By Ulrike W. Kaunzner, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
The current study of herpes simplex virus (HSV) encephalitis demonstrated an association of encephalitis with preexisting autoimmune disease and/or exposure to immunosuppressive and immunomodulatory medications. The findings underscore the potential underestimation of antecedent immune-related dysregulation in HSV encephalitis cases to date.
Tang A, Yoshida K, Lahey H, et al. Herpes simplex virus encephalitis in patients with autoimmune conditions or exposure to immunomodulatory medications. Neurology 2024;102:e209297.
Herpes simplex virus type 1 (HSV-1) is the most common cause of viral encephalitis, accounting for approximately 15% to 40% of adult cases, yet the correlation between immune status and HSV-1 encephalitis (HSVE) remains obscure. Unlike opportunistic infections, HSVE typically is not associated with immunocompromised states. The annual incidence of HSVE is estimated to range from two to four cases per 1 million individuals. Prior to the introduction of antiviral agents, mortality in HSVE cases was approximately 70%. With the introduction of acyclovir as treatment for HSVE, mortality rates have decreased to 20%. Despite this improvement, 70% of survivors experience various chronic symptoms, such as seizures, memory changes, and psychiatric disorders.
HSV-1 and HSV-2 are very common globally, with about 3.7 billion people younger than 50 years of age infected with HSV-1 and 0.5 billion people aged 15-49 years infected with HSV-2. However, HSVE is rare, and its pathogenesis is unclear. Large studies have not shown a significant predisposition to HSVE in immunocompromised individuals, unlike other herpes virus infections such as herpes zoster, which are more common in this group. HSVE in adults may arise from primary infection or reactivation from latency in the trigeminal ganglion, leading to brain infection. In immunocompromised patients, HSVE may present with fewer focal neurological symptoms but tends to be more severe with a poor outcome.
In a recent study conducted by Tang et al analyzing a U.S. Medicaid database comprising 75.6 million individuals, researchers aimed to elucidate the potential link between autoimmune disorders, exposure to immunosuppressive/immunomodulatory medications, and the onset of HSVE. Using data from 2007-2010 across 29 populous American states, the study team analyzed the incidence of HSVE within the population and conducted age- and sex-matched comparisons of adult HSVE cases against a larger control cohort without HSVE.
The comparison between 951 HSVE cases and 95,100 age- and sex-matched controls revealed a heightened prevalence of medical comorbidities within the HSVE population. Notably, a robust association emerged between HSVE and autoimmune conditions, yielding an adjusted odds ratio (OR) of 2.6 (95% confidence interval). Similarly, the association between HSVE and immunomodulating medications retained a strong association (OR, 2.2). Even when both exposures were concurrently incorporated into regression models, the associations persisted for both autoimmune disease and immunosuppressive/immunomodulatory medications.
COMMENTARY
These findings highlight the need for further investigation into the relationship between autoimmune diseases, immunosuppressive medications, and HSVE. Incidence rates of HSVE in the study population were consistent with previous estimates using a much larger sample size. However, the study focused on a narrow definition of immunosuppression, specifically autoimmune diseases and their treatments, and did not include patients with a cancer diagnosis or primary immunodeficiency syndrome.
Overall, the study provides observational evidence of a clinical association that has the potential to change clinical practice. These observational data may increase awareness, surveillance, and possible management for an increased rate of HSVE in patients with autoimmune disease and/or taking immunosuppressive and immunomodulatory medication.
