An Association Between Morgellons Disease and Lyme Disease?
An Association Between Morgellons Disease and Lyme Disease?
Despite compelling evidence to the contrary, MD continues to be attributed to delusions of parasitosis or delusional infestation. The earlier studies demonstrating Borrelia spirochetes in MD dermatological specimens have involved only a small number of study subjects, and therefore a study involving a larger number of subjects was needed.
A major strength of our study is that MD patients were identified based on the presence of multicolored fibers within skin lesions or detectable under unbroken skin. Some of our patients did suffer from neuropsychiatric symptoms, and we do not deny that primary delusional infestation can occur in rare cases. By selecting only MD patients meeting our dermopathy criterion, however, we have presumably excluded primary delusional infestation patients from our study. Although some MD patients suffering from neuropsychiatric symptoms with Borrelia-associated intradermal filaments may claim to have worms, parasites or the like, the skin crawling and stinging sensations that these patients feel coupled with visible skin lesions, anxiety and anthropomorphic thinking may result in complaints that are misinterpreted by clinicians as a primary delusional disorder. Other MD patients in our study had no neuropsychiatric symptoms and yet had the same Borrelia-associated dermopathy, so it appears that in our well-defined MD patient cohort these symptoms, when they occurred, were the result rather than the cause of the infectious dermopathy, as previously described.
We have provided evidence linking Borrelia infection with MD in a study group consisting of 25 patients. We detected Borrelia DNA by PCR and/or staining with Bb-specific DNA probes in 24/25 patients. We were able to demonstrate the presence of Borrelia in dermatological tissue and we were able to culture viable Bb spirochetes from skin, blood and vaginal secretions in some patients. The presence of spirochetes was confirmed by numerous testing methodologies, including culture, histology, anti-Bb immunostaining, electron microscopy, PCR and in situ Bb DNA hybridization. Laboratory testing methodologies were performed at five independent laboratories. Histological staining and electron microscopy of Morgellons dermatological tissue and cultures was performed at three different laboratories, while molecular testing for Borrelia was performed at three different laboratories using real-time PCR, nested PCR and in situ Bb DNA hybridization. Furthermore, Borrelia DNA amplicon sequencing was conducted at two different laboratories. We have thus provided corroborating evidence of Borrelia infection in MD patients that should be difficult to refute.
Recent studies reported similarities between MD and bovine digital dermatitis (BDD), a disease that is common in dairy herds. BDD is characterized by skin lesions that commonly occur on and directly above the heel bulb of the hind feet of cattle. Chronic BDD lesions demonstrate proliferative keratin filaments, and histological examination of diseased tissue reveals spirochetes identified as Treponema spp. dispersed among enlarged keratinocytes throughout the stratum spinosum and dermal papillae. Though spirochetes are consistently detected in tissue from lesions, coinvolvement of other bacterial pathogens has been proposed as a contributing etiologic factor. Treponemal spirochetes were confirmed as the primary etiologic agents when the condition was duplicated via experimental infection with pure cultured treponemes.
As with BDD, MD filaments are not textile fibers. MD fibers are biofilaments of human cellular origin produced by epithelial cells and stemming from deeper layers of the epidermis and the root sheath of hair follicles. Immunohistochemical and histological staining has demonstrated that these multicolored filaments are composed of collagen and keratin. They are nucleated at the base of attachment to adjacent epithelial cells, and the cells at the filament base are continuous in appearance with the surrounding skin cells. Although the cause of coloration of red fibers has not been defined, the blue coloration is the result of melanin pigmentation rather than a dye, as shown by Fontana Masson histological staining. There are no known textile fibers that are collagen in composition, nucleated at their base of attachment, or pigmented blue with melanin. Thus the characteristic fibers in MD are clearly distinct from textile fibers.
Histological sections of MD dermatological tissue reacted with anti-Bb immunostain in 19/19 of the dermatological specimens submitted for histological examination. Motile Borrelia spirochetes were cultured in medium inoculated with skin scrapings from 4 patients, thus demonstrating that Borrelia spirochetes in MD lesions are viable. Borrelia spirochetes were also detected in blood cultures from some MD patients in our study, confirming systemic Lyme borreliosis. Spirochetes characterized as strains of Borrelia were detected by PCR and/or in situ DNA hybridization in tissue or culture specimens from 24/25 patients; 15 of these patients had Borrelia gene products detected in dermatological specimens and/or skin cultures taken from MD lesions, and DNA amplicons from 14 patients were sequenced and confirmed to be Borrelia strains. Vaginal secretions from four patients were cultured, and three isolates were identified as Borrelia strains by PCR and in situ DNA hybridization.
Lyme borreliosis is a systemic infection that is commonly associated with dermatological manifestations. Given that most MD patients are serologically reactive to Bb antigens, the presence of Lyme spirochetes in MD dermatological lesions is predictable and supports an etiologic role of the spirochetal disease. Bb sensu stricto and Bb sensu lato have been associated with numerous dermatological manifestations including erythema migrans, borrelial lymphocytoma, acrodermatitis chronica atrophicans, morphea, lichen sclerosus, cutaneous B-cell lymphoma, scleroderma, lymphadenosis cutis and prurigo pigmentosa. Likewise it appears that MD is associated with Lyme disease in a subgroup of patients with this spirochetal illness. It is possible that spirochetes other than Bb sensu stricto and the Bb sensu lato complex, such as the agent of syphilis, Treponema pallidum, could be responsible for similar manifestations in other patients. In support of this supposition, Ekbom's original 1945 description of delusions of parasitosis reported that many of the patients in that study were diagnosed with syphilis, thus linking treponemal infection with pruritus, crawling sensations and belief of infestation. Furthermore, treponemal spirochetes have been shown to induce the formation of filamentous lesions in animal models.
The mechanism of filament formation in MD is not yet elucidated. The filaments are composed of keratin and collagen and arise from proliferative keratinocytes and fibroblasts in human epithelial tissue. Bb appears to have a predilection for fibroblasts and keratinocytes, and invasion of these cells by Borrelia spirochetes has been reported. Bb appears to attach to fibroblasts followed by engulfment of the spirochetes, formation of vacuoles and intracellular replication. Intracellular sequestration of Bb in skin fibroblasts and keratinocytes may protect the spirochetes from host defense mechanisms. It is therefore reasonable to hypothesize that Bb intracellular infection of keratinocytes and fibroblasts may alter keratin and collagen expression and that the presence of Borrelia spirochetes in dermatological tissue is a primary etiologic factor in the evolution of MD lesions.
Viable Bb spirochetes have been isolated from lysates of fibroblast and keratinocyte monolayers treated with antibiotics. Therefore, in addition to protection from host defenses, sequestration within fibroblasts and keratinocytes may protect Bb from antibiotic therapy. Spirochetes in MD dermatological tissue from Patients 1 and 12 were reactive to anti-Bb immunostains and we detected Borrelia DNA in dermatological tissue taken from these two patients. These patients were receiving aggressive antibiotic therapy at the time of this study. Patients 2, 8, 13, 19 and 20 had previously received antibiotic therapy for Lyme disease, yet still had detectable spirochetal infection. Persistent infection refractory to antibiotic treatment may therefore result from sequestration of Borrelia spirochetes within keratinocytes and fibroblasts in MD patients.
Although spirochetes appear to be the primary etiologic agents of MD, evidence suggests that the etiology is multifactorial. Secondary etiologic factors, such as female predominance, immune dysfunction, and other tickborne coinfections appear to play a role in the development of this dermopathy. As noted in Table 1, we found serological evidence of tickborne coinfections including Babesia, Anaplasma, Ehrlichia, Bartonella and Rickettsia spp. in five of six patients who were tested. The role of these coinfections in MD remains undefined. Although we demonstrated the presence of Borrelia spirochetes in all of the patients in our study group, T. denticola was detected in dermatological specimens from five patients. The role of these commonly occurring oral spirochetes in the evolution of MD dermatological lesions and subsequent filament formation is uncertain, and we speculate that coinvolvement of these and perhaps other pathogens could be contributing or exacerbating factors in MD.
A study from the Centers for Disease Control and Prevention (CDC) concluded that pathogens were not involved in MD. The search for spirochetal pathogens in that study was limited to Warthin-Starry staining on a small number of tissue samples and commercial two-tiered serological Lyme disease testing as interpreted by the CDC Lyme surveillance criteria. It should be noted that only two of the patients in our study group were positive for Lyme disease based on the CDC Lyme surveillance criteria and yet Borrelia spirochetes were readily detectable in this group of 25 MD patients.
The diagnosis of Lyme disease is a controversial topic in the medical literature. Serological tests for Lyme disease lack sensitivity, and seronegativity has been demonstrated in patients with Bb infection. PCR detection is not standardized, and sensitivity and specificity of testing therefore varies from laboratory to laboratory. We detected Borrelia strains using different primers and different methodologies, and our findings show that primer hybridization differed between samples. Likewise Borrelia antigen detection may be unreliable, and immunostaining may lack sensitivity or specificity. Although our dermatological and culture pellet sections were consistently reactive with anti-Bb polyclonal antibodies, we were not certain of the specificity of our testing. We wish to emphasize, however, that repeated detection of Borrelia spirochetes using a combination of diverse laboratory methods makes false-positive testing highly unlikely in these MD patients.
Borrelia culture is not available in many laboratories and can be challenging because of fastidious growth requirements and spirochetal pleomorphism. The formation of spherical forms, truncated forms, straight forms, wavy forms and the like could result in positive cultures being overlooked. Our cultures demonstrated significant pleomorphism, and cystic or truncated variants were present, more so in blood cultures than skin cultures. In our experience histological identification is complicated because pleomorphism occurs in vivo as well as in vitro. Sensitivity and specificity differences between laboratory methodologies to detect Borrelia spirochetes necessitate the use of several different methodologies to confirm the presence of Borrelia infection. If MD is determined to be pathognomonic for Lyme borreliosis it will aid in the diagnosis of Lyme disease in this group of patients. A recent study from Australia found MD in 6% of patients diagnosed with Lyme disease on that continent.
We achieved a high degree of success in detecting Bb and closely-related spirochetes from MD dermatological tissue. We attribute our success to several key factors. First, as stated previously we had a clear diagnostic criterion that allowed us to select the appropriate clinical cohort. Second, in contrast to T. pallidum, the treponemal agent of syphilis, Borrelia spp. can be cultured, thereby magnifying their numbers in vitro and increasing the opportunity for detection. Third, unlike secondary and tertiary syphilitic skin lesions where treponemes are seldom detected, we observed that MD lesions carry a high spirochetal load that allows for relatively easy detection, similar to lesions seen in cattle with BDD. Finally, we used a variety of sensitive microscopic and molecular methodologies to detect Borrelia spp., including molecular hybridization and PCR techniques that can detect spirochetal DNA in the picogram range.
The detection of Borrelia spirochetes in dermatological samples from a larger group of MD patients further validates the infectious nature of this dermopathy. As noted above, T. pallidum spirochetes are seldom detected in secondary and tertiary syphilitic skin lesions, even when sensitive molecular techniques such as PCR are performed, yet syphilis spirochetes are acknowledged to be the causative agent of these lesions. The use of a clinical classification system for syphilis has helped with diagnosis and treatment of this systemic treponemal infection. In contrast to syphilis, we were able to consistently isolate and/or detect Borrelia spirochetes from MD dermatological specimens. Also in contrast to syphilis, no clinical classification system exists for MD.
Based on our experience with several hundred MD patients, we propose a clinical classification scheme that reflects the duration and location of MD lesions, as follows:
The classification scheme provides a medical framework that should help to validate and standardize the diagnosis of MD. Further studies are needed to determine whether this classification will have therapeutic and prognostic significance for MD patients.
Discussion
Despite compelling evidence to the contrary, MD continues to be attributed to delusions of parasitosis or delusional infestation. The earlier studies demonstrating Borrelia spirochetes in MD dermatological specimens have involved only a small number of study subjects, and therefore a study involving a larger number of subjects was needed.
A major strength of our study is that MD patients were identified based on the presence of multicolored fibers within skin lesions or detectable under unbroken skin. Some of our patients did suffer from neuropsychiatric symptoms, and we do not deny that primary delusional infestation can occur in rare cases. By selecting only MD patients meeting our dermopathy criterion, however, we have presumably excluded primary delusional infestation patients from our study. Although some MD patients suffering from neuropsychiatric symptoms with Borrelia-associated intradermal filaments may claim to have worms, parasites or the like, the skin crawling and stinging sensations that these patients feel coupled with visible skin lesions, anxiety and anthropomorphic thinking may result in complaints that are misinterpreted by clinicians as a primary delusional disorder. Other MD patients in our study had no neuropsychiatric symptoms and yet had the same Borrelia-associated dermopathy, so it appears that in our well-defined MD patient cohort these symptoms, when they occurred, were the result rather than the cause of the infectious dermopathy, as previously described.
We have provided evidence linking Borrelia infection with MD in a study group consisting of 25 patients. We detected Borrelia DNA by PCR and/or staining with Bb-specific DNA probes in 24/25 patients. We were able to demonstrate the presence of Borrelia in dermatological tissue and we were able to culture viable Bb spirochetes from skin, blood and vaginal secretions in some patients. The presence of spirochetes was confirmed by numerous testing methodologies, including culture, histology, anti-Bb immunostaining, electron microscopy, PCR and in situ Bb DNA hybridization. Laboratory testing methodologies were performed at five independent laboratories. Histological staining and electron microscopy of Morgellons dermatological tissue and cultures was performed at three different laboratories, while molecular testing for Borrelia was performed at three different laboratories using real-time PCR, nested PCR and in situ Bb DNA hybridization. Furthermore, Borrelia DNA amplicon sequencing was conducted at two different laboratories. We have thus provided corroborating evidence of Borrelia infection in MD patients that should be difficult to refute.
Recent studies reported similarities between MD and bovine digital dermatitis (BDD), a disease that is common in dairy herds. BDD is characterized by skin lesions that commonly occur on and directly above the heel bulb of the hind feet of cattle. Chronic BDD lesions demonstrate proliferative keratin filaments, and histological examination of diseased tissue reveals spirochetes identified as Treponema spp. dispersed among enlarged keratinocytes throughout the stratum spinosum and dermal papillae. Though spirochetes are consistently detected in tissue from lesions, coinvolvement of other bacterial pathogens has been proposed as a contributing etiologic factor. Treponemal spirochetes were confirmed as the primary etiologic agents when the condition was duplicated via experimental infection with pure cultured treponemes.
As with BDD, MD filaments are not textile fibers. MD fibers are biofilaments of human cellular origin produced by epithelial cells and stemming from deeper layers of the epidermis and the root sheath of hair follicles. Immunohistochemical and histological staining has demonstrated that these multicolored filaments are composed of collagen and keratin. They are nucleated at the base of attachment to adjacent epithelial cells, and the cells at the filament base are continuous in appearance with the surrounding skin cells. Although the cause of coloration of red fibers has not been defined, the blue coloration is the result of melanin pigmentation rather than a dye, as shown by Fontana Masson histological staining. There are no known textile fibers that are collagen in composition, nucleated at their base of attachment, or pigmented blue with melanin. Thus the characteristic fibers in MD are clearly distinct from textile fibers.
Histological sections of MD dermatological tissue reacted with anti-Bb immunostain in 19/19 of the dermatological specimens submitted for histological examination. Motile Borrelia spirochetes were cultured in medium inoculated with skin scrapings from 4 patients, thus demonstrating that Borrelia spirochetes in MD lesions are viable. Borrelia spirochetes were also detected in blood cultures from some MD patients in our study, confirming systemic Lyme borreliosis. Spirochetes characterized as strains of Borrelia were detected by PCR and/or in situ DNA hybridization in tissue or culture specimens from 24/25 patients; 15 of these patients had Borrelia gene products detected in dermatological specimens and/or skin cultures taken from MD lesions, and DNA amplicons from 14 patients were sequenced and confirmed to be Borrelia strains. Vaginal secretions from four patients were cultured, and three isolates were identified as Borrelia strains by PCR and in situ DNA hybridization.
Lyme borreliosis is a systemic infection that is commonly associated with dermatological manifestations. Given that most MD patients are serologically reactive to Bb antigens, the presence of Lyme spirochetes in MD dermatological lesions is predictable and supports an etiologic role of the spirochetal disease. Bb sensu stricto and Bb sensu lato have been associated with numerous dermatological manifestations including erythema migrans, borrelial lymphocytoma, acrodermatitis chronica atrophicans, morphea, lichen sclerosus, cutaneous B-cell lymphoma, scleroderma, lymphadenosis cutis and prurigo pigmentosa. Likewise it appears that MD is associated with Lyme disease in a subgroup of patients with this spirochetal illness. It is possible that spirochetes other than Bb sensu stricto and the Bb sensu lato complex, such as the agent of syphilis, Treponema pallidum, could be responsible for similar manifestations in other patients. In support of this supposition, Ekbom's original 1945 description of delusions of parasitosis reported that many of the patients in that study were diagnosed with syphilis, thus linking treponemal infection with pruritus, crawling sensations and belief of infestation. Furthermore, treponemal spirochetes have been shown to induce the formation of filamentous lesions in animal models.
The mechanism of filament formation in MD is not yet elucidated. The filaments are composed of keratin and collagen and arise from proliferative keratinocytes and fibroblasts in human epithelial tissue. Bb appears to have a predilection for fibroblasts and keratinocytes, and invasion of these cells by Borrelia spirochetes has been reported. Bb appears to attach to fibroblasts followed by engulfment of the spirochetes, formation of vacuoles and intracellular replication. Intracellular sequestration of Bb in skin fibroblasts and keratinocytes may protect the spirochetes from host defense mechanisms. It is therefore reasonable to hypothesize that Bb intracellular infection of keratinocytes and fibroblasts may alter keratin and collagen expression and that the presence of Borrelia spirochetes in dermatological tissue is a primary etiologic factor in the evolution of MD lesions.
Viable Bb spirochetes have been isolated from lysates of fibroblast and keratinocyte monolayers treated with antibiotics. Therefore, in addition to protection from host defenses, sequestration within fibroblasts and keratinocytes may protect Bb from antibiotic therapy. Spirochetes in MD dermatological tissue from Patients 1 and 12 were reactive to anti-Bb immunostains and we detected Borrelia DNA in dermatological tissue taken from these two patients. These patients were receiving aggressive antibiotic therapy at the time of this study. Patients 2, 8, 13, 19 and 20 had previously received antibiotic therapy for Lyme disease, yet still had detectable spirochetal infection. Persistent infection refractory to antibiotic treatment may therefore result from sequestration of Borrelia spirochetes within keratinocytes and fibroblasts in MD patients.
Although spirochetes appear to be the primary etiologic agents of MD, evidence suggests that the etiology is multifactorial. Secondary etiologic factors, such as female predominance, immune dysfunction, and other tickborne coinfections appear to play a role in the development of this dermopathy. As noted in Table 1, we found serological evidence of tickborne coinfections including Babesia, Anaplasma, Ehrlichia, Bartonella and Rickettsia spp. in five of six patients who were tested. The role of these coinfections in MD remains undefined. Although we demonstrated the presence of Borrelia spirochetes in all of the patients in our study group, T. denticola was detected in dermatological specimens from five patients. The role of these commonly occurring oral spirochetes in the evolution of MD dermatological lesions and subsequent filament formation is uncertain, and we speculate that coinvolvement of these and perhaps other pathogens could be contributing or exacerbating factors in MD.
A study from the Centers for Disease Control and Prevention (CDC) concluded that pathogens were not involved in MD. The search for spirochetal pathogens in that study was limited to Warthin-Starry staining on a small number of tissue samples and commercial two-tiered serological Lyme disease testing as interpreted by the CDC Lyme surveillance criteria. It should be noted that only two of the patients in our study group were positive for Lyme disease based on the CDC Lyme surveillance criteria and yet Borrelia spirochetes were readily detectable in this group of 25 MD patients.
The diagnosis of Lyme disease is a controversial topic in the medical literature. Serological tests for Lyme disease lack sensitivity, and seronegativity has been demonstrated in patients with Bb infection. PCR detection is not standardized, and sensitivity and specificity of testing therefore varies from laboratory to laboratory. We detected Borrelia strains using different primers and different methodologies, and our findings show that primer hybridization differed between samples. Likewise Borrelia antigen detection may be unreliable, and immunostaining may lack sensitivity or specificity. Although our dermatological and culture pellet sections were consistently reactive with anti-Bb polyclonal antibodies, we were not certain of the specificity of our testing. We wish to emphasize, however, that repeated detection of Borrelia spirochetes using a combination of diverse laboratory methods makes false-positive testing highly unlikely in these MD patients.
Borrelia culture is not available in many laboratories and can be challenging because of fastidious growth requirements and spirochetal pleomorphism. The formation of spherical forms, truncated forms, straight forms, wavy forms and the like could result in positive cultures being overlooked. Our cultures demonstrated significant pleomorphism, and cystic or truncated variants were present, more so in blood cultures than skin cultures. In our experience histological identification is complicated because pleomorphism occurs in vivo as well as in vitro. Sensitivity and specificity differences between laboratory methodologies to detect Borrelia spirochetes necessitate the use of several different methodologies to confirm the presence of Borrelia infection. If MD is determined to be pathognomonic for Lyme borreliosis it will aid in the diagnosis of Lyme disease in this group of patients. A recent study from Australia found MD in 6% of patients diagnosed with Lyme disease on that continent.
We achieved a high degree of success in detecting Bb and closely-related spirochetes from MD dermatological tissue. We attribute our success to several key factors. First, as stated previously we had a clear diagnostic criterion that allowed us to select the appropriate clinical cohort. Second, in contrast to T. pallidum, the treponemal agent of syphilis, Borrelia spp. can be cultured, thereby magnifying their numbers in vitro and increasing the opportunity for detection. Third, unlike secondary and tertiary syphilitic skin lesions where treponemes are seldom detected, we observed that MD lesions carry a high spirochetal load that allows for relatively easy detection, similar to lesions seen in cattle with BDD. Finally, we used a variety of sensitive microscopic and molecular methodologies to detect Borrelia spp., including molecular hybridization and PCR techniques that can detect spirochetal DNA in the picogram range.
The detection of Borrelia spirochetes in dermatological samples from a larger group of MD patients further validates the infectious nature of this dermopathy. As noted above, T. pallidum spirochetes are seldom detected in secondary and tertiary syphilitic skin lesions, even when sensitive molecular techniques such as PCR are performed, yet syphilis spirochetes are acknowledged to be the causative agent of these lesions. The use of a clinical classification system for syphilis has helped with diagnosis and treatment of this systemic treponemal infection. In contrast to syphilis, we were able to consistently isolate and/or detect Borrelia spirochetes from MD dermatological specimens. Also in contrast to syphilis, no clinical classification system exists for MD.
Based on our experience with several hundred MD patients, we propose a clinical classification scheme that reflects the duration and location of MD lesions, as follows:
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 classification scheme provides a medical framework that should help to validate and standardize the diagnosis of MD. Further studies are needed to determine whether this classification will have therapeutic and prognostic significance for MD patients.
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