By Hai H. Hoang, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: The relationship between childhood infections and the risk of multiple sclerosis is supported by increasing evidence. Using the Swedish Total Population Register, researchers found that patients diagnosed with infection in adolescence showed an increased risk of multiple sclerosis, even after exclusion of infectious mononucleosis, pneumonia, and central nervous system infection.

SOURCE: Xu Y, Smith KA, Hiyoshi A, et al. Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis. Brain 2021;144:2390-2400.

There are many theories on the etiology of multiple sclerosis. Frequently cited in increasing the risk of multiple sclerosis is the involvement of infections. Two meta-analyses found that infectious mononucleosis, a clinical manifestation of Epstein-Barr virus infection, in adolescents and young adults more than doubled the multiple sclerosis risk. Other infectious pathogens that have been linked with multiple sclerosis include human herpesvirus 6 (HHV-6) and Chlamydia pneumoniae.

However, the underlying mechanism between infections and an increased risk of multiple sclerosis is not known. One theory includes the molecular mimicry hypothesis, which suggests that infectious agents with homologous sequences or structures to a host’s myelin antigens could trigger cross-activation of autoreactive T cells to attack host tissue. Another theory suggests that macrophages and natural killer cells activated by infectious agents elsewhere in the body, such as the lungs, can result in pro-inflammatory cytokine production and nonspecific activation of pre-primed T cells. This allows them to cross the blood-brain barrier, causing inflammation in the central nervous system (CNS), and inducing multiple sclerosis pathogenesis by triggering autoimmune responses against myelin.

Xu et al used a large population-based cohort in Sweden to assess the risk of a multiple sclerosis diagnosis from age 20 years associated with hospital-diagnosed infection in adolescence (ages 11-19 years) and earlier childhood (between birth and age 10 years). The researchers hypothesized that during adolescence, environmental exposures are likely to be more causally associated with an increased risk of a subsequent diagnosis of multiple sclerosis and that exposures in earlier childhood are less likely to contribute to such a diagnosis.

A total of 462,157 and 338,352 individuals had hospital-diagnosed infections between birth and age 10 years and between ages 11 and 19 years, respectively. Only infections before age 20 years were considered in patients older than 25 years of age with first multiple sclerosis diagnosis, so that there was a delay of at least five years between exposure and multiple sclerosis diagnosis.

Any infection from birth to 10 years of age was not statistically significantly associated with an increased risk of a subsequent diagnosis of multiple sclerosis when compared to no infection from birth to 10 years of age. Those at greater risk of a multiple sclerosis diagnosis were individuals with any infection in adolescence, defined as at between the ages of 11 and 19 years. Infectious mononucleosis in adolescence, between ages 11 and 19 years, increased the risk of being diagnosed with multiple sclerosis after adjustment for pneumonia, sex, and parental socioeconomic position. Viral infection (excluding infectious mononucleosis in adolescence) did not statistically significantly increase the risk of being diagnosed with a subsequent case of multiple sclerosis, compared with no viral infection. However, there was an increased risk of being diagnosed with multiple sclerosis associated with bacterial infection in adolescence, which remained statistically significant when individuals with bacterial infection but without CNS infection, infectious mononucleosis, and pneumonia diagnoses were compared with those without bacterial infection.

This study concluded that any hospital-treated infection in adolescence increased the risk of a multiple sclerosis diagnosis from age 20 years, although the effect size was small (hazard ratio, 1.33).

COMMENTARY

Given that this study relied on patients hospitalized for an infection, the total number of infections in adolescence and earlier childhood was underestimated, because infections diagnosed in outpatient clinics were not included. Another limitation was the inability to analyze the risk of a multiple sclerosis diagnosis associated with specific types of CNS infection, because of small numbers of patients with multiple sclerosis and earlier CNS infections. Although this study was able to identify multiple infectious pathogens rather than a single pathogen contributing to the risk of a multiple sclerosis diagnosis, the study did not consider whether multiple infectious pathogens act independently or interact with each other in an additive or multiplier effect. Overall, this was a well-designed cohort study, which further supports the theory that infections during childhood and adolescence may play a role in the underlying cause for multiple sclerosis.