Sex and menopause-based differences in presentation of early Lyme disease: A prospective cohort study

Although prior research has established sex and menopausal status-based differences in immune response, susceptibility, and severity to a variety of pathogens, their relevance in early Lyme disease is understudied. We examined the clinical and serologic presentation of patients with early Lyme disease, stratified first by sex then by menopausal status. We also explored the hypothesis that males would present with more severe early Lyme disease. In this prospective cohort study from the Mid-Atlantic US, 243 adult, antibiotic-naïve patients were enrolled with a diagnostic erythema migrans rash present. Demographic, physical exam, symptom, laboratory, and two-tier serology data were collected at a baseline, and a post-treatment visit 3 weeks later. Lyme disease severity was operationalized through six indicators: rash size, number of acute symptoms, dermatologic dissemination, positive serology, liver function elevation, and elevated neutrophil-lymphocyte ratio. Unadjusted group comparisons and multivariate regression adjusting for potential confounders were used to assess difference. In logistic models adjusted for age, Lyme disease duration, systemic steroid use, and co-morbid thyroid disease, males had higher odds of testing two-tier positive (OR = 1.77 [1.03, 3.04], p = 0.039). This difference was more pronounced between males and pre-menopausal females (OR = 2.93 [1.26-6.79], p = 0.012) and no significant difference was found comparing males to post-menopausal females. In ordinal logistic models with Lyme disease severity as the outcome adjusted for age and Lyme disease duration, males had higher odds of being in a higher disease severity score category (OR = 1.94 [1.20,3.15], p = 0.028); again, particularly in comparison to pre-menopausal females (OR = 2.26 [1.13,4.58], p = 0.044). Heart palpitations (p = 0.023), vomiting (p = 0.007), and photophobia (p = 0.057) trended towards higher reporting among females, while sleep difficulty (p = 0.010) was higher among males. No differences were found on non-dermatologic components of the physical exam. We found sex and menopausal status to be relevant in accounting for variability in two-tier serologic status and severity of early Lyme disease in a well-characterized group of patients. Lower rates of seroreactivity among females is unexpected but may be consistent with lower acute severity of disease. Our clinical findings underscore the need for additional research to understand possible contributing biologic and/or social behavioral factors, as well as their impact on timely diagnosis and post-treatment conditions.