ABSTRACT.
The erythema migrans (EM) rash is an important initial diagnostic sign of early Lyme disease. We tested the hypothesis that patients who noticed EM first differed from those who noticed viral-like symptoms first. “EM First” participants (167/271, 61.6%) had shorter illness duration before treatment (5.0 versus 6.2 days, P = 0.019), were more likely to have seen or removed a tick (P = 0.048) and to be non-Hispanic White (P = 0.025), and were less likely to present with disseminated lesions at the time of diagnosis (P = 0.003) than “Symptoms First” participants (104/271, 38.4%). In multivariate analyses, EM First participants had a 22% decrease in time to treatment (P = 0.012) compared with Symptoms First participants, suggesting that initial presentation affects time to treatment. In a large minority of patients, EM may not be the initial sign or symptom of early Lyme disease. There is a need for rapid diagnostics and improved physician awareness of the varied manifestations of early Lyme disease.
Lyme disease is the most commonly reported tick-borne disease in the United States.1 The characteristic sign of early Lyme disease is the erythema migrans (EM) skin rash, which initially occurs at the site of the inoculating tick bite.2 Secondary EM lesions can occur following subsequent dissemination of the bacteria to other regions of the skin.3 Although EM is often described as the first sign of infection with Borrelia burgdorferi, it may or may not be accompanied by concurrent, viral-like symptoms such as fatigue, fever, or myalgia.4
We have noted clinically that a subset of patients with early Lyme disease report that initial, nonspecific disease symptoms appeared prior to the subsequent development or observation of EM. Because these patients are rarely described in the literature, the primary objective of this study is to describe the characteristics and significance of this subset in a large sample of patients with early Lyme disease. We hypothesize that this clinical presentation will be associated with increased risk for treatment delays and initial misdiagnosis. This is important because prompt initiation of appropriate antibiotic treatment is essential to reduce the risk of later-stage manifestations of Lyme disease.5–7
These cross-sectional analyses draw on data from a broader, longitudinal cohort study conducted in the mid-Atlantic region of the United States. Adult patients (≥ 18 years) with visible, diagnostic EM (either single or multiple) self-referred or were recruited from primary or urgent care settings during the spring, summer, and fall months of 2008–2020. Additional eligibility details and baseline characterization of these participants have been previously described.8
A trained interviewer administered demographic and Lyme disease history questionnaires. Participants were categorized as either “EM First” or “Symptoms First” based on the order of the initial symptoms they observed. Those who noticed both the EM and viral-like symptoms on the same day were categorized as EM First. The number of days to appropriate antibiotic treatment initiation (“time to treatment”) was calculated from the participants’ self-reported, first Lyme disease sign or symptom. Additional questions were added in 2016 and administered to a subset of participants (107/271, 39.5%) to determine whether they had originally received an alternative diagnosis (“misdiagnosis”) for their Lyme disease in this interval. The Institutional Review Board of the Johns Hopkins University School of Medicine approved this study, and written informed consent was obtained for all participants prior to initiation of study-related activities.
Descriptive results were presented as percentages for categorical variables, and measures of central tendency and variation for continuous variables. Select characteristics of the EM First and Symptoms First groups were compared using Fisher’s exact, χ2, or Wilcoxon rank-sum tests. To test the hypothesis that EM First versus Symptoms First would be associated with differences in time to treatment, we generated simple linear regression models. Robust standard errors were applied to all models to account for minor problems with normality, heteroscedasticity, and influential points. Factors with P < 0.150 were included in a final multiple linear regression model. A P value less than 0.05 was considered statistically significant. Analyses were performed using SAS (version 9.3, SAS Institute, Cary, NC) or R (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria) and the graph was produced using Prism version 8.4.3 (GraphPad Software, San Diego, CA).
Demographic and clinical details of this sample of 271 participants are shown in Table 1 and have been described elsewhere.8 Of these, 104 (38.4%) were characterized as Symptoms First, with symptoms starting a median of 3.0 days (interquartile range [IQR]: 2.0–6.0; range: 1.0–31.0) prior to noticing EM. Fatigue/weakness was the most prominent of these pre-EM viral-like symptoms and was reported by 42 (45.7%) of the 92 who reported specific symptoms prior to their EM (Figure 1). For 14/92 (15.2%), it was the only symptom reportedly experienced prior to EM.
Table 1.
Participants with early Lyme disease whose first symptom was the EM skin lesion were compared with those who first noticed viral-like symptoms prior to their EM
| Participant characteristics | All N = 271 | EM First N = 167 | Symptoms First N = 104 | P value |
|---|---|---|---|---|
| Age (years) | 52 (38–62) [18–82] | 54 (37–64) [18–82] | 51 (40–60) [20–80] | 0.545 |
| Sex | ||||
| Male | 152 (56.1%) | 97 (58.1%) | 55 (52.9%) | 0.402 |
| Female | 119 (43.9%) | 70 (41.9%) | 49 (47.1%) | |
| Education (years) | 16 (16–18) [9–26] | 16 (15–18) [9–26] | 16 (16–19) [10–26] | 0.240 |
| Race/ethnicity | ||||
| Non-Hispanic White | 260 (95.9%) | 164 (98.2%) | 96 (92.3%) | 0.025 |
| Other | 11 (4.1%) | 3 (1.8%) | 8 (7.7%) | |
| Time from disease onset to antibiotic treatment (days) | 6.0 (3.5–10.0) [0.0–70.0] | 5.0 (3.0–9.0) [0.0–70.0] | 6.2 (4.0–11.1) [1.3–39.3] | 0.019 |
| EM largest diameter on exam (cm) | 12.0 (8.0–16.0) [5.0–35.0] | 11.0 (7.0–17.0) [5.0–35.0] | 12.0 (9.0–15.5) [5.0–26.0] | 0.395 |
| Disseminated EM | ||||
| Yes | 88 (32.5%) | 43 (25.7%) | 45 (43.3%) | 0.003 |
| No | 183 (67.5%) | 124 (74.3%) | 59 (56.7%) | |
| EM central clearing | 123 (45.4%) | 81 (48.5%) | 42 (40.4%) | 0.192 |
| Initial misdiagnosis | ||||
| Yes | 15/107 (14.0%) | 7/69 (10.1%) | 8/38 (21.1%) | 0.120 |
| No | 92/107 (86.0%) | 62/69 (89.9%) | 30/38 (78.9%) | |
| Noticed or removed tick | ||||
| Yes | 41/257 (16.0%) | 31/159 (19.5%) | 10/98 (10.2%) | 0.048 |
| No | 216/257 (84.0%) | 128/159 (80.5%) | 88/98 (89.8%) | |
EM = erythema migrans. N (%) is presented for categorical variables and median (interquartile range) [range] is presented for continuous variables. One participant (0.4%) missed years of education. Fourteen (5.2%) were not asked whether they had noticed or removed the tick that caused their illness, and 164 (60.5%) were not asked whether they had received a prior diagnosis for their Lyme disease (these questions were added partway through the study).
Figure 1.
The percentage of 92 Symptoms First participants who reported specific new-onset symptoms prior to developing or observing the erythema migrans skin lesion. Participants indicated all symptoms that occurred in that time frame, and therefore symptoms listed are not mutually exclusive.
By definition, all Symptoms First participants had at least one new-onset symptom besides EM, compared with 136/167 (81.4%) of EM First participants. Compared with Symptoms First participants, EM First participants were more likely to have noticed or removed the tick that bit them (P = 0.048) and less likely to present with disseminated lesions at the time of diagnosis and study enrollment (P = 0.003) (Table 1). Symptoms First participants had a longer overall time from first symptom to treatment compared with EM First participants (P = 0.019). Once the EM was observed, however, time to treatment was shorter in this group (median: 2.3; IQR: 1.0–5.0; range: 0.0–17.5; P < 0.0001). There were only 11 participants in our sample who did not self-identify as non-Hispanic White; however, they were overrepresented in the Symptoms First group (P = 0.025). Although not statistically significant, misdiagnoses occurred approximately twice as frequently in the Symptoms First group. Among EM First participants, all initial misdiagnoses were for alternative dermatologic conditions, including cellulitis, shingles, fungal infections, or other insect or arachnid bites. Although dermatologic misdiagnoses were also found among the Symptoms First group, participants were more commonly diagnosed with other nondermatologic infections, including an unspecified virus, sinus infection, or urinary tract infection.
In unadjusted models, EM First and a central clearing EM pattern were significantly associated with shorter time to treatment (Table 2) (P < 0.05). In the final adjusted model, being in the EM First group corresponded to a 22% decrease in time to treatment and was the most statistically significant predictor (P = 0.012). Additionally, each added year of education corresponded to a 4% decrease in time to treatment (P = 0.048). The remaining factors tested were not significant in the adjusted model.
Table 2.
Log linear regression models with the natural logarithm of estimated days to initiation of appropriate antibiotic treatment as the dependent variable and select demographic and clinical factors as the independent variables
| Unadjusted | Adjusted | |||
|---|---|---|---|---|
| Independent variables | Estimated coefficient (95% CI) | P value | Estimated coefficient (95% CI) | P value |
| EM First | −0.26 (−0.45, −0.06) | 0.011 | −0.25 (−0.44, −0.06) | 0.012 |
| Education (1 year) | −0.03 (−0.07, 0.00) | 0.076 | −0.04 (−0.07, 0.00) | 0.048 |
| Age (10 years) | 0.06 (0.00, 0.12) | 0.068 | 0.06 (0.00, 0.12) | 0.063 |
| EM central clearing | −0.21 (−0.42, −0.01) | 0.039 | −0.15 (−0.35, 0.06) | 0.162 |
| Male sex | −0.06 (−0.27, 0.15) | 0.587 | N/A | – |
| Non-Hispanic White | −0.14 (−0.60, 0.31) | 0.542 | N/A | – |
| Noticed or removed tick | −0.20 (−0.50, 0.10) | 0.182 | N/A | – |
EM = erythema migrans. One participant (0.4%) missed years of education. Fourteen (5.2%) were not asked whether they had noticed or removed the tick that caused their illness. Two outliers with 0 days to initiation of antibiotic treatment were removed from all models because a natural log could not be calculated. The final adjusted model included data from 268 participants and had an adjusted R2 of 0.05. N/A = P value > 0.15 in unadjusted models and not included in adjusted models.
Despite its varied presentations,8 EM at the site of the tick bite is often considered the earliest and hallmark sign of infection with B. burgdorferi. Indeed, clinical diagnosis of EM is the most specific tool currently available to physicians early in the infection, when serologic tests have poor sensitivity.9 However, it has been appreciated for some time that a subset of patients with early Lyme disease may not develop or notice EM before it typically resolves after approximately 4 weeks, regardless of treatment.10,11 Our findings indicate that even among those with subsequent EM, 38% report viral-like symptoms beginning 3 days prior, on average (Symptoms First).
This is important because viral-like symptoms alone likely contribute significantly to appraisal delays among patients and treatment delays among physicians.6,12 The Symptoms First subset reported disease durations on average 1–2 days longer than the EM First group, with this statistically significant trend persisting in adjusted models as well. Surprisingly, this effect was more significant than those of other hypothesized independent risk factors such as age, sex, and education, or the classic central clearing EM presentation. Furthermore, the Symptoms First group had higher rates of multiple EM present at diagnosis, indicating that they are generally presenting later in their illness, when the bacteria have had more time to disseminate.
It is also notable that darker-skinned patients were overrepresented in our Symptoms First group. We also observed a trend for increased time to treatment among participants identifying as Hispanic and/or non-White; however, this was not statistically significant. Previous studies have found that African-American and Hispanic patients with Lyme disease are more likely to present with later manifestations, suggesting delays in recognition and treatment of early stages.13,14 As others have noted, we hypothesize that these trends may exist because EM is less visible on darker skin. Additionally, the historic underrepresentation of darker skin in teaching images,15 in conjunction with real or imagined differences in exposure risk, may contribute to more limited physician awareness of early Lyme disease in darker-skinned patients.
Despite advances in patient identification in the approximately 45 years since Lyme disease was first recognized in the United States, misdiagnosis still occurs with some frequency in the community practice of medicine.12,16 In the current study, the overall rate of initial misdiagnosis was 14% among patients presenting with a visible, diagnostic EM in a highly endemic area. This rate was 21% among the subset of these patients who initially developed viral-like symptoms prior to EM. The rates of misdiagnosis and/or treatment delays among patients presenting without EM may be higher still due to the nonspecific nature of their initial presentation and the lack of any pathognomonic features to guide diagnosis.6,16
This study’s primary limitation is the lack of direct bacterial detection to confirm participants’ Lyme disease diagnoses. Furthermore, we did not gather appropriate data on other factors that could significantly affect time to treatment, and thus their impact is left for future studies. Specifically, EM bodily location may impact the likelihood of prompt rash recognition. Finally, the small number of participants identifying as non-White and/or Hispanic renders evaluation of the impact of race/ethnicity on time to treatment difficult. Future studies with more diverse racial/ethnic sample distributions will be needed to adequately examine these questions.
Viral-like symptoms alone in the absence of another highly specific sign or symptom pose perhaps the most significant challenge for physicians diagnosing Lyme and other tick-borne diseases, especially in the SARS-CoV-2 era.17,18 Given its ubiquity, fatigue poses a particular challenge to both the sensitivity and specificity of Lyme disease diagnosis; in our sample, it was the most common symptom reported by the Symptoms First group. There is a need for sensitive, clinically available, rapid diagnostics and improved physician awareness of the varied manifestations of early Lyme disease to reduce the burden of treatment delays and subsequent risk of later-stage complications.5–7
ACKNOWLEDGMENTS
We thank Erica Kozero and Cheryl Novak for their assistance with participant study visits. We are grateful to the research participants who contributed their time and efforts to this study.
REFERENCES
- 1. Kugeler KJ, Schwartz AM, Delorey MJ, Mead PS, Hinckley AF, 2021. Estimating the frequency of Lyme disease diagnoses, United States, 2010–2018. Emerg Infect Dis 27: 616–619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, Li X, Mead PS, 2016. Lyme borreliosis. Nat Rev Dis Primers 2: 16090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Wormser GP, McKenna D, Carlin J, Nadelman RB, Cavaliere LF, Holmgren D, Byrne DW, Nowakowski J, 2005. Brief communication: hematogenous dissemination in early Lyme disease. Ann Intern Med 142: 751–755. [DOI] [PubMed] [Google Scholar]
- 4. Nadelman RB, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Cooper D, Aguero-Rosenfeld M, Wormser GP, 1996. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med 100: 502–508. [DOI] [PubMed] [Google Scholar]
- 5. Shadick NA. et al. , 1994. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 121: 560–567. [DOI] [PubMed] [Google Scholar]
- 6. Hirsch A, Poulsen M, Nordberg C, Moon K, Rebman A, Aucott J, Heaney C, Schwartz B, 2020. Risk factors and outcomes of treatment delays in Lyme disease: a population-based retrospective cohort study. Front Med 7: 560018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Luft BJ, Dattwyler RJ, Johnson RC, Luger SW, Bosler EM, Rahn DW, Masters EJ, Grunwaldt E, Gadgil SD, 1996. Azithromycin compared with amoxicillin in the treatment of erythema migrans. A double-blind, randomized, controlled trial. Ann Intern Med 124: 785–791. [DOI] [PubMed] [Google Scholar]
- 8. Rebman AW, Yang T, Mihm EA, Novak CB, Yoon I, Powell D, Geller SA, Aucott J, 2021. The presenting characteristics of erythema migrans vary by age, sex, duration, and body location. Infection 49: 685–692. [DOI] [PubMed] [Google Scholar]
- 9. Branda JA. et al. , 2018. Advances in serodiagnostic testing for Lyme disease are at hand. Clin Infect Dis 66: 1133–1139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Feder HM, Gerber MA, Krause PJ, Ryan R, Shapiro ED, 1993. Early Lyme disease: a flu-like illness without erythema migrans. Pediatrics 91: 456–459. [PubMed] [Google Scholar]
- 11. Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW, Sigal LH, Spieler PN, Stenn KS, Malawista SE, 1983. The early clinical manifestations of Lyme disease. Ann Intern Med 99: 76–82. [DOI] [PubMed] [Google Scholar]
- 12. Hirsch AG, Herman RJ, Rebman A, Moon KA, Aucott J, Heaney C, Schwartz BS, 2018. Obstacles to diagnosis and treatment of Lyme disease in the USA: a qualitative study. BMJ Open 8: e021367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Fix AD, Pena CA, Strickland GT, 2000. Racial differences in reported Lyme disease incidence. Am J Epidemiol 152: 756–759. [DOI] [PubMed] [Google Scholar]
- 14. Nelson CA, Starr JA, Kugeler KJ, Mead PS, 2016. Lyme disease in Hispanics, United States, 2000–2013. Emerg Infect Dis 22: 522–525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Lester JC, Taylor SC, Chren M-M, 2019. Under‐representation of skin of colour in dermatology images: not just an educational issue. Br J Dermatol 180: 1521–1522. [DOI] [PubMed] [Google Scholar]
- 16. Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK, 2009. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infect Dis 9: 79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Novak CB, Scheeler VM, Aucott JN, 2021. Lyme disease in the era of COVID-19: a delayed diagnosis and risk for complications. Case Rep Infect Dis 2021: 6699536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Wormser GP, Jacobson E, Shanker EM, 2021. Negative impact of the COVID-19 pandemic on the timely diagnosis of tick-borne infections. Diagn Microbiol Infect Dis 99: 115226. [DOI] [PMC free article] [PubMed] [Google Scholar]