Further expanding the defined tree of genetic determinants will improve Borrelia diagnosis, in support of other study, DNA extract polymerase chain reaction (PCR) was most effective; however there are reported diagnosis suggesting direct tissue study is superior to serological testing. And case report analyses of Borrelia pathogenesis in atypical clinical presentations of Lyme disease (LD) accompanied prolonged diagnosis until PCR tests were implemented, with each case report having effective treatment outcomes with either doxycycline or intravenous ceftiaxone with most effect. Furthermore, revealed false negatives associated with antibody testing and the duration of pathogenesis, suggests the importance of different clinical stages and antibody reactivity during the testing phases, in addition, immunodeficiency reveals reduced responses to antibody tests. However, indications of molecular mimicry can lead to Borrelia autoimmunity and DNA persistence which is maladptive for PCR diagnosis and treatment evaluation.
Spirochetes, Borrelia, originate from tick saliva., Ixodes, species listed: North Americak Ixodes scapularis and Ixodes pacificuc; European Ixodes ricinus, and Asian Ixodes persulcatus; with the adult tick as the predominant vector of their lifecycle (Steere er al. 2017; Stanek et al. 2012). The two Borrelia subcategories: B. miyamotoi causing febrile relapse, and B. burgdorferi sensu lato causing Lyme Disease (LD), the latter the focus group of this review (Boden et al, 2016). Borrelia spread was originally regionally specific, AMerican B. burgdorferi, predominantly cardiological; B. garinii mainly neurological; and B. afzelii primarily dermatological, both found Europe and Asia (Steere. 2001), there are the three primary genetic variants that cause LD. The aim of this review is to compare descriptive observation of each distinct Borrelia pathogenesis across a series of cases reporting atypical clinical presenetation in LD, with critical analysis of diagnostic tools evidencing polymerase chain reaction (PCR) effectiveness, followed by evaluation of specific treatment methods (Pritt et al. 2016; Lebech et al. 2002).
Paim et al. (2018) reported a 68 year-old, avid outdoorsman of whom stated prior exposure to a tick-borne infection caught years ago; suggesting long-term microbial epitope exposure that may cause chronic autoimmunity through molecular mimicry (Wilke et al. 2000; Sigh et al. 2004). The case reported a two-week dysponea and orthopnoea, however no prior cardiothoracic treatment or historical premature cardiovascular disease (CVD) stated whcich could have contributed to the progression of respiratory dysfunction. The case denied typical LD symptons: athralgia and rashes capable of erythema migrans, additionally, the patient was afebrile, hemodynamically stable, with a normal leukocyte range and haematocrit, as well as, normal renal function, potential rule out of relapsing fever (Boden et al. 2016).
Respectively, erythrocyte sedimentation rate (ESR) was valued normal with negative finding for procalcitonin, indicating no abnormal haemolysis or bacterial sepsis markers. However, tissue injury in the patient was revealed through elevated C reactive proteins (CRP) levels, possible of Borrelia infiltration. Respiratory irregularities were found colloquial to tachycardia and diminished bilateral lung sound; chest radiography showed bilateral pleural effusions with bibasilar atelectasis and possible lung infiltrates, the authors suggested the possible of community-acquired pneumonia and treated accordingly with ceftriaxone and azithromycin, and diuretic therapy preventing the outcome of heart failure.
The authors further tested for CVD with transthoracic echo-diagram revealing severe valvular dysfunction, subsequently evaluated by transoesophageal echo-diagram showing mitral valve perforation and regurgitation, collectively indicating endocarditis. Mitral valve histopathology exposed endocarditic inflammation; however, no microorganism was identified through staining. Further evaluation proved LD positive, as enzyme-linked immunosorbent assay (ELISA) found two Immunoglobulin (Ig) M and ten IgG bands, indicating active or previous B. burgdorferi infection, therefore not proving the possible persistence of infection, (Glatz et al. 2006; Panelius et al. 2007). Although initial implemented serological PCR tests proved negative, however, further 16S rRNA PCR sequencing on mitral valve tissue paired with targeted primer, plasminogen-binding protein, oppA2 variant, proved positive for B. burgdorferi. Additional studies have also shown PCR testing effective for diagnosis where false seronegative results are possible (Wagemakers et al. 2018; Gooskens et al. 2006; Moniuszko et al. 2015).
Conclusive mechanical treatment involved mitral valve repair and aortic valve replacement. Pharmacological treatment involved six-week intravenous (IV) administration for ceftriaxone, which has also shown desirable results in other cases (Topakian et al. 2016; Wagemakers et al. 2018). The patient eventually showed no evidence of infection and CRP returned to normal.
Ghislain et al. (2003) showcased misdiagnosis possibilities in case report of Borrelia lymphocytoma, which, the authors emphasised, initial PCR tests would efficiently avoid. Over a three-month period, a 57-year old developed an erythematous macule in an areola infiltrate. Assessment of the homogenous, inflamed tissue, using two mammograms revealed thickening of areolar plaque. Through fine-needle aspiration, the authors failed finding atypical/malignant cell types, as well as, negative findings for tumour cell markers, collectively suggesting psuedolymphoma not Borrelia infiltration.
Conversely, conducted ELISA missed Borrelia and proved negative of IgM and IgG bands, also shown in other study to not be entirely effective for diagnosis (Maraspin et al. 2016). Also, further misleading diagnosis, the patient had not noticed a tick bite prior. Although the authors suggested such skin diseases can resolve without treatment, whilst risking possible future autoimmune relapse, however, the skin biopsy showed possible lymphohistiocytic infiltration, which can cause fatal excessive systemic inflammation (Hoornstra et al. 2018; Sudhindra et al. 2016; Cascio et al. 2012).
Consequently, PCR test of cryopreserved skin-specimen proved highly positive for B. afzelii, like that of ‘Case Study 1’, the PCR test only proved effective when direct with affected tissue, the authors suggest the density of the fibrous changes in the connective tissue to be causation of serological misdiagnosis. Comparatively, where ‘Case study 1’ symptoms were visibly two-weeks old, here the negative result could be due to ELISA sensitivity dependent on clinical stage, antigen heterogeneity, and primer selection (Dessau et al. 2015; Scholz et al. 2013; Sillanpaa et al. 2014). The patient was put on daily doxycycline, an also highly effective antibiotic, especially in early dissemination due to available oral administration and simple monitoring, however ceftriaxone proves more effective in crossing the blood-brain barrier and does not cause as many cases of increased photosensitivity and gastrointestinal symptoms, therefore preferable for children and pregnant women (Ljostad et al. 2008; Borg et al. 2005; Stanek et al. 2012; Ogrinc et al. 2006; Drenckhahn et al. 2016). Also, both amoxicillin and doxycycline, compared to ceftriaxone, prove less effective in cases of Borrelia resistance and chronic disease, particularly in cases where dissemination reaches the cerebral spinal fluid (CSF) and synovial infection (Markowicz et al. 2015; Kouge et al. 2015; Wu et al. 2018; Shimizu et al. 2016; Wilke et al. 2000; Limbach et al. 2001). The breast tissue returned to normal after treatment.
Dietrich et al. (2008) reported a 67-year old patient with persistence of both arthritis, intraocular inflammation, had now exhibited progressive keratopathy. Later the authors suggest, the contributing factors are the multiple years of immunosuppressive treatments: methotrexate and corticosteroids, for the presented autoinflammation, also possibly due to overreactive long-term exposure of Borrelia epitopes (Romero-Trevejo et al. 2019). Treatment involved keratoplasty, performed twice because after initial attempt keratopathy reoccurred with deep stromal deposits on the corneal graft.
Light-microscopy showed spirochete fragments, with electron-microscopy further detecting Borrelia on the corneal specimen. 16S rDNA PCR detected Borrelia, further amplification of primers: ospA and flaB, which study has shown effective for at least fourteen-genetic variants, found B. garinii (Wodecka, 2011). Additional serological and antibody tests were not provided. Treatment involved IV ceftriaxone, and continued immunosuppression and topical eyedrops for other disease.
Interestingly, immunosuppression typically involve lymphopenia, which cause weakened antibody responses, therefore greater possibilities of false-negative in antibody testing (Wagemakers et al. 2018; Alexandra et al. 2013). As neuroborreliosis, neurological deterioration following Borrelia dissemination, commonly causes CSF pleocytosis (Shimizu et al. 2016; Drenckhahn et al. 2016; Kouge et al. 2015). Therefore, combining neuroborreliosis related pleocytosis with leukemic chemotherapy, involving immunosuppressants, like: rituximab, known to target B cell CD20 antigen, potentially causes immunodeficiency, rendering responses inadequate for antibody testing, furthering undetected Borrelia pathogenesis, already known effective in immune evasion, in a vulnerable patient type (Boden et al. 2016; Walter et al. 2019). The described seronegative patient with leukaemia was diagnosed with B. garinii by flaB specific PCR, with treatment including ceftriaxone, appropriate for late, established dissemination (Harrer et al. 2007). With one study, based on mouse models, hypothesising doxycycline less effective in immunosuppressant patients when compared to both ceftriaxone and vancomycin (Wuet al. 2018).
To conclude, prolonged diagnosis was found present with atypical LD presentation, caused by false seronegative results from diagnostic tools not including DNA extraction-based PCR, most probably solved by earlier PCR testing. Cases reporting ceftriaxone and doxycycline in antibiotic therapies most effective. Developments in phylogenetics and genetic determinant investigation would expand available molecular markers and quality of PCR identification against diverse, evasive genotypes. Further investigation into molecular mimicry and DNA persistence would aid in tackling the effects of longterm exposure in autoimmunity and treatment evaluation (Picha et al. 2014; Moravcova et al. 2009; Strle et al. 1995).
Boden, K., Lobenstein, S., Hermann, B., Margos, G., & Fingerle, V. (2016) Borrelia miyamotoiAssociated Neuroborreliosis in Immunocompromised Person. Emerging infectious diseases, 22 (9) pp. 1617–1620.
Borg, R., Dotevall, L., Hagberg, L., Maraspin, V., Lotric-Furlan, S., Cimperman, J., & Strle, F. (2005) Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scandinavian journal of infectious diseases. 37 (6-7) pp. 449–454. DOI: 10.1080/00365540510027228
Cascio, A., Pernice, L. M., Barberi, G., Delfino, D., Biondo, C., Beninati, C., Mancuso, G., Rodriguez-Morales, A. J., & Iaria, C. (2012) Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review. European Review for Medical and Pharmacological Sciences. 16 (10) pp. 1324–1337. PMID: 23104648
Choi, Y. B., & Yi, D. Y. (2018) Fatal case of hemophagocytic lymphohistiocytosis associated with group B streptococcus sepsis. Medicine (Baltimore). 97 (40) e12210. DOI: 10.1097/MD.0000000000012210
Dessau, R. B., Fryland, L., Wihelmsson, P., Ekerfelt, C., Nyman, D., Forsberg, P., & Lindgren, P. (2015) Study of a Cohort of 1,886 Persons To Determine Changes in Antibody Reactivity to Borrelia Burgdorferi 3 Months After a Tick Bite. Clinical and Vaccine Immunology: CVI. 22 (7) pp. 823–827. DOI: 10.1128/CVI.00026-15
Dietrich, T., Geidorfer, W., Schlotzer-Schrehardt, U., Holbach, L., Schoerner, C., & Seitz, B. (2008) Borrelia-associated Crystalline Keratopathy with Intracornea; Detection of Borrelia garinii by Electron Microscopy and Polymerase Chain Reaction. The Journal of Cornea and External Disease. 27 (4) pp. 498–500. DOI: 10.1097/ICO.0b013e318162a8f5
Drenckhahn, A., Spors, B., & Knierim, E. (2016) Acute isolated partial oculomotor nerve palsy due to Lyme neuroborreliosis in a 5 year old girl. European Journal of Pediatric Neurology. 20 (6) pp. 977–979. DOI: 10.1016/j.ejpn.2016.05.022
Ghislain, P. D., Woestyn, S., Tennstedt, D., Lachapelle, J. M., Bigaignon, G., & Delmée, M. (2003). Borrelia afzelii evidenced by polymerase chain reaction in a biopsy of nipple lymphocytoma. The British journal of dermatology, 148 (2) pp. 377–379. DOI: 10.1046/j.1365-
Glatz, M., Golestani, M., Kerl, H., & Mullegger, R. R. (2006) Clinical Relevance of Different IgG and IgM Serum Antibody Responses to Borrelia Burgdorferi After Antibiotic Therapy for Erythema Migrans: Long-Term Follow-Up Study of 113 Patients. Archives of Dermatology. 142 (7) pp. 862–868. DOI: 10.1001/archderm.142.7.862
Gooskens, J., Templeton, K. E., Claas, E. C., & van Dam, A. P. (2006) Evaluation of an Internally Controlled Real-Time PCR Targeting the ospA Gene for Detection of Borrelia Burgdorferi Sensu Lato DNA in Cerebrospinal Fluid. Clinical Microbiology and Infection. 12 (9) 894–900. DOI: 10.1111/j.1469-0691.2006.01509.x
Harrer T, Geissdörfer W, Schoerner C, Lang E, Helm G. Seronegative Lyme neuroborreliosis in a patient on treatment for chronic lymphatic leukemia. Infection. 35 (2) pp. 110–113. DOI: 10.1007/s15010-007-6121-0
Hoornstra, D., Koetsveld, J., Sprong, H., Platonov, A. E., & Hovius, J. W. (2018). Borrelia miyamotoi Disease in an Immunocompetent Patient, Western Europe. Emerging infectious diseases. 24 (9) pp. 1770–1772. DOI: 10.3201/eid2409.180806
Kouge, J., Hayashida, S., Imaki, H., & Mitsuo, K. (2015) A Japanese Case of Neuroborreliosis With Papillitis. Rinsho shinkeigaku = Clinical neurology. 55 (4) pp. 248–253. DOI: 10.5692/clinicalneurol.55.248
Lebech, A. (2002) Polymerase Chain Reaction in Diagnosis of Borrelia Burgdorferi Infections and Studies on Taxonomic Classification. APMIS. Supplementum. 105 pp. 1–40.
Limbach, F. X., Jaulhac, B., Puechal, X., Monteil, H., Kuntz, J. L., Piemont, Y., & Sibilia, J. (2001). Treatment resistant Lyme arthritis caused by Borrelia garinii. Annals of the rheumatic diseases. 60 (3) pp. 284–286. DOI: 10.1136/ard.60.3.284
Ljostad, U., Skogvoll, E., Eikeland, R., Midgard, R., Skarpaas, T., Berg, A., & Mygland, A. (2008) Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. The Lancet Neurology. 7 (8) pp. 690–695. DOI: 10.1016/S1474-4422(08)70119-4
Moniuszko, A., Dunaj, J., Zajkowska, J., Czupryna, P., Świerzbińska, R., Guziejko, K., Aleksiejczuk, P., Barry, G., Kondrusik, M., & Pancewicz, S. (2015) Comparison of detection of Borrelia burgdorferi DNA and anti-Borrelia burgdorferi antibodies in patients with erythema migrans in north-eastern Poland. Postepy dermatologii i alergologii; 32 (1) pp. 11–14. DOI: 10.5114/pdia.2014.40940
Maraspin, V., Klevisar, M. N., Ruzic-Sabljic, E., Lusa, L., & Strle, F. (2016) Borrelial Lymphocytoma in Adult Patients. Clinical Infectious Diseases. 63 (7) pp. 914–921. DOI: 10.1093/cid/ciw417
Markowicz, M., Ladstatter, S., Schotta, A. M., Reiter, M., Pomberger, G., & Stanek, G. (2015). Oligoarthritis caused by Borrelia bavariensis, Austria, 2014. Emerging infectious diseases. 21 (6), 1052–1054. DOI: 10.3201/eid2106.141516
Moravcová, L., Pícha, D., Vanousová, D., & Hercogová, J. (2009) Detection of borrelia DNA from patients with neuroborreliosis and erythema migrans. Klinicka mikrobiologie a infekcni lekarstvi. 15 (5) pp. 160–165
Ogrinc, K., Logar, M., Lotric-Furlan, S., Cerar, D., Ruzić-Sabljić, E., & Strle, F. (2006). Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wiener klinische Wochenschrift, 118 (21-22), 696–701. DOI: 10.1007/s00508-006-0698-7
Paim, A. C., Baddour, L. M., Pritt, B. S., Schuetz, A. N., & Wilson, J. W. (2018) Lyme Endocarditis. The American Journal of Medicine. 131 (9) pp. 1126–1129. DOI: 10.1016/j.amjmed.2018.02.032
Panelius, J., Sillanpää, H., Seppälä, I., Sarvas, H., & Lahdenne, P. (2007) Antibodies to recombinant decorin-binding proteins A and B in the cerebrospinal fluid of patients with Lyme neuroborreliosis. Scandinavian journal of infectious diseases. 39 (9) pp. 775–780. DOI: 10.1080/00365540701367744
Pícha, D., Moravcová, L., Vaňousová, D., Hercogová, J., & Blechová, Z. (2014) DNA persistence after treatment of Lyme borreliosis. Folia microbiologica, 59 (2) pp. 115–125. DOI: 10.1007/s12223-013-0272-4
Pritt, B. S., Mead, P. S., Johnson, D., Neitzel, D. F., Respicio-Kingry, L. B., Davis, J. P., Schiffman, E., Sloan, L. M., Schriefer, M. E., Replogle, A. J., Paskewitz, S. M., Ray, J. A., Bjork, J., Steward, C. R., Deedon, A., Lee, X., Kingry, L. C., Miller, T. K., Feist, M. A., Theel, E. S., Patel, R., Irish, C. J., & Petersen, J. M. (2016) Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. The Lancet. Infectious diseases, 16(5), 556–564. DOI: 10.1016/S1473-3099(15)00464-8
Romero-Trevejo, J. L., Boosch-Gili, R., Jimenez-Rodriguez, E., & de Gor-Crooke, J. L. G. (2019) Infectious crystalline keratopathy: Management of three cases with different risk factors. Saudi Journal of Ophthalmology. 33 (4) pp. 409–412. DOI: 10.1016/j.sjopt.2019.01.002
Scholz, H. C., Margos, G., Derschum, H., Speck, S., Tserennorov, D., Erdenebat, N., Undraa, B., Enkhtuja, M., Battsetseg, J., Otgonchimeg, C., Otgonsuren, G., Nymadulam, B., Römer, A., Thomas, A., Essbauer, S., Wölfel, R., Kiefer, D., Zöller, L., Otgonbaatar, D., & Fingerle, V. (2013). High prevalence of genetically diverse Borrelia bavariensis-like strains in Ixodes persulcatus from Selenge Aimag, Mongolia. Ticks and tick-borne diseases. 4 (1-2) pp. 89–92. DOI: 10.1016/j.ttbdis.2012.08.004
Shimizu, H., Haratani, K., Miyazaki, M., Kakehi, Y., Nagami, S., Katanami, Y., Kawabata, H., & Takahashi, N. (2016) A Case of Hemifacial Paresis in a Patient With Lyme Neuroborreliosis Treated With Antibiotics in Whom Borrelia Meningitis Developed. Rinsho shinkeigaku = Clinical neurology. 56 (7) pp. 495–498. DOI: 10.5692/clinicalneurol.cn-000880
Sillanpaa, H. Skogman, B. H., Sarvas, H., Seppala, I. J. T., & Lahdenne, P. (2014) Antibodies to Decorin-Binding Protein B (DbpB) in the Diagnosis of Lyme Neuroborreliosis in Children. International Journal of Infectious Diseases. 28, pp. 160–163. DOI: 10.1016/j.ijid.2014.07.006
Singh, S. K., & Girschick, H. J. (2004) Lyme borreliosis: from infection to autoimmunity. Clinical Microbiology and Infection. 10 (7) pp. 598 – 614. DOI: 10.1111/j.1469-0691.2004.00895.x
Stanek, G., Wormser, G. P., Gray, J., & Strle, F. (2012) Lyme borreliosis. The Lancet. 379 (9814) pp. 461–473. DOI: 10.1016/S0140-6736(11)60103-7
Steere, A. C. (2001) Lyme Disease. The New Journal of Medicine. 345 (2) pp. 115–125. DOI: 10.1056/NEJM200107123450207
Steere, A. C., Strle, F., Wormser, G. P., Hu, L. T., Branda, J. A., Hovius, J. W., Li, X., & Mead, P. S. (2016) Lyme borreliosis. Nature reviews. Disease primers. 2, 16090. DOI: 10.1038/nrdp.2016.90
Strle, F., Cheng, Y., Cimperman, J., Maraspin, V., Lotric-Furlan, S., Nelson, J. A., Picken, M. M., Ruzic-Sabljic, E., & Picken, R. N. (1995). Persistence of Borrelia burgdorferi sensu lato in resolved erythema migrans lesions. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 21(2) pp. 380–389. DOI: 10.1093/clinids/21.2.380
Sudhindra, P., Wang, G., Schriefer, M. E., McKenna, D., Zhuge, J., Krause, P. J., Marques, A. R., & Wormser, G. P. (2016). Insights into Borrelia miyamotoi infection from an untreated case demonstrating relapsing fever, monocytosis and a positive C6 Lyme serology. Diagnostic microbiology and infectious disease. 86 (1) pp. 93–96. DOI: 10.1016/j.diagmicrobio.2016.06.015
Topakian, R., Artemian, H., Metschitzer, B., Lugmayr, H., Kuhr, T., & Pischinger, B. (2016) Dramatic response to a 3-week course of ceftriaxone in late neuroborreliosis mimicking atypical dementia and normal pressure hydrocephalus. Journal of the Neurological Sciences. 366, pp. 146–148. DOI: 10.1016/j.jns.2016.05.002
van Dop, W. A., Kersten, M. J., de Wever, B., & Hovius, J. W. (2013) Seronegative lyme neuroborreliosis in a patient using rituximab. BMJ case reports. 2013. DOI: 10.1136/bcr-2012-007627
Wagemakers, A., Visser, M. C., de Wever, B., Hovius, J. W., van de Donk, N., Hendriks, E. J., Peferoen, L., Muller, F. F., & Ang, C. W. (2018). Case report: persistently seronegative neuroborreliosis in an immunocompromised patient. BMC infectious diseases. 18 (1) pp. 362. DOI: 10.1186/s12879-018-3273-8
Walter, L., Sürth, V., Röttgerding, F., Zipfel, P. F., Fritz-Wolf, K., & Kraiczy, P. (2019) Elucidating the Immune Evasion Mechanisms of Borrelia mayonii, the Causative Agent of Lyme Disease. Frontiers in immunology. 10, 2722. DOI: 10.3389/fimmu.2019.02722
Wilke, M., Eiffert, H., Christen, H., & Hanefeld, F. (2000) Primarily chronic and cerebrovascular course of Lyme neuroborreliosis: case reports and literature review. Archives of Disease in Childhood. 83 (1) pp. 67–71.
Wodecka, B. (2011) flaB Gene as a Molecular Marker for Distinct Identification of Borrelia Species in Environmental Samples by the PCR-restriction Fragment Length Polymorphism Method. Applied and environmental mocorbiology. 77 (19) pp. 7088–1092. DOI: 10.1128/AEM.05437-11
Wu, X., Sharma, B., Niles, S., O’Connor, K., Schilling, R., Matluck, N., D’Onofrio, A., Hu, L. T., & Lewis, K. (2018). Identifying Vancomycin as an Effective Antibiotic for Killing Borrelia burgdorferi. Antimicrobial agents and chemotherapy. 62 (11), e01201–01218. DOI: 10.1128/AAC.01201-18