Cutaneous melioidosis: An updated review and primer for the dermatologist.

Melioidosis is an emerging infection with increasing endemic foci and global distribution. It is underrecognized and underdiagnosed because of factors including limited awareness of the disease, nonspecific clinical presentation, lack of diagnostic facilities in some locations, misidentification in laboratories inexperienced with culture, and identification of Burkholderia pseudomallei. Cutaneous findings are reported in approximately 10% to 20% of melioidosis cases and dermatologists may play a significant role in its recognition and management. The most dynamic situation of melioidosis recognition and/or expansion currently is in the United States. Global modeling had predicted that B. pseudomallei were potentially endemic in the southern United States and endemicity with local cases of melioidosis was confirmed in 2022. With the distribution and prevalence of melioidosis increasing globally and with this recent recognition that melioidosis is now endemic in the southern United States, it is important for dermatologists to maintain high clinical suspicion in appropriate patients and be familiar with its diagnosis and treatment. Here we review the available literature on cutaneous melioidosis to evaluate its epidemiology, etiology, pathophysiology and clinical presentation and provide guidance for diagnosis and management in dermatology practice.

Monkeypox outbreak, vaccination, and treatment implications for the dermatologic patient: Review and interim guidance from the Medical Dermatology Society.

Rapid human-to-human transmission of monkeypox has created a public health emergency requiring prompt, multidisciplinary attention. Dermatologists are at the forefront of diagnosis due to the disease-defining skin lesions. Moreover, patients with pre-existing skin disease and those who are on immunosuppressive medications for skin disease may be at increased risk of severe infection. In this review, a panel of authors with expertise in complex medical dermatology and managing patients on immunosuppression reviews the literature and provides initial guidance for diagnosis and management in dermatology practices. Though there are knowledge gaps due to a lack of controlled studies, we support use of replication-deficit vaccines in all dermatologic patients who meet qualifying risk or exposure criteria. We offer strategies to optimize vaccine efficacy in patients with immunosuppression. We discuss alternative post-exposure treatments and their safety profiles. Finally, we outline supportive care recommendations for cutaneous manifestations of monkeypox. Large scale epidemiologic investigations and clinical trials will ultimately revise and extend our guidance.

Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by medications. In addition to tertiary-level supportive care, various systemic therapies have been used including glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporin, N-acetylcysteine, thalidomide, infliximab, etanercept, and plasmapheresis. There is an unmet need to understand the efficacy of these interventions. OBJECTIVES: To assess the effects of systemic therapies (medicines delivered orally, intramuscularly, or intravenously) for the treatment of SJS, TEN, and SJS/TEN overlap syndrome. SEARCH METHODS: We searched the following databases up to March 2021: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched five clinical trial registers, the reference lists of all included studies and of key review articles, and a number of drug manufacturer websites. We searched for errata or retractions of included studies. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and prospective observational comparative studies of participants of any age with a clinical diagnosis of SJS, TEN, or SJS/TEN overlap syndrome. We included all systemic therapies studied to date and permitted comparisons between each therapy, as well as between therapy and placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as specified by Cochrane. Our primary outcomes were SJS/TEN-specific mortality and adverse effects leading to discontinuation of SJS/TEN therapy. Secondary outcomes included time to complete re-epithelialisation, intensive care unit length of stay, total hospital length of stay, illness sequelae, and other adverse effects attributed to systemic therapy. We rated the certainty of the evidence for each outcome using GRADE. MAIN RESULTS: We included nine studies with a total of 308 participants (131 males and 155 females) from seven countries. We included two studies in the quantitative meta-analysis. We included three RCTs and six prospective, controlled observational studies. Sample sizes ranged from 10 to 91. Most studies did not report study duration or time to follow-up. Two studies reported a mean SCORe of Toxic Epidermal Necrosis (SCORTEN) of 3 and 1.9. Seven studies did not report SCORTEN, although four of these studies reported average or ranges of body surface area (BSA) (means ranging from 44% to 51%). Two studies were set in burns units, two in dermatology wards, one in an intensive care unit, one in a paediatric ward, and three in unspecified inpatient units. Seven studies reported a mean age, which ranged from 29 to 56 years. Two studies included paediatric participants (23 children). We assessed the results from one of three RCTs as low risk of bias in all domains, one as high, and one as some concerns. We judged the results from all six prospective observational comparative studies to be at a high risk of bias. We downgraded the certainty of the evidence because of serious risk of bias concerns and for imprecision due to small numbers of participants. The interventions assessed included systemic corticosteroids, tumour necrosis factor-alpha (TNF-alpha) inhibitors, cyclosporin, thalidomide, N-acetylcysteine, IVIG, and supportive care. No data were available for the main comparisons of interest as specified in the review protocol: etanercept versus cyclosporin, etanercept versus IVIG, IVIG versus supportive care, IVIG versus cyclosporin, and cyclosporin versus corticosteroids. Corticosteroids versus no corticosteroids It is uncertain if there is any difference between corticosteroids (methylprednisolone 4 mg/kg/day for two more days after fever had subsided and no new lesions had developed) and no corticosteroids on disease-specific mortality (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.72 to 9.03; 2 studies; 56 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. IVIG versus no IVIG It is uncertain if there is any difference between IVIG (0.2 to 0.5 g/kg cumulative dose over three days) and no IVIG in risk of disease-specific mortality (RR 0.33, 95% CI 0.04 to 2.91); time to complete re-epithelialisation (mean difference (MD) -2.93 days, 95% CI -4.4 to -1.46); or length of hospital stay (MD -2.00 days, 95% CI -5.81 to 1.81). All results in this comparison were based on one study with 36 participants, and very low-certainty evidence. Adverse effects leading to discontinuation of therapy were not reported. Etanercept (TNF-alpha inhibitor) versus corticosteroids Etanercept (25 mg (50 mg if weight > 65 kg) twice weekly "until skin lesions healed") may reduce disease-specific mortality compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day "until skin lesions healed") (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low-certainty evidence); however, the CIs were consistent with possible benefit and possible harm. Serious adverse events, such as sepsis and respiratory failure, were reported in 5 of 48 participants with etanercept and 9 of 43 participants with corticosteroids, but it was not clear if they led to discontinuation of therapy. Time to complete re-epithelialisation and length of hospital stay were not reported. Cyclosporin versus IVIG  It is uncertain if there is any difference between cyclosporin (3 mg/kg/day or intravenous 1 mg/kg/day until complete re-epithelialisation, then tapered off (10 mg/day reduction every 48 hours)) and IVIG (continuous infusion 0.75 g/kg/day for 4 days (total dose 3 g/kg) in participants with normal renal function) in risk of disease-specific mortality (RR 0.13, 95% CI 0.02 to 0.98, 1 study; 22 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. No studies measured intensive care unit length of stay. AUTHORS' CONCLUSIONS: When compared to corticosteroids, etanercept may result in mortality reduction. For the following comparisons, the certainty of the evidence for disease-specific mortality is very low: corticosteroids versus no corticosteroids,  IVIG versus no IVIG and cyclosporin versus IVIG. There is a need for more multicentric studies, focused on the most important clinical comparisons, to provide reliable answers about the best treatments for SJS/TEN.

Comparison of transfusion-outcome in patients with massive bleeding receiving pathogen-reduced platelets prepared with two different technologies.

BACKGROUND: Platelet concentrates(PCs) prepared with pathogen reduction technologies(PRT) are being used in routine treatment of onco-haematological patients since several years but less data are available for other pathologies. STUDY DESIGN AND METHODS: The aim of the study was to compare the efficacy of PCs prepared with two PRT for the treatment of patients with massive bleeding. The primary endpoint was the overall survival and in addition we analyzed the consumption of blood components in patients undergoing massive transfusion(MT). Subsequently we wanted to analyze additional known factors associated with higher in-hospital mortality. Retrospective analysis of two consecutive periods in which the PRT used were INTERCEPT and Mirasol, respectively. RESULTS: A total of 313 patients were included (76 % males; median age: 63 years; 160 in the INTERCEPT group and 153 in the Mirasol group). We found significantly higher use of platelets in the Mirasol cohort, measured either in absolute per patient number of units (3vs.4; p = 0.002) or after adjustment for the number of transfused red blood cells. The risk of death increased with age and the outof-hospital onset of bleeding, even after adjustment for one another (sub-distribution hazard ratio[sHR] 2.53, 95 % confidence interval [CI] 1.75-3.66, p < 0.001, and sHR 2.56, 95 % CI 1.82-3.60, p < 0.001, respectively). CONCLUSION: PRT applied to platelets did not influence MT-related mortality, but differences were found for the efficacy of the PCs treated with the different PRT which were reflected in a heightened demand for transfusion when utilizing Mirasol-treated PCs. Factors associated with higher mortality were older age and out-of-hospital bleeding.

Histologic and clinical cross-sectional study of chronic hair loss in patients with cutaneous chronic graft-versus-host disease.

BACKGROUND: While scalp alopecia represents a distinctive feature of chronic graft-versus-host disease (cGVHD), little is known about the clinical and histologic presentation of hair loss. OBJECTIVES: We sought to classify the clinical presentations and histologic findings of chronic hair loss in patients with cutaneous cGVHD. METHODS: A prospective cohort of 17 adult hematopoietic cell transplantation (HCT) recipients with cutaneous cGVHD was enrolled. Dermatologic examinations were performed, and punch biopsy specimens of the scalp were obtained. Biopsy specimens were analyzed with hematoxylin-eosin and immunohistochemical stains in all cases and fluorescence in situ hybridization analyses in specific cases. RESULTS: Clinically, 4 patterns of hair loss were described-patchy nonscarring (41.2%), diffuse nonscarring (11.8%), diffuse sclerotic (11.8%), and patchy sclerotic (5.9%). The location of the inflammatory infiltrate on hematoxylin-eosin-stained specimens correlated with the hair loss pattern patients had clinically, with cell populations around the bulb and bulge in nonscarring and sclerotic cases, respectively. Fluorescence in situ hybridization studies in female cGVHD patients with male donors demonstrated green Y chromosomes limited to the area of the hair follicle affected by inflammatory cells. CONCLUSION: This study describes the various clinical and histologic subtypes of long-standing alopecia in adult cGVHD patients and suggests that this alopecia may be a direct manifestation of cGVHD of the hair follicle.

Cutaneous extramedullary haematopoiesis: Implications in human disease and treatment.

The skin and bone marrow are two of the most dynamic organ systems of the human body. While the skin is only transiently involved in haematopoiesis in utero, cutaneous extramedullary haematopoiesis (CEMH) has been appreciated in various neonatal and adult diseases. The mechanism by which CEMH occurs remains poorly understood, but may be associated with the plasticity of blood and skin tissues. Extensive studies have documented expansion and differentiation of haematopoietic lineages from cutaneous tissues and vice versa. This review will discuss CEMH, potential mechanisms and laboratory findings that shed light on the interaction between both tissues. Further, we will discuss the implications of understanding the role of the skin in haematopoiesis, including the potential therapeutic function of manipulating either organ system in the treatment of pathologic processes in the other.

A Reactive Peripheral Gamma-Delta T-cell Lymphoid Proliferation After a Tick Bite.

Peripheral gamma-delta T-cell proliferations are encountered in reaction to certain infections and in primary malignancies. Identifying sources of benign reactions is key in avoiding unnecessary workup and surveillance of these aggressive malignancies. Borrelia infections have been implicated in a number of lymphoproliferative disorders, but rarely, if ever, in this setting. While gamma-delta T-cells are known to play a prominent role in the immune response to Borrelia infection, B-cell differentiation is encountered in the majority of Borrelia-associated proliferations. We present here a unique case of benign-appearing peripheral gamma-delta T-cell lymphoid proliferation in the setting of a tick-bite with subsequent erythema migrans-like skin findings.

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

A pilot study comparing histological and immunophenotypic patterns in stage 4 skin graft vs host disease from toxic epidermal necrolysis.

BACKGROUND: Stage 4 skin graft-versus-host disease (GVHD) is associated with poor prognosis and high mortality rates. Clinical and histologic similarities with toxic epidermal necrolysis (TEN) make it difficult to distinguish between these 2 life-threatening conditions. METHODS: A retrospective cohort study was conducted from a tertiary referral center. Skin biopsies were obtained from 11 patients who developed stage 4 skin GVHD and 11 patients who developed TEN between 2005 and 2012. The CD8+/CD4+ T lymphocyte ratios were assessed in lesional skin specimens. RESULTS: Average CD8+and CD4+ cell counts co-expressing CD3 were 126.29 (range 86.42-173.06) and 84.60 (29.87-197.20) for stage 4 skin GVHD patients, and 61.97 (45.79-146.67) and 7.65 (0.00-39.50) for TEN patients, respectively. Immunohistochemical studies of stage 4 skin GVHD and TEN skin demonstrated average CD8+/CD4+ ratios of 1.78 (range 0.69-3.09) and 7.33 (1.16-12.3), respectively (P = .013). CONCLUSIONS: Stage 4 skin GVHD and TEN are processes with cytotoxic profiles. TEN is notable for a greater relative depletion of CD4+ T lymphocytes compared with stage 4 skin GVHD, while stage 4 skin GVHD tends to be more inflammatory than TEN. These data suggest an immunohistologic method by which these 2 entities may be distinguished.

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy.

BACKGROUND: Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS: The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS: Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration. CONCLUSION: Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02019355. FUNDING: Not applicable (investigator-initiated clinical trial).