Racial Disparities in Lyme Disease Treatment Onset

Tick-borne diseases are a major cause of global morbidity and mortality. With a recent estimate of 476,000 new cases annually,¹ Lyme disease, also known as Lyme borreliosis (LB), is the most common tick-borne disease in the United States. LB is an inflammatory condition caused by the bacterium Borrelia burgdorferi and transmitted by Ixodes scapularis (“blacklegged” or “deer” ticks).² Although LB has been reported across the United States, its incidence is greatest in the Northeast, upper Midwest, and Northwestern states.³

B. burgdorferi infection is divided into 3 stages: early localized, early disseminated, and late.⁴ In 70% to 80% of cases,⁵ early localized disease is accompanied by a red, slowly growing rash at the site of the tick bite, termed erythema migrans (EM), which appears a median 7 to 10 days following a tick bite,⁶ and is the most common clinical manifestation of LB.⁷ Prompt antibiotic treatment is necessary to prevent disseminated and late infection, which may present with arthralgia, myalgia, cranial nerve palsies, cardiac manifestations, and arthritis.⁴

Delayed time to treatment, the time between initial infection and treatment onset, has been associated with poor outcomes.^8,9 Ljøstad and Mygland found that a pretreatment symptom duration of 6 weeks or greater was associated with remaining complaints and objective findings 1 year following treatment.⁸ In addition, using self-report questionnaires, Eikeland et al found delayed treatment initiation to be a predictor of poorer perceived health and greater fatigue 30 months following treatment.⁹

Although antibiotic treatment often resolves most cases of LB, chronic symptoms occurring for longer than 6 months following treatment are collectively referred to as posttreatment Lyme disease syndrome (PTLDS). Potentially lasting years, PTLDS can greatly impact quality of life. A study assessing the clinical, symptom, and quality of life characterization of patients with PTLDS found that these individuals reported significantly greater fatigue, pain, sleep disturbance, and depression than healthy controls.¹⁰ Interestingly, 59% of the cohort reported initial delayed or misdiagnosis. Similarly, Hirsch et al found that treatment delay increased the risk of PTLDS. Using mailed questionnaires to individuals with an LB diagnosis in the medical record of a Pennsylvania health system, they noted that those whose time to treatment was greater than 30 days had an increased risk of PTLDS compared with those treated within 30 days of symptom onset.¹¹

Not only can delayed diagnosis and treatment onset prolong B. burgdorferi infection, but it may also increase one’s risk of persistent symptoms following treatment. Any factors contributing to diagnosis delay can have drastic consequences on quality of life. Despite its scarcity, literature suggests that Black patients may be at an increased risk for misdiagnosis or delayed diagnosis, with delayed time to treatment. Misdiagnosis or delayed diagnosis of patients with melanin-rich skin represents a greatly understudied potential health disparity with significant clinical implications. A systematic literature search was performed in August 2022. Following the removal of duplicates, 170 articles underwent title and abstract screening. Due to the scarcity of literature directly assessing racial disparities in LB treatment onset, clinical studies or case reports broadly detailing racial disparities in initial presentation, diagnosis, treatment onset, and outcomes were included. Three relevant studies and 2 case reports were retrieved.

Racial Differences in Timing of Initial Diagnosis

A 2021 study utilized claims data from 2015 to 2016 to analyze clinical manifestations and timing of initial LB diagnoses for Black vs White patients.¹² Included in the analysis were 6171 White Medicare patients and 167 Black Medicare patients. Nine percent of White patients presented with neurologic manifestations of LB on initial diagnosis, whereas 34% of Black patients had neurologic manifestations, suggesting that Black patients are more likely to present with disseminated disease when initially diagnosed.¹² Differences in clinical manifestations may be due to differential recognition of LB, both by physicians and patients themselves. Because presentation with disseminated disease reflects delayed treatment onset, this study depicts the potential for Black patients with LB to be at increased risk for poor outcomes and persistent symptoms following treatment.

Racial Differences in Inpatient Burden

Another 2021 study assessed the baseline characteristics and inpatient financial burden of LB among White and non-White patients, including Black, Hispanic, Asian, Pacific Islander, Native American, and other patients.¹³ The analysis utilized data from the 2016 National Inpatient Sample, including 9540 hospitalizations. White patients had an average length of stay (LOS) of 4.9 days, whereas non-White patients had an average LOS of 6.9 days. Delayed diagnosis and treatment may contribute to increased financial burden and LOS among non-White patients. The study authors suggested that future studies should assess racial disparities in presentation severity and time to diagnosis.

Causative Factors of Late LB in Patients With Darker Skin Tones

A historically lower reporting frequency and nontraditional early symptoms and clinical presentation may contribute to missed diagnosis of acute B. burgdorferi infection among patients with dark skin.¹⁴ The characteristic EM rash is less visible during general examination of patients scoring high on the von Luschan chromatic scale, with higher scores corresponding to darker skin tones (Figure 1).

Case Reports

In 2019, Dennison et al published a case report detailing an African American man in his 30s who presented with a possible “bug bite” with a subsequent skin lesion, chills, and fatigue.¹⁵ He was initially diagnosed with cellulitis and prescribed a 10-day course of cephalexin. After developing facial weakness, neck pain, headache, irritability, mood swings, and left leg numbness over the following 3 weeks, he was prescribed 60 mg of prednisone for a suspected allergic reaction. He presented to the emergency department 3 days later, where enzyme-linked immunosorbent assay and IgM and IgG immunoblot depicted positive Lyme serology. Treatment failed to improve his symptoms 7 weeks following illness onset, and he was subsequently diagnosed with Lyme neuroborreliosis. Eight months after the completion of LB treatment, symptoms of fatigue, muscle and low back pain, and cognitive difficulties persisted, and he was ultimately diagnosed with PTLDS. This patient’s misdiagnosis and subsequent delayed diagnosis may have fostered the progression of disease, and his persisting symptoms continued to negatively impact his quality of life months following initial infection.

Although this report details a single case of an African American man experiencing persistent symptoms of LB likely due to delayed treatment onset, it demonstrates the potential effects of disparity in the quality of medical care for non-White patients with B. burgdorferi infection. The authors stated that it is not clear if implicit bias affected the outcome; however, the case highlights the importance of prompt diagnosis and treatment of LB and broadly how medical care can be shaped by demographic factors.¹⁵

A second case report detailed LB in a 9-year-old Black child who presented with inflammatory arthritis.¹⁶ The patient presented with unilateral left knee swelling 4 days after falling from a tree branch and developed right knee swelling after admission. His serum depicted markedly elevated antibodies against B. burgdorferi, suggesting inflammatory arthritis associated with LB. EM may be difficult to recognize in Black patients, which may contribute to individuals presenting with late-stage manifestations such as arthritis.

Discussion

Black patients may be at increased risk for misdiagnosis or delayed diagnosis, thereby differentially increasing duration to treatment. However, no studies have directly assessed time to treatment among different racial groups. The differential presentation and incidence of EM may contribute to delayed or missed diagnosis in patients with melanin-rich skin. Although EM is the only physical symptom distinctive enough for diagnosis of LB in the absence of confirmatory testing,¹⁷ the rash is often more apparent on White skin and depicts the characteristic “bullseye” pattern.

Because EM can be missed on skin of color, providers must have heightened awareness when examining patients with dark skin with concomitant LB-associated symptoms even though they may be less equipped with the tools and knowledge to recognize EM on melanin-rich skin. For example, Lester et al described a study in which 47% of dermatologists felt their training was inadequate to diagnose skin disease in patients with skin of color—almost half of the participating dermatologists.¹⁸ A dearth of representation in taught material may perpetuate stereotypes, delay diagnosis and treatment, and ultimately contribute to health disparities. Similarly, skin of color is underrepresented in dermatologic^19,20 and general educational²¹ resources.

In addition to differential presentation on skin of color, EM may be less likely to present among Black patients with LB, and the absence of a Lyme-associated rash is positively associated with treatment delays.¹¹ In the Maryland Lyme Disease Registry, created in 1993, White patients with LB were more likely to have EM than Black patients with LB (69.7% and 25.0%, respectively) and less likely to have arthritis.²² There may be a negative association between Lyme-associated arthritis and EM, an early marker of infection.²² Arthritis is the most common complication among untreated patients with EM, affecting up to 60% of untreated individuals.²³ If patients with melanin-rich skin are less likely to show signs of EM, they may be more likely to remain untreated for underlying infection and develop Lyme-associated arthritis. As such, events that delay treatment onset, such as misdiagnosis or delayed diagnosis, may act as confounding factors influencing the negative association between arthritis and EM.

Lastly, the lower reported incidence of LB among Black patients may reduce clinical suspicion when they present with associated symptoms. Only 1.4% of patients with LB were Black/ non-Hispanic compared with 97% of White/non-Hispanic patients.²⁴ Suburban communities spatially close to wooded, brushy, or grassy landscapes favored by Borrelia-carrying ticks were more likely to be occupied by White individuals, increasing their risk of LB. Reported LB incidence is highest in counties with greater proportions of White individuals.²⁵ The higher odds ratio for LB among White patients may perpetuate bias, leading practitioners to consider other possibilities when Black patients present to the clinic with LB-associated symptoms in the absence of EM.

Future Research

Patients with melanin-rich skin may be at increased risk for misdiagnosis and delayed diagnosis. Delayed time to treatment is associated with worse outcomes^8,9 and increases the risk of PTLDS.¹¹ If patients with darker skin tones are at increased risk for delayed treatment onset, they may similarly be at increased risk for PTLDS. Ultimately, additional research is required to compare time to treatment among different racial groups.

A prospective study analyzing time to treatment, PTLDS incidence, and overall LB outcomes based on racial background and skin color could be useful to confirm this hypothesis. Furthermore, researchers could analyze the incidence and characterization of EM to determine if aspects of this clinical manifestation may be associated with PTLDS incidence. A colorimeter could be utilized to quantitatively measure skin color differences between the EM-affected area and surrounding skin to determine if an inverse relationship exists between rash-skin contrast and time to treatment.

Limitations

Due to the scarcity of published literature broadly detailing racial disparities and LB, included studies differed in methodology and outcomes. The results of studies could be utilized to infer differential treatment onset based on race; however, no studies directly analyzed racial differences in time to treatment. Furthermore, 2 case reports were included in the review to illustrate delayed diagnosis of LB in Black patients. The absence of representative samples of all subpopulations limits the utility of such reports. Ultimately, racial disparity in LB treatment onset is a vastly understudied topic, and novel research is required to further assess the severity and clinical impact of disparities on LB time to treatment. Conclusion Black patients with LB are more likely than White patients to present with disseminated disease. In addition, they may be at increased risk for misdiagnosis and delayed diagnosis, likely owing to differential presentation and incidence of EM, underrepresentation in medical resources, and implicit biases resulting from a historically low reporting frequency of LB among patients with skin of color. These findings together suggest that there may a racial disparity in onset of LB treatment, although novel studies are required to directly test this hypothesis. Given the difficulty visualizing EM on skin of color and the increased risk of PTLDS with delayed treatment onset, which can greatly impact quality of life, having a low threshold for considering Lyme disease in these patients may be prudent.

References

1. Kugeler KJ, Schwartz AM, Delorey MJ, Mead PS, Hinckley AF. Estimating the frequency of Lyme disease diagnoses, United States, 2010–2018. Emerg Infect Dis. 2021;27(2):616-619. doi:10.3201/eid2702.202731
2. Bernard Q, Phelan JP, Hu LT. Controlling Lyme disease: new paradigms for targeting the ick-pathogen-reservoir axis on the horizon. Front Cell Infect Microbiol. 2020;10:607170. doi:10.3389/fcimb.2020.607170.
3. Ticks and Lyme disease. Johns Hopkins Medicine. Accessed June 28, 2023. https://www.hopkinsmedicine.org/health/conditions-and-diseases/lyme-disease/ ticks-and-lyme-disease
4. Skar GL, Simonsen KA. Lyme disease. StatPearls [Internet]. StatPearls Publishing LLC; 2022.
5. Lyme disease. Centers for Disease Control and Prevention. August 5, 2022. Accessed June 28, 2023. https://www.cdc.gov/ticks/tickbornediseases/lyme.html
6. Nadelman RB, Wormser GP. Erythema migrans and early Lyme disease. Am J Med. 1995;98(4A):15S-23S; discussion 23S-24S. doi:10.1016/s0002- 9343(99)80040-0
7. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-134. doi:10.1086/508667
8. Ljøstad U, Mygland A. Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. Eur J Neurol. 2010;17(1):118-123. doi:10.1111/j.1468-1331.2009.02756.x
9. Eikeland R, Mygland Å, Herlofson K, Ljøstad U. Risk factors for a nonfavorable outcome after treated European neuroborreliosis. Acta Neurol Scand. 2013;127(3):154-160. doi:10.1111/j.1600-0404.2012.01690.x
10. Rebman AW, Bechtold KT, Yang T, et al. The clinical, symptom, and qualityof- life characterization of a well-defi ned group of patients with posttreatment Lyme disease syndrome. Front Med (Lausanne). 2017;4:224. doi:10.3389/ fmed.2017.00224
11. Hirsch AG, Poulsen MN, Nordberg C, et al. Risk factors and outcomes of treatment delays in Lyme disease: a population-based retrospective cohort study. Front Med (Lausanne). 2020;7:560018. doi:10.3389/fmed.2020.560018
12. Ly DP. Black-white differences in the clinical manifestations and timing of initial Lyme disease diagnoses. J Gen Intern Med. 2022;37(10):2597-2600. doi: 10.1007/ s11606-021-07129-1
13. Khanna R, Makhani SS, Nguyen B. Inpatient burden of Lyme disease in skin of color. J Invest Dermatol. 2021;141(5 Supplement):S96.
14. Palmieri JR, Kushwaha-Wagner A, Bekele AM, et al. Missed diagnosis and the development of acute and late Lyme disease in dark skinned populations of Appalachia. Biomed J Sci Technol Res. 2019;21(2):15782-15787.
15. Dennison R, Novak C, Rebman A, Venkatesan A, Aucott J. Lyme disease with erythema migrans and seventh nerve palsy in an African-American man. Cureus. 2019;11(12):e6509. doi:10.7759/cureus.6509
16. Newman JH. A case of Lyme disease in a 9-year-old black male. Arthritis Rheum. 1987;30(2):237. doi:10.1002/art.1780300223
17. Pachner AR. Neurologic manifestations of Lyme disease, the new "great imitator." Rev Infect Dis. 1989;11(Suppl 6):S1482-S1486.
18. Lester JC, Taylor SC, Chren MM. Under-representation of skin of colour in dermatology images: not just an educational issue. Br J Dermatol. 2019;180(6):1521- 1522. doi:10.1111/bjd.17608
19. Ebede T, Papier A. Disparities in dermatology educational resources. J Am Acad Dermatol. 2006;55(4):687-690. doi:10.1016/j.jaad.2005.10.068
20. Adelekun A, Onyekaba G, Lipoff JB. Skin color in dermatology textbooks: an updated evaluation and analysis. J Am Acad Dermatol. 2021;84(1):194-196. doi:10.1016/j.jaad.2020.04.084
21. Louie P, Wilkes R. Representations of race and skin tone in medical textbook imagery. Soc Sci Med. 2018;202:38-42. doi:10.1016/j.socscimed.2018.02.023
22. Fix AD, Peña CA, Strickland GT. Racial diff erences in reported Lyme disease incidence. Am J Epidemiol. 2000;152(8):756-759. doi:10.1093/aje/152.8.756
23. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107(5):725-731. doi:10.7326/0003-4819-107-5-725
24. Moon KA, Pollak J, Hirsch AG, et al. Epidemiology of Lyme disease in Pennsylvania 2006–2014 using electronic health records. Ticks Tick Borne Dis. 2019;10(2):241-250. doi:10.1016/j.ttbdis.2018.10.010
25. Springer YP, Johnson PTJ. Large-scale health disparities associated with Lyme disease and human monocytic ehrlichiosis in the United States, 2007–2013. PLoS ONE. 2018;13(9):e0204609. doi:10.1371/journal.pone.0204609