Association of Spirochetal Infection with Morgellons Disease Marianne J

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2013 Association of Spirochetal Infection with Morgellons Disease Marianne J. Middelveen Atkins Veterinary Services, Calgary, Canada

Divya Burugu Advanced Laboratories Services, Norwood, Pennsylvania

Akhila Poruri IGeneX.Inc, Palo Alto, Calif.

Jennie Burke Australian Biologics, Sydney, Australia

Peter J. Mayne Laurieton Medical Centre, NSW, Australia

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Publisher Citation Middelveen MJ, Burugu D, Poruri A et al. Association of spirochetal infection with Morgellons disease [version 1; referees: 2 approved] F1000Research 2013, 2:25 (doi: 10.12688/f1000research.2-25.v1)

Comments Copyright: © 2013 Middelveen MJ et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Authors Marianne J. Middelveen, Divya Burugu, Akhila Poruri, Jennie Burke, Peter J. Mayne, Eva Sapi, Douglas G. Kahn, and Raphael B. Stricker

This article is available at Digital Commons @ New Haven: http://digitalcommons.newhaven.edu/biology-facpubs/32 ʸʷʷʷ»É»·È¹¾ʹʷʸʺƑʹƓʹʼ·ÉÊËÆº·Ê»ºƓʷˀʹʷʸʼ

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,QWURGXFWLRQ 0DWHULDOVDQGPHWKRGV Morgellons disease (MD) is an evolving skin disease associated Patient selection and dermatological samples with filaments found beneath unbroken skin or projecting from Representative non-biopsy dermatological specimens were col- spontaneously-appearing, slowly-healing skin lesions1. In addition lected from four randomly-selected patients who met the key clini- to dermopathy, patients may also exhibit debilitating musculoskel- cal criterion for MD, namely that filaments visible with a hand-held etal and neurological manifestations resembling the symptoms of microscope at 60X magnification must be present under unbroken Lyme disease1,2. Similarities were found between MD and bovine skin or projecting from spontaneously appearing skin lesions. digital dermatitis (BDD), a disease common in dairy herds and Patients 1 and 2 are Americans residing in Texas while patients 3 characterized by keratin filament formation in skin lesions that fre- and 4 are Canadians residing in Alberta, Canada (Table 1). Written quently occur above the hind feet of cows3,4. Chronic BDD lesions informed consent for submission of clinical samples and publica- demonstrate proliferation of long keratin filaments, and microscopic tion of clinical details and clinical images was obtained from each examination of histological sections from this tissue has revealed study subject. Patient anonymity and confidentiality were strictly the presence of various Treponema spp. among enlarged keratino- maintained. The study was exempt from Institutional Review Board cytes throughout the stratum spinosum and dermal papillae5–9. approval because all testing was performed as part of routine clinical care, and patient anonymity and confidentiality were strictly The etiology of BDD is considered to be multifactorial with coin- maintained. volvement of spirochetes and other bacterial pathogens10–14. In the animal disease, repeated detection of spirochetes from lesions and The detailed histopathological findings in these patients were sero-reactivity to Borrelia burgdorferi antigens provides evidence reported previously17. All patients were seroreactive to Borrelia of spirochetal involvement10–14. Successful experimental infection burgdorferi antigens (strains B31 and 297, IGeneX Laboratory, with tissue homogenates and pure cultured treponemes has con- Palo Alto, CA) and negative on rapid plasma reagin (RPR) testing firmed that spirochetes are primary etiologic agents15,16. (RPR Card Test Kit, BD Diagnostic Systems, Sparks, MD). Patient 1 was on doxycycline therapy for Lyme disease at the time of the Like BDD, MD filaments are produced by epithelial cells and stem study, while patient 2 had previously been treated with doxycycline from the stratum basale and from the root sheath of hair follicles, for Lyme disease but had been off treatment for several years at the thus providing evidence that the filaments are cellular in origin3,4. time of the study. Patients 3 and 4 were not on antibiotic therapy at Furthermore, immunohistochemical and histological staining the time of the study. None of the study patients had evidence of has demonstrated that these filaments have a collagen as well as a delusional disorder, as determined by standard neuropsychiatric a keratin component5,17. Like cattle with BDD, patients with MD testing using the Rorschach, Minnesota Multiphasic Personality also produce antibodies reactive to Borrelia burgdorferi antigens18. Inventory (MMPI), Millon Clinical Multiaxial Inventory (MCMI) Multisystemic symptoms resembling Lyme disease also imply a and Wechsler Adult Intelligence Scale (WAIS) formats. possible spirochetal etiology for MD1–3,18,19. The frequent clinical diagnosis of Lyme disease and coinfecting tick-borne pathogens in The late-stage BDD biopsies used for comparison were kindly pro- MD patients suggests a multifactorial etiology and possible vector- vided by Dr. Dorte Döpfer, Faculty of Veterinary Medicine, Uni- ing by ticks1–3,18,19. versity of Wisconsin, Madison, WI. Biopsies were taken as part of an intervention study conducted by the University of Wisconsin15. In light of the proven spirochetal association with BDD and the The diagnostic criterion for late-stage BDD was the presence of possible association with MD, we undertook a histological, electron pronounced keratin projections from ulcerative lesions that were at microscopic and PCR study of MD dermatological tissue samples least two centimeters in diameter and located above the heel bulb of to investigate the presence of spirochetes in these samples. In addi- the hind feet of cattle. Biopsy samples were stored and shipped in tion, bacterial culture was conducted to investigate the possibility of a fixative of 1.5% glutaraldehyde/1.0% formaldehyde in Sorensen’s viable spirochetes in MD tissue. Buffer at pH 7.35 (Tousimis Research Corporation, Rockville, MD).

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Duplicate samples were used for each of the light and electron TEM. Glutaraldehyde-fixed samples were washed in buffer, microscopic studies described below. followed by dehydration in a graded series of ethanol concentrations. Samples were then immersed in a 50:50 mixture of LR White™ Light microscopy embedding resin and 100% ethanol for 30 minutes, followed by pure The gross morphology of dermatological specimens collected from LR White™ resin until samples settled on the bottom of the vial. The Patients 1–4 was observed at 8X, 40X, and 100X magnification resin-immersed samples were then placed into pure resin in beam with illumination superior to the specimen, thus verifying the pres- capsules and put into a 60°C oven overnight for polymerization. ence of filaments within and protruding from epithelial tissue. BDD Sections were cut on an Ultracut E microtome to produce sections biopsy material was examined at 8X to observe gross morphologi- 60–90 nm thick, placed onto copper grids and stained in uranyl cal characteristics. acetate for 20 minutes. Images were taken on a Hitachi 7600 microscope. Morgellons samples were formalin-fixed and embedded in paraffin, sectioned, and stained with Warthin-Starry and/or Dieterle silver PCR nitrate-based staining for the light microscopic detection of spiro- Morgellons calluses from patients 1–4 were forwarded to Australian chetes under oil immersion at 1000X magnification. Warthin-Starry Biologics (Sydney, Australia) for B. burgdorferi detection by PCR staining and Dieterle staining were performed by Interscope Pathol- using the Eco™ Real-Time PCR system with software version ogy Medical Group, Canoga Park, CA, and McClain Laboratories 3.0.16.0. DNA was extracted from the tissue samples using the LLC, Smithtown, NY, respectively. QIAamp DNA Mini Kit (QIAGEN). The four samples were ana- lyzed in duplicate with positive and negative controls using prim- ers AB-B1 for the Borrelia 16S rRNA gene target, as previously BDD biopsies were formalin-fixed and embedded in paraffin, sec- described21. The thermal profile for all analyses involved incubation tioned, and stained for the detection of spirochetes by Warthin- for 2 mins at 50°C, polymerase activation for 10 mins at 95°C then Faulkner silver nitrate-based staining at Prairie Diagnostics, Uni- PCR cycling for 40 cycles of 10 secs at 95°C dropping to 60°C versity of Saskatchewan, Saskatoon, Saskatchewan. sustained for 45 secs. Formalin-fixed paraffin-embedded MD sections were processed The magnitude of the PCR signal generated ('R) for each sample for immunofluorescent anti-Borrelia staining and imaging as pre- was interpreted as positive or negative compared to positive and 20 viously described at the University of New Haven, West Haven, negative controls. CT, by the following protocol: fixed specimens were pre-incubated with 10% normal goat serum (Thermo Fisher Scientific, Waltham, Borreliaspp. culture MA) in PBS containing 0.5% bovine serum albumin (BSA) (Sigma- Borrelial culture was performed as described previously22. B. burg- Aldrich, St. Louis, MO) for 30 minutes to block non-specific bind- dorferi was cultured in Barbour–Stoner–Kelly H (BSK-H) com- ing of the secondary antibody. The slides were washed with PBS plete medium, with 6% rabbit serum (Sigma Aldrich, #B8291) and containing 0.5% BSA and then incubated for 1 hour with fluores- the following antibiotics: phosphomycin (0.02 mg/l), rifampicin cein isothiocyanate (FITC)-labelled Borrelia-specific polyclonal (0.05 mg/l), and amphotericin B (2.5 μg/l) (Sigma-Aldrich) and antibody (Thermo Fisher Scientific, #73005) at a 1:50 dilution in incubated at 32°C with 5% CO2. Cultured spirochetes were observed PBS containing 1% BSA pH 7.4. The slides were washed and then by dark-field microscopy and/or heat-fixed and stained with crystal counterstained with 4’, 6-diamidino-2-phenylindole (DAPI) for violet (Dalynn Biologicals, Calgary, AB) under oil immersion at 10 minutes. In negative control samples, anti-specifically targeted 1000X. For the immunofluorescence studies, cultured spirochetes antibody was replaced with normal rabbit IgG (Vector Laborato- (1×107 individual spirochete cells) were centrifuged at 8,000×g ries, Burlingame, CA, #I-1000). Mounted slides were imaged using for 10 minutes at room temperature, washed once with PBS pH fluorescent microscopy. 7.4, and then centrifuged again at 8,000×g for 10 minutes at room temperature. The pellet was resuspended in 100 μl of PBS pH 7.4, Electron microscopy and then spread on microscope slides (SuperFrost+, Thermo Fisher Morgellons and BDD samples were fixed in buffered 2.5% glu- Scientific). Spirochetes were fixed by incubating the slides in cold taraldehyde. Scanning electron microscopy (SEM) and transmis- acetone for 10 minutes at -20ºC. Slides were then washed twice sion electron microscopy (TEM) were performed by the Electron with PBS pH 7.4 at room temperature, and.immunofluorescent Microscopy Facility, Department of Materials Science and Engi- staining with polyclonal anti-Borrelia antibodies was performed as neering, Clemson University, Anderson, SC, according to the pro- described above. tocols below: 5HVXOWV SEM. Glutaraldehyde-fixed samples for SEM were washed in Gross microscopic observations buffer and dehydrated in a graded series of ethanol concentrations. Calluses from the four MD patients demonstrated white, red and Samples were then immersed in hexamethyldisilazane (Electron blue filaments, alone or in any color combination, each 10 to 40 μm Microscopy Sciences, Hatfield, PA) for 5–15 minutes and air in diameter, embedded in or projecting from epithelial tissue dried at room temperature. Dried samples were mounted on A-1 (Figure 1A). BDD biopsies demonstrated pronounced, unusual ker- mounts. Samples were not coated but placed into a Hitachi TM3000 atin filament production typical of late-stage proliferative infection microscope and imaged in the variable pressure mode. (Figure 1B).

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Light microscopy Silver nitrate-based staining. Staining of dermatological tissue from patients 1–4 revealed visible black-stained spirochetes among keratinocytes and inﬂammatory cells (Figure 2A). These spiral or curved structures ranged from 0.1 μm to 0.5 μm in diameter and up to 30 μm long, and they were present mostly in the interior areas of the sections and not along the peripheral edge.

)LJXUH $) Morgellons disease filaments embedded in and Staining of BDD dermatological tissue revealed visible black- projecting from epithelial tissue, 100X magnification. %) Proliferative stained spirochetes among enlarged keratinocytes (Figure 2B). bovine digital dermatitis (BDD) keratin filaments, 8x magnification. Spirochetes were approximately 0.1 μm to 0.2 μm in diameter and approximately 10 μm to 15 μm in length, and they varied A summary of the following histological, culture, electron micro- in morphology from visibly spiral-shaped to straight or wavy in scopic and PCR results is shown in Table 2. appearence.

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6LOYHUQLWUDWH 3DWLHQW &XOWXUH ,)$VWDLQLQJ 6(07(0 3&5 VWDLQLQJ Spirochetes Positive, histological Spirochetes observed, Weak 1 Not performed detected sections TEM positive Spirochetes Positive, histological Spirochetes observed, 2 Not performed Positive detected sections both SEM and TEM Positive, motile spirochetes Positive, both histological Spirochetes 3 detected, conﬁrmed by IFA sections and cultured Not performed Positive detected staining spirochetes Spirochetes Positive, motile spirochetes Positive, histological 4 Not performed Negative detected detected sections IFA, immunoﬂuorescence assay; SEM, scanning electron microscopy; TEM, transmission electron microscopy; PCR, polymerase chain reaction.

)LJXUH$) Black-stained spirochetes in representative tissue sample from patient 2. Dieterle stain, 1000X oil immersion. %) Black-stained spirochetes in bovine digital dermatitis (BDD) tissue sample, Warthin-Faulkner stain, 1000X oil immersion. &) Distinct patches of anti-Borrelia fluorescence in histological section of callus from patient 1, 400X magnification. ') Distinct patches of anti-Borrelia fluorescence in histological section of callus from patient 2, 400X magnification.

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Immunofluorescent anti-Borrelia staining. Immunofluorescent Borreliaspp. culture anti-Borrelia staining of fixed Treponema denticola spirochetes was Motile spirochetes ranging from approximately 0.1 μm to 0.5 μm performed as a negative control and immunofluorescence was not in diameter and up to 30 μm long were visible in cultures inocu- observed for these specimens (data not shown). Histological sections lated with dermatological tissue from both patients 3 and 4 of dermatological material from patients 1–4 all demonstrated (Figures 5A and 5B). Cultured spirochetes from patient 3 were distinct patches of immunofluorescence at a magnification of identified as Borrelia by immunofluorescent staining with FITC- 400X (Figures 2C and 2D). Patches of fluorescence appeared to labelled polyclonal antibodies at 1000X magnification (Figure 5C). occur most often in areas of sections corresponding to fibroblasts. The culture obtained from the inoculum from patient 4 was lost due Cultured spirochetes from patient 3 also demonstrated positive to contamination and generic identification was not obtained. immunofluorescent staining with anti-Borrelia antibodies (see below and Figure 5C). 'LVFXVVLRQ The presence of spirochetes in MD dermatological specimens dem- SEM and TEM onstrates that Morgellons lesions are associated with spirochetal SEM revealed high-resolution surface imaging of a spirochete infection. Unlike Treponema pallidum spirochetes, which are sel- lying beneath a layer of dermatological tissue of a Morgellons cal- dom detected in secondary and tertiary syphilitic skin lesions23–25, lus and images consistent with morphological forms of Borrelia spirochetes were readily detectable in dermatological tissue from spp. (Figures 3A and 3B). TEM imaging of both Morgellons cal- four MD patients using a combination of immunohistochemical, luses and BDD biopsies revealed spirochetes in cross-section electron microscopic and PCR techniques. Motile spirochetes were (Figures 3C and 3D). also observed in cultures inoculated with MD dermatological tissue, thus indicating that our specimens contained viable organ- PCR isms. These findings are similar to the observation of significant Real-time PCR analysis was positive for Borrelial DNA in tissue spirochetal loads in lesions of cattle with BDD, suggesting that spi- samples from MD patients 1–3 and negative in the sample from rochetes could be associated with unusual filament production in Patient 4. Samples from Patients 2 and 3 were clear positives and both bovines and humans. Although Ekbom reported that syphilitic the sample from Patient 1 was a weak positive. The PCR profiles infection was associated with feelings of infestation26, to our knowl- are shown in Figure 4. edge dermal fibers have not been reported in patients with syphilis.

)LJXUH$) SEM from patient 2 tissue sample showing spirochete images that are consistent with morphological forms of Borrelia (arrows). %) SEM from patient 2 tissue sample showing single spirochete, upper middle right (long arrow) and morphological forms consistent with Borrelia, center (short arrow). &) TEM from patient 1 tissue sample showing sectioned spirochetes. ') TEM from BDD tissue sample showing sectioned spirochetes.

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)LJXUH5HVXOWVRISRO\PHUDVHFKDLQUHDFWLRQ 3&5 DPSOLILFDWLRQ LQWLVVXHVDPSOHVIURPSDWLHQWV±See text for PCR protocol. Samples from patients 2 and 3 were strongly positive, while the sample from patient 1 was weakly positive. The sample from patient 4 was negative.

)LJXUH$) Cultured spirochetes from patient 3 tissue samples, 1000X darkfield microscopy, oil immersion. %) Cultured spirochetes in clumps from patient 4 tissue sample, heat fixed and stained with crystal violet, 1000X oil immersion. &) Borrelial spirochetes demonstrating fluorescence from tissue culture of patient 3, 1000X oil immersion, enlarged and cropped.

Unlike BDD, which is associated with a variety of treponemal filaments are associated with spirochetes belonging to other genera spirochetes15,16, the MD dermatological tissue in this study con- as well as Borrelia. tained spirochetes that were identified as Borrelia by immunofluorescent staining with anti-Borrelia antibodies. Furthermore The etiology of MD appears to be multifactorial, and at this stage the MD spirochetes were specifically classified by targeted PCR secondary etiologic factors are not well understood. MD is most as Borrelia burgdorferi. Given the fact that all four MD patients in often reported in middle-aged Caucasian females. It is a disease this study were seroreactive to Borrelia burgdorferi antigens, some reported mostly in the Northern Hemisphere, and it is often asso- of which are thought to be species-specific, and were RPR nega- ciated with known tick exposure, a Lyme disease diagnosis, and tive, we speculate that the Morgellons phenomenon observed in serological evidence of coinfecting tick-borne agents1,2,18,19. Two of our group of study patients is a manifestation of Lyme disease. At our study patients had laboratory-confirmed tick-borne coinfections present it is not understood if MD filaments are associated exclu- (see Table 1), and these coinfections may contribute to the pathol- sively with Borrelia burgdorferi sensu stricto, perhaps a particular ogy of this disease. genotype, or with a Borrelia species more appropriately placed in the Borrelia burgdorferi sensu lato complex. As our study sample The filaments seen in MD are composed of keratin and collagen was small, we cannot ascertain at this stage whether Morgellons derived from keratinocytes and fibroblasts, respectively4,17. We

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hypothesize that spirochetes associated with MD trigger the pro- resulted in social isolation, loss of employment, loss of custody duction of unusual collagen and keratin filaments. In our study, of children, and a high rate of suicide (Casey C. 2012. Personal spirochetes were detected in Morgellons dermatological tissue communication. http://www.thecehf.org/). Further MD research is from both Patient 1, who was currently taking antibiotics, and from urgently needed to delineate the possible infectious etiology of the Patient 2, who had been on antibiotic therapy in the past but was disease and to assure that patients can be appropriately diagnosed not on treatment at the time that samples were obtained. B. burg- and treated in the future. dorferi has been reported to invade human fibroblasts, and viable B. burgdoferi spirochetes have been isolated from lysates of fibro- &RQFOXVLRQV blast monolayers, even after antibiotic therapy27. Our findings sug- This report demonstrates the presence of Borrelia spirochetes in gest that Borrelia spirochetes may be capable of sequestering within dermatological samples collected from four MD patients who were keratinocytes and fibroblasts, causing both persistent infection that seroreactive to Borrelia burgdorferi antigens. The findings suggest is refractory to antibiotic therapy and aberrant fiber production by that MD has a spirochetal etiology and raises the possibility that these infected cells in MD patients. this emerging dermopathy may be a manifestation of Lyme disease in a subgroup of tickborne disease patients. The demonstration of Despite contrary evidence, some medical professionals have attrib- an infectious agent associated with MD contradicts the belief that uted MD to delusions of parasitosis or delusional infestation. MD patients with this disease suffer from a factitious or delusional ill- is thought to result from psychiatric illness and is diagnosed on the ness. Although our sample size was small, our study indicates that, basis of patient belief in infestation by parasites, or the presence of at least in some patients, MD appears to be an important emerging inanimate objects such as fibers that are thought to be deliberately infectious disease. Further research is needed to assure the correct self-implanted28–32. As stated above, spirochetal infection associated diagnosis and define the optimal treatment for this spirochetal with itching and crawling sensations and feelings of infestation infection so that MD patients are not stigmatized with a diagnosis dates as far back as 1945 in Ekbom’s original description of delu- of mental illness. sions of parasitosis26, and many of the patients in that study were diagnosed with syphilis. This clinical observation provides valuable insight into MD. Author contributions MJM performed the light microscopic studies and spirochete cul- The insistence that MD is delusional has prevented the establish- tures, coordinated the electron microscopic studies and wrote the ment of universally accepted, objective diagnostic criteria for this original manuscript. DB, AP and ES performed the IFA studies. JB disease. Consequently, some studies have included diverse groups and PJM performed the PCR studies. DGK performed the immu- of research subjects, including patients who may not actually have nohistochemical studies. RBS coordinated all studies, rewrote the had MD30–32. In the present study, the key diagnostic criterion is manuscript and edited it for publication. All authors approved the that filaments visible with a hand-held microscope at 60X magni- manuscript for publication. fication must be present under unbroken skin or projecting from 1,2 spontaneously-appearing skin lesions . This important clinical Competing interests feature forms the basis for an accurate MD diagnosis. RBS serves without compensation on the medical advisory panel for QMedRx Inc. He has no financial ties to the company. MJM Although a study from the Centers for Disease Control and Preven- serves without compensation on the scientific advisory panel of the tion (CDC) found no evidence that pathogens play a role in MD, Charles E. Holman Foundation. PJM and RBS serve without com- the search for spirochetal pathogens in that study was confined to pensation on the medical advisory panel of the Charles E. Holman Warthin-Starry staining on limited tissue samples and commercial Foundation. DB, AP, JB, ES and DGK have no conflicts to declare. serological testing for Borrelia burgdorferi31. Tissue staining in that study was performed on samples from patients who reportedly did Grant information 32 not have confirmed clinical evidence of MD , and serological test- Partial funding for this study was provided by the Charles E. ing was interpreted in accordance with Lyme surveillance criteria Holman Foundation. that are inappropriate for clinical diagnosis33. Thus the findings in the CDC study were influenced by failure to examine the appropri- The funders had no role in study design, data collection and analysis, ate group of patients and by the clinical insensitivity of surveillance decision to publish, or preparation of the manuscript. testing for tickborne disease32,33. These limitations leave open the possibility that a spirochetal association with MD could have been Acknowledgments missed in the CDC study. The authors thank Drs. Stewart Adams, Gordon Atkins, Robert Bransfield, Douglas Demetrick, Dorte Dopfer, JoAnn Hudson, Controversy surrounding MD has been detrimental to those afflicted Alan MacDonald, Elizabeth Rasmussen, Virginia Savely, Matthew with this illness. It has stifled scientific research and has prevented Shawkey, Jyotsna Shah, Leo Shea, Janet Sperling, and Michael appropriate treatment and control strategies from being investigated Sweeney for helpful discussion. We thank Dr. Robert B. Allan for and implemented. In some cases it has resulted in treatment with technical support and Lorraine Johnson for manuscript review, and ineffective and potentially harmful antipsychotic drugs28–32. Some we are grateful to Harriet Bishop and Cindy Casey for providing patients have been stigmatized by a diagnosis of mental illness that first-hand information about Morgellons disease.

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Borgmann JE, Bailey J, Clark EG: 6SLURFKHWHDVVRFLDWHGERYLQHGLJLWDOGHUPDWLWLV 25. Pereira TM, Fernandes JC, Viera AP, et al.: 7HUWLDU\V\SKLOLV Int J Dermatol. 2007; Can Vet J. 1996; (1): 35–37. (11): 1192–1195. 3XE0HG$EVWUDFW| )UHH)XOO7H[W 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 10. Read DH, Walker RL, Castro AE, et al.: $QLQYDVLYHVSLURFKDHWHDVVRFLDWHGZLWK 26. Ekbom KA, Yorston G, Miesch M, et al.: 7KHSUHVHQLOHGHOXVLRQRILQIHVWDWLRQ LQWHUGLJLWDOSDSLOORPDWRVLVRIGDLU\FDWWOH Vet Rec. 1992; (3): 59–60. 1945. Translation: Hist Psychiatry. 2003; (54 Pt 2): 229–256. 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 11. Grund S, Nattermann H, Horsch F: (OHFWURQPLFURVFRSLFGHWHFWLRQRI 27. Klempner MS, Rogers RA, Noring R: ,QYDVLRQRIKXPDQVNLQILE REODVWVE\WKH VSLURFKHWHVLQGHUPDWLWLVGLJLWDOLVRIFDWWOH Zentralbl Veterinarmed B. 1995; /\PHGLVHDVHVSLURFKHWH%RUUHOLDEXUJGRUIHUL J Infect Dis. 1993; (5): (9): 533–542. 1074–1081. 3XE0HG$EVWUDFW 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 12. Döpfer D, Koopmans A, Meijer FA, et al.: +LVWRORJLFDODQGEDFWHULRORJLFDO 28. Lorenzo CR, Koo J: 3LPR]LGHLQGHUPDWRORJLFSUDFWLFH$FRPSUHKHQVLYH HYDOXDWLRQRIGLJLWDOGHUPDWLWLVLQFDWWOHZLWKVSHFLDOUHIHUHQFHWRVSLURFKDHWHV UHYLHZ Am J Clin Dermatol. 2004; (5): 339–349. DQG&DPS\OREDFWHUIDHFDOLV Vet Rec. 1997; (24): 620–623. 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 29. Freudenmann RW, Kölle M, Schönfeld-Lecuona C, et al.: 'HOXVLRQDOSDUDVLWRVLV 13. Demirkan I, Carter SD, Murray RD, et al.: 7KHIUHTXHQWGHWHFWLRQRIDWUHSRQHPH DQGWKHPDWFKER[VLJQUHYLVLWHGWKHLQWHUQDWLRQDOSHUVSHFWLYH Acta Derm LQERYLQHGLJLWDOGHUPDWLWLVE\LPPXQRFKHPLVWU\DQGSRO\PHUDVHFKDLQ Venereol. 2010; (5): 517–519. UHDFWLRQ Vet Microbiol. 1998; (2–4): 285–292. 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 3XE0HG$EVWUDFW| 3XEOLVKHU)XOO7H[W 30. Hylwa SA, Bury JE, Davis MD, et al.: 'HOXVLRQDOLQIHVWDWLRQLQFOXGLQJGHOXVLRQV 14. 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