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Clinical, Epidemiologic, Histopathologic and Molecular Features of an Unexplained Dermopathy
ResultsCase Finding and Characteristics, Prevalence Estimates and Geospatial MappingThe summary of case-finding and study enrollment efforts are shown in Figure 1. A total of 115 KPNC enrollees met our case definition; 104 (90.4%) were identified by search of electronic health records, representing a prevalence of 3.65 (95% CI = 2.98, 4.40) per 100,000 enrollees. The rate was higher among females than males and highest amongst persons 45–64 years of age (Table 1). Eleven additional KPNC members who self-identified also met the case definition and eligibility criteria for study participation. There was no geospatial clustering of cases within the 13-county catchment area served by KPNC (p = .113) (Figure 2). Figure 1. Summary of Case Finding and Study Enrollment Efforts, Unexplained Dermopathy, Calilfornia. doi:10.1371/journal.pone.0029908.g001Figure 2. Geospatial Mapping of UD Cases By Place of Residence, California. doi:10.1371/journal.pone.0029908.g002Table 1. Age-and Sex-specific Prevalence Rates of Unexplained Dermopathy, California, July 2006–June 2008. doi:10.1371/journal.pone.0029908.t001Case-patients had a median age of 55 years (range: 17–93); 89 (77.4%) were female. When screened for study eligibility, 81/115 (70.4%) case-patients identified the material emerging from their skin as “fibers” (alone or in combination with other materials); the remaining 34 (29.6%) identified the materials as other than fibers, including specks (59%), granules (56%), dots (50%), worms (35%), sand (32%), eggs (32%), fuzzballs (21%), and larvae (15%). Cross-sectional SurveyA total of 70 (61%) case-patients completed the cross-sectional survey. Case-patients who completed the survey were more likely to be female (p = .04), but did not differ by age when compared with case-patients who did not complete the survey (data not shown). The sociodemographic features of survey completers are shown in Table S1. The reported duration of symptoms ranged from 1.3 to 28.6 years (median: 3.7 years), with 69% participants reporting an illness duration of 2–5 years. The distribution of cases by reported year of illness onset is shown in Figure 3. Case-patients who reported “non-fibers” tended to report later illness onset (p = .057), but otherwise were similar to those who identified the material emerging from their skin as “fibers.” Figure 3. Distribution of Case-patients by Self-reported year of Onset, California. doi:10.1371/journal.pone.0029908.g003Symptoms, Habits and Potential Exposures.Case-patients' symptoms are summarized in Table S2. There was no specific distribution to the skin symptoms, with 74% of case-patients stating that all areas of their body were affected. Half of case-patients described onset of skin symptoms as gradual. The reported sequence of skin symptom onset varied, with 57% of case-patients reporting disturbing skin sensations as the initial manifestation (followed either by skin lesions and/or solid material); 16% reported skin lesions as the initial manifestation; 10% the appearance of solid material as the initial manifestation; and 13% reported the triad of skin symptoms began simultaneously. Ten (14%) and seven (10%) case-patients, respectively, reported similar skin symptoms in a family member or friend. No predominant temporal, diurnal or seasonal pattern to occurrence of skin symptoms or the emergence of material from the skin was reported, with 84% of respondents indicating that they had experienced skin symptoms “frequently” or “all the time” and 66% indicating that they noted fibers/solid material “anytime of the day.” Of the 14 (20%) who reported a seasonal occurrence of skin symptoms, 50% reported their symptoms as being worse during summer, 36% during spring, and 14% during winter. Fibers and other material emerging from the skin were described as having a wide range of colors, with most (86%) being detected on skin areas with abnormal sensation; 73% reported having experienced the emergence of fibers or solid material from areas where there were no breaks in the skin. Case-patients also reported a variety of non-skin symptoms involving multiple organ systems; non-skin symptoms reported by at least 50% of cases are shown (Table S2). Fatigue of ≥6 months duration and musculoskeletal complaints were among the most commonly reported, affecting 70% and 71% of case-patients, respectively. When queried about habits and other potential exposures, some case-patients reported sharing personal items such as hairbrushes (18%), razors (13%), and towels (11%) or sharing a bed with another person (41%) or a pet (57%). Few case-patients reported using a hot tub (17%) or Jacuzzi (15%), residing in proximity to a land fill (3%), hazardous waste (3%) or industrial site (4%), or near live stock (3%) or orchards (1%) or travel in relation to symptom onset (20%). Most (78%) reported engaging, or having a household member who engaged, in hobbies or activities that involved the use of solvents (e.g., furniture stripper, paint thinner, turpentine, charcoal lighter fluid). Case-patients reported using a wide range of topical and systemic over-the-counter, prescription and alternative therapies to alleviate their skin symptoms; no drug or treatment was consistently reported to be effective. Health-related Quality of Life.Over 50% of case-patients rated their overall health status as fair or poor, a proportion significantly higher than reported among California residents or nationally (Table 2). Case-patients' PCS (mean = 36.63, SD = 12.9) and MCS (mean = 35.45, SD = 12.89) scores also were significantly lower than expected national norms (mean = 50). Table 2. Prevalence of Fair or Poor Self-rated Health Among Case-patients Completing Web-based Survey, Unexplained Dermopathy, California. doi:10.1371/journal.pone.0029908.t002Clinical EvaluationsForty-one case-patients received clinical evaluation; they did not differ in sociodemographics from those who completed the survey but did not receive clinical evaluation (data not shown). On general clinical examination, six case-patients had muscle tenderness, one had cervical spine tenderness, and one had a positive Romberg. None had fever or lymphadenopathy. At the time of clinical evaluation, 60% of case-patients rated the severity of their skin symptoms as five or greater (10 = most severe); 15 (37%) and 25 (61%), respectively, reported having fiber/material currently present or emerging from their skin within the previous 24 hours. Type, Distribution and Severity of Skin Lesions.Clinical presentations varied substantially, including papules, scars, plaques, patches, macules, and one cyst. No case-patient had vesicles, bullae or burrows (suggestive of scabies). Many lesions were crusted, including some that were ulcerated or eroded. Some lesions and the surrounding area showed signs of inflammation (redness, warmth, tenderness). A median 17 lesions (range, 0–59) were documented per patient. The forearms (right, 83%; left, 71%), back (68%), chest (66%), face (66%) and lower legs (right, 63%; left, 66%) were the most commonly affected areas. Most arm lesions were on the posterior surface with sparing of the anterior surface. When back lesions were present, there was usually sparing of a dumbbell-shaped area in the center of the back. Clinically, the findings were most consistent with excoriations or chronic irritation, some with evidence of secondary infection. Representative skin findings are shown (Figure 4A–D). Figure 4. Representative skin lesions detected on clinical examination. A. Three erythematous scaly plaques with a fourth more proximal eroded and crusted plaque. B. Close-up of the eroded plaque in image 4A showing blue fibers. C. Excoriated erythematous papules suggestive of arthropod bites, dermatitis or possible excoriated folliculitis. D. Close-up of excoriated lesion in image 4C. doi:10.1371/journal.pone.0029908.g004Neurocognitive and Neuropsychiatric Assessments.Of 41 case-patients who underwent clinical evaluation, 36 (88%) completed the full battery of neuropsychological tests. Case-patients had estimated IQ scores ranging from 84 (low average) to 126 (high average), with a mean score of 109.9 (SD = 12.2). On cognitive testing, 59% (23/39) case-patients demonstrated impairment in at least one domain; attention (18%) and memory (16%) were the most common areas of impairment. On the PAI, 63% (25/40) of case-patients had clinically significant elevations (T>70) in scores for one or more of the clinical domains, with somatic concerns the most frequent (63%), followed by depression (11%) (Table S3). Of the 24 case-patients with scores suggesting clinically significant somatic complaints, 14 (39%) had evidence of co-existing depression, 10 (37%) evidence of other co-existing neuropsychiatric conditions, and 12 (50%) had T scores >87, suggesting severe impairment arising from the somatic complaints. Four (24%) had evidence of clinically significant past or present drug or alcohol use. Laboratory ResultsFew case-patients had abnormalities detected among the battery of blood tests; most were borderline abnormalities or abnormalities consistent with previously diagnosed conditions (e.g., diabetes, thyroid disease). Some case-patients had elevated markers suggestive of inflammation; five (12.5%) each had elevated RF or ESR, four (10%) elevated ANA, and three (7.5%) CRP. Three (8%) case-patients had anti-HCV antibodies and five (12.5%, 2 borderline) anti-HBs antibodies. No case-patients had anti-HBc or HBsAg antibodies. One case-patient each had a positive or borderline EIA for B. burgdorferi, but none had a positive IgG WB. Three (8%) case-patients had positive serologies for Toxocara and three (8%) for Strongyloides. At least one drug was detected in hair samples of 20/40 (50%) case-patients; these included amphetamines (3), barbiturates (1), benzodiazepines (8), cannabinoids (7), cocaine (2), opiates (8), and propoxyphene (1). All chest radiographs were interpreted as normal. Histopathologic and Microbiologic Features of Skin BiopsiesOf 41 case-patients who received clinical evaluation, 31 (75%) were deemed to have lesions amenable to biopsy or to have material that was present on the skin for collection. Biopsies (n = 62) were distributed across the entire body surface; 37 were from lesions, 22 from clinically normal skin and three were from undocumented sites. Histopathologic features of the biopsied skin lesions were varied and representative findings are shown (Figures 5 and 6). Solar elastosis was the most common histopathologic abnormality, present in 19 (51%) biopsied lesions. Fifteen (40%) biopsied skin lesions showed histopathologic evidence of excoriation or chronic irritation (lichen simplex chronicus or prurigo nodularis); six (16%) others had features consistent with an arthropod bite or drug allergy. Figure 5. Representative histopathologic features of case-patient skin lesions. A. Epidermal hyperplasia with compact orthokeratosis and hypergranulosis and perivascular inflammatory infiltrates in the dermis consistent with lichen simplex chronicus. B. Focal erosion with superficial ulceration and scale-crust consistent with excoriation. C. Mixed perivascular inflammatory cell infiltrates comprised of lymphocytes, neutrophils and eosinophils, suggestive of arthropod bite or drug reaction. D. Suppurative folliculitis comprised of eosinophils and neutrophils. Hematoxylin and eosin stain, original magnifications ×25 (A, B), ×100 (C), and ×50 (D). doi:10.1371/journal.pone.0029908.g005Figure 6. Superficial infectious processes identified in impetiginous skin lesions of case patients. A. Superficial and deep perivascular dermatitis with epidermal hyperplasia and prominent scale-crust. A heavy growth of Stenotrophomonas maltophilia was obtained in culture of this site. B. Ulcerated skin with purulent exudates and serum-crust containing numerous colonies of coccoid bacteria (C) that stain intensely by using an immunohistochemical technique for Streptococcus pyogenes D and E. Purulent serum-crust from an impetiginous lesion, with abundant colonies of gram-positive coccoid bacteria (F). A heavy growth of Staphylococcus aureus was obtained in culture of this site. Hematoxylin and eosin stain (A, B, C, F), immunoalkaline phosphatase with naphthol fast-red and hematoxylin counterstain (D), and Lillie-Twort stain (F). Original magnifications ×12.5 (A), ×25 (B), ×50 (C), ×100 (D, E), and ×158 (F). doi:10.1371/journal.pone.0029908.g006Birefringent material was detected in 16 (43%) biopsied skin lesions. Most materials detected had the spectral characteristics of cellulose, compatible with cotton fibers. In all but two specimens, the birefringent material was located either in the superficial scale-crust, at the edge of or separate from the tissue, or on the biopsy surface and did not elicit a tissue reaction. Foreign-body-type giant cells were identified in two biopsies, one containing cellulose (most consistent with cotton fiber fragments), the other a silicon (Si)-containing material (likely silicates). Both of these biopsies had features suggestive of prior ulceration or trauma at the biopsy site. By special stains, gram-positive bacteria or fungi were detected in 12 (11 participants) and eight (eight participants) specimens, respectively. For six of these specimens, IHC or PCR testing of the formalin-fixed tissues confirmed the bacteria as Streptococcus pyogenes (3), Staphylococcus aureus (2), or a Streptococcus sp. (1). Culture swabs/specimens (n = 53) were obtained from open or purulent skin lesions of 28 case-patients. Organisms grew from the lesions of 15 case-patients; the histopathologic features of the culture-positive skin lesions were consistent with secondary infection (Figure 6). No skin lesions had detectable mycobacteria or parasites. The 22 biopsies obtained from clinically normal sites were interpreted as histologically normal, except for solar elastosis (n = 5), sparse superficial perivascular inflammation (n = 5), chronic inflammation with rare eosinophils (n = 1), focal spongiosis, exocytosis and solar elastosis (n = 1) and a benign focal intradermal nevus. Five of these non-lesional biopsies contained cellulose fibers (resembling cotton), either adjacent to, or at the edge of, the biopsy; one had chronic perivascular inflammation and a birefringent material consistent with polyglycolic acid, a substance used in resorbable suture. None of the biopsies containing cellulose or polyglycolic acid had accompanying tissue reaction. Analysis of Fibers or Materials From Non-biopsy Skin SitesTwenty-three fiber or other material specimens were obtained from diverse intact skin sites in 12 case-patients. The materials were largely composed of protein (83%), likely superficial skin or cellulose consistent with cotton fibers (43%), some with evidence of dyes (Figures 7 A–B). Three samples contained other materials alone or in combination, including polyamide (probably nylon); cellulose nitrate containing bismuth (Bi) consistent with nail polish; and polyethylene (possible contaminant from specimen container lid). Figure 7. Spectral characteristics of fibers/materials. A. Photograph of formalin-fixed material with the IR spectral characteristics of cellulose consistent with a cotton fiber. B. Upper panel IR spectrum obtained from unidentified fiber, lower panel spectrum is a cellulose reference. doi:10.1371/journal.pone.0029908.g007DiscussionIn this study, we collected detailed epidemiologic, clinical and laboratory data to better characterize the features of an unexplained dermopathy often referred to as Morgellons. Among this study population, this unexplained dermopathy was rare, predominately affecting middle-aged, Caucasian, women. Over 75% of our cases reported onset of their symptoms during or after 2002, but the epidemiologic importance of this is unclear as it also corresponds to the time when Internet postings related to this condition began to surface. We did not identify clustering of illness within the geographic area served by KPNC and from which cases were drawn. Case-patients had a wide range of skin lesions, suggesting that the condition cannot be explained by a single, well-described inflammatory, infectious, or neoplastic disorder. A substantial proportion (40%) of biopsied lesions had histopathologic features compatible with the sequelae of chronic rubbing or excoriation, without evidence of an underlying etiology. The most common histopathologic abnormality was solar elastosis, a degeneration of dermal connective tissue and increased amounts of elastic tissue due to prolonged sun exposure. However, this finding might be expected among a population residing in California and does not necessarily suggest a causal relationship. Histopathologic examination of skin areas with normal appearance were essentially normal, arguing against systemic or subclinical skin abnormalities. Among the differential diagnoses for the skin presentations detected are neurotic excoriations [16], atopic dermatitis, brachioradial pruritis [17], [18], and arthropod bites. Previous reports of this condition have described the material emerging from the skin being like fibers, hairs or filaments [1], [19], but we found a more heterogeneous description of materials emerging from the skin, with many case-patients describing materials other than fibers including specks, dots, granules, or worms. We found no difference in the sociodemographic, clinical, or histopathologic characteristics of case-patients who did and did not report fibers. The fibers and materials collected from case-patients' skin were largely consistent with skin fragments or materials such as cotton and were either entrapped in purulent crust or scabs, suggesting the materials were from environmental sources (e.g., clothing) or possibly artifacts introduced at the time of specimen collection and processing. We explored several possible etiologies and exposures. Our population had few clinical or laboratory signs of medical conditions that may be responsible for the symptoms, despite a wide range of accompanying multisystem complaints. We also did not find a pattern of clinical or epidemiologic abnormality that suggested any specific infectious etiology and, where data were available, the prevalence of specific parasitic infections in our population was no higher than that found in larger population-based studies [20]. We found evidence of drug use in 50% of participants. Formication can be a side affect drug use (prescription and illicit) and drug withdrawal, but the extent to which case-patients' drug use contributed to, or was being used as a treatment for, the condition was not determined. The high prevalence of drug use also may represent some case-patients' attempts to alleviate frustration or symptoms associated with the illness. Also, we found that over 75% of case-patients reported some exposure to solvents during hobbies. The prevalence of such exposures in the general population is unknown and we did not gather specific information regarding the types and duration of solvent exposures. The prevalence of co-existing neuropsychiatric morbidity appeared to be high among our population based on measurements obtained by standardized screening instruments. Nearly 60% of case-patients had evidence of some cognitive impairment that could not be explained by deficits in IQ. Additionally, 63% of case-patients had clinically significant somatic complaints; nearly a third had somatic complaint scores that were elevated to levels rarely documented among other clinical populations but, when present, have been associated with chronic, multisystem complaints and incapacitating fatigue [5]. Lastly, we found functional impairment and disability (as measured by the SF-12) among the case-patients that exceeded that of the general population and comparable to that detected among persons who have serious medical illnesses and concurrent psychiatric disorders [21]–[23]. There are few studies of Morgellons in the medical literature with which to compare our study findings. In a report of 25 self-referred Morgellons patients, a minority (<1/3) had fibers detected at the time of examination and the most frequent dermatologic diagnosis was senile angiomas (72%); several patients had elevated cytokines (TNF-alpha, IL-6, IFN-gamma) [24]. We did not measure such markers in our study, but did find that a minority (15%) of case-patients had elevations in non-specific markers of inflammation, such as CRP and ESR. In another study of a convenience sample of Morgellons suffers from multiple states (46% from California), similar to our findings, those experiencing illness were predominantly Caucasian females and co-morbid conditions were common including a previous history of substance abuse (12%) and depression (29%) [25]. Neither study included biopsies or characterization of the materials obtained from patients' skin. Our study had a number of limitations. This study was limited to KPNC enrollees who had current or recent symptoms (<3 months) thereby limiting our ability to describe the full clinical course of illness and to generalize the findings. However, our focus on persons with active or recent illness likely increased our ability to detect abnormalities and recover fibers or other materials. Our cross-sectional study design and lack of a comparison group did not allow us to determine the temporal relationship between symptoms and potential exposures or co-morbidities or to assess risk factors for illness. As there is no established definition or diagnostic test for this condition, our case definition was based on self-reported symptoms and hence subject to reporting biases and potential misclassification of cases. Some case-patients did not complete all phases of the study, but those who completed all phases of the study were demographically similar to those who did not. Lastly, we limited enrollment to persons at least 13 years of age. Despite these limitations, our study provides a number of insights. The study was done among a well-defined and highly representative population of California, allowing generation of the first prevalence estimates of the condition and allowing us to look systematically for illness clustering. We extensively characterized the skin lesions afflicting case-patients, including systematic examination of intact and involved skin. We also performed detailed spectral and molecular analyses of fibers and other materials that have been reported as the condition's hallmark. Lastly, we assessed cognitive deficits, psychiatric co-morbidity and functional impairment among those affected. To our knowledge, this represents the most comprehensive, and the first population-based, study of persons who have symptoms consistent with the unexplained dermopathy referred to as Morgellons. We were not able to conclude based on this study whether this unexplained dermopathy represents a new condition, as has been proposed by those who use the term Morgellons, or wider recognition of an existing condition such as delusional infestation, with which it shares a number of clinical and epidemiologic features [26]–[31]. We found little on biopsy that was treatable, suggesting that the diagnostic yield of skin biopsy, without other supporting clinical evidence, may be low. However, we did find among our study population co-existing conditions for which there are currently available therapies (drug use, somatization). These data should assist clinicians in tailoring their diagnostic and treatment approaches to patients who may be affected. In the absence of an established cause or treatment, patients with this unexplained dermopathy may benefit from receipt of standard therapies for co-existing medical conditions and/or those recommended for similar conditions such delusions infestation [31], [32]. Supporting InformationSociodemographic Characteristics of Case-patients Completing Web Survey, Unexplained Dermopathy, California (N = 70). doi:10.1371/journal.pone.0029908.s001 (DOCX) Skin and Non-Skin Symptoms Reported by Case-patients Completing Web Survey, Unexplained Dermopathy, California (N = 70). doi:10.1371/journal.pone.0029908.s002 (DOCX) Results of Personality Assessment Inventory Among Case-patients Completing Clinical Evaluation (N = 36). doi:10.1371/journal.pone.0029908.s003 (DOCX) AcknowledgmentsThe authors thank the study participants; Melissa Nelson, Deborah Burman, Joanna Truman, Karen Silva and Sharon Matthews at KNPC; Angela Austin, Binny, John Stamper, and Mark Lamias at CDC for assistance with database design and deployment; and the members of the CDC's Unexplained Dermopathy Task Force. The additional Unexplained Dermopathy Study Team Members: Patricia Adem, April Bolin, Lynn M. Blubaugh, Clare A. Dykewicz, Bruce F. Folck, James R. Hallman, Edmund T. Lonergan, George P. Lupton, Isabel T. McAuliffe, Florabel G. Mullick, Martin E. Schriefer, Wun-Ju Shieh, Patricia P. Wilkins, Sherif Zaki. DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, Kaiser Permanente or the Armed Forces Institute of Pathology. Author ContributionsConceived and designed the experiments: M. Pearson JS CB KK MLE CP ML-S VK CD M. Parise BL. Performed the experiments: KK VC M. Pearson CP SZ ML-S VK LB PA GL MES W-JS PW JH GL SM EL IM FM. Analyzed the data: AB BF AWH AP FCG. Contributed reagents/materials/analysis tools: CP SZ ML-S VK LB GL MES W-JS PW IM JH SM. Wrote the paper: M. Pearson JS CP ML-S. Источник: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0029908 | |
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