What causes the reactivation of herpes zoster (shingles)?

Causes of Herpes Zoster Reactivation

Herpes zoster (shingles) results from reactivation of varicella-zoster virus (VZV) that has remained dormant in dorsal root ganglia or cranial sensory ganglia following primary varicella infection, with reactivation occurring primarily due to declining cell-mediated immunity. 1, 2, 3

Primary Mechanism of Reactivation

The fundamental cause of VZV reactivation is decline in zoster-specific cell-mediated immunity, which allows the latent virus in sensory ganglia to travel along nerve pathways, causing inflammation and nerve damage that manifests as the characteristic dermatomal rash. 1, 2

Age-Related Immunosenescence

• Aging is the most common reason for reactivation, with more than two-thirds of herpes zoster cases occurring in people ≥60 years of age due to natural immunosenescence (age-related decline in cellular immunity). 2, 3
• The lifetime risk of herpes zoster is estimated at 20-30% in the general population, with incidence rates of 7-10 cases per 1,000 person-years after age 50. 4, 5

Immunocompromising Conditions

Disease-related immunosuppression significantly increases reactivation risk: 2, 6

• HIV/AIDS: Herpes zoster incidence is approximately 15-fold higher in HIV-infected adults compared to age-matched controls, and can occur at any CD4+ count (though frequency is highest with CD4+ counts <200 cells/µL). 7, 1
• Malignancies, particularly lymphoma and other hematologic cancers 2, 6
• Diabetes mellitus 2
• Autoimmune diseases requiring immunosuppressive therapy 5

Iatrogenic Immunosuppression

Medical treatments that suppress immunity are major triggers: 2, 6

• Chemotherapy and radiotherapy 2
• High-dose corticosteroids (particularly ≥7.5 mg/day prednisolone) 7, 6
• Organ transplantation with therapeutic immune suppression 2
• JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib) with incidence rates 3-4 times higher than placebo, particularly dose-dependent and more frequent in Asian populations 7
• Biologic DMARDs, though less frequently than with JAK inhibitors 7

Other Recognized Triggers

Additional factors that may precipitate reactivation include: 7, 6

• Ultraviolet light exposure 7
• Fever 7
• Psychological stress and emotional stress 7, 5
• Menstruation 7

Important Clinical Considerations

• Herpes zoster can occur in otherwise healthy young people despite the absence of obvious immunosuppression, though this is less common. 2
• Genital herpes zoster may be an indicator of undiagnosed HIV infection and should prompt HIV testing, as reactivated VZV infection may be the first clinical evidence of HIV. 5
• The development of herpes zoster in immunocompromised individuals correlates with decline in CD4 count and cell-mediated immunity. 5

Prevention Context

Vaccination is the most effective strategy to prevent VZV reactivation, as it boosts specific T-cell production and VZV-specific immunity. 4, 8 The recombinant zoster vaccine (RZV) reduces herpes zoster incidence by 92% (RR 0.08) at 3.2 years follow-up, while live attenuated zoster vaccine (LZV) reduces incidence by 51% (RR 0.49) at up to 3 years. 8