Atypical presentation of Lyme disease in a returning traveler: A case report

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Salcedo, Xosse Carreras, Joe Saavedra, Sandy Saldaña, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6594928/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Tropical Diseases, Travel Medicine and Vaccines → Version 1 posted 9 You are reading this latest preprint version Abstract Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes ticks, is rare in South America and is often misdiagnosed in returning travelers. We report the case of a 19-year-old Peruvian male who presented with pruritic erythematous maculopapular lesions and abdominal pain after travel to Maryland, USA. His atypical cutaneous findings, including a crusted lesion with ill-defined borders and a maculopapular rash, were initially misinterpreted as bacterial cellulitis, resulting in multiple unsuccessful courses of antibiotics. Further evaluation, guided by his travel history, led to the diagnosis of Lyme disease through serological testing and histopathology. Treatment with doxycycline achieved complete resolution. This case illustrates the diagnostic challenges posed by atypical presentations of Lyme disease in nonendemic regions. Greater awareness among clinicians in South America is essential to recognize imported cases, facilitate early diagnosis, and prevent complications associated with delayed treatment. Lyme disease travel medicine atypical skin lesions Borrelia burgdorferi global health Figures Figure 1 Figure 2 Figure 3 Introduction Lyme disease is a zoonotic infection transmitted by tick bites. 1 The main vectors include Ixodes scapularis (deer tick) in the northeastern and midwestern United States (US), where there is a high incidence of this disease. 2 Borrelia burgdorferi, a microaerophilic spirochete, is the main infectious agent in reported cases in North America. 3,4 The geographical distribution of the disease has expanded significantly in almost all Latin American countries. 5 In a recent review, the presence of B. burgdorferi in Peru was identified in several studies since 1991, with 36 cases reported with positive serology, of which only two cases had clinical manifestations. 3 However, suspicion and diagnostic confirmation in South America is challenging even with the large influx of tourists and immigrants from endemic areas. 6 The diagnosis is complicated by the diversity of symptoms, which mainly affect the skin, nervous system, heart and joints. 7 One of the greatest challenges, both in endemic and nonendemic areas, is the diverse clinical presentations of this disease, of which the skin is one of the most frequently affected organs. In addition to classic erythema migrans, multiple atypical skin manifestations complicate the early detection of the disease. Herein, we present a case of Lyme disease with atypical skin manifestations in a Peruvian patient from Maryland, US. Case description A 19-year-old Peruvian male resident of Maryland, US, was admitted to the emergency room with a one-month history of pain in the right flank of the abdomen associated with pruritic erythematous maculopapular lesions on the inner region of the left leg. He denied fever, dyspnea, fatigue, headache, weight loss or joint pain. He lived in Maryland between February and July in a wooded area but did not recall any insect or tick bites. He arrived at Lima, Peru, from Maryland, US, 3 weeks before admission. He was evaluated by a dermatologist and treated with oral clindamycin and topical mupirocin for 14 days for presumptive cellulitis. Owing to a lack of improvement, he saw a second dermatologist who started him on oral cephalexin and continued with clindamycin for 3 days. On physical examination, vital signs were within the normal range. He was oriented to time, place and person. In the right lateral region of the abdomen, there was a crusty lesion of approximately 2 cm × 1 cm with an erythematous indurated area of undefined borders and slight tenderness on palpation (Figure 1A). On the left leg, there was a tender erythematous lesion with undefined borders (Figure 1B). None of the lesions had edema. Laboratory studies revealed high C-reactive protein (113.75 mg/L) and an elevated erythrocyte sedimentation rate (45 mm/h). The complete blood count, peripheral blood smear, renal and liver profile, electrolytes, creatine kinase, urine exam and LDH were within normal limits. Direct examination for mites in the lesion of the left leg, serial parasitological examination of feces and urine toxicology were negative. At this point, empiric treatment was initiated with vancomycin due to suspicion of methicillin-resistant Staphylococcus aureus (MRSA) cellulitis. A biopsy of the lesions was performed. Owing to the patient's place of origin, Lyme disease, other types of borreliosis and rickettsiosis were also suspected; thus, serological studies were ordered. The enzyme-linked immunosorbent assay (ELISA) IgM and IgG results for B . burgdorferi were 45.1 U/ml (NV < 1.2 U/ml) and 4.2 U/ml (NV < 25 U/ml), respectively. Other tests, such as tube agglutinations for Brucella (2-mercaptoethanol and Rose Bengal), HIV, anti-HBsAg, HBc antigen IgM and IgG, HBsAg, IgM and IgG for different Rickettsia species, Cytomegalovirus IgM, VDRL, Epstein‒Barr IgM and serology for Leptospira, were negative. A Western blot test was performed to confirm the diagnosis of atypical Lyme disease, which was negative for IgG bands and positive for IgM against Borrelia spp. proteins in the serum, with bands corresponding to the OspC (gariniii) and p41 (weak intensity) proteins detected by immunoblotting. The biopsy revealed moderate chronic inflammatory infiltration consisting of lymphocytes and few plasma cells in the deep dermis (Figure 2). Multiple spirochetes were observed with Warthin-Starry stain (Figure 3). The patient was treated with 100 mg doxycycline orally every 12 hours for four weeks. At the 6-month follow-up, the skin lesions had disappeared, and the patient reported no symptoms. Discussion Lyme disease is a multisystem infectious disease with a wide range of clinical presentations. It typically begins with a pathognomonic skin lesion, known as erythema migrans, and flu-like symptoms. If left untreated, it can be followed for weeks to months later by cardiac (i.e., carditis, atrioventricular block, etc.), neurological (i.e., seizures, ataxia, peripheral neuropathies, etc.), and joint disease (especially intermittent inflammatory arthritis of one or more large joints). 8 Some prominent skin findings, in addition to erythema migrans, include borrelial lymphocytoma and acrodermatitis chronica atrophicans (ACA). 9 The former is described as an erythematous annular rash with a centrifugal extension or bull's-eye appearance. 10 The other two occur exclusively in Europe. 11 Borrelial lymphocytoma is described as a solitary bluish-red nodule or plaque located on the ear lobe in children or the breast in adults. 11 The ACA is a late manifestation that, if left untreated, causes atrophic changes in the distal extremities. 11 The diagnosis of Lyme disease is based on classic clinical findings, serological tests and epidemiological data. In the US, the Northeastern, Mid-Atlantic and Northcentral states are endemic for Lyme disease, including Maryland, especially around late spring and summer (May-August). 2,12 The CDC recommends a two-tier approach for diagnosis involving first an ELISA screening test result for IgM/IgG, followed by a confirmatory western blot. 13 The CDC criterion for positive IgM immunoblotting requires at least 2 out of the following 3 bands: 23, 39, and 41 kDa. For IgG, at least 5 of the following ten bands were detected: 18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa. 13 IgM is only recommended for the first 30 days of symptoms. 13 The sensitivity is approximately 57.7%, and the specificity is 98.0% 13 . Despite two decades of clinical familiarity with two-tier testing, misdiagnosis remains prevalent owing to misinterpretation of serologic test results 14 . In our case, the patient's travel history to Maryland during the peak Lyme season, combined with 2 positive IgM bands, supported the diagnosis. When there is a high index of suspicion, treatment with doxycycline is recommended. 9 Atypical cutaneous manifestations of Lyme disease include vesicular eruptions, erythematous papules, purpura, lymphangitic streaks, and cellulitis-like lesions.⁹˒¹⁵ In such presentations, serological testing and skin biopsy are often necessary to establish the diagnosis.⁹˒¹⁵ Histopathological examination commonly reveals a perivascular dermal lymphohistiocytic infiltrate with occasional plasma cells. Spirochetes can be detected in approximately 50% of erythema migrans lesions via Warthin-Starry staining. Despite increasing recognition of Lyme disease, atypical presentations may contribute to diagnostic delays, particularly in nonendemic settings. Early identification of cutaneous features remains critical for prompt diagnosis and treatment.¹⁵ In this case, the use of ancillary serological studies facilitated the diagnosis, highlighting the importance of maintaining a high index of suspicion in patients with a compatible clinical and epidemiological context. Syphilis was initially considered; however, serological testing was negative, and no risk factors for Treponema pallidum infection were identified. Notably, our patient was evaluated by two different dermatologists who diagnosed and treated him with oral antibiotics for cellulitis. He also received vancomycin during hospitalization due to suspicion of MRSA infection. However, the patient improved only after treatment with doxycycline for Lyme disease. Interestingly, even in endemic countries, Lyme misdiagnosis is very common. 14 In more recent studies in the USA and United Kingdom, an accurate Lyme diagnosis was made in only 27.8% and 23.0% of the cases, respectively. 14 After the introduction of the two-tier approach, improved diagnostic accuracy was expected; nonetheless, current findings have suggested the opposite, with results falling within a range of 9.6% - 15.0% in endemic countries. 14 This diagnostic challenge is further compounded by the distinctive epidemiological and clinical complexities encountered when evaluating travelers returning from endemic regions. 16 The diagnostic challenge of Lyme disease, specifically in travelers, has been described previously. 16 Especially in South America, the low prevalence of disease makes the threshold for suspicion even higher. One case of classical erythema migrans misdiagnosed as cellulitis was reported in a Colombian hospital. 17 The increase in international travel has led to the spread of infectious diseases not commonly seen in nonendemic areas. 1 8 This may confuse healthcare professionals who are not familiar with the new clinical and epidemiological pictures. One of the diseases with increased incidence in travelers in the last decade is Lyme disease. Although it is the most frequently reported arthropod-borne disease among non-US resident travelers, 6 it can be especially challenging to diagnose in nonendemic areas such as Peru. Conclusion Lyme disease should be considered in the differential diagnosis of patients presenting with dermatologic lesions and a history of travel to endemic regions. Diagnostic challenges persist even in endemic areas, and the increasing incidence of Lyme disease among travelers, combined with the potential for atypical clinical manifestations, as demonstrated in this case, underscores the need for greater awareness in nonendemic countries such as Peru. Early recognition is critical to prevent misdiagnosis, facilitate timely treatment, and reduce the risk of complications. Declarations Funding: None Consent for publication: Patient written consent was obtained. Ethical approval: Not applicable. Competing interests: No disclosure Availability of data and materials: Not applicable Authors' contributions: AS and XC: Drafting the study and writing the manuscript. JA and ND: designing and collecting data. AS, XC, JS, SS, ND, JGZ and JA revised and finalized the manuscript. All the authors discussed the results and commented on the manuscript. All the authors contributed to the article and approved the submitted version. Acknowledgments: Not applicable References Kugeler KJ, Schwartz AM, Delorey MJ, Mead PS, Hinckley AF. Estimating the frequency of lyme disease diagnoses, United States, 2010–2018. Emerging Infectious Diseases. Centers Disease Control Prev (CDC). 2021;27:616–9. Kugeler KJ, Farley GM, Forrester JD, Mead PS. Geographic Distribution and Expansion of Human Lyme Disease, United States. Emerg Infect Dis. 2015;21(8):1455–7. 10.3201/eid2108.141878 . Cervantes Jorge. Enfermedad de Lyme en el Perú: una revisión clínica y epidemiológica. Rev perú med exp salud publica. 2018;35(2):292–6. 10.17843/rpmesp.2018.352.3418 . Radolf JD, Strle K, Lemieux JE, Strle F. Lyme disease in humans. Curr Issues Mol Biol. 2020;42:333–84. 10.21775/cimb.042.333 . Stanchi NO, Olivia D, Lucca AV, Nuñez S, Lopez G, Del Curto B, et al. Retrospective Analysis of Potential Lyme Disease Clinical Cases in Argentina. Microorganisms. 2024;1(7). 10.3390/microorganisms12071374 . Stoney RJ, Esposito DH, Kozarsky P, Hamer DH, Grobusch MP, Gkrania-Klotsas E, et al. Infectious diseases acquired by international travelers visiting the USA. J Travel Med. 2018;25(1). 10.1093/jtm/tay053 . Bailón Pinargote FD, Alejandro Torres PX, Vargas Ramón MM, Camacho Muñoz JR, Núñez Chariguamám MA. Reporte de Caso Ciencia Latina Revista Científica Multidisciplinar. 2023;1(5):5255–65. 10.37811/cl_rcm.v7i5.8123 . Enfermedad de Lyme en Paciente Masculino con Antecedentes De Microadenoma Hipofisiario y Síndrome de Kallman. Hatchette TF, Davis I, Johnston BL. Lyme disease: clinical diagnosis and treatment. Can Commun Dis Rep. 2014;29(11):194–208. 10.14745/ccdr.v40i11a01 . Sharma U. Disseminated Lyme disease presenting as multiple non-target cellulitic-appearing skin lesions and oral pseudomembrane. BMJ Case Rep. 2018. https://doi.org/10.1136/bcr-2018-225921 . Eldin C, Raffetin A, Bouiller K, Hansmann Y, Roblot F, Raoult D, Parola P. Review of European and American guidelines for the diagnosis of Lyme borreliosis. Med Mal Infect. 2019;49(2):121–32. 10.1016/j.medmal.2018.11.011 . Marques AR, Strle F, Wormser GP. Comparison of lyme disease in the United States and Europe. Emerg Infect Dis Centers Disease Control Prev (CDC). 2021;27:2017–24. Moore SM, Eisen RJ, Monaghan A, Mead P. Meteorological influences on the seasonality of Lyme disease in the United States. Am J Trop Med Hyg. 2014;90(3):486–96. 10.4269/ajtmh.13-0180 . Porwancher R, Levin A, Trevejo R. Immunoblot Criteria for Diagnosis of Lyme Disease: A Comparison of CDC Criteria to Alternative Interpretive Approaches. Pathogens. 2023;26(11):1282. 10.3390/pathogens12111282 . Kobayashi T, Higgins Y, Samuels R, Moaven A, Sanyal A, Yenokyan G, Lantos PM, Melia MT, Auwaerter PG. Misdiagnosis of Lyme Disease With Unnecessary Antimicrobial Treatment Characterizes Patients Referred to an Academic Infectious Diseases Clinic. Open Forum Infect Dis. 2019;1(7):ofz299. 10.1093/ofid/ofz299 . Sharma A, Guleria S, Sharma R, Sharma A, Lyme Disease. A Case Report with Typical and Atypical Lesions. Indian Dermatol Online J-. 2017;8(2):124–7. 10.4103/2229-5178.202271 . Eldin C, Parola P. Update on Tick-Borne Bacterial Diseases in Travelers. Curr Infect Dis Rep. 2018;1(7). 10.1007/s11908-018-0624-y . Mantilla-Flórez YF, Faccini-Martínez ÁA, Pérez-Díaz CE. American woman with early Lyme borreliosis diagnosed in a Colombian hospital. Travel Med Infect Dis. 2017;16:72–3. 10.1016/j.tmaid.2017.01.005 . Jorge LMA, Hozannah AR, Lupi O, Filho FB. Lyme disease in a Brazilian traveler who returned from Germany. Bras Dermatol Sociedade Brasileira de Dermatologia. 2017;92:148–9. 10.1590/abd1806-4841.20175584 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Tropical Diseases, Travel Medicine and Vaccines → Version 1 posted Editorial decision: Revision requested 07 Jun, 2025 Reviews received at journal 06 Jun, 2025 Reviewers agreed at journal 01 Jun, 2025 Reviews received at journal 29 May, 2025 Reviewers agreed at journal 08 May, 2025 Reviewers invited by journal 07 May, 2025 Editor assigned by journal 07 May, 2025 Submission checks completed at journal 07 May, 2025 First submitted to journal 05 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6594928","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":453981050,"identity":"38743bb9-cf33-48a0-bf8e-e180a8786214","order_by":0,"name":"Andrea S. 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Gonzales-Zamora","email":"","orcid":"","institution":"Peruvian American Medical Society. Albuquerque","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"A.","lastName":"Gonzales-Zamora","suffix":""},{"id":453981056,"identity":"efb40a44-d449-451b-a3e4-f5034c49600d","order_by":6,"name":"Jorge Alave","email":"","orcid":"","institution":"Universidad Peruana Union","correspondingAuthor":false,"prefix":"","firstName":"Jorge","middleName":"","lastName":"Alave","suffix":""}],"badges":[],"createdAt":"2025-05-05 13:38:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6594928/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6594928/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40794-025-00279-8","type":"published","date":"2025-11-11T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82607154,"identity":"c46321e2-75fd-49ff-b0c5-3e213f1f4fb0","added_by":"auto","created_at":"2025-05-13 10:12:41","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83267,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Right lateral region of the abdomen with a crusty lesion of approximately 2 cm × 1 cm with an erythematous indurated area of undefined borders. (b) Left leg with an erythematous lesion with undefined borders and no indurated area.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6594928/v1/02f255d5c66e84fc33bf95dd.jpg"},{"id":82606008,"identity":"830ee375-3422-43ab-9d54-726d7d4baa01","added_by":"auto","created_at":"2025-05-13 10:04:41","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":158173,"visible":true,"origin":"","legend":"\u003cp\u003eHematoxylin and eosin-stained histopathology of the right lateral abdominal lesion revealed a deep dermis with moderate chronic inflammatory infiltrate surrounding the adnexa, which consisted of lymphocytes and few plasma cells. Magnification: x40\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6594928/v1/4eada62d9f9d71d35ab3ebf5.jpg"},{"id":82606016,"identity":"1087103b-a086-481d-82ac-55a0dae19189","added_by":"auto","created_at":"2025-05-13 10:04:41","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":176629,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathology of the right lateral abdominal lesion revealing multiple spirochetes on the Warthin-Starry stain. Magnification: x100\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6594928/v1/490224756d8880725db49643.jpg"},{"id":96104960,"identity":"26011efe-410b-4a25-8152-80a2e5e40d37","added_by":"auto","created_at":"2025-11-17 16:04:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":791393,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6594928/v1/4ddc778d-32a7-4980-a983-8a19b1f4c138.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Atypical presentation of Lyme disease in a returning traveler: A case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLyme disease is a zoonotic infection transmitted by tick bites.\u003csup\u003e1\u003c/sup\u003e The main vectors include \u003cem\u003eIxodes scapularis\u003c/em\u003e (deer tick) in the northeastern and midwestern United States (US), where there is a high incidence of this disease.\u003csup\u003e2\u003c/sup\u003e \u003cem\u003eBorrelia burgdorferi,\u003c/em\u003e a microaerophilic spirochete, is the main infectious agent in reported cases in North America.\u003csup\u003e3,4\u003c/sup\u003e The geographical distribution of the disease has expanded significantly in almost all Latin American countries.\u003csup\u003e5\u003c/sup\u003e In a recent review, the presence of\u0026nbsp;\u003cem\u003eB. burgdorferi\u003c/em\u003e in Peru was identified in several studies since 1991, with 36 cases reported with positive serology, of which only two cases had clinical manifestations.\u003csup\u003e3\u003c/sup\u003e However, suspicion and diagnostic confirmation in South America is challenging even with the large influx of tourists and immigrants from endemic areas.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis is complicated by the diversity of symptoms, which mainly affect the skin, nervous system, heart and joints.\u003csup\u003e7\u003c/sup\u003e One of the greatest challenges, both in endemic and nonendemic areas, is the diverse clinical presentations of this disease, of which the skin is one of the most frequently affected organs. In addition to classic erythema migrans, multiple atypical skin manifestations complicate the early detection of the disease.\u003c/p\u003e\n\u003cp\u003eHerein, we present a case of Lyme disease with atypical skin manifestations in a Peruvian patient from Maryland, US.\u003c/p\u003e"},{"header":"Case description","content":"\u003cp\u003eA 19-year-old Peruvian male resident of Maryland, US, was admitted to the emergency room with a one-month history of pain in the right flank of the abdomen associated with pruritic erythematous maculopapular lesions on the inner region of the left leg. He denied fever, dyspnea, fatigue, headache, weight loss or joint pain.\u0026nbsp;He lived in Maryland between February and July in a wooded area but did not recall any insect or tick bites. He arrived at Lima, Peru, from Maryland, US, 3 weeks before admission. He was evaluated by a dermatologist and treated with oral clindamycin and topical mupirocin for 14 days for presumptive cellulitis. Owing to a lack of improvement, he saw a second dermatologist who started him on oral cephalexin and continued with clindamycin for 3 days.\u003c/p\u003e\n\u003cp\u003eOn physical examination, vital signs were within the normal range. He was oriented to time, place and person. In the right lateral region of the abdomen, there was a crusty lesion of approximately 2 cm \u0026times; 1 cm with an erythematous indurated area of undefined borders and slight tenderness on palpation (Figure 1A). On the left leg, there was a tender erythematous lesion with undefined borders (Figure 1B).\u003c/p\u003e\n\u003cp\u003eNone of the lesions had edema. Laboratory studies revealed high C-reactive protein (113.75 mg/L) and an elevated erythrocyte sedimentation rate (45 mm/h). The complete blood count, peripheral blood smear, renal and liver profile, electrolytes, creatine kinase, urine exam and LDH were within normal limits. Direct examination for mites in the lesion of the left leg, serial parasitological examination of feces and urine toxicology were negative. At this point, empiric treatment was initiated with vancomycin due to suspicion of methicillin-resistant\u003cem\u003e\u0026nbsp;Staphylococcus aureus\u003c/em\u003e (MRSA) cellulitis. A biopsy of the lesions was performed. Owing to the patient\u0026apos;s place of origin, Lyme disease, other types of borreliosis and rickettsiosis were also suspected; thus, serological studies were ordered. The enzyme-linked immunosorbent assay (ELISA) IgM and IgG results for \u003cem\u003eB\u003c/em\u003e\u003cem\u003e. burgdorferi\u003c/em\u003e were 45.1 U/ml (NV \u0026lt; 1.2 U/ml) and 4.2 U/ml (NV \u0026lt; 25 U/ml), respectively. Other tests, such as tube agglutinations for Brucella (2-mercaptoethanol and Rose Bengal), HIV, anti-HBsAg, HBc antigen IgM and IgG, HBsAg, IgM and IgG for different Rickettsia species, Cytomegalovirus IgM, VDRL, Epstein‒Barr IgM and serology for Leptospira, were negative. A Western blot test was performed to confirm the diagnosis of atypical Lyme disease, which was negative for IgG bands and positive for IgM against Borrelia spp. proteins in the serum, with bands corresponding to the OspC (gariniii) and p41 (weak intensity) proteins detected by immunoblotting. The biopsy revealed moderate chronic inflammatory infiltration consisting of lymphocytes and few plasma cells in the deep dermis (Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMultiple spirochetes were observed with Warthin-Starry stain (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient was treated with 100 mg doxycycline orally every 12 hours for four weeks. At the 6-month follow-up, the skin lesions had disappeared, and the patient reported no symptoms.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eLyme disease is a multisystem infectious disease with a wide range of clinical presentations. It typically begins with a pathognomonic skin lesion, known as erythema migrans, and flu-like symptoms. If left untreated, it can be followed for weeks to months later by cardiac (i.e., carditis, atrioventricular block, etc.), neurological (i.e., seizures, ataxia, peripheral neuropathies, etc.), and joint disease (especially intermittent inflammatory arthritis of one or more large joints).\u003csup\u003e8\u003c/sup\u003e Some prominent skin findings, in addition to erythema migrans, include borrelial lymphocytoma and acrodermatitis chronica atrophicans (ACA).\u003csup\u003e9\u003c/sup\u003e The\u0026nbsp;former is described as an erythematous annular rash with a centrifugal extension or bull's-eye appearance.\u003csup\u003e10\u003c/sup\u003e The other two occur exclusively in Europe.\u003csup\u003e11\u003c/sup\u003e Borrelial lymphocytoma is described as a solitary bluish-red nodule or plaque located on the ear lobe in children or the breast in adults.\u003csup\u003e11\u003c/sup\u003e The ACA is a late manifestation that, if left untreated, causes atrophic changes in the distal extremities.\u003csup\u003e11\u003c/sup\u003e The diagnosis of Lyme disease is based on classic clinical findings, serological tests and epidemiological data. In the US, the Northeastern, Mid-Atlantic and Northcentral states are endemic for Lyme disease, including Maryland, especially around late spring and summer (May-August).\u003csup\u003e2,12\u003c/sup\u003e The CDC recommends a two-tier approach for diagnosis involving first an ELISA screening test result for IgM/IgG, followed by a confirmatory western blot.\u003csup\u003e13\u003c/sup\u003e The CDC criterion for positive IgM immunoblotting requires at least 2 out of the following 3 bands: 23, 39, and 41 kDa. For IgG, at least 5 of the following ten bands were detected: 18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa.\u003csup\u003e13\u003c/sup\u003e IgM is only recommended for the first 30 days of symptoms.\u003csup\u003e13\u003c/sup\u003e The sensitivity is approximately 57.7%, and the specificity is 98.0%\u003csup\u003e13\u003c/sup\u003e. Despite two decades of clinical familiarity with two-tier testing, misdiagnosis remains prevalent owing to misinterpretation of serologic test results\u003csup\u003e14\u003c/sup\u003e. In our case, the patient's travel history to Maryland during the peak Lyme season, combined with 2 positive IgM bands, supported the diagnosis. When there is a high index of suspicion, treatment with doxycycline is recommended.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAtypical cutaneous manifestations of Lyme disease include vesicular eruptions, erythematous papules, purpura, lymphangitic streaks, and cellulitis-like lesions.⁹˒¹⁵ In such presentations, serological testing and skin biopsy are often necessary to establish the diagnosis.⁹˒¹⁵ Histopathological examination commonly reveals a perivascular dermal lymphohistiocytic infiltrate with occasional plasma cells. Spirochetes can be detected in approximately 50% of erythema migrans lesions via Warthin-Starry staining. Despite increasing recognition of Lyme disease, atypical presentations may contribute to diagnostic delays, particularly in nonendemic settings. Early identification of cutaneous features remains critical for prompt diagnosis and treatment.¹⁵ In this case, the use of ancillary serological studies facilitated the diagnosis, highlighting the importance of maintaining a high index of suspicion in patients with a compatible clinical and epidemiological context. Syphilis was initially considered; however, serological testing was negative, and no risk factors for \u003cem\u003eTreponema pallidum\u003c/em\u003e infection were identified.\u003c/p\u003e\n\u003cp\u003eNotably, our patient was evaluated by two different dermatologists who diagnosed and treated him with oral antibiotics for cellulitis. He also received vancomycin during hospitalization due to suspicion of MRSA infection. However, the patient improved only after treatment with doxycycline for Lyme disease.\u0026nbsp;Interestingly, even in endemic countries, Lyme misdiagnosis is very common.\u003csup\u003e14\u003c/sup\u003e In more recent studies in the USA and United Kingdom, an accurate Lyme diagnosis was made in only 27.8% and 23.0% of the cases, respectively.\u003csup\u003e14\u003c/sup\u003e After the introduction of the two-tier approach, improved diagnostic accuracy was expected; nonetheless, current findings have suggested the opposite, with results falling within a range of 9.6% - 15.0% in endemic countries.\u003csup\u003e14\u003c/sup\u003e This diagnostic challenge is further compounded by the distinctive epidemiological and clinical complexities encountered when evaluating travelers returning from endemic regions. \u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The diagnostic challenge of Lyme disease, specifically in travelers, has been described previously.\u003csup\u003e16\u003c/sup\u003e Especially in South America, the low prevalence of disease makes the threshold for suspicion even higher. One case of classical\u0026nbsp;erythema migrans misdiagnosed as cellulitis was reported in a Colombian hospital.\u003csup\u003e17\u003c/sup\u003e The increase in international travel has led to the spread of infectious diseases not commonly seen in nonendemic areas.\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e This may confuse healthcare professionals who are not familiar with the new clinical and epidemiological pictures. One of the diseases with increased incidence in travelers in the last decade is Lyme disease. Although it is the most frequently reported arthropod-borne disease among non-US resident travelers,\u003csup\u003e6\u003c/sup\u003e it can be especially challenging to diagnose in nonendemic areas\u0026nbsp;such as Peru.\u003c/p\u003e\n\n"},{"header":"Conclusion","content":"\u003cp\u003eLyme disease should be considered in the differential diagnosis of patients presenting with dermatologic lesions and a history of travel to endemic regions. Diagnostic challenges persist even in endemic areas, and the increasing incidence of Lyme disease among travelers, combined with the potential for atypical clinical manifestations, as demonstrated in this case, underscores the need for greater awareness in nonendemic countries such as Peru. Early recognition is critical to prevent misdiagnosis, facilitate timely treatment, and reduce the risk of complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Patient written consent was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e No disclosure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u0026nbsp;\u003c/strong\u003eAS and XC: Drafting the study and writing the manuscript. JA and ND: designing and collecting data. AS, XC, JS, SS, ND, JGZ and JA revised and finalized the manuscript. All the authors discussed the results and commented on the manuscript. All the authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKugeler KJ, Schwartz AM, Delorey MJ, Mead PS, Hinckley AF. Estimating the frequency of lyme disease diagnoses, United States, 2010\u0026ndash;2018. Emerging Infectious Diseases. Centers Disease Control Prev (CDC). 2021;27:616\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKugeler KJ, Farley GM, Forrester JD, Mead PS. Geographic Distribution and Expansion of Human Lyme Disease, United States. 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Bras Dermatol Sociedade Brasileira de Dermatologia. 2017;92:148\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1590/abd1806-4841.20175584\u003c/span\u003e\u003cspan address=\"10.1590/abd1806-4841.20175584\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"tropical-diseases-travel-medicine-and-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tdtm","sideBox":"Learn more about [Tropical Diseases, Travel Medicine and Vaccines](http://tdtmvjournal.biomedcentral.com)","snPcode":"40794","submissionUrl":"https://submission.nature.com/new-submission/40794/3","title":"Tropical Diseases, Travel Medicine and Vaccines","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lyme disease, travel medicine, atypical skin lesions, Borrelia burgdorferi, global health","lastPublishedDoi":"10.21203/rs.3.rs-6594928/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6594928/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes ticks, is rare in South America and is often misdiagnosed in returning travelers. We report the case of a 19-year-old Peruvian male who presented with pruritic erythematous maculopapular lesions and abdominal pain after travel to Maryland, USA. His atypical cutaneous findings, including a crusted lesion with ill-defined borders and a maculopapular rash, were initially misinterpreted as bacterial cellulitis, resulting in multiple unsuccessful courses of antibiotics. Further evaluation, guided by his travel history, led to the diagnosis of Lyme disease through serological testing and histopathology. Treatment with doxycycline achieved complete resolution. This case illustrates the diagnostic challenges posed by atypical presentations of Lyme disease in nonendemic regions. Greater awareness among clinicians in South America is essential to recognize imported cases, facilitate early diagnosis, and prevent complications associated with delayed treatment.","manuscriptTitle":"Atypical presentation of Lyme disease in a returning traveler: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 10:04:36","doi":"10.21203/rs.3.rs-6594928/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-07T10:34:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-07T02:16:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275558677607041309894901026775392551388","date":"2025-06-01T13:08:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-29T22:13:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"100833878356867453934062452913807525650","date":"2025-05-08T06:09:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-07T15:02:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-07T07:11:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-07T07:09:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Tropical Diseases, Travel Medicine and Vaccines","date":"2025-05-05T13:28:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"tropical-diseases-travel-medicine-and-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tdtm","sideBox":"Learn more about [Tropical Diseases, Travel Medicine and Vaccines](http://tdtmvjournal.biomedcentral.com)","snPcode":"40794","submissionUrl":"https://submission.nature.com/new-submission/40794/3","title":"Tropical Diseases, Travel Medicine and Vaccines","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"177c2b34-fe92-43e8-a4f8-e2041d51683e","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T15:59:42+00:00","versionOfRecord":{"articleIdentity":"rs-6594928","link":"https://doi.org/10.1186/s40794-025-00279-8","journal":{"identity":"tropical-diseases-travel-medicine-and-vaccines","isVorOnly":false,"title":"Tropical Diseases, Travel Medicine and Vaccines"},"publishedOn":"2025-11-11 15:57:09","publishedOnDateReadable":"November 11th, 2025"},"versionCreatedAt":"2025-05-13 10:04:36","video":"","vorDoi":"10.1186/s40794-025-00279-8","vorDoiUrl":"https://doi.org/10.1186/s40794-025-00279-8","workflowStages":[]},"version":"v1","identity":"rs-6594928","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6594928","identity":"rs-6594928","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}