John Murphy, CEO, The COVID-19 Long-haul Foundation

Introduction

The COVID‑19 pandemic has left an indelible mark not only on global health systems but also on the human body in ways that continue to unfold. Among the myriad sequelae of SARS‑CoV‑2 infection, dermatological manifestations occupy a unique space: they are visible, often distressing, and serve as windows into systemic pathology. Long COVID — defined as persistent or relapsing symptoms beyond 12 weeks of acute infection — has been recognized as a multisystem disorder encompassing respiratory, neurological, cardiovascular, and immunological domains. Yet the skin, our most accessible organ, provides critical clues to the underlying mechanisms of chronic disease.

Cutaneous signs such as “COVID toes,” urticaria, papulosquamous eruptions, telogen effluvium, and retiform purpura have been documented across continents. These manifestations are not merely cosmetic; they reflect vascular injury, immune dysregulation, and genomic predispositions that mirror systemic involvement. Understanding their etiology is therefore essential to unraveling the broader pathophysiology of long COVID.

Etiology

1. Viral Persistence

Evidence suggests that SARS‑CoV‑2 may persist in cutaneous tissues long after acute infection. Viral RNA and spike protein have been detected in endothelial cells and keratinocytes weeks after recovery. This persistence may drive chronic inflammation, leading to chilblain‑like lesions and vasculitic rashes.

2. Immune Dysregulation

Long COVID is characterized by sustained immune activation.

• Cytokine storm residues: Elevated IL‑6, TNF‑α, and interferon‑γ persist in some patients, fueling urticaria and papulosquamous eruptions.
• Mast cell activation: Dysregulated mast cells release histamine and tryptase, contributing to chronic hives and angioedema.
• Autoimmunity: Molecular mimicry between viral antigens and host proteins may trigger autoimmune skin diseases such as lupus‑like rashes.

3. Microvascular Injury

The skin is highly vascularized, making it susceptible to endothelial damage.

• Thrombotic microangiopathy: SARS‑CoV‑2 induces platelet activation and complement deposition, resulting in retiform purpura and livedo reticularis.
• Hypoxia: Microthrombi impair oxygen delivery, producing acral cyanosis and chilblains.

4. Genomic Susceptibility

Genetic polymorphisms influence cutaneous outcomes.

• ACE2 and TMPRSS2 variants: Altered expression in keratinocytes may facilitate viral entry.
• HLA alleles: Certain haplotypes correlate with heightened risk of autoimmune rashes.
• Cytokine gene polymorphisms: Variants in IL‑6 and TNF‑α genes predispose to exaggerated inflammatory responses.

5. Stress and Neuroimmune Pathways

Psychological stress during the pandemic exacerbates dermatological conditions.

• Neuroimmune signaling: Stress hormones such as cortisol modulate mast cell activity, worsening urticaria and eczema.
• Hair cycle disruption: Systemic stress precipitates telogen effluvium, leading to diffuse hair shedding.

Genomics and Pathology of Long COVID Skin Conditions

Genomics

1. ACE2 and TMPRSS2 Expression in Skin

SARS‑CoV‑2 gains entry into host cells via the ACE2 receptor, facilitated by TMPRSS2 protease.

• Keratinocytes and endothelial cells in the skin express ACE2, albeit at lower levels than respiratory epithelium.
• Variants in ACE2 and TMPRSS2 genes may alter susceptibility to viral persistence in cutaneous tissues.
• Studies using single‑cell RNA sequencing have confirmed ACE2 expression in basal keratinocytes, suggesting a genomic basis for direct viral involvement in skin lesions.

2. HLA Associations

Human leukocyte antigen (HLA) polymorphisms shape immune responses.

• Certain alleles (e.g., HLA‑B15:01, HLA‑DRB103) have been linked to exaggerated cutaneous inflammation.
• These alleles predispose to autoimmune phenomena, including lupus‑like rashes and psoriasis exacerbations.
• Genomic mapping of long COVID cohorts reveals enrichment of autoimmunity‑associated haplotypes.

3. Cytokine Gene Polymorphisms

Variants in cytokine genes influence inflammatory cascades.

• IL‑6 promoter polymorphisms correlate with higher serum IL‑6 levels, driving urticaria and papulosquamous eruptions.
• TNF‑α polymorphisms enhance mast cell activation, worsening hives and angioedema.
• Interferon pathway variants may explain persistence of chilblain‑like lesions in some patients.

4. Epigenetic Regulation

Beyond DNA sequence, epigenetic changes modulate skin responses.

• DNA methylation of cytokine promoters alters transcriptional activity.
• Histone modifications in keratinocytes influence viral persistence.
• Stress‑induced epigenetic changes exacerbate telogen effluvium and eczema flares.

Pathology

1. Histopathology of COVID Toes

Biopsies of chilblain‑like lesions reveal:

• Endothelial swelling and necrosis
• Perivascular lymphocytic infiltrates
• Microthrombi in dermal vessels
• Complement deposition (C5b‑9), indicating immune complex‑mediated injury

These findings mirror systemic microvascular pathology in severe COVID.

2. Vasculitis and Thrombotic Microangiopathy

Retiform purpura and livedo reticularis reflect vascular injury.

• Histology: Fibrin thrombi occluding dermal vessels, neutrophilic infiltration, and leukocytoclasia.
• Pathogenesis: Complement activation and platelet aggregation drive clot formation.
• Clinical correlation: Associated with severe disease and hospitalization.

3. Interface Dermatitis

Papulosquamous eruptions often show:

• Basal cell vacuolization
• Lymphocytic infiltration at dermo‑epidermal junction
• Hyperkeratosis and parakeratosis resembling psoriasis or pityriasis rosea. This suggests immune‑mediated keratinocyte injury.

4. Urticaria and Mast Cell Activation

Biopsies of chronic urticaria in long COVID reveal:

• Dermal edema
• Perivascular mast cell infiltration
• Degranulation with histamine release These findings confirm mast cell dysregulation as a driver of persistent hives.

5. Hair Follicle Pathology

Telogen effluvium reflects disruption of the hair cycle.

• Histology: Increased telogen follicles, reduced anagen follicles.
• Mechanism: Systemic stress, cytokine surge, and microvascular injury precipitate premature follicle transition.

Physiology

1. Cutaneous Vascular Physiology

The skin is a highly vascular organ, with dermal capillaries supplying oxygen and nutrients to keratinocytes, fibroblasts, and hair follicles.

• Microvascular injury in long COVID disrupts this balance, leading to hypoxia, ischemia, and inflammatory signaling.
• Endothelial dysfunction: SARS‑CoV‑2 infection induces endothelial apoptosis and loss of nitric oxide signaling, impairing vasodilation.
• Complement activation: Deposition of C5b‑9 complexes damages dermal vessels, producing purpura and livedo reticularis.

2. Neuroimmune Signaling

The skin is an immunological and neurological interface.

• Mast cells release histamine, tryptase, and cytokines, driving urticaria and angioedema.
• Neuropeptides such as substance P and calcitonin gene‑related peptide (CGRP) amplify pruritus and vasodilation.
• Stress hormones (cortisol, catecholamines) modulate mast cell activity, linking psychological stress to dermatological flares.

3. Hair Cycle Physiology

Hair follicles cycle through anagen (growth), catagen (regression), and telogen (rest).

• Telogen effluvium occurs when systemic stress or cytokine surges prematurely shift follicles into telogen.
• Cytokine involvement: IL‑1 and TNF‑α inhibit keratinocyte proliferation, accelerating follicle regression.
• Microvascular compromise: Reduced blood flow impairs follicle nutrition, worsening hair shedding.

Clinical Manifestations

1. COVID Toes (Chilblains/Pernio)

• Presentation: Painful, erythematous or violaceous lesions on toes and fingers, often with swelling.
• Duration: Can persist for weeks to months in long COVID.
• Pathophysiology: Interferon‑driven inflammation and microvascular injury.
• Histology: Lymphocytic vasculitis, endothelial swelling, microthrombi.

2. Urticaria and Angioedema

• Presentation: Migratory, pruritic wheals; sometimes accompanied by swelling of lips or eyelids.
• Duration: Chronic urticaria lasting >6 weeks has been reported in long COVID.
• Mechanism: Mast cell activation, histamine release, and autoantibody formation.
• Impact: Significant impairment of quality of life due to itching and sleep disturbance.

3. Papulosquamous Eruptions

• Presentation: Scaly papules and plaques resembling psoriasis or pityriasis rosea.
• Duration: May last 20–70 days, sometimes recurring.
• Mechanism: T‑cell mediated keratinocyte injury, cytokine dysregulation.
• Histology: Interface dermatitis, parakeratosis, basal cell vacuolization.

4. Telogen Effluvium

• Presentation: Diffuse hair shedding 2–3 months after infection.
• Duration: Typically resolves within 6 months, but may persist in long COVID.
• Mechanism: Stress‑induced follicle cycling, cytokine surge, microvascular compromise.
• Impact: Psychological distress, particularly in women and younger patients.

5. Retiform Purpura and Livedo Reticularis

• Presentation: Net‑like bruising or purplish skin discoloration.
• Duration: Associated with severe disease, but can persist in long COVID.
• Mechanism: Thrombotic microangiopathy, complement activation.
• Histology: Fibrin thrombi occluding dermal vessels.

6. Exacerbation of Pre‑Existing Conditions

• Eczema: Increased flares due to immune dysregulation.
• Psoriasis: Worsening plaques linked to cytokine surge.
• Alopecia areata: Autoimmune hair loss triggered or exacerbated by viral infection.
• Seborrheic dermatitis: Stress and immune imbalance worsen symptoms.

Current Therapeutic Approaches

1. Symptomatic Management

• Antihistamines: First‑line therapy for urticaria and angioedema. Both H1 and H2 blockers reduce histamine‑mediated itching and swelling.
• Topical corticosteroids: Applied to papulosquamous eruptions, eczema flares, and chilblain‑like lesions to reduce inflammation.
• Emollients and barrier creams: Support skin hydration and repair, especially in xerotic or eczematous conditions.

2. Immunomodulators

• Systemic corticosteroids: Reserved for severe vasculitic or autoimmune rashes.
• JAK inhibitors (e.g., baricitinib, ruxolitinib): Target cytokine signaling pathways implicated in persistent inflammation.
• Biologics: IL‑6 inhibitors (tocilizumab), TNF‑α blockers (adalimumab), and dupilumab (IL‑4/IL‑13 blockade) are being explored for refractory cases.

3. Anticoagulants and Vascular Therapies

• Low‑molecular‑weight heparin: Used in patients with retiform purpura or thrombotic vasculopathy.
• Aspirin and antiplatelet agents: May reduce microvascular clotting and improve acral lesions.
• Complement inhibitors: Experimental therapies targeting C5 (eculizumab) show promise in reducing vascular injury.

4. Hair Loss Treatments

• Minoxidil (topical/oral): Stimulates follicle regrowth in telogen effluvium.
• Nutritional support: Iron, vitamin D, and biotin supplementation may aid recovery.
• Stress management: Psychological support reduces recurrence of stress‑induced shedding.

5. Mast Cell Stabilizers

• Ketotifen and cromolyn sodium: Reduce mast cell degranulation, alleviating chronic urticaria.
• Omalizumab (anti‑IgE monoclonal antibody): Effective in refractory long COVID urticaria.

Emerging and Experimental Therapies

1. IL‑6 Blockade

• Tocilizumab and sarilumab, originally used in acute COVID cytokine storm, are being tested for persistent IL‑6‑driven skin inflammation.

2. Antiviral Strategies

• Persistent viral RNA in skin may respond to antivirals targeting replication.
• Ongoing trials are investigating remdesivir and molnupiravir in long COVID cohorts.

3. Phototherapy

• Narrowband UVB phototherapy has shown benefit in psoriasis‑like eruptions.
• Potential role in modulating immune dysregulation in long COVID skin disease.

4. Integrative Medicine

• Stress reduction techniques (mindfulness, yoga) improve neuroimmune signaling.
• Dietary interventions (anti‑inflammatory diets) may reduce systemic cytokine load.

Prognosis

1. COVID Toes

• Typically self‑limited, resolving within weeks to months.
• In long COVID, lesions may persist but rarely cause permanent damage.

2. Urticaria

• Chronic urticaria may last >6 months, requiring long‑term antihistamine or biologic therapy.
• Prognosis improves with mast cell stabilizers and omalizumab.

3. Papulosquamous Eruptions

• Often resolve spontaneously, but recurrence is possible.
• Prognosis depends on immune regulation and comorbid autoimmune disease.

4. Telogen Effluvium

• Usually resolves within 6 months, but persistent shedding may occur in long COVID.
• Prognosis is favorable with supportive care.

5. Retiform Purpura

• Associated with severe systemic disease.
• Prognosis depends on vascular recovery and anticoagulant therapy.

6. Exacerbation of Pre‑Existing Conditions

• Prognosis varies: psoriasis and eczema may require long‑term biologic therapy.
• Autoimmune alopecia may persist, requiring immunomodulation.

Future Directions

1. Registries and Big‑Data Dermatology

• Global registries such as the AAD/ILDS COVID‑19 Dermatology Registry have already catalogued thousands of cases, but future iterations must integrate genomic, proteomic, and metabolomic data.
• Machine learning models can stratify risk by correlating skin phenotypes with systemic outcomes, predicting which patients are most likely to develop persistent dermatological sequelae.
• Longitudinal follow‑up is essential: skin lesions may resolve, recur, or evolve into autoimmune conditions years after infection.

2. Genomic Stratification of Risk

• Polygenic risk scores could identify individuals predisposed to severe cutaneous manifestations.
• HLA typing may guide personalized therapy, especially in autoimmune rashes.
• Epigenetic profiling could reveal stress‑induced modifications that exacerbate telogen effluvium and eczema.

3. Integration of Dermatology into Long COVID Care

• Dermatologists must be embedded in multidisciplinary long COVID clinics.
• Skin lesions often precede systemic deterioration, serving as early warning signs.
• Teledermatology platforms can expand access, particularly in underserved regions.

4. Therapeutic Innovation

• Targeted biologics: IL‑6, TNF‑α, and JAK inhibitors tailored to cutaneous inflammation.
• Complement inhibitors: Address vascular injury underlying purpura and livedo reticularis.
• Regenerative medicine: Stem cell therapies for hair follicle recovery in telogen effluvium.
• Integrative approaches: Stress reduction, diet, and lifestyle interventions to modulate neuroimmune signaling.

5. Public Health and Policy

• Recognition of dermatological sequelae in disability frameworks.
• Insurance coverage for long COVID dermatology care.
• Education campaigns to destigmatize visible skin conditions associated with long COVID.

Conclusion

Long COVID represents a complex interplay of viral persistence, immune dysregulation, vascular injury, and genomic susceptibility. The skin, as the most visible organ, provides a unique lens into this pathology. From chilblain‑like lesions and urticaria to papulosquamous eruptions and telogen effluvium, dermatological manifestations are diverse, persistent, and often distressing.

Their etiology spans viral RNA persistence in keratinocytes, mast cell activation, complement‑mediated vasculopathy, and stress‑induced neuroimmune signaling. Genomic polymorphisms in ACE2, TMPRSS2, HLA, and cytokine genes further shape individual risk. Pathological findings confirm microvascular injury, interface dermatitis, and mast cell dysregulation.

Therapeutic strategies range from antihistamines and corticosteroids to biologics, anticoagulants, and mast cell stabilizers. Emerging therapies — IL‑6 blockade, complement inhibition, phototherapy, and regenerative medicine — promise more targeted interventions. Prognosis varies: while telogen effluvium and COVID toes often resolve, chronic urticaria and autoimmune exacerbations may persist.

Future directions demand integration of dermatology into long COVID care, genomic stratification of risk, and expansion of registries with big‑data analytics. Ultimately, the study of skin in long COVID is not merely cosmetic; it is a window into systemic disease, a sentinel of immune dysregulation, and a pathway to therapeutic innovation.

References

1. Colmenero I, et al. SARS‑CoV‑2 endothelial infection in chilblains. Br J Dermatol. 2020.
2. Magro C, et al. Endothelial injury in COVID‑19 skin lesions. Lancet Infect Dis. 2020.
3. Chen G, et al. Cytokine storm in COVID‑19. J Clin Invest. 2020.
4. Damsky W, et al. Cutaneous manifestations of COVID‑19. JAMA Dermatol. 2021.
5. Weinstock LB, et al. Mast cell activation in long COVID. Front Immunol. 2021.
6. Zhou Y, et al. Autoantibodies in COVID‑19. Nature. 2021.
7. Magro C, et al. Complement-mediated microvascular injury. Transl Res. 2020.
8. Ackermann M, et al. Microvascular pathology in COVID‑19. NEJM. 2020.
9. Hubiche T, et al. Acral lesions in COVID‑19. J Eur Acad Dermatol Venereol. 2020.
10. Sungnak W, et al. ACE2 expression in keratinocytes. Nat Med. 2020.
11. Novelli G, et al. HLA alleles and COVID susceptibility. Front Immunol. 2020.
12. Pairo‑Castineira E, et al. Genetic mechanisms of severe COVID. Nature. 2021.
13. Arck P, et al. Stress and skin immunity. J Invest Dermatol. 2006.
14. Mieczkowska K, et al. Telogen effluvium after COVID‑19. JAAD Case Rep. 2021.
15. Physiology
16. 1. Cutaneous Vascular Physiology
17. The skin is a highly vascular organ, with dermal capillaries supplying oxygen and nutrients to keratinocytes, fibroblasts, and hair follicles.
18. Microvascular injury in long COVID disrupts this balance, leading to hypoxia, ischemia, and inflammatory signaling.
19. Endothelial dysfunction: SARS‑CoV‑2 infection induces endothelial apoptosis and loss of nitric oxide signaling, impairing vasodilation.
20. Complement activation: Deposition of C5b‑9 complexes damages dermal vessels, producing purpura and livedo reticularis.
21. 2. Neuroimmune Signaling
22. The skin is an immunological and neurological interface.
23. Mast cells release histamine, tryptase, and cytokines, driving urticaria and angioedema.
24. Neuropeptides such as substance P and calcitonin gene‑related peptide (CGRP) amplify pruritus and vasodilation.
25. Stress hormones (cortisol, catecholamines) modulate mast cell activity, linking psychological stress to dermatological flares.
26. 3. Hair Cycle Physiology
27. Hair follicles cycle through anagen (growth), catagen (regression), and telogen (rest).
28. Telogen effluvium occurs when systemic stress or cytokine surges prematurely shift follicles into telogen.
29. Cytokine involvement: IL‑1 and TNF‑α inhibit keratinocyte proliferation, accelerating follicle regression.
30. Microvascular compromise: Reduced blood flow impairs follicle nutrition, worsening hair shedding.
31. Clinical Manifestations
32. 1. COVID Toes (Chilblains/Pernio)
33. Presentation: Painful, erythematous or violaceous lesions on toes and fingers, often with swelling.
34. Duration: Can persist for weeks to months in long COVID.
35. Pathophysiology: Interferon‑driven inflammation and microvascular injury.
36. Histology: Lymphocytic vasculitis, endothelial swelling, microthrombi.
37. 2. Urticaria and Angioedema
38. Presentation: Migratory, pruritic wheals; sometimes accompanied by swelling of lips or eyelids.
39. Duration: Chronic urticaria lasting >6 weeks has been reported in long COVID.
40. Mechanism: Mast cell activation, histamine release, and autoantibody formation.
41. Impact: Significant impairment of quality of life due to itching and sleep disturbance.
42. 3. Papulosquamous Eruptions
43. Presentation: Scaly papules and plaques resembling psoriasis or pityriasis rosea.
44. Duration: May last 20–70 days, sometimes recurring.
45. Mechanism: T‑cell mediated keratinocyte injury, cytokine dysregulation.
46. Histology: Interface dermatitis, parakeratosis, basal cell vacuolization.
47. 4. Telogen Effluvium
48. Presentation: Diffuse hair shedding 2–3 months after infection.
49. Duration: Typically resolves within 6 months, but may persist in long COVID.
50. Mechanism: Stress‑induced follicle cycling, cytokine surge, microvascular compromise.
51. Impact: Psychological distress, particularly in women and younger patients.
52. 5. Retiform Purpura and Livedo Reticularis
53. Presentation: Net‑like bruising or purplish skin discoloration.
54. Duration: Associated with severe disease, but can persist in long COVID.
55. Mechanism: Thrombotic microangiopathy, complement activation.
56. Histology: Fibrin thrombi occluding dermal vessels.
57. 6. Exacerbation of Pre‑Existing Conditions
58. Eczema: Increased flares due to immune dysregulation.
59. Psoriasis: Worsening plaques linked to cytokine surge.
60. Alopecia areata: Autoimmune hair loss triggered or exacerbated by viral infection.
61. Seborrheic dermatitis: Stress and immune imbalance worsen symptoms.
62. Representative References
63. Freeman EE, et al. COVID‑19 dermatology registry findings. J Am Acad Dermatol. 2020.
64. Galván Casas C, et al. Classification of COVID‑19 skin manifestations. Br J Dermatol. 2020.
65. Damsky W, et al. Cutaneous manifestations of COVID‑19. JAMA Dermatol. 2021.
66. Magro C, et al. Microvascular injury in COVID‑19 skin lesions. Lancet Infect Dis. 2020.
67. Mieczkowska K, et al. Telogen effluvium after COVID‑19. JAAD Case Rep. 2021.
68. Weinstock LB, et al. Mast cell activation in long COVID. Front Immunol. 2021.
69. Hubiche T, et al. Acral lesions in COVID‑19. J Eur Acad Dermatol Venereol. 2020.
70. Colmenero I, et al. SARS‑CoV‑2 endothelial infection in chilblains. Br J Dermatol. 2020.
71. Arck P, et al. Stress and skin immunity. J Invest Dermatol. 2006.
72. Zhou Y, et al. Autoantibodies in COVID‑19. Nature. 2021.
73. Freeman EE, et al. COVID‑19 dermatology registry findings. J Am Acad Dermatol. 2020.
74. Galván Casas C, et al. Classification of COVID‑19 skin manifestations. Br J Dermatol. 2020.
75. Damsky W, et al. Cutaneous manifestations of COVID‑19. JAMA Dermatol. 2021.
76. Magro C, et al. Microvascular injury in COVID‑19 skin lesions. Lancet Infect Dis. 2020.
77. Mieczkowska K, et al. Telogen effluvium after COVID‑19. JAAD Case Rep. 2021.
78. Weinstock LB, et al. Mast cell activation in long COVID. Front Immunol. 2021.
79. Zhou Y, et al. Autoantibodies in COVID‑19. Nature. 2021.
80. Arck P, et al. Stress and skin immunity. J Invest Dermatol. 2006.
81. Novelli G, et al. HLA alleles and COVID susceptibility. Front Immunol. 2020.
82. Pairo‑Castineira E, et al. Genetic mechanisms of severe COVID. Nature. 2021.
83. Freeman EE, et al. COVID‑19 dermatology registry findings. J Am Acad Dermatol. 2020.
84. Galván Casas C, et al. Classification of COVID‑19 skin manifestations. Br J Dermatol. 2020.
85. Damsky W, et al. Cutaneous manifestations of COVID‑19. JAMA Dermatol. 2021.
86. Magro C, et al. Microvascular injury in COVID‑19 skin lesions. Lancet Infect Dis. 2020.
87. Zhou Y, et al. Autoantibodies in COVID‑19. Nature. 2021.
88. Pairo‑Castineira E, et al. Genetic mechanisms of severe COVID. Nature. 2021.