 23 However, in a study by Estebanez et al 24 they reported confluent erythematous plaques on the heels of their patient. Such clinical findings of extremity involvement may be due to increased bradykinin production that results in increased vasodilation and vascular permeability. Increased bradykinin levels may result in the observed edematous urticarial plaques due to its host exuberant inflammatory response. 25, 26, 27

Polymorphic cutaneous lesions (Figure 4A and 4B) in the same host are being reported in greater frequency and may be due to infection from multiple variants because of viral mutation. 11, 28 However, such polymorphous manifestations could also represent the entire effect of the coronavirus on the immune system. One of our patients experienced three different skin variants-urticarial, maculopapular and pseudovesicular over a period of 120 days (Figure 1, Figure 2, and Figure 3). Angioedema of the lips have also been reported (Figure 6). Angiotensin-converting enzyme 2 (ACE2) is the primary functional host receptor for SARS-CoV-2 and plays a key role in the pathogenesis of Covid-19 infections. It is expressed in many different organs, including the mucosa of the oral and nasal cavities. 29 ACE2 cleaves bradykinin and down-regulation leads to increased bradykinin production and angioedema.

3. Conclusion

Such post-viral cutaneous manifestations are present with other COVID-19 symptoms and may be correlated with immune or inflammatory mechanisms in the pathogenesis of coronavirus infection. The presence of cutaneous manifestations after COVID-19 recovery needs to more fully understood and may suggest that viral infection may not be completely resolved and is part of the multisystem inflammatory syndrome.

References

[1]  Rubin R. As their number grow, Covid-19. “Long Haulers” stump experts. JAMA. 2020; 324(14): 1381-1383.
In article      View Article  PubMed
 
[2]  Alwan NA. Surveillance is underestimating the burden of the Covid-19 pandemic. Lancet. 2020; 396 (10252):e24.
In article      View Article
 
[3]  Tenforde M, Kim S, Lindsell C, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020, ePub. 24 July 2020.
In article      
 
[4]  Ladds E, Rushforth A, Wieringa S, et al. Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality principles for services. BMC Health Services Research. 2020; 20: 1144.
In article      View Article  PubMed
 
[5]  Carfi A, Bernabei R, Landi F. Persistent symptoms in patients after acute Covid-19. JAMA. 2020; 324(6): 603-605.
In article      View Article  PubMed
 
[6]  Greenhalgh, T, Knight M, Burton M, et al. Management of post-acute covid-19 in primary care. BMJ. 2020; 370m3026.
In article      View Article  PubMed
 
[7]  Arnold DT, Hamilton FW, Milne A, et al. Patient outcomes after hospitalization with COVID-19 and implications for follow-up; results from a prospective UK cohort. medRxiv. 2020.
In article      View Article
 
[8]  Goertz YMJ, Van Herck M, Delbressine JM, et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post COVID-19 syndrome? ERJ Open Res. 2020; Oct 26; 6(4): 00542-2020.
In article      View Article  PubMed
 
[9]  Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries. J Am Acad Dermatol. 83: 1118-1129. 2020.
In article      View Article  PubMed
 
[10]  Dhont S, Derom E, Van Braeckel E, et al. The pathophysiology of ‘happy’ hypoxemia in Covid-19. Respir Res. 21, 198 (2020).
In article      View Article  PubMed
 
[11]  Galvan Casas C, Catala A, Carretero Hernandez G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020.
In article      
 
[12]  Marzano AV, Cassano N, Genovese G, et al. Cutaneous manifestations in patients with COVID-19: a preliminary review of an emerging issue. Br J Dermatol. 2020; 183: 431-442.
In article      View Article  PubMed
 
[13]  Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020.
In article      View Article
 
[14]  De Giorgi V, Recalcati S, Jia Z, et al. Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): a prospective study from China and Italy. J Am Acad Dermatol. 83: 674-675. 2020.
In article      View Article  PubMed
 
[15]  Lee CYS. Cutaneous rash: A clinical manifestation prior to respiratory symptoms of Covid-19 infection. J Fam Med Dis Prev. 7: 137. 2021.
In article      View Article
 
[16]  Daneshgaran G, Dubin DP, Gould DJ. Cutaneous manifestations of COVID-19: An evidenced based review. Am J Clin Dermatol. 2020.
In article      View Article
 
[17]  Fernandez-Nieto D, Ortega-Quijano D, Jimenez-Cauhe J, et al. Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital. Clin Exp Dermatol. 2020.
In article      View Article  PubMed
 
[18]  Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: A worldwide review. JAAD Int. 2021. 2: 119-133.
In article      View Article  PubMed
 
[19]  Sanchez A, Sohier P, Benghane S, et al. Digitate papulosquamous eruption associated with severe acute respiratory syndrome Coronavirus-2 infection. JAMA Dermatol. April 30, 2020.
In article      View Article  PubMed
 
[20]  Gianotti R, Veraldi S, Recalcati S, et al. Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of Milan, Italy. Acta Derm Venereol. 2020. [published online ahead of print, 2020 Apr 21].
In article      View Article  PubMed
 
[21]  Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020. [S1931-5244(20)30070- 0.
In article      
 
[22]  Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020; 382: 1653-1659.
In article      View Article  PubMed
 
[23]  Kroumpouzos G. Cutaneous manifestations of COVID-19: An unusual presentation with edematous plaques and pruritic, erythematous papules, and comment on the role of bradykinin storm and its therapeutic implications. Dermatol Ther. 2021, e14753.
In article      View Article  PubMed
 
[24]  Estebanez A, Perez-Santiago L, Silva E, et al. Cutaneous manifestations in COVID-19: new contribution. J Eur Acad Dermatol Venereol. 2020; 34: e250-e251.
In article      View Article  PubMed
 
[25]  Liang J, He Y, Ji W. Bradykinin-evoked scratching responses in complete Freund’s adjuvant-inflamed skin through activation of B1 receptor (Maywood). 2012; 37: 318-326.
In article      View Article  PubMed
 
[26]  Ghahestani SM, Mahmoudi J, Hajebrahimi S, et al. Bradykinin as a probable aspect in SARS-CoV-2 scenarios: is bradykinin sneaking out of our sight? Iran J Allergy Asthma Immunol. 2020; 19(S1): 13-17.
In article      View Article
 
[27]  Kaushik A, Parsad, D, Kumaran MS. Urticaria in the times of COVID-19. Dermatol Ther. 2020; e13817.
In article      
 
[28]  Matar S, Oules B, Sohier P, et al. Cutaneous manifestations in SARS-CoV-2 infections (COVID-19): a French experience and a systematic review of the literature. J Eur Acad Dermatol Venereol. 2020. Jun: jdv. 16775.
In article      View Article  PubMed
 
[29]  Hamming I, Timens W, Bulthius MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.
In article      View Article  PubMed
 

Published with license by Science and Education Publishing, Copyright © 2021 Cameron Y. S. Lee

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Cite this article:

Normal Style
Cameron Y. S. Lee. Cutaneous Manifestations in COVID-19 “Long Haulers”: Is This A Part of the Multisystem Inflammatory Syndrome?. American Journal of Infectious Diseases and Microbiology. Vol. 9, No. 2, 2021, pp 48-50. http://pubs.sciepub.com/ajidm/9/2/3
MLA Style
Lee, Cameron Y. S.. "Cutaneous Manifestations in COVID-19 “Long Haulers”: Is This A Part of the Multisystem Inflammatory Syndrome?." American Journal of Infectious Diseases and Microbiology 9.2 (2021): 48-50.
APA Style
Lee, C. Y. S. (2021). Cutaneous Manifestations in COVID-19 “Long Haulers”: Is This A Part of the Multisystem Inflammatory Syndrome?. American Journal of Infectious Diseases and Microbiology, 9(2), 48-50.
Chicago Style
Lee, Cameron Y. S.. "Cutaneous Manifestations in COVID-19 “Long Haulers”: Is This A Part of the Multisystem Inflammatory Syndrome?." American Journal of Infectious Diseases and Microbiology 9, no. 2 (2021): 48-50.
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  • Figure 4A. Polymorphic rash. Scarlatiniform eruptions on the upper half of the trunk and the confluent erythematous rash on the lower half of the patient
[1]  Rubin R. As their number grow, Covid-19. “Long Haulers” stump experts. JAMA. 2020; 324(14): 1381-1383.
In article      View Article  PubMed
 
[2]  Alwan NA. Surveillance is underestimating the burden of the Covid-19 pandemic. Lancet. 2020; 396 (10252):e24.
In article      View Article
 
[3]  Tenforde M, Kim S, Lindsell C, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network- United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020, ePub. 24 July 2020.
In article      
 
[4]  Ladds E, Rushforth A, Wieringa S, et al. Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality principles for services. BMC Health Services Research. 2020; 20: 1144.
In article      View Article  PubMed
 
[5]  Carfi A, Bernabei R, Landi F. Persistent symptoms in patients after acute Covid-19. JAMA. 2020; 324(6): 603-605.
In article      View Article  PubMed
 
[6]  Greenhalgh, T, Knight M, Burton M, et al. Management of post-acute covid-19 in primary care. BMJ. 2020; 370m3026.
In article      View Article  PubMed
 
[7]  Arnold DT, Hamilton FW, Milne A, et al. Patient outcomes after hospitalization with COVID-19 and implications for follow-up; results from a prospective UK cohort. medRxiv. 2020.
In article      View Article
 
[8]  Goertz YMJ, Van Herck M, Delbressine JM, et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post COVID-19 syndrome? ERJ Open Res. 2020; Oct 26; 6(4): 00542-2020.
In article      View Article  PubMed
 
[9]  Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries. J Am Acad Dermatol. 83: 1118-1129. 2020.
In article      View Article  PubMed
 
[10]  Dhont S, Derom E, Van Braeckel E, et al. The pathophysiology of ‘happy’ hypoxemia in Covid-19. Respir Res. 21, 198 (2020).
In article      View Article  PubMed
 
[11]  Galvan Casas C, Catala A, Carretero Hernandez G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020.
In article      
 
[12]  Marzano AV, Cassano N, Genovese G, et al. Cutaneous manifestations in patients with COVID-19: a preliminary review of an emerging issue. Br J Dermatol. 2020; 183: 431-442.
In article      View Article  PubMed
 
[13]  Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020.
In article      View Article
 
[14]  De Giorgi V, Recalcati S, Jia Z, et al. Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): a prospective study from China and Italy. J Am Acad Dermatol. 83: 674-675. 2020.
In article      View Article  PubMed
 
[15]  Lee CYS. Cutaneous rash: A clinical manifestation prior to respiratory symptoms of Covid-19 infection. J Fam Med Dis Prev. 7: 137. 2021.
In article      View Article
 
[16]  Daneshgaran G, Dubin DP, Gould DJ. Cutaneous manifestations of COVID-19: An evidenced based review. Am J Clin Dermatol. 2020.
In article      View Article
 
[17]  Fernandez-Nieto D, Ortega-Quijano D, Jimenez-Cauhe J, et al. Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital. Clin Exp Dermatol. 2020.
In article      View Article  PubMed
 
[18]  Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: A worldwide review. JAAD Int. 2021. 2: 119-133.
In article      View Article  PubMed
 
[19]  Sanchez A, Sohier P, Benghane S, et al. Digitate papulosquamous eruption associated with severe acute respiratory syndrome Coronavirus-2 infection. JAMA Dermatol. April 30, 2020.
In article      View Article  PubMed
 
[20]  Gianotti R, Veraldi S, Recalcati S, et al. Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of Milan, Italy. Acta Derm Venereol. 2020. [published online ahead of print, 2020 Apr 21].
In article      View Article  PubMed
 
[21]  Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020. [S1931-5244(20)30070- 0.
In article      
 
[22]  Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020; 382: 1653-1659.
In article      View Article  PubMed
 
[23]  Kroumpouzos G. Cutaneous manifestations of COVID-19: An unusual presentation with edematous plaques and pruritic, erythematous papules, and comment on the role of bradykinin storm and its therapeutic implications. Dermatol Ther. 2021, e14753.
In article      View Article  PubMed
 
[24]  Estebanez A, Perez-Santiago L, Silva E, et al. Cutaneous manifestations in COVID-19: new contribution. J Eur Acad Dermatol Venereol. 2020; 34: e250-e251.
In article      View Article  PubMed
 
[25]  Liang J, He Y, Ji W. Bradykinin-evoked scratching responses in complete Freund’s adjuvant-inflamed skin through activation of B1 receptor (Maywood). 2012; 37: 318-326.
In article      View Article  PubMed
 
[26]  Ghahestani SM, Mahmoudi J, Hajebrahimi S, et al. Bradykinin as a probable aspect in SARS-CoV-2 scenarios: is bradykinin sneaking out of our sight? Iran J Allergy Asthma Immunol. 2020; 19(S1): 13-17.
In article      View Article
 
[27]  Kaushik A, Parsad, D, Kumaran MS. Urticaria in the times of COVID-19. Dermatol Ther. 2020; e13817.
In article      
 
[28]  Matar S, Oules B, Sohier P, et al. Cutaneous manifestations in SARS-CoV-2 infections (COVID-19): a French experience and a systematic review of the literature. J Eur Acad Dermatol Venereol. 2020. Jun: jdv. 16775.
In article      View Article  PubMed
 
[29]  Hamming I, Timens W, Bulthius MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.
In article      View Article  PubMed