Carrie Ann Cusack

The Presence and Impact of Biofilm-Producing Staphylococci in Atopic Dermatitis

IMPORTANCE Atopic dermatitis (AD) is thought to be a double-hit phenomenon with an unknown environmental component and a genetic abnormality likely centered on the filaggrin gene. Biologically, the presence of Staphylococcus aureus in AD was reported more than 2 decades ago, but the relationship to AD has been elusive. OBJECTIVE To explore the bacteria that produce the biofilms in the lesions of AD and the response of the innate immune system to these biofilm occlusions of the sweat ducts by specifically evaluating Toll-like receptor 2. DESIGN, SETTING, AND PARTICIPANTS University hospital dermatologic clinic study involving the environmental component related to the characterization, correlation, and impact of staphylococci and their biofilms in AD. We processed routine skin swabs from lesional and nonlesional skin from 40 patients with AD and performed scrapings and biopsies. We also obtained 20 samples from controls (10 inflamed skin samples and 10 normal skin samples). EXPOSURES Gram staining, bright-field microscopy, hematoxylin and eosin, periodic acid-Schiff, Congo red, and light microscopy. MAIN OUTCOMES AND MEASURES Association of staphylococcal biofilms with AD pathogenesis. RESULTS All AD-affected samples contained multidrug-resistant staphylococci, with S aureus (42.0%) and Staphylococcus epidermidis (20.0%) as the predominant species. All isolates were positive for extracellular polysaccharide and biofilm (85.0% strong biofilm producers and 15.0% moderately to weakly positive). Polymerase chain reaction revealed the biofilm-mediating icaD (93.0%) and aap (12.5%) genes in the isolates (some contained both). We also examined tissues for microbial identification, extracellular biomass formation, biofilm formation, and staphylococcal biofilm in skin tissues. Occlusion of sweat ducts with periodic acid-Schiff-positive and Congo red-positive material was noted on microscopic tissue examination. Toll-like receptor 2 was shown to be activated in AD lesional skin (immediately proximal to the sweat ducts), which likely led to the initiation of proteinase-activated receptor 2-mediated pruritus and MyD88-mediated spongiosis. CONCLUSIONS AND RELEVANCE Biofilm formation by AD-associated staphylococci almost certainly plays a major role in the occlusion of sweat ducts and leads to inflammation and pruritus. We believe the environmental hit in AD relates to staphylococci and their biofilms, which occlude sweat ducts.

Human papillomavirus-associated squamous cell carcinoma of the nail bed in African-American patients

Background  Human papillomavirus (HPV) has been implicated in the development of digital squamous cell carcinoma (SCC). Case reports in the literature mostly identify HPV type 16 present in tumors, but HPV types 2, 31, 34, 35, and 73 have also been isolated.

Palisaded neutrophilic and granulomatous dermatitis in association with sarcoidosis

Palisaded and neutrophilic granulomatous dermatitis (PNGD) has been associated with many conditions including rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, and other diseases with circulating immune complexes. Lymphoproliferative conditions, bacterial endocarditis, and various drugs can also induce this condition. Many patients also have symmetric polyarthritis with various serological abnormalities. We present a case of a 46‐year‐old female who presented with painful erythematous annular plaques and nodules on her legs. The lesions started a week prior to visit and increased in number over the course of the week. The patient had an established history of sarcoidosis with past episodes of uveitis and erythema nodosum. The histopathological findings included a diffuse pandermal infiltrate mostly composed of neutrophils, nuclear debris, and strands of deeply eosinophilic degenerated collagen. Vasculitis was not present. No significant increase in dermal mucin was detected. Based on the clinical and pathological findings, the patient was diagnosed with late‐stage PNGD. To our knowledge, this is the first case of PNGD described in an adult patient of sarcoidosis.

The Oldest New Finding in Atopic Dermatitis: Subclinical Miliaria as an Origin

IMPORTANCE In 1947, Sulzberger and colleagues published a micrograph of a blocked acrosyringium in a patient with atopic dermatitis (AD), believing that it had a large role in the disease process. Lacking appropriate probes, they could not confirm the finding. OBJECTIVE To confirm the observations by Sulzberger et al on the blockage of sweat ducts in AD in pathologic specimens. DESIGN AND SETTING Biopsy specimens diagnostic of various inflammatory diseases and with a secondary differential diagnosis of eczema were evaluated at an academic medical center. EXPOSURES Evidence of ductal obstruction in each specimen was examined following staining with hematoxylin-eosin, periodic acid-Schiff, and Gram stain. MAIN OUTCOMES AND MEASURES Comparison of biopsy specimens with control specimens and additional controls consisting of noninflamed skin. RESULTS Using 36 biopsy specimens, this study confirmed the observations by Sulzberger et al on the blockage of sweat ducts in AD. Blocked acrosyringia were noted in each specimen on routine staining with hematoxylin-eosin. The study also confirmed the findings by earlier investigators about the blockage of sweat ducts in miliaria, showing eosinophilic material in the ducts that was positive for periodic acid-Schiff. Previous researchers also observed bacteria in the blockages, and this study demonstrated the same findings in AD, rather than miliaria. CONCLUSION AND RELEVANCE Subclinical miliaria may be the earliest change in AD and likely initiates the process that causes intense pruritus.

Chronic cutaneous lupus in childhood: a report of two cases and review of the literature

International Journal of Dermatology 2008, 47 , 525–526 525 Chronic cutaneous lupus in childhood: a report of two cases and review of the literature Discoid lupus erythematosus (DLE) is the most common form of chronic cutaneous lupus, although its presentation is rare in children. We present two cases of childhood DLE and review the clinical characteristics and treatment options. An 8-year-old African-American boy presented with a 1-month history of an eruption involving the right cheek and ear. The patient had previously been treated with a topical antifungal cream and oral griseofulvin without effect. On examination, the patient had three violaceous, scaly plaques on the right cheek and one in the right conchal bowl (Fig. 1). A punch biopsy showed hyperkeratosis with follicular plugging, an attenuated epidermis, and a superficial and deep dermal and periadnexal lymphocytic infiltrate. A diagnosis of DLE was made, and treatment was initiated with topical fluocinonide 0.05% ointment twice daily for 4 weeks, followed by topical tacrolimus 0.1% ointment twice daily for 8 weeks. The primary lesions improved, and there continues to be no evidence of systemic involvement after 6 months. A 10-year-old Hispanic girl presented with a 1-year history of an eruption involving the left chin. She had recently noticed an increase in size of the lesions. On examination, the patient had two hyperpigmented, violaceous papules on the left side of the face below the lower lip (Fig. 2). A punch biopsy showed hyperkeratosis with follicular plugging, epidermal atrophy, basal cell vacuolopathy, and a band-like lymphocytic infiltrate. A diagnosis of DLE was made, and treatment was initiated with topical tacrolimus 0.1% ointment twice daily. The primary lesions improved, and there was no evidence of progressive disease after 6 weeks. The clinical presentation of childhood DLE is similar to that of the adult form. A review of all the pediatric cases reported in the literature has enabled us to obtain information on the epidemiology of the disease. Over 50% (44/78) of patients presented with lesions before the age of 10 years. The remainder presented between the ages of 10 and 16 years. Unlike adults, in whom there is a female predominance ranging from 2 : 1 to 5 : 1, 1 there does not seem to be a sex association in children. In the 78 cases reported, there is a ratio of approximately 1 : 1. Some authors suggest that childhood DLE is associated with a milder clinical course, and decreased progression to systemic disease; 2 however, others note a higher frequency of transition from DLE to systemic lupus erythematosus (SLE). 3

Nonmelanoma Skin Cancer in Nonwhite Organ Transplant Recipients

Importance Organ transplant recipients have a higher incidence of skin cancer. This risk is magnified over time and with continued exposure to immunosuppression. Skin cancer in nonwhite patients is associated with greater morbidity and mortality owing to diagnosis at a more advanced stage, which suggests that nonwhite organ transplant recipients are at even higher risk. Objective To describe demographic and clinical factors and the incidence of skin cancer in nonwhite organ transplant recipients. Design, Setting, and Participants We performed a retrospective medical record review of patients who were organ transplant recipients (154 were white and 259 nonwhite [black, Asian, Hispanic, Pacific Islander]) seen from November 1, 2011, to April 18, 2016 at an academic referral center. Main Outcomes and Measures Variables were analyzed and compared between racial groups, including sex, age, race/ethnicity, Fitzpatrick type, type and location of skin cancer, type of organ transplanted, time to diagnosis of skin cancer after transplantation, and history of condyloma acuminata and/or verruca vulgaris. Results Most of the 413 patients (62.7%) evaluated were nonwhite organ transplant recipients; 264 were men, and 149 were women. Their mean (SD) age was 60.09 (13.59) years. Nineteen skin cancers were identified in 15 patients (5.8%) representing 3 racial/ethnic groups: black (6 patients), Asian (5), and Hispanic (4). All squamous cell carcinomas in blacks were diagnosed in the in situ stage, located on sun-protected sites, and occurred in patients whose lesions tested positive for human papilloma virus (HPV) and/or who endorsed a history of condyloma acuminata or verruca vulgaris. Most skin cancers in Asians were located on sun-exposed areas and occurred in individuals who emigrated from equatorial locations. Conclusions and Relevance Nonwhite organ transplant recipients are at risk for developing skin cancer posttransplantation. Follow-up in a specialized transplant dermatology center and baseline total-body skin examination should be part of posttransplantation care in all organ transplant recipients, including nonwhite patients. A thorough inspection of the groin and genitalia is imperative in black organ transplant recipients. History of HPV infection, particularly in black organ transplant recipients, and sun exposure/emigration history in Asian organ transplant recipients should be documented. Vigilant photoprotection may be of lesser importance in the prevention of skin cancer in black organ transplant recipients. Risk factors for nonwhite organ transplant recipients differ between races/ethnicities and warrant further study in efforts to better counsel and prevent skin cancer in these patients.

Vismodegib for Locally Advanced Basal Cell Carcinoma in a Heart Transplant Patient

IMPORTANCE Immunosuppressed patients with solid organ transplants have an increased risk for nonmelanoma skin cancer. Vismodegib has been reported to be effective for select locally advanced or metastatic basal cell carcinomas. However, there is no data documenting the use and safety of vismodegib in immunosuppressed organ transplant patients. OBSERVATIONS We describe a 78-year-old white man with a history of orthotopic heart transplant, immunosuppressed with low-dose cyclosporine, who presented to a specialty dermatology transplant clinic with multiple, recurrent, locally aggressive facial basal cell carcinomas. Through a multidisciplinary approach, the patient was started on vismodegib therapy. The pharmacokinetics of cyclosporine in the setting of vismodegib administration and weekly monitoring of cyclosporine levels ensured that therapeutic immunosuppression levels were achieved without toxic effects. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report that details vismodegib use in an immunosuppressed heart transplant patient receiving cyclosporine therapy. With a growing immunosuppressed organ transplant population at high risk for basal cell carcinoma, therapeutic options for locally advanced or metastatic disease are limited. Vismodegib appears to be a safe option for patients receiving cyclosporine therapy with routine monitoring. Future research is needed to evaluate the safety profile of vismodegib with other immunosuppressive agents.

Comparison of Posttransplant Dermatologic Diseases by Race

Importance The risk for skin cancer has been well characterized in white organ transplant recipients (OTRs); however, most patients on the waiting list for organ transplant in the United States are nonwhite. Little is known about cutaneous disease and skin cancer risk in this OTR population. Objective To compare the incidence of cutaneous disease between white and nonwhite OTRs. Design, Setting, and Participants This retrospective review of medical records included 412 OTRs treated from November 1, 2011, through April 22, 2016, at an academic referral center. Prevalence and characteristics of cutaneous disease were compared in 154 white and 258 nonwhite (ie, Asian, Hispanic, and black) OTRs. Clinical factors of cutaneous disease and other common diagnoses assessed in OTRs included demographic characteristics, frequency and type of cancer, anatomical location, time course, sun exposure, risk awareness, and preventive behavior. Main Outcomes and Measures Primary diagnosis of malignant or premalignant, infectious, and inflammatory disease. Results The 412 patients undergoing analysis included 264 men (64.1%) and 148 women (35.9%), with a mean age of 60.1 years (range, 32.1-94.3 years). White OTRs more commonly had malignant disease at their first visit (82 [67.8%]), whereas nonwhite OTRs presented more commonly with infectious (63 [37.5%]) and inflammatory (82 [48.8%]) conditions. Skin cancer was diagnosed in 64 (41.6%) white OTRs and 15 (5.8%) nonwhite OTRs. Most lesions in white (294 of 370 [79.5%]) and Asian (5 of 6 [83.3%]) OTRs occurred in sun-exposed areas. Among black OTRs, 6 of 9 lesions (66.7%) occurred in sun-protected areas, specifically the genitals. Fewer nonwhite than white OTRs reported having regular dermatologic examinations (5 [11.4%] vs 8 [36.4%]) and knowing the signs of skin cancer (11 [25.0%] vs 10 [45.4%]). Conclusions and Relevance Early treatment of nonwhite OTRs should focus on inflammatory and infectious diseases. Sun protection should continue to be emphasized in white, Asian, and Hispanic OTRs. Black OTRs should be counseled to recognize the signs of genital human papillomavirus infection. Optimal posttransplant dermatologic care may be determined based on the race or ethnicity of the patients, but a baseline full-skin assessment should be performed in all patients. All nonwhite OTRs should be counseled more effectively on the signs of skin cancer, with focused discussion points contingent on skin type and race or ethnicity.

Pruritus of Healing Wounds: why Scabs Itch

We demonstrate herein the novel finding of occluded sweat ducts in healing wounds. We also show these occlusions are from biofilms because they are periodic acid Schiff positive which indicates they are polysaccharides and Congo red positive which shows they contain amyloid, which forms the infrastructure of biofilms. Further, from the skin immediately adjacent to the wounds, we have cultured staphylococci, all of which have the capability of forming biofilms as indicated by a colorimetric assay. These findings are similar to the findings in eczema, and we believe trigger the same response of the innate immune system in healing wounds, just as in eczema. The activated immune system (Toll-like receptor 2) then initiates the pathway leading to pruritus.

Eccrine Sweat Duct Occlusion by Staphylococcal-Derived Biofilms: AnUnexpected Signature Finding of Eczema in Dermatologic Diseases

We believe that axillary granular parakeratosis, tinea pedis, and Seborrheic dermatitis are likely to be variants of eczema. All had culturable staphylococci capable of producing biofilms, as in eczema. This was confirmed on XTT assays, Congo red cultures, and PCR for gene analysis of the biofilm-forming icaD and aap genes. The pathology showed eccrine ductal occlusion that was noted on H+E and PAS stains (PAS stains positively the extracellular polysaccharide substance that makes up the bulk of the biofilm.) Toll-like receptor 2 (TLR 2) activities was found in the stratum corneum adjacent to the sweat ducts and not in its control location in the basal zone. The stratum corneum seemingly becomes altered by the fungi, yeasts, or tiny granules instead of by the filaggrin gene (1st in the double hit phenomenon); and, the sweat ducts become occluded causing activation of TLR 2. This leads to activation of the innate immune system (2nd hit), just as in eczema. Further, treatment with the mild topical corticoids and/or moisturizers helps restore the integrity of the skin.