Clinical, Epidemiologic, Histopathologic and Molecular Features of an Unexplained Dermopathy

Michele L. Pearson, Joseph V. Selby, Kenneth A. Katz, Virginia Cantrell, Christopher R. Braden, Monica E. Parise, Christopher D.  Paddock, Michael R. Lewin-Smith, Victor F. Kalasinsky, Felicia C. Goldstein, Allen W. Hightower, Arthur Papier, Brian Lewis, ...,

for the Unexplained Dermopathy Study Team

Published: January 25, 2012

DOI: 10.1371/journal.pone.0029908

Abstract

Background

Morgellons is a poorly characterized constellation of symptoms, with the primary manifestations involving the skin. We conducted an investigation of this unexplained dermopathy to characterize the clinical and epidemiologic features and explore potential etiologies.

Methods

A descriptive study was conducted among persons at least 13 years of age and enrolled in Kaiser Permanente Northern California (KPNC) during 2006–2008. A case was defined as the self-reported emergence of fibers or materials from the skin accompanied by skin lesions and/or disturbing skin sensations. We collected detailed epidemiologic data, performed clinical evaluations and geospatial analyses and analyzed materials collected from participants' skin.

Results

We identified 115 case-patients. The prevalence was 3.65 (95% CI = 2.98, 4.40) cases per 100,000 enrollees. There was no clustering of cases within the 13-county KPNC catchment area (p = .113). Case-patients had a median age of 52 years (range: 17–93) and were primarily female (77%) and Caucasian (77%). Multi-system complaints were common; 70% reported chronic fatigue and 54% rated their overall health as fair or poor with mean Physical Component Scores and Mental Component Scores of 36.63 (SD = 12.9) and 35.45 (SD = 12.89), respectively. Cognitive deficits were detected in 59% of case-patients and 63% had evidence of clinically significant somatic complaints; 50% had drugs detected in hair samples and 78% reported exposure to solvents. Solar elastosis was the most common histopathologic abnormality (51% of biopsies); skin lesions were most consistent with arthropod bites or chronic excoriations. No parasites or mycobacteria were detected. Most materials collected from participants' skin were composed of cellulose, likely of cotton origin.

Conclusions

This unexplained dermopathy was rare among this population of Northern California residents, but associated with significantly reduced health-related quality of life. No common underlying medical condition or infectious source was identified, similar to more commonly recognized conditions such as delusional infestation.

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Methods

Study Population

This study was conducted among enrollees of Kaiser Permanente of Northern California (KPNC) during July 2006 through June 2008. KPNC is an integrated, managed care consortium that has approximately 3.2 million enrollees, representing nearly 30% of the population in 13 Northern California counties. The membership is sociodemographically and culturally diverse, but highly representative of the general population [3].

Study Design and Eligibility Criteria

This descriptive case series study had three major components: a cross-sectional survey, clinical evaluations, and histopathologic studies. To be eligible for study enrollment, a KPNC member had to be ≥13 years of age and English-speaking. Participants provided written informed consent for the clinical examination, including photographic documentation of their skin (total body and lesion images) and collection of all clinical samples, including biopsies, blood, urine and fibers/materials. The study was reviewed and approved by Institutional Review Boards at CDC, KPNC, the Armed Forces Institute of Pathology (AFIP), and the University of Rochester.

Case definition

A case-patient was defined as any person who was a member of, and received care at, KPNC for any period between July 1, 2006 and June 30, 2008 (case-finding period) and reported fibers, threads, specks, dots, fuzzballs, granules or other forms of solid material coming out of his/her skin; AND one or both of the following:

• a skin lesion such as a rash, wound, ulcer, or nodule; OR

• a disturbing skin symptom such as pruritus, feeling that something is crawling on top of or under the skin, or stinging, biting, or a pins and needles sensation.

Case-finding

To identify cases, we first searched the electronic health records of KNPC enrollees to identify clinic visits with certain keywords (i.e, “Morgellons”, “fiber”, “thread”, “fuzzball”, “dots”, “specks”, “granules”, “delusion”) recorded in the progress notes or with the ICD-9-CM code 300.29 (delusions, parasitosis), the code used at KPNC for patients with Morgellons. The search was limited to dermatology, psychiatry, infectious diseases, pediatric, and primary care clinic visits.

Next, study team members used pre-defined criteria to review the medical records of all persons identified by the electronic search to determine if they had suggestive signs and symptoms. Finally, persons who met medical records review criteria were screened by telephone by a member of the research team using a standardized tool to determine if they met the case definition; those who met the case definition were invited to enroll in the study.

Persons who were not captured by the electronic search but contacted KPNC research staff seeking study participation also were screened by telephone to determine if they met the case definition. If so, they were invited to enroll in the study.

Prevalence Estimates and Geospatial Analysis

To estimate the prevalence of cases, we used as our denominator the average monthly KPNC enrollment during July 2006–June 2008. We enumerated total, and age- and sex-specific monthly enrollment. Because the electronic health record (EHR) was being introduced during the case-finding period, we used only data from facilities in which the EHR was functioning (and therefore identifying potential cases) in each monthly denominator. Case-patients who self-identified were not included in the numerators of the rate estimates. Geospatial analysis was done to evaluate the possibility of geographic clustering of cases in KPNC's 13-county catchment area.

Cross-sectional Survey

Persons who were study eligible were invited to complete a self-administered, Internet-based survey (or alternatively a telephone administered survey) to collect detailed epidemiologic data. Information collected at the survey included additional demographic data, household information, prior medical history, details regarding skin symptoms, pet ownership, travel history, tobacco, alcohol and illicit drug use history, and potential environmental exposures in the home or community. The SF-12 v2 Health Survey® (QualityMetrics) was used to assess measures of health-related quality of life, including self-perceived health status and well-being and Physical Component Scores (PCS) and Mental Component Scores (MCS). Mean PCS and MCS were compared with expected norms of 50 (standard deviation [SD] of 10) for the US population [4].

Clinical Evaluation

Additional inclusion criteria for the clinical examination were: age ≥18 years; self-reported active skin symptoms (consistent with the case definition) within the preceding 2 weeks, and current membership in KPNC. All components of the clinical evaluation were done at a Kaiser Permanente's Division of Research in Oakland. Standardized data collection forms were used for all components of the examination.

Clinical examinations.

A medical history and a general physical examination were administered by an internist. A dermatologist administered a separate examination which included documentation of skin findings, collection of skin biopsies, and collection of fibers or other material present on the skin. Total body photographs were done by a medical photographer to document case-patients' overall skin condition and the distribution of lesions.

Standardized criteria were used to categorize lesions and grade (normal, mild, moderate, severe) the extent of skin abnormalities. The number, location and types of lesions were recorded by body area. Additional comments were included, as appropriate, to record clinical impressions that were not captured adequately by the standardized form. Participants self-rated the severity of their skin symptoms within the 24 hours preceding examination, using a Likert scale.

Collection of Skin Samples and Foreign Material.

Skin samples were obtained using a 4 mm punch biopsy. Biopsies, up to five per participant, were obtained from abnormal and clinically normal skin areas. An abnormal skin area was defined as one that had either abnormal appearance (to both participant and examiner) or abnormal sensation (although appearing normal). Two biopsies were possible per abnormal skin area (one for histopathologic analysis and, if clinically indicated, one for microbiologic culture); a single biopsy was obtained from normal skin. A dermatoscope was used to photograph each biopsy site before and after the procedure. Fibers or potential foreign material present on the participant's skin were photographed, then collected and placed in a formalin-filled plastic container and sent for analysis. Only materials collected from participants' skin by the dermatologist were sent for analysis. At study completion, an independent review of all dermatologic examination reports, dermatologic photographs and pathology reports was done by a second dermatologist.

Neurocognitive and Neuropsychiatric Testing.

Participants were administered a battery of standardized neuropsychological tests. The Wechsler Test of Adult Reading (WTAR) was used to provide an estimate of intellectual functioning. Cognitive function was assessed using the: Stroop Color and Word Test; the Proverbs and Verbal Fluency measures of the Delis-Kaplan Executive Function System™ (D-KEFS™); Ruff 2 & 7 Selective Attention Test; Brief Visuospatial Memory Test-Revised (BVMT-R™); Hopkins Verbal Learning Test-Revised™; and the Trail Making Test (TMT) Parts A & B. The PAI® (Personality Assessment Inventory™) was used to assess personality functioning and to screen for evidence of major psychiatric disorders [5]. All tests were administered in-person, scored and interpreted by trained neuropsychologists.

Raw scores on the cognitive tests and PAI scales were converted to T-scores using demographically adjusted normative data. T-scores ≤30 (corresponding to 2 Standard Deviations (SD) below the normative mean [50, SD = 10]) on the cognitive measures were considered clinically significant. T-scores >70 on the Personality Scales were considered clinically significant.

Laboratory Studies

Blood samples and serologic tests.

Blood was obtained for complete blood count with differential, erythrocyte sedimentation rate (ESR), serum glucose, serum ferritin, serum IgE, liver function tests, albumin, total protein, serum total calcium, phosphorus, serum blood urea nitrogen (BUN) and creatinine, Vitamin B12 and folate, serum Vitamin B1, antinuclear antibody (ANA), rheumatoid factor (RF), thyroid function tests, and C-reactive protein (CRP).

Serum samples were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (anti-HBs), and hepatitis C (anti-HCV). Past or present HBV infection was defined as the presence of anti-HBc. Persons with test results positive for anti-HBs and negative for anti-HBc were considered to have vaccine-induced immunity.

At CDC, serum samples were tested for the presence of antibodies to Borrelia burgdorferi, Toxocara and Strongyloides. B. burgdorferi seroreactivity was determinedusing a polyvalent (IgM/IgG) enzyme immunoassay (EIA) (Vidas; BioMérieux Vitek, Hazelwood, MO) and separate IgM and IgG Western blot (WB) (Marblot; MarDx Diagnostics, Carlsbad, CA). Low-passage B. burgdorferi, strain B31, was used as the antigen source for both assays. B. burgdorferi seropositivity was defined based on the IgG WB as serum specimens were collected 130 days after illness onset [6]. Specimens with at least 5 of 10 IgG diagnostic bands by WB were considered positive, in accordance with the CDC-recommended criteria [6].

To detect Toxocara antibodies, a Toxocara EIA that detects both T. canis and T. cati infections was used. The assay utilizes T. canis excretory-secretory (TES) antigens from infective-stage larvae and antibodies are measured and reported as a titer. A positive Toxocara result was defined as a titer ≥1:32 [7].

Seropositivity to Strongyloides was determined using a quantitative ELISA which measures antibodies to a crude larval extract purified from infective third-stage larvae of S. stercoralis. A positive Strongyloides result was defined as a value ≥1:7 [8].

Non-blood samples and tests.

Urine was obtained for microscopy and, if pyuria or bacteriuria was detected, sent for culture. Because of the association between drug use and formication, participants' hair samples were tested to determine the presence of amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, methadone, opiates, phencyclidine and propoxyphene (HairConfirm, Craig Medical Distribution, Inc., Vista CA). Chest radiographs also were performed.

Swabs obtained from open skin lesions were sent to Quest Diagnostics® for microbiologic analysis, including gram stain, bacterial and fungal cultures. Viral cultures were performed if the lesions were clinically consistent with a viral etiology.

Histopathologic, immunohistochemical, molecular qnd chemical evaluation of biopsy specimens.

Skin biopsy samples were placed in 10% formalin and sent to CDC. 3 µm sections were prepared, stained with hematoxylin and eosin (H&E) and evaluated by a team of infectious diseases pathologists for histopathologic changes, using light microscopy and for exogenous material, using polarized light. Specimens showing inflammatory cell infiltrates on light microscopy were further evaluated on additional sections using special stains (i.e., Lillie-Twort, Warthin-Starry, and Grocott methenamine silver techniques) to detect bacteria or fungi and, if an infectious agent was identified, by immunohistochemical (IHC) stains, and/or PCR assays [9]–[13].

H&E-stained slides prepared at CDC were anonymized and sent to AFIP, along with two unstained, consecutive cuts from the same biopsy (one mounted on a carbon disc, the other on an aluminum coated slide) to maximize the probability of detection and analysis of fibers or material in the sections. At AFIP, H&E-stained sections were evaluated by light microscopy by two dermatopathologists who were blinded to the clinical diagnosis of the cases and under polarized light by a pathologist with experience in the evaluation of unidentified materials in tissue sections. Tissue sections containing unidentified material were further analyzed by scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDXA) to determine the material's elemental composition and by infrared spectroscopy (IR) to identify molecular characteristics [14], [15]. The measured infrared spectra were compared with those of authentic samples such as cotton gauze (for cellulose), and to spectra stored in a digital spectral library.

Molecular and Spectral Analysis of Fibers and Other Material.

Fibers or other materials collected from participants' skin were analyzed at AFIP. Submitted materials were photographed, attached to aluminized slides by drying, crushing or by using conducting adhesive tabs (Polysciences Inc., Warrington, PA) and then analyzed by SEM/EDXA and IR [14], [15].

Statistical analysis

Continuous data were summarized using descriptive statistics, including mean, standard deviation, minimum, maximum, median and inter quartile range. Categorical data was summarized using frequency counts and percents; confidence limits around point estimates were determined, where indicated. Categorical variables were compared using chi-square tests. Census block data were analyzed using ArcGIS Geographic Information System software and SaTScan cluster analysis software to determine geospatial patterns and assess geographic clustering of the cases by place of residence.