Clinician
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Viral Infections Associated With Granuloma Annulare
April 3rd, 2025
A benign, inflammatory skin condition, granuloma annulare (GA) is characterized by annular, erythematous plaques or papules. While its exact etiology remains unclear, several infectious and non-infectious triggers have been proposed.
Understanding granuloma annulare
GA is commonly classified into different variants, including localized, generalized, subcutaneous, perforating, and patch-type forms. The condition is often asymptomatic but may be cosmetically concerning to patients.
Histologically, GA is marked by dermal granulomas, mucin deposition, and a palisading pattern of histiocytes surrounding degenerated collagen fibers.
Variants of granuloma annulare
- Localized granuloma annulare
- This is the most common type, typically affecting children and young adults.
- This presents as small, annular, flesh-colored, or erythematous plaques, commonly on the hands, feet, wrists, and ankles.
- Lesions usually resolve spontaneously within months to years.
- Generalized granuloma annulare
- This is characterized by widespread, multiple annular lesions distributed symmetrically across the trunk and extremities.
- This is more frequently seen in adults and often associated with systemic conditions such as diabetes.
- This is chronic and more resistant to treatment compared to localized GA.
- Subcutaneous granuloma annulare
- This primarily affects children and presents as deep, firm nodules, often on the lower extremities.
- Unlike other variants, it lacks annular configuration and can be mistaken for soft tissue tumors.
- Perforating granuloma annulare
- This is a rare variant characterized by umbilicated papules with central crusting due to transepidermal elimination of necrotic debris.
- It commonly affects the dorsum of the hands and is often chronic.
- Patch-type granuloma annulare
- This manifests as non-annular, violaceous, or erythematous patches that can resemble morphea or cutaneous lymphoma.
- It can be misdiagnosed due to its atypical presentation.
Viral infections linked to granuloma annulare
Several viral infections have been associated with GA, either as a triggering factor or as an exacerbating condition. The most notable viral agents include:
1. Hepatitis B and hepatitis C virus (HBV and HCV)
- Studies have suggested a potential link between GA and chronic hepatitis infections.
- HCV, in particular, has been associated with various dermatologic manifestations, including GA.
- Proposed mechanisms include immune complex deposition, chronic inflammation, and direct viral effects on the skin.
2. Human immunodeficiency virus (HIV)
- GA has been reported in HIV-infected individuals, sometimes presenting as an atypical or widespread form.
- The immunosuppression seen in HIV may predispose individuals to reactive dermatoses like GA.
- Antiretroviral therapy (ART) has also been associated with both improvement and exacerbation of GA.
3. Epstein-Barr virus (EBV)
- As a herpesvirus known for its role in various autoimmune and dermatologic conditions, EBV has been proposed as a potential trigger for GA.
- The immune dysregulation caused by EBV infection might contribute to granulomatous inflammation.
4. Varicella-Zoster virus (VZV)
- Some case reports have linked GA with prior or concurrent VZV infection.
- The inflammatory response following viral reactivation may contribute to granuloma formation.
5. Human papillomavirus (HPV)
- Although less commonly reported, HPV has been suggested as a possible trigger for GA, particularly in immunocompromised individuals.
6. Parvovirus B19
- Known for causing erythema infectiosum, Parvovirus B19 has been linked to various autoimmune and inflammatory conditions, including GA.
- Some studies suggest molecular mimicry and immune response alterations as possible mechanisms.
Mechanisms of viral-induced granuloma annulare
Several hypotheses explain how viral infections may contribute to GA:
Immune dysregulation
- Chronic viral infections may alter immune function, leading to inappropriate inflammatory responses in the skin.
- Studies indicate that persistent viral antigens can overstimulate T-helper cells, promoting granuloma formation.
Molecular mimicry
- Viral antigens can also look like self-antigens, triggering an autoimmune-like response.
- This cross-reactivity can lead to chronic inflammation and immune-mediated tissue damage.
Direct viral skin involvement
- Certain viruses may directly infect or interact with skin cells, leading to granuloma formation.
- Viral replication in dermal fibroblasts may contribute to persistent inflammation.
Cytokine imbalance
- Viral infections can disrupt cytokine signaling pathways, promoting granulomatous inflammation.
- Elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) have been observed in GA patients with underlying viral infections.
Clinical and diagnostic considerations
- A thorough history, including past viral infections and vaccination status, is crucial in evaluating GA cases.
- Laboratory tests such as hepatitis serologies, HIV testing, and PCR assays for viral DNA/RNA may help identify underlying infections.
- Skin biopsy can confirm GA and rule out other granulomatous conditions.
Treatment and management
- GA is often self-limited, but persistent cases may require treatment.
- Identifying and addressing underlying viral infections may improve GA outcomes.
- Treatment options include topical and intralesional corticosteroids, phototherapy, systemic immunosuppressants, and antiviral therapy if a viral trigger is confirmed.
While GA remains an idiopathic condition in many cases, increasing evidence supports a connection between viral infections and their onset.
Understanding these associations can help with diagnosing and managing affected patients. Further research is needed to clarify the exact mechanisms linking viral infections to GA and to explore targeted treatment approaches.
References
- Durgin J.S., Shields B.E., & Rosenbach M. (August 2020). Generalized granuloma annulare: A widespread response to limited application of compounded 2% topical tofacitinib. Journal of the American Academy of Dermatology Case Reports. Retrieved from https://pubmed.ncbi.nlm.nih.gov/33005718/
- Yousaf, A., Boustany, O., Gerbo, M., et al. (September 2021). 27540 Localized versus generalized granuloma annulare: A retrospective review of 407 patients. Journal of the American Academy of Dermatology. Retrieved from https://www.jaad.org/article/S0190-9622(21)01270-6/abstract
- Lapidus A.H., Lee S., Khandewal T., et al. (February 2025). Subcutaneous granuloma annulare: a systematic review of a rare and underdiagnosed disease. International Journal of Dermatology. Retrieved from https://pubmed.ncbi.nlm.nih.gov/39090834/
- Joshi T.P. & Duvic M. (January 2022). Granuloma annulare: An updated review of epidemiology, pathogenesis, and treatment options. American Journal of Clinical Dermatology. Retrieved from https://pubmed.ncbi.nlm.nih.gov/34495491/
- Khanna U. & North J.P. (September 2020). Patch-type granuloma annulare: An institution-based study of 23 cases. Journal of Cutaneous Pathology. Retrieved from https://pubmed.ncbi.nlm.nih.gov/32279342/
- Alsahafi M., AlJasser M.I., Kalia S., et al. (February 2017). Chronic hepatitis with liver granulomas in a patient with granuloma annulare: A case report and review of the literature. Case Reports in Gastrointestinal Medicine. Retrieved from https://pubmed.ncbi.nlm.nih.gov/28326206/
- Toro, J.R., Chu, P., Yen, T.S.B, et al. (November 1999). Granuloma annulare and human immunodeficiency virus infection. Archives of Dermatology. Retrieved from https://jamanetwork.com/journals/jamadermatology/fullarticle/478080
- Spencer S.A., Fenske N.A., Espinoza C.G., et al. (February 1988). Granuloma annulare-like eruption due to chronic Epstein-Barr virus infection. Archives of Dermatology. Retrieved from https://pubmed.ncbi.nlm.nih.gov/2829748/
- Kachlik, Z., Kaczmarek, A., Grych, K., Dorobek, M., et al. (May 2024). Granuloma annulare: A clinical update. Current Dermatology Reports. Retrieved from https://link.springer.com/article/10.1007/s13671-024-00430-2