Long COVID and Chronic Pruritus,

John Murphy, President, The COVID Long-haul Foundation

Chronic pruritus, or persistent itching, has emerged as a notable symptom among individuals experiencing long COVID. This condition, often overlooked, can significantly impact quality of life and may be linked to underlying immune dysregulation triggered by SARS-CoV-2 infection.

Background

Long COVID encompasses a wide range of symptoms that persist beyond the acute phase of infection. Among these, dermatologic manifestations such as rashes, urticaria, and pruritus have been increasingly reported. Chronic pruritus in long COVID patients may present without visible skin lesions, complicating diagnosis and management.

Pathophysiology

The mechanisms behind chronic pruritus in long COVID are not fully understood but may involve:

Immune dysregulation: Persistent inflammation and cytokine imbalance can sensitize peripheral nerves.
Neurological involvement: SARS-CoV-2 may affect small nerve fibers, contributing to neuropathic itch.
Histamine and mast cell activation: Elevated histamine levels and mast cell degranulation have been observed in some long COVID cases.

Clinical Presentation

Patients may report:

Persistent itching lasting weeks to months
Itch localized to specific areas or generalized
Absence of primary skin lesions
Exacerbation with stress or heat

Diagnostic Considerations

Evaluation should include:

Detailed history of COVID-19 infection and symptom onset
Exclusion of other causes (e.g., liver disease, renal dysfunction, dermatologic conditions)
Skin biopsy or nerve conduction studies if neuropathic itch is suspected

Management Strategies

Treatment is often symptomatic and may include:

Antihistamines: For histamine-mediated itch
Gabapentinoids: For neuropathic components
Topical agents: Such as menthol or pramoxine
Phototherapy: Narrowband UVB may offer relief
Psychological support: Addressing stress and anxiety

Research Directions

Further studies are needed to:

Clarify the immunological and neurological pathways involved
Develop targeted therapies
Establish diagnostic criteria for pruritus in long COVID

Conclusion

Chronic pruritus is a potentially debilitating symptom of long COVID that warrants greater clinical attention. Understanding its mechanisms and developing effective treatments are essential for improving patient outcomes.

Immune Dysregulation and Chronic Pruritus in Long COVID: Mechanisms, Manifestations, and Management

Abstract

This article explores the emerging intersection of immune dysregulation and chronic pruritus in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as long COVID. We synthesize findings from over 25 peer-reviewed studies to examine the immunopathogenic mechanisms underlying persistent itch, including mast cell activation, autoimmunity, and neuroimmune crosstalk. We also review clinical presentations, diagnostic challenges, and therapeutic strategies, proposing a multidisciplinary framework for managing this underrecognized symptom.

1. Introduction

Define long COVID (PASC) and its systemic nature
Introduce chronic pruritus as an emerging but underreported symptom
State the article’s objective: to explore immune-mediated mechanisms of itch in long COVID and propose diagnostic and therapeutic pathways

2. Immunopathogenesis of Long COVID

2.1 Persistent Immune Activation

Evidence of elevated cytokines (IL-6, IL-1β, TNF-α) months after infection
Role of non-resolving inflammation and immune exhaustion

2.2 Autoimmunity and Molecular Mimicry

Autoantibody profiles in long COVID (ANA, anti-IFN, anti-GPCR)
Cross-reactivity between viral and host antigens

2.3 Viral Persistence and Latent Reactivation

Detection of SARS-CoV-2 RNA/proteins in tissues months post-infection
Reactivation of EBV, HHV-6, and their role in immune dysregulation

3. Mechanisms of Chronic Itch in Immune Dysregulation

3.1 Mast Cell Activation Syndrome (MCAS)

Histamine, tryptase, prostaglandins, and leukotrienes
Triggers and diagnostic criteria for MCAS in long COVID

3.2 Neuroimmune Crosstalk

Role of IL-31, substance P, and nerve growth factor
Peripheral and central sensitization of itch pathways

3.3 Autoimmune Skin and Nerve Involvement

Small fiber neuropathy and autoimmune urticaria
Skin biopsy findings and nerve conduction studies

4. Clinical Manifestations of Itch in Long COVID

Urticaria, papulosquamous eruptions, “COVID toes,” and pruritus without rash
Case reports and registry data (e.g., COVID-19 Dermatology Registry)
Duration, severity, and impact on quality of life

5. Diagnostic Workup

History and symptom mapping
Laboratory tests: CBC, tryptase, ANA, histamine, IgE, cytokine panels
Skin biopsy, nerve fiber density, and autonomic testing
Differential diagnosis: MCAS, autoimmune dermatoses, neuropathic itch

6. Therapeutic Strategies

6.1 Antihistamines and Mast Cell Stabilizers

H1/H2 blockers (cetirizine, famotidine)
Cromolyn sodium, ketotifen

6.2 Immunomodulatory Therapies

Low-dose corticosteroids
IVIG, omalizumab, or rituximab in select autoimmune cases

6.3 Neuropathic Agents

Gabapentin, pregabalin, duloxetine
Topical capsaicin or lidocaine

6.4 Integrative and Supportive Approaches

Phototherapy, acupuncture, dietary triggers
Psychological support for chronic symptoms

7. Discussion

Synthesis of immune and neurological contributors to chronic itch
Limitations in current research and need for longitudinal studies
Implications for clinical practice and interdisciplinary care

8. Conclusion

Chronic pruritus in long COVID is a multifactorial symptom rooted in immune dysfunction
Early recognition and targeted therapy can improve outcomes
Calls for inclusion of dermatologic and neurologic symptoms in long COVID guidelines

9. References

A curated list of 25–40 peer-reviewed articles will be inserted here, including:

Proal & VanElzakker (2021) on immune persistence in long COVID
Novak et al. (2022) on mast cell activation and COVID
Yong (2021) on neuroimmune mechanisms in PASC
Dermatology registry studies on COVID-related skin symptoms
NIH RECOVER and Yale long COVID immunology data