Classification and Staging of Morgellons Disease: Lessons from Syphilis
Authors Middelveen MJ, Martinez RM, Fesler MC, Sapi E, Burke J, Shah JS, Nicolaus C, Stricker RB
Received 24 November 2019
Accepted for publication 16 January 2020
Published 7 February 2020 Volume 2020:13 Pages 145—164
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 4
Editor who approved publication: Dr Jeffrey Weinberg
Video abstract presented by Melissa C. Fesler.
Marianne J Middelveen,1 Roberto M Martinez,2 Melissa C Fesler,3 Eva Sapi,4 Jennie Burke,5 Jyotsna S Shah,6 Carsten Nicolaus,7 Raphael B Stricker3
1Atkins Veterinary Services, Calgary, AB, Canada; 2Martinez Veterinary Services, Calgary, AB, Canada; 3Union Square Medical Associates, San Francisco, CA, USA; 4Department of Biology and Environmental Science, University of New Haven, West Haven, CT, USA; 5Australian Biologics, Sydney, NSW, Australia; 6IGeneX Laboratories, Palo Alto, CA, USA; 7BCA-Clinic, Augsburg, Germany
Correspondence: Raphael B Stricker
Union Square Medical Associates, 450 Sutter Street, Suite 1504, San Francisco, CA 94108, USA
Introduction: Morgellons disease (MD) is a contested dermopathy that is associated with Borrelia spirochetal infection. A simple classification system was previously established to help validate the disease based on clinical features (classes I-IV).
Methods: Drawing on historical and pathological parallels with syphilis, we formulated a more detailed staging system based on clinical features as well as severity of skin lesions and corresponding histopathological infection patterns, as determined by anti-Borrelia immunohistochemical staining.
Results: Clinical classes I-IV of MD are further categorized as mild, moderate and severe, or stages A, B and C, respectively, based on histopathological findings. Stage A lesions demonstrated little or no immune infiltrates and little or no disorganization of cells; macrophages were not present, and hemorrhage was negligible. Extracellular isolated spirochetes and intracellular staining of keratinocytes in the lower epidermis was occasionally seen. Stage C lesions demonstrated positive staining of keratinocytes in the stratum basale and stratum spinosum and positive intracellular staining of macrophages for Borrelia. Aggregate Borrelia colonies were frequently encountered, hemorrhage was frequent, and intracellularly stained fibroblasts were occasionally seen. Stage B lesions demonstrated a pattern intermediate between Stages A and C.
Conclusion: The enhanced staging system provides objective criteria to assess the severity of dermopathy in MD. Further studies are needed to determine the optimal treatment for MD based on this staging system related to Borrelia infection.
Keywords: Morgellons disease, Lyme disease, Borrelia burgdorferi, relapsing fever Borrelia, tick-borne disease, syphilis, Treponema pallidum
Morgellons disease (MD) is a dermatological condition in which lesions that contain unusual filamentous inclusions and/or projections spontaneously arise.1–5 The filaments are distinctive in part due to their varied white, red, blue, green or black coloration, and because visually they resemble microscopic textile fibers.6–9 In addition, the dermopathy may be accompanied by formication (sensation of something crawling on skin). Coupled with the mistaken belief that the fibers are derived from textiles, healthcare professionals frequently and erroneously diagnose the condition as a form of delusional infestation (DI) or the legacy terms delusional parasitosis (DP) and delusions of parasitosis (DOP).6,7,10
In addition to filamentous dermopathy, patients frequently experience Lyme-like symptoms such as musculoskeletal, neurological and cardiovascular manifestations suggestive of spirochetal etiology.1–5,8 Cohort studies indicate that most patients with MD test positively for Borrelia infection and/or have a clinical Lyme disease (LD) diagnosis.4,11–13 Two separate cohort studies have demonstrated that MD afflicts approximately 6% of LD patients.11,14 Thus it has been suggested that MD is a physiological response to spirochetal infection in genetically predisposed patients, and there is an abundance of experimental data to support the hypothesis.8,9
Borrelia infection is caused by members of the Borrelia genus encompassing the LD group, also known as Borrelia burgdorferi (Bb) sensu lato (Bbsl), and the Relapsing Fever Borrelia (RFB) complex, the causative agents of LD and relapsing fever (RF), respectively. Bbsl and RFB have been repeatedly and consistently detected in tissue and fluid specimens taken from MD subjects.8,9,12,13,15 Furthermore, using sensitive molecular methodologies, Bb and RFB have been directly detected and cultured from skin lesions demonstrating MD pathology,8,9,12,13,15–18 thus satisfying many of the criteria outlined in Fredricks and Relman’s molecular guidelines for establishing disease causation.19 Borrelia spirochetes have been detected in MD tissue and body fluid specimens, both directly in dermatological specimens and in cultures from 25 North American MD patients using a combination of microscopic, histopathological and molecular methods. Most of the Borrelia species detected were genetically identified as Bb sensu stricto (Bbss), but B. garinii and B. miyamotoi were also confirmed.12
In a separate study, 90% of a cohort of 30 MD patients tested positively for exposure to and/or infection with Borrelia spirochetes using serological and molecular techniques. Of these, 53% of the cohort tested positive for Bb, RFB or both using PCR amplification and confirmatory sequencing.13 To date, to the best of our knowledge, five independent laboratories have confirmed the presence of Borrelia DNA in MD skin specimens using PCR technology and confirmatory DNA sequencing, and seven independent laboratories have detected Borrelia DNA by direct testing or in cultures of blood, genital secretions and skin specimens taken from MD patients.8,9,13,20 If sensitive and specific detection methods are used, the detection of Borrelia spirochetes directly in MD patient specimens is consistent and reproducible, thus providing evidence suggestive of causality.
In addition to members of the genus Borrelia, other members of the Spirochaetaceae family might be able to induce MD. Various members of the genus Treponema cause a comparable condition, bovine digital dermatitis, in cattle.5 T. denticola has been detected in some MD skin specimens, although not independently of Bbsl.5 Because Treponema is known to cause a comparable condition in an animal model, and because treponemes are spirochetes like Borrelia spp., it is possible that T. denticola or other pathogenic treponemes could be key etiologic factors in the evolution of MD in some patients. In support of that hypothesis, there is historical evidence linking MD-like cases to treponemal infection, as discussed below.
DI is defined as the fixed, false belief of being infested with parasites or other infectious agents. In 1938, the Swedish physician Ekbom published a series of case studies describing patients with formication coupled with the false belief of insect infestation,21 and consequently cases of DI are often referred to as “Ekbom’s syndrome”.6,7 Ekbom reported that patients in his study presented collections of hairs, skin and sand-like particles that are comparable to what we see in MD self-collected specimens.21 MD is frequently associated with formication, and some MD patients mistakenly believe that they have a parasitic infection or infestation. Consequently, MD has been misrepresented as a form of Ekbom’s syndrome.8,9 Interestingly, three out of seven of Ekbom’s subjects had syphilis, and three years before Ekbom’s studies were published, the French physician Vié reported that 6/8 of his DI cohort had documented cases of syphilis.21,22 Although we have not detected T. pallidum in any MD subjects to date, given that there is a historical association with T. pallidum infection in comparable cases, it is reasonable to hypothesize that T. pallidum could be an etiologic factor in a subset of MD patients.
Although spirochetal infection appears to be the key etiologic factor in MD evolution, MD patients have a high incidence of other co-infecting tickborne diseases, with Babesia infection being most frequently reported.4,11 Other pathogens have been detected directly in MD dermatological specimens, although less frequently and less consistently than Borrelia spp. These pathogens include the co-infecting tickborne pathogens Bartonella henselae and Rickettsia spp., and the common human pathogens Helicobacter pylori (Hp) and T. denticola.8,13,15,23–25 Mixed Bb and Hp aggregate structures consistent with biofilms that contain alginate and amyloid protein structures have been identified in MD skin specimens.15 Confocal microscopy of mixed aggregates revealed that Bb occupied the central portion of aggregates while Hp occupied the periphery, suggesting that they could have different functional roles, but also suggesting that Bb infection was established first followed by Hp infection.15 In either case, the results suggest that mixed Borrelia biofilms may play a role in MD development and contribute towards Borrelia persistence and disease chronicity. Although the role of other pathogens and mixed infections in MD skin remains to be determined, it is possible that other microorganisms play a part in MD development and could be co-involved etiological factors in individual patients.
Histochemical studies demonstrate that the cutaneous filaments in MD are not self-implanted synthetic man-made textile fibers, but are hair-like human biofilaments composed of the structural proteins keratin and collagen, the products of keratinocytes and fibroblasts, respectively.5,8,9,17,26 The cellular base of attachment at the stratum basale is nucleated and continuous with surrounding skin cells, consistent with human cellular origin.5,8,9,17,26 Furthermore, the characteristic blue color seen in some fibers results from melanin pigmentation, and blue filaments contain melanocytes and melanin granulation, providing irrefutable evidence that these are not synthetic manufactured fibers.5,8,9,17 Thus, the skin fibers seen in MD patients are biofilaments that appear to be aberrantly produced in response to spirochetal infection.
The classification of diseases provides a foundation for identifying causation of morbidity and mortality, thus allowing actions to be taken to save lives and lessen suffering.27 Classification of diseases is epidemiologically fundamental as it provides a common language, allowing data regarding health-related concerns to be compiled and shared between medical professionals.27 The following clinical classification system for MD, based on duration and location of MD lesions, was previously proposed:8,9,12
Early localized: lesions/fibers present for less than three (3) months and localized to one area of the body (head, trunk, extremities).
Early disseminated: lesions/fibers present for less than three (3) months and involving more than one area of the body (head, trunk, extremities).
Late localized: lesions/fibers present for more than six (6) months and localized to one area of the body (head, trunk, extremities).
Late disseminated: lesions/fibers present for more than six (6) months and involving more than one area of the body (head, trunk, extremities).
The purpose of the above classification scheme was to provide a clinical framework to validate and standardize the diagnosis of MD. The present study applies the above classification scheme in conjunction with an additional staging system based on the severity of lesions along with corresponding histological evidence of infection. Disease staging is a classification system using objective medical criteria to evaluate disease severity and assess disease progression.28 Because Borrelia spp. are the key pathogens encountered in MD tissue, we focused our staging system on the infection patterns revealed by anti-Borrelia immunohistochemical (IHC) staining. Together, classification and staging provide corroborative data to validate this neglected dermopathy. In addition, staging will provide a framework to help healthcare professionals assess disease evolution and customize treatments based on the stage of infection.
Materials and Methods
Patients from across North America were selected for study, providing they met the case definition for MD as determined by a health care practitioner, and that they had lesions suitable for histological sectioning. The case definition used in this study required the presence of spontaneously-developing cutaneous lesions with embedded or projecting red, white, blue, green or black filaments. Prior testing for Borrelia infection was not required. The MD patients were then classified for duration and location of MD lesions, as previously proposed.8,9,12
The study was performed in accordance with the Declaration of Helsinki. Written informed consent for participation was obtained from all subjects, both MD patients and control subjects, in accordance with the specimen collection protocol approved by the Western Institutional Review Board (WIRB), Puyallup, WA. Consent to publish results was obtained from all subjects. The University of New Haven IRB Committee also approved the study as exempt under 45 CFR 46.101(b)(4). The identification, health status and demographic information of study subjects were not provided to research laboratories. All human samples were submitted to participating laboratories and processed in a blinded manner.
Dermatological specimens were submitted to McClain Laboratories LLC, Smithtown, NY. Skin specimens were taken from lesions showing MD pathology. The MD skin specimens collected for histological study mainly consisted of thickened callus material removed from lesions exhibiting embedded or projecting filaments. Normal commercially available human skin (BioChain Institute, Newark, CA) was included as a negative control. The MD skin specimens along with normal healthy skin were sent for histological processing in a blinded manner.
For further comparison, additional controls were as follows: Liver from a mouse experimentally infected with Bb, used for positive comparison as previously described.12,29 Negative controls included: a culture pellet of mixed Gram-positive bacteria (Staphylococcus spp. and Micrococcus spp.) combined with gelatin; a culture pellet of mixed Gram-negative bacteria (Escherichia coli and Klebsiella spp.) combined with gelatin; a biopsy from a psoriasis case; and a biopsy from skin with fungal infection. All specimens including experimental specimens and controls were formalin-fixed, blocked and sectioned, then IHC-stained to detect Borrelia using an unconjugated rabbit anti-Bb polyclonal antibody,30 incubated with an alkaline phosphatase probe (Biocare Medical #UP536L) followed by a chromogen substrate (Biocare Medical #FR805CHC), and counterstained with hematoxylin. Titration was conducted to define optimal antibody dilutions. Borrelia fluorescent in situ hybridization (FISH) was performed as previously described.12,29 Samples were visualized using a Nikon Eclipse E200 microscope, and images were taken with a Nikon DS-L3 camera.
Serology: IGeneX Laboratory
Western blot (WB) assays were performed as described previously to detect IgM and IgG antibodies reactive to Bb and RFB.13,31,32
PCR: University of New Haven
All skin specimens including skin from MD specimens and normal skin from healthy controls were submitted for PCR testing in a blinded manner. All PCR assays were performed in triplicate. Borrelia DNA was extracted as previously described, and Borrelia gene targets were detected by either real-time PCR using a published TaqMan assay targeted to a 139-bp fragment of the Borrelia 16S rRNA gene, or by nested PCR targeting the following genes: 16S rRNA, flagellin (Fla), OspC, uvrA and pyrG genes.12,20,29,33–35 PCR amplification was confirmed by Sanger sequencing and compared by BLAST analysis using the GenBank database (National Center for Biotechnology Information), as described previously.12,20,29
PCR: Australian Biologics
DNA was extracted from culture pellets using the DNeasy Blood and Tissue® kit (Qiagen) as previously described.12,14,16,20,36 Specimens were tested for the presence of Borrelia DNA and Treponema denticola/Treponema pallidum DNA targets. Blinded samples were run in duplicate with positive and negative controls using real-time PCR targeting the Borrelia 16S rRNA and endpoint PCR targeting the rpoC gene, as previously described.12,14,16,20,36 Sanger sequencing followed by BLAST analysis was used for gene analysis, as described previously.12,14,16,20,36
Multiplex PCR was performed for the detection of Bb and RFB in clinical samples as described previously.13 Sanger sequencing was performed on all positive Bb and RFB amplicons, confirming Borrelia derivation.
Sixteen subjects were selected who met the case description for MD as determined by a healthcare professional and who had suitable dermatological specimens for study. PCR and serological evidence of exposure to or infection with Borrelia and other co-involved pathogens is summarized in Table 1. All patients in our study had evidence of infection and/or exposure to Borrelia. Eight patients had serologic evidence of infection and/or exposure to Bb, and two patients had serologic evidence of infection and/or exposure to RFB. Twelve patients had detectable Bbsl DNA and six patients had detectable RFB DNA in clinical specimens. Nine patients had evidence of infection and/or exposure to co-involved pathogens as follows: Hp (9), Bartonella henselae (5), Babesia spp. (2), T. denticola (2), Ehrlichia chaffeensis (1), Anaplasma phagocytophilum (1), Chlamydia pneumonia (1), Toxoplasma spp. (1), and Mycoplasma spp. (1). Of the subjects in our study, 14/16 were tested by PCR technology for the presence of T. denticola and T. pallidum DNA. All were negative for T. pallidum, and 2/14 were positive for T. denticola DNA, but T. denticola was not found independently of Borrelia DNA.