Early Cutaneous Manifestations of COVID-19: A Systematic Review and Public Health Implications.

INTRODUCTION: Cutaneous manifestations before other symptoms have great potential for early COVID-19 diagnosis to prevent surge. METHODS: We conducted a search of PubMed and Embase databases through April 11, 2021 to include 39 studies reporting skin manifestations occurring prior to any other COVID-19 symptoms in laboratory-confirmed cases. RESULTS: Ninety-seven patients were included. Urticarial (24.7%) and maculopapular (22.7%) lesions were most common, followed by pernio (17.5%), vesicular (14.4%), papulosquamous (8.2%), and purpuric (5.1%) lesions. Cutaneous to systemic symptom latency ranged from 2 to 20 days in cases that reported it (26%), while skin lesions were the only presentation in 23 cases (23.7%). Skin lesions were the only COVID-19 manifestation in 58.8% of pernio, 40% of vesicular, 16.6% of urticarial, 18.2% of maculopapular, and 12.5% of papulosquamous presymptomatic cases. Although sample size is limited, all purpuric cases developed other symptom(s) later. CONCLUSIONS: Pernio and purpuric lesions have been well-associated with COVID-19, but papulosquamous, vesicular, mild maculopapular, and urticarial lesions can easily be dismissed as unrelated to COVID-19. Pernio lesions are thought to be related to strong immune response and low contagiousness, while purpuric and vesicular cases are speculated to be related to higher SARS-CoV2 viral load, severity, and contagiousness. All rashes, even without other symptoms, should necessitate high level of suspicion for isolation or contact tracing.

Histopathologic PD-L1 Tumor Expression and Prognostic Significance in Nonmelanoma Skin Cancers: A Systematic Review.

ABSTRACT: PD-L1 and PD-1 inhibitors are being increasingly used to treat a variety of nonmelanoma skin cancers (NMSCs). This systematic review summarizes PD-L1 expression in NMSCs and determines its use for prognosis using targeted immunotherapy. A primary search of peer-reviewed English-language medical literature was conducted for studies on PD-L1 tumor expression in biopsied or excised NMSCs. Fifty-nine articles met criteria for inclusion. PD-L1 expression in advanced NMSCs ranged from 22%-89% for basal cell carcinomas, 42%-50% for Merkel cell carcinomas, and 26%-100% for squamous cell carcinomas. Study limitations included clone heterogeneity across studies, complicating comparison of PD-L1 expression. Differences were also noted in the selection of tumor reactivity threshold. We conclude that there is insufficient evidence to determine the prognostic significance of PD-L1 expression in NMSCs as a whole, but this remains a promising area. More investigation into the role of tumor PD-L1 as a biomarker for predicting clinical response to PD-L1 and PD-1 inhibitors in NMSCs is needed.

Combining Deep Learning With Optical Coherence Tomography Imaging to Determine Scalp Hair and Follicle Counts.

BACKGROUND AND OBJECTIVES: One of the challenges in developing effective hair loss therapies is the lack of reliable methods to monitor treatment response or alopecia progression. In this study, we propose the use of optical coherence tomography (OCT) and automated deep learning to non-invasively evaluate hair and follicle counts that may be used to monitor the success of hair growth therapy more accurately and efficiently. STUDY DESIGN/MATERIALS AND METHODS: We collected 70 OCT scans from 14 patients with alopecia and trained a convolutional neural network (CNN) to automatically count all follicles present in the scans. The model is based on a dual approach of both detecting hair follicles and estimating the local hair density in order to give accurate counts even for cases where two or more adjacent hairs are in close proximity to each other. RESULTS: We evaluate our system on 70 OCT manually labeled scans taken at different scalp locations from 14 patients, with 20 of those redundantly labeled by two human expert OCT operators. When comparing the individual human predictions and considering the exact locations of hair and follicle predictions, we find that the two human raters disagree with each other on approximately 22% of hairs and follicles. Overall, the deep learning (DL) system predicts the number of follicles with an error rate of 11.8% and the number of hairs with an error rate of 18.7% on average on the 70 scans. The OCT system can capture one scalp location in three seconds, and the DL model can make all predictions in less than a second after processing the scan, which takes half a minute using an unoptimized implementation. CONCLUSION: This approach is well-positioned to become the standard for non-invasive evaluation of hair growth treatment progress in patients, saving significant amounts of time and effort compared with manual evaluation. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Optical Coherence Tomography in the Evaluation of the Scalp and Hair: Common Features and Clinical Utility.

BACKGROUND AND OBJECTIVE: Early diagnosis and treatment of hair loss disorders is vital in providing patients with improved psychological outcomes. Non-invasive imaging with optical coherence tomography (OCT) may be useful in characterizing and managing alopecia. Despite expanding clinical applications of OCT in dermatology, guidelines demonstrating in vivo features of normal and alopecic scalp images remain scant. This pilot study aims to provide an atlas of OCT findings of healthy and alopecia subjects, explore diagnostic quantitative endpoints of alopecia, and compare epidermal thickness and follicular density between scalp regions. STUDY DESIGN/MATERIALS AND METHODS: A total of 32 patients (19-76 years old) were enrolled in the study, including healthy patients (n = 6), and patients with scarring alopecia (n = 12) or non-scarring alopecia (n = 14). An in-line fiber-based swept source OCT was used to image five scalp locations at baseline and 6-month visits. Three investigators evaluated each image for gross features, epidermal thickness, and follicular density. RESULTS: Only data from baseline imaging analysis is discussed in this manuscript. Qualitative differences of OCT images are identified in sample images from healthy scalp and each subtype of alopecia studied. Scarring alopecia is characterized by significantly increased epidermal thickness (average Image J pixel units 32 ± 2 compared with non-scarring alopecia [average 28 ± 3] and control [average 27 ± 3]) (P = 0.022) and decreased follicle count (average 35 ± 5 in a 5 × 7 mm2 area compared with control (50 ± 3) and non-scarring patients (47 ± 6)) (P = 0.0052). Scalp location had no impact on epidermal thickness (P = 0.861) or follicular density (P = 0.15). CONCLUSION: OCT holds promise as a non-invasive technique to further characterize and objectively measure alopecia. Larger sample sizes and longitudinal data are needed to improve reliability and determine if additional distinction between alopecia subtypes and treatment monitoring is possible. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Monitoring Response to Platelet-Rich Plasma in Patients with Alopecia Areata with Optical Coherence Tomography: A Case Series.

Alopecia areata (AA) is an autoimmune hair loss condition that is difficult to treat and frequently disruptive to the psychosocial well-being of patients. Platelet-rich plasma (PRP) is an innovative therapy that provides concentrated GFs that impart anti-inflammatory effects. Optical coherence tomography (OCT) is a noninvasive imaging modality with the potential for providing quantitative monitoring of AA response to PRP. Our objective is to share our experience using OCT to monitor the therapeutic progress of patients with AA treated with PRP. Two patients with patchy AA and one with alopecia universalis were treated with PRP three times at 6-week intervals as part of a larger clinical trial. Patients were followed from baseline to week 24 with OCT imaging. OCT demonstrates an increase in hair density associated with improvement in inflammation at week 24. Conversely, the patient with alopecia universalis did not experience any significant change in follicular activity. This case series exemplifies the potential of PRP in inflammatory regulation as well as hair regrowth in patchy AA, whereas there is no notable advantage in alopecia universalis. Our findings add evidence on the possible value of OCT in quantitatively assessing hair growth progress throughout a treatment course.

Oral Metformin for Treating Dermatological Diseases: A Systematic Review.

Introduction:Metformin is an antihyperglycemic medication most commonly used to treat Type II Diabetes Mellitus with promising off-label application for the treatment of hidradenitis suppurativa, psoriasis, acne, acanthosis nigricans, and hirsutism. Objective: To comprehensively assess evidence regarding the use of metformin for treating primary cutaneous disorders. Materials and Methods: A systematic literature search was conducted through PubMed, Cochrane, Web of Science, and CINAHL to identify the role of metformin in primary skin disease. Results: Sixty-four studies met inclusion criteria. Metformin demonstrates promising clinical response and favorable safety profile for treatment of HS, with most patients experiencing a decrease in frequency or severity of HS flares, and some experiencing full resolution of HS lesions. Patients with psoriasis treated with metformin experienced quantifiable clinical responses. Application of metformin on polycystic ovarian disease (PCOS) related acne, acanthosis nigricans, and hirsutism yielded mixed clinical results. No serious adverse effects were reported. Conclusion: Metformin is safe and efficacious and may be considered as an adjunctive therapy for the treatment of psoriasis and hidradenitis suppurativa in addition to first line therapies as well as PCOS related acne, acanthosis nigricans, and hirsutism. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.4874.

Adverse Events of Injectable Deoxycholic Acid.

BACKGROUND: Injectable deoxycholic acid (DCA) may be used to remove excess submental fat and off-label for local adipose reduction. Despite DCA's widespread use, rare incidences of severe, systemic, long-term adverse events (AEs) have been reported. OBJECTIVE: To evaluate the potential side effects associated with injectable DCA. METHODS AND MATERIALS: A systematic review was conducted using PubMed, Cochrane, CINAHL, and Web of Science using PRISMA guidelines to gather the literature relating to DCA or deoxycholate-associated AEs and their management. RESULTS: Twenty-eight manuscripts were included after full article review. Most commonly, patients experienced mild localized AEs, whereas a small number of patients experienced severe pain, alopecia, nasopharyngitis, dysphagia, dizziness/lightheadedness, and gastrointestinal upset. Severe, long-term AEs were reported as rare in the evaluated literature. Deoxycholic acid injections in large volumes were more likely to cause severe adverse effects. CONCLUSION: Self-resolving, mild side effects and severe but rare adverse effects have been reported with DCA use making it a safe treatment for local adipose reduction. Further studies are necessary to determine its safety profile, especially when using DCA in off-label areas.

Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review.

BACKGROUND: Immunotherapy using programmed cell death 1 protein (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors has been increasingly reported in a variety of nonmelanoma skin cancers (NMSCs). OBJECTIVE: To analyze the evidence of PD-1 and PD-L1 inhibitors in the treatment of NMSC. METHODS: A primary literature search was conducted with the PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases through October 28, 2018, to include studies on the use of PD-1 or PD-L1 inhibitors in patients for NMSC. Two reviewers independently performed study selection, data extraction, and critical appraisal. RESULTS: This systematic review included 51 articles. The most robust evidence was in the treatment of Merkel cell carcinoma and cutaneous squamous cell carcinomas, as supported by phase 1 and 2 clinical trials. Treatment of basal cell carcinoma, cutaneous sarcoma, sebaceous carcinoma, and malignant peripheral nerve sheath tumor also showed benefit with PD-1/PD-L1 inhibitors, but data are limited. There does not appear to be efficacy for PD-1/PD-L1 inhibitors in cutaneous lymphomas. LIMITATIONS: More investigation is needed to determine the efficacy, tumor responsiveness, and the safety profile of PD-1 and PD-L1 inhibitors in NMSC. CONCLUSION: PD-1 and PD-L1 inhibitors exhibit treatment efficacy in a variety of NMSCs.

Dietary and metabolic factors in the pathogenesis of hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a systemic recalcitrant inflammatory condition characterized by debilitating lesions with high morbidity. Its known association with obesity and smoking indicate correlation with other environmental factors, such as diet, suggesting a larger role for lifestyle modifications in disease treatment. This study seeks to assess the contribution of weight loss and dietary intake in HS management. A primary literature search was conducted using PubMed, Web of Science, and CINAHL in November 2018 to include association and intervention studies on the influence of diet and weight on HS. Twenty-five articles were included. Meta-analysis of nine case-control studies across Asia, Europe, and the United States showed that HS patients are four times more likely to be obese compared to the general population; random effects pooled odds ratio 4.022 (2.667-6.065), P < 0.001. Five articles assessed weight-loss interventions and revealed mixed findings. The remaining articles included three association studies on micronutrient levels, eight dietary intervention studies, and one article analyzing both micronutrient association and dietary intervention. Included articles in this systematic review reveal that low serum zinc and vitamin D levels are associated with increased lesion count in HS. Supplementation of zinc, vitamin D, vitamin B12, or exclusion of dairy or brewer's yeast can be effective in partial or complete lesion resolution. Reviewed data show that weight loss from bariatric surgery may lead to HS improvement but often results in more severe malnutrition that worsens or even leads to new onset HS post bariatric surgery. Future reporting is needed to conclusively determine the role of diet in HS.

The Immunological Association between Alopecia Areata and Respiratory Diseases: A Systematic Review.

BACKGROUND: While alopecia areata (AA) has been associated with atopy, the immunological relationship is unclear, with the association of specific atopic and systemic respiratory diseases not established. The relationship between T-helper (Th)1-mediated AA and Th2-mediated atopy challenges the conventional Th1/Th2 paradigm of autoimmune disease categorization. OBJECTIVES: To determine the association between AA and atopic respiratory diseases in adults and children, and respiratory diseases in general. METHOD: All primary literature, excluding case reports, were identified within PubMed/MEDLINE, CINAHL, and Web of Science in May 2018 using the following search terms: "(alopecia OR hair loss) AND (respiratory OR pulmonary OR lungs OR asthma OR rhinitis OR bronchitis OR COPD OR atopy OR atopic)." Information from 32 articles meeting the inclusion and exclusion criteria was reviewed. RESULTS: Among the 32 articles identified for inclusion, the prevalence of AA was more strongly associated with allergic rhinitis compared to asthma among pediatric and adult populations. While a significant association was identified between AA, allergic rhinitis, and a late age of onset, the association of AA and asthma remains controversial despite asthma's prevalence among AA patients. No significant difference was identified with regard to the association of AA and non-atopic respiratory diseases between adult and pediatric patients. CONCLUSIONS: Adult and pediatric patients with AA warrant further workup for atopic respiratory diseases such as allergic rhinitis. AA may have an underlying Th2-mediated immunological component, which supports its association with atopic respiratory diseases and provides a new avenue for targeted therapies in select cases.

Non-Submental Applications of Injectable Deoxycholic Acid: A Systematic Review

Introduction: Injectable deoxycholic acid (DCA; Kybella; Allergan, Irvine, CA) is currently approved only for treatment of persistent submental fat (SMF). Many cosmetic surgeons use DCA off-label to treat fat tissue in other areas of the body. There is no review summarizing the off-label uses of injectable DCA. Methods: A systematic literature search was conducted through PubMed, Cochrane, CINAHL, and Web of Science databases using search terms "ATX-101 OR Kybella OR deoxycholic OR deoxycholate NOT amphotericin NOT bile" in accordance to PRISMA guidelines to identify off-label uses for injectable DCA or ATX-101. Results: Ten pertinent articles were identified for review. Anatomic areas treated include the face, brassiere line, foot, and gluteotrochanteric region. Indications include facial contouring, paradoxical adipose hyperplasia, HIV/HAART-associated buccal fat pad lipodystrophy, and reduction of lipomatous tumors. DCA is efficacious at causing lipolysis and safe with minimal side effects. Most patients treated for cosmetic indications reported high patient satisfaction. Conclusion: Off-label use of injectable DCA demonstrate a similar safety profile, effectiveness, and overall patient satisfaction compared to FDA-approved use for persistent SMF. DCA appears to be a safe and efficacious alternative to surgical reduction of unwanted adipose tissue in non-submental areas. Larger-scale studies are warranted to explore further cosmetic and potential medical applications. J Drugs Dermatol. 2019;18(7):675-680.

The Efficacy of Topical Minoxidil for Non-Scarring Alopecia: A Systematic Review

Introduction: Topical minoxidil is the first-line therapy for treating both male and female androgenetic alopecia. Currently there are no comprehensive reviews on the clinical efficacy of minoxidil on hair loss. Method: A literature search was conducted to identify clinically relevant studies regarding the efficacy of topical minoxidil for human subjects for hair loss. Results: Twenty-three pertinent studies were identified for inclusion in this review. Topical minoxidil has been studied in concentrations ranging from 0.01% to 15% for the treatment of AGA resulting in hair growth ranging from 17% to 70%. Concentrations from 3% to 5% have been used to treat alopecia areata, 2% to treat traction alopecia, and 1% to 5% for congenital hair disorders with varying levels of treatment success. Efficacy varies by ethnic groups, but topical minoxidil has been demonstrated to significantly improve quality of life even in the absence of hair regrowth. Conclusion: Topical minoxidil is efficacious for the treatment of hair loss due to male and female androgenic alopecia, alopecia areata, with case-by-case application for traction alopecia, hair transplantation, and congenital hair disorders. Combination therapies using minoxidil with systemic, topical, and injectable therapies demonstrate increased effectiveness over monotherapies. J Drugs Dermatol. 2019;18(2):155-160.

Oral Collagen Supplementation: A Systematic Review of Dermatological Applications

Importance: The use of nutraceuticals such as collagen for skincare has been rising, but regulations are lacking on quality, absorption, and efficacy. To address this knowledge gap, clinical studies regarding the potential effects of collagen-based dietary supplements on skin are being completed. Objective: To review the literature and assess available randomized-controlled trials using collagen supplementation for treatment efficacy regarding skin quality, anti-aging benefits, and potential application in medical dermatology. Evidence Review: A literature search was conducted with PubMed using search criteria (collagen) AND (supplement OR food OR nutrition). No lower limit on the year of publication was set. Inclusion criteria were: randomized, placebo-controlled trials using collagen supplementation in human subjects related to dermatology and written in English. Findings: Eleven studies with a total of 805 patients were included for review. Eight studies used collagen hydrolysate, 2.5g/d to 10g/d, for 8 to 24 weeks, for the treatment of pressure ulcers, xerosis, skin aging, and cellulite. Two studies used collagen tripeptide, 3g/d for 4 to 12 weeks, with notable improvement in skin elasticity and hydration. Lastly, one study using collagen dipeptide suggested anti-aging efficacy is proportionate to collagen dipeptide content. Conclusions and Relevance: Preliminary results are promising for the short and long-term use of oral collagen supplements for wound healing and skin aging. Oral collagen supplements also increase skin elasticity, hydration, and dermal collagen density. Collagen supplementation is generally safe with no reported adverse events. Further studies are needed to elucidate medical use in skin barrier diseases such as atopic dermatitis and to determine optimal dosing regimens. J Drugs Dermatol. 2019;18(1):9-16.

Topical ketoconazole: a systematic review of current dermatological applications and future developments.

Introduction: Although labeling changes and market withdrawal have been implemented for oral ketoconazole (KTZ) due to serious adverse effects (AEs), topical KTZ is generally thought to be effective and safe for the treatment of superficial fungal infections. New dermatologic indications for the use of topical KTZ have arisen such as onychomycosis, blepharitis, and hair loss. This article aims to review the literature on topical KTZ's efficacy and AEs, as well as provide an overview on current insights regarding its mechanism of action and upcoming developments. Methods: A PubMed search was done to include randomized controlled trials (RCTs) focusing on the use of topical KTZ in human subjects. Results: Forty studies with 4566 patients were included in this review. Topical KTZ is clinically effective for the treatment of Malassezia-related conditions such as seborrheic dermatitis (SD) and pityriasis versicolor (PV) with a reported efficacy of 63-90% and 71-89%, respectively. Conclusions: Topical KTZ demonstrates high clinical efficacy for Malassezia-related conditions. More efficacious alternatives are now available for Tinea and Candida. Although topical KTZ is safe, clinicians should be aware that allergic contact dermatitis may occur. Further studies should be completed to investigate the use of topical KTZ for hair loss and inflammatory dermatoses.