Gender Bias in Chronic Lyme Disease

Wormser and Shapiro ¹ claim that women are overrepresented in studies of chronic Lyme disease compared with reported cases of the tick-borne illness from the Centers for Disease Control and Prevention (CDC) or studies of “post-Lyme disease syndrome.” The authors conclude that chronic Lyme disease due to infection with Borrelia burgdorferi, the spirochetal agent of Lyme disease, must be an incorrect diagnosis because of the apparent preponderance of women with this condition. The flawed reasoning and conclusions of the authors threaten to perpetuate bias against women with tick-borne diseases.

Cases of Lyme disease reported by the CDC depend on standard surveillance criteria, including a physician-diagnosed erythema migrans (EM) rash, objective musculoskeletal, neurological and cardiac symptoms, and positive CDC-defined serological testing using commercial test kits. ² From 1992 to 2006, including the years examined by Wormser and Shapiro, the rate of Lyme disease reported by the CDC “increased disproportionately among young males compared to young females” for reasons that are “not known.” ³ A plausible explanation is that commercial Lyme immunoblot testing recommended by the CDC promotes gender bias because men tend to have an average of six reactive bands on the IgG immunoblot, whereas women have only four reactive bands on average. ^4,5 The number needed to satisfy CDC surveillance criteria for a positive test is five bands. Thus, the CDC-defined test system used to support the diagnosis of Lyme disease is biased against women in the formal reporting of tick-borne illness, which allegedly underestimates the true number of cases by a factor of 6–12. ⁶ The same gender bias affects the diagnosis of “post-Lyme disease” syndrome: in the studies by Klempner et al. and Krupp et al. cited by Wormser and Shapiro, ¹ patients were required to have positive CDC-defined Lyme disease testing. Thus, this newly proposed and unvetted diagnostic category also favors men over women based on the CDC surveillance criteria. ^{3 –5}

In contrast to CDC surveillance cases and “post-Lyme disease” syndrome, chronic Lyme disease is diagnosed in men and women based on persistent clinical symptoms and supporting serological testing. ⁷ In the studies by Donta cited by the authors, ¹ diagnosis of chronic Lyme disease was supported by a test system that is gender-neutral because it only requires two of six specific bands for diagnosis on a Lyme immunoblot that includes the OspA and OspB bands. ^8,9 Contrary to the poorly documented assertion by Wormser and Shapiro that this testing has a specificity of “only about 60%,” the gender-neutral test system has a specificity of 93%–94% for B. burgdorferi infection. ^8,9

When gender-neutral serological testing is used to support a clinical diagnosis, women appear to be diagnosed with chronic Lyme disease more often than men for the following reason: studies have shown that women may have an exaggerated immune response to B. burgdorferi infection that evolves over time. ^{10 –12} This immune response involves cytokine dysregulation that may cause recurrent and/or persistent multisystem symptoms as well as complaints that eventually are more likely to come to the attention of a Lyme-literate physician and trigger gender-neutral serological testing. ^{7,10 –12} The immune dysregulation of chronic Lyme disease is reflected by a decrease in CD57 natural killer cells and an increase in complement C4a levels. ^{13 –15} Studies of these immune markers in patients with persistent tick-borne illness demonstrate female/male ratios of 1.6:1 and 2.4:1, respectively. Thus, although women may be overrepresented in studies that examine the sequelae of chronic B. burgdorferi infection, the sex ratio is consistent with the pathophysiology of the disease. ^{10 –12}

In summary, the article by Wormser and Shapiro fails to recognize the diagnostic bias against women in CDC-defined surveillance testing for Lyme disease. Conversely when gender-neutral testing is used to support the diagnosis, women may be overrepresented in studies of chronic Lyme disease because of an exaggerated immune response to persistent B. burgdorferi infection. Gender bias in Lyme testing ^{3 –5} and gender-specific immunopathology ^{10 –12} are important issues that are overlooked in the faulty Lyme guidelines authored by Wormser and Shapiro, which are currently underreview. ¹⁶