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Introduction: Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease., Methods: To characterize the human immunological responses developed against saliva of Phlebotomus duboscqi , a Leishmania major (L. major) vector, we repeatedly exposed the arms of 14 healthy U.S volunteers to uninfected P. duboscqi bites. Blood was collected a week after each exposure and used to assess total IgG antibodies against the proteins of P. duboscqi salivary gland homogenate (SGH) and the levels of IFN-gamma and IL-10 from peripheral blood mononuclear cells (PBMCs) stimulated with SGH or recombinant sand fly proteins. We analyzed skin punch biopsies of the human volunteer arms from the insect bite site and control skin site after multiple P. duboscqi exposures (four volunteers) using immunohistochemical staining., Results: A variety of immediate insect bite skin reactions were observed. Late skin reactions to insect bites were characterized by macular hyperpigmentation and/or erythematous papules. Hematoxylin and eosin staining showed moderate mononuclear skin infiltrate with eosinophils in those challenged recently (within 2 months), eosinophils were not seen in biopsies with recall challenge (6 month post bites). An increase in plasma antigen-specific IgG responses to SGH was observed over time. Western Blot results showed strong plasma reactivity to five P. duboscqi salivary proteins. Importantly, volunteers developed a cellular immunity characterized by the secretion of IFN-gamma upon PBMC stimulation with P. duboscqi SGH and recombinant antigens., Discussion: Our results demonstrate that humans mounted a local and systemic immune response against P. duboscqi salivary proteins. Specifically, PduM02/SP15-like and PduM73/adenosine deaminase recombinant salivary proteins triggered a Th1 type immune response that might be considered in future development of a potential Leishmania vaccine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 de Araujo, Abdeladhim, Teixeira, Hummer, Wilkerson, Ressner, Lakhal-Naouar, Ellis, Meneses, Nurmukhambetova, Gomes, Tolbert, Turiansky, Pazgier, Oliveira, Valenzuela, Kamhawi and Aronson.)

Introduction: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT., Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses., Results: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G)., Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among travelers and pediatric populations worldwide. The tip-localized adhesin of colonization factor antigen (CFA)/I fimbriae was engineered as a donor strand complemented variant (dscCfaE) and delivered via transcutaneous immunization. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. A series of open-label dose-escalating phase 1 studies evaluated a 3-dose (days 0, 21, 42) regimen via a transcutaneous skin patch. A total of forty-six subjects were enrolled into one of four vaccine dose levels (10, 50, 250, or 1250 µg) co-administered with single-mutant heat-labile enterotoxin (LTR(192G)). At the 50 µg dose level, ten subjects received the dscCfaE vaccine without LT(R192G). The vaccine was well tolerated with mild local vaccine site reactions characterized by an erythematous papular rash and pruritus, which were less frequent and reactive in the group not receiving LT(R192G). The frequency of responses to dscCfaE were moderate, whereas anti-toxin responses (serum IgA/IgG) ranged from 75 to 100% across groups that received LT(R192G). Antigen-specific antibody-secreting cell responses were elicited at all dose levels, but were generally low. Follow-on studies will optimize construct and route of delivery and assess efficacy in an ETEC challenge study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Trials assessing the safety of novel vaccine candidates are essential in the evaluation and development of candidate vaccines. Immunogenicity and dose-sparing features of vaccination approaches which target skin and associated tissues have garnered increased interest; for enteric vaccines, cutaneous vaccination has been of particular interest. Cutaneous vaccine site reactions are among the most common and visible vaccine related adverse events (AEs) when skin routes are used. Regulatory guidelines governing classification of severity focus on functional impact but are insufficient to characterize a spectrum of skin reaction and allow for comparisons of routes, doses and products with similar local cutaneous AEs., Objectives: Our group developed a grading scale to evaluate and compare cutaneous vaccine site reactions ahead of early-phase clinical trials of intradermal (ID) and transcutaneous immunization (TCI) with enterotoxigenic E.coli (ETEC) vaccine candidates (adhesin-based vaccine co-administered with LTR192G). We reviewed existing methods for characterizing the appearance and severity of local vaccine site reactions following TCI and ID vaccination and devised a standardized vaccine site appearance grading scale (VSAGS) for use in the clinical development of novel ETEC vaccine candidates which focused on pathophysiologic manifestation of skin findings., Results: Available data from published reports revealed erythematous papules and pruritus were the most common local AEs associated with TCI. Frequency of reactions varied notably across studies as did TCI vaccination methodologies and products. ID vaccination commonly results in erythema and induration at the vaccine site as well as pigmentation changes. There was no published methodology to characterize the spectrum of dermatologic findings., Conclusion: ID and TCI vaccination are associated with a largely predictable range of cutaneous AEs. A grading scale focused on the appearance of cutaneous changes was useful in comparing cutaneous AEs. A standardized grading scale will facilitate documentation and comparison of cutaneous AEs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited.

Squamous cell carcinoma of the anal canal (SCCAC) is an increasing concern in the human immunodeficiency virus (HIV)-positive population in the highly active antiretroviral therapy (HAART) era. A discussion of the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of SCCAC is presented.

Unlabelled: Myiasis is the infestation of living tissue by the larvae of flies in the order Diptera. Cutaneous involvement is the most common type of myiasis. Cutaneous myiasis can be subdivided into furuncular, migratory, and wound myiasis. Each subtype is reviewed with discussion of the larvae involved, presenting signs and symptoms, clinical differential diagnoses, and treatment. Preventive measures are also described., Learning Objectives: At the conclusion of this learning activity, participants should be familiar with the causal agents, clinical manifestations, and treatment of human cutaneous myiasis.

Anetoderma is a rare benign dermatosis caused by a loss of mid-dermal elastic tissue resulting in well-circumscribed areas of pouchlike herniations of flaccid skin. Anetoderma is classically categorized as either primary (idiopathic) or secondary (following an inflammatory dermatosis in the same location). We report a case of primary anetoderma (PA) occurring in a human immunodeficiency virus 1 (HIV-1)-infected man. We review the clinical presentation, possible etiologies, associated conditions, and limited treatment options of this disease.

Cutaneous endometriosis is a rare condition, especially in patients without a history of abdominal or pelvic surgery or known preexisting endometriosis. Most cases present with cyclic pain and bleeding at the site of an umbilical cutaneous nodule correlating with menses. We present an atypical case of primary cutaneous endometriosis of the umbilicus without a prior history of abdominal or pelvic surgery and without cyclic pain or bleeding.

Waldenström macroglobulinemia (WM) is an immunoglobulin M-producing lymphoproliferative disorder in elderly individuals. Cutaneous manifestations of WM are rare and typically consist of plaques or nodules. We describe a case of a man with WM who presented with an extensive erythematous patch on the scalp that clinically mimicked an angiosarcoma.

Pyoderma gangrenosum (PG) is an uncommon cutaneous disease of unknown etiology. In 50 percent of affected patients, PG is associated with systemic disease including inflammatory bowel disease, arthritis, and hematologic malignancies.(1) Diagnosis of PG is based on clinical presentation, histopathology and on the exclusion of other diseases that can produce clinically similar lesions, e.g. infection, vasculitis, malignancy, collagen vascular diseases, diabetes, and trauma. Four variants of PG have been described: ulcerative, pustular, bullous, and vegetative.(2) We report a woman with renal failure who developed PG in the absence of any obvious triggering trauma in a distinctive unilateral crop just distal to an arteriovenous dialysis shunt.

A case report of cutaneous onchocercias acquired during travels to Africa is presented. The salient epidemiologic, clinical, diagnostic, and therapeutic aspects are reviewed. Clinical and laboratory differences between onchocerciasis patients who are inhabitants of endemic areas and those who are occasional visitors to such areas are discussed. Parasitic infections, including onchocerciasis, should be considered in the differential diagnosis of pruritic eruptions in patients with a history of foreign travel to Africa, Central and South America.

Granulomatous periorificial dermatitis (GPD) is a distinct facial eruption in prepubertal children that should be distinguished from granulomatous rosacea, perioral dermatitis, and cutaneous sarcoidosis. We describe a case of GPD and review the key distinguishing features of this condition.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare cutaneous diseases marked by substantial epidermal denudation and are often complicated by sepsis and multiple organ failure. They are most commonly caused by drug therapy. Patients afflicted with these diseases require care that may exhaust the capabilities of medicine wards and medical intensive care units alike; however, their mortality is reduced when treated at burn centers, which are better equipped to treat extensive skin denudation. We report a case of TEN and propose an algorithm to provide guidance for making the critical decision to transfer patients with SJS and TEN to burn units.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder. Less than 50 cases have been reported. We report the first case of CNL with an associated leukemia cutis. CNL was diagnosed in a 74-year-old white woman in 1998, based on neutrophilic infiltration of the bone marrow and absence of the Philadelphia chromosome. The patient presented to the dermatology service in August 1998 with a 2-week history of a pruritic eruption on the arms, hands, and legs. Physical examination revealed red to violaceous plaques on both thighs and knees, in addition to purpuric patches and plaques on the dorsal hands, arms, and legs. Leukemia cutis was demonstrated on biopsy specimens of several lesional sites. The eruption progressed, despite treatment with topical and systemic corticosteroids. Treatment with systemic chemotherapy did affect partial resolution of the eruption, with parallel decreases in bone pain and white blood cell count, but the disease progressed and the patient ultimately died 5 months after her initial skin findings. Only one other case of CNL with dermatologic manifestations has been reported, CNL associated with a reactional neutrophilic dermatosis. Comparison to and differentiation from this case is discussed. The importance of distinguishing the specific infiltrates of leukemia from the nonspecific infiltrates of reactional dermatoses, such as Sweet's syndrome, is illustrated.

In the setting of HIV infection, chronic genital ulcerations may be challenging both diagnostically and therapeutically. The differential diagnosis of these lesions is very broad, and the causes can be multifactorial. We present a case of a chronic, extensive, ulcerating scrotal mass and review the salient clinical, diagnostic, and therapeutic considerations.

Due to diverse clinical and histopathological presentations, diagnosis of secondary syphilis can occasionally prove challenging. This is especially true in the setting of human immunodeficiency virus (HIV) infection. Variable clinical presentations of secondary syphilis in HIV disease may result in an incorrect diagnosis and an inappropriate treatment regimen. Similarly, the histology of secondary syphilitic lesions may show considerable variation, depending on the clinical morphology of the eruption. We report 2 cases of secondary syphilis in HIV-1-infected patients with cutaneous lesions of variable clinical presentation and an unusual lymphoid infiltrate simulating mycosis fungoides.

Fox-Fordyce disease (FFD) is an uncommon chronic follicular based dermatosis with distinctive clinical characteristics consisting of pruritic papules confined to apocrine gland-bearing skin. Histologic confirmation of this entity is often time-consuming and difficult with conventional histologic sectioning. We describe a case of FFD occurring in a 26-year-old woman, in which we used transverse histologic sectioning to easily demonstrate the histopathologic features of this condition. With conventional sectioning of a punch biopsy specimen of an affected area, more than 23 serial sections were required to locate a follicle with pathognomonic features of the disease. In contrast, only one transverse section of a biopsy specimen was required to confirm the diagnosis. We propose that transverse histologic sectioning of biopsy specimens of patients suspected of having FFD more effectively demonstrates the diagnostic features.

A case of acute generalized exanthematous pustulosis (AGEP) due to chromium picolinate is described. This supplemental form of chromium has received a great deal of interest recently because of its possible beneficial effects on both muscle strength and body composition. There have been no previous reports to our knowledge of adverse cutaneous reactions to this agent. Various aspects of AGEP are reviewed.

Viral folliculitis is an infrequently reported entity. We describe two patients with viral folliculitides, including a case of herpetic sycosis caused by herpes simplex (HSV) and a case of herpes zoster (HZ) without blisters. Clinicians should consider viral etiologies in the differential diagnosis of superficial infectious folliculitis, especially those cases refractory to antibacterial or antifungal therapy.

We describe a 53-year-old woman with a 4-month history of palpable purpuric papules on the upper and lower extremities. Biopsy of the skin lesions revealed leukocytoclastic vasculitis. Although she denied any systemic symptoms, urinalysis demonstrated hematuria and proteinuria. Although the patient's skin lesions responded to prednisone, her urinalysis did not improve. A 10-cm complex mass involving the left ovary and adnexa was incidentally discovered on renal ultrasound. Serum CA-125, an ovarian cancer marker, was elevated. Laparotomy revealed ovarian carcinoma confined to the left ovary. After the cancer was resected, the patient's urinalysis slowly improved. Leukocytoclastic vasculitis (LCV) is infrequently associated with underlying malignancy and only rarely with solid tumors. We postulate that the patient's vasculitis represented a paraneoplastic phenomenon that allowed a diagnosis of asymptomatic ovarian carcinoma. To our knowledge, this is the first report of LCV occurring as the presenting sign of ovarian cancer.

Felodipine is a calcium channel blocking agent used in the management of hypertension and angina. We report a case of gingival hyperplasia in a patient with chronic use of this drug. Gingival changes occurred soon after initiation of felodipine and improved upon its discontinuation. The clinical characteristics, inciting agents, proposed pathogenetic mechanisms, as well as prevention and treatment of drug-induced gingival hyperplasia are briefly reviewed.

Background: In AIDS, nodular skin disease can result from various causes., Objective: To report a new manifestation of microsporidial infection presenting as nodular skin disease with underlying osteomyelitis., Design: Case report., Setting: Tertiary-care military medical center in Washington, D.C., Patient: A 36-year-old woman with late-stage AIDS who presented with disseminated, nodular cutaneous lesions and underlying osteomyelitis., Measurements: Disseminated microsporidial infection with an Encephalitozoon-like species was diagnosed by electron microscopic examination of material obtained from the skin lesions., Intervention: The patient received long-term oral clindamycin therapy, which cured her disseminated infection., Conclusions: Microsporidia can cause disseminated cutaneous infections in AIDS patients. The response of this patient to long-term clindamycin therapy merits further evaluation.

Background: Viral folliculitis is an infrequently reported entity. The patients described herein were seen over a 12-year period of practice in a referral dermatologic setting. The cases involve a variety of viral infections limited to the hair follicle., Observations: We describe 5 patients with a variety of viral folliculitides: 2 with herpetic sycosis caused by herpes simplex; 1 with herpex simplex folliculitis (this patient also had human immunodeficiency virus); 1 with herpes zoster without blisters; and 1 with molluscum contagiosum., Conclusions: These 5 cases demonstrate that viral folliculitis has varied causes and presentations. Clinicians should consider viral agents in the differential diagnosis of superficial infectious folliculitis, especially in cases that are refractory to antibacterial or antifungal therapy.

A 29-year-old Thai woman had draining sinus tracts, tumefaction, and granules on the plantar aspect of the foot. Phialophora verrucosa was isolated from the lesion. P. verrucosa is a major agent of chromoblastomycosis, which is known to rarely cause subcutaneous phaeohyphomycosis. This dematiaceous fungus has not been previously reported to cause mycetoma. This case illustrates the clinical spectrum of disease of this fungus. The salient features of mycetoma and management options are presented.

Background: Cutaneous disease is common in patients infected with HIV-1., Objective: The aim of our study was to identify cutaneous markers associated with HIV-1 infection and disease progression as measured by Walter Reed (WR) stage., Methods: For 42 months we have observed 912 HIV-1-positive patients in all WR stages. All patients had an extensive past and present medical history taken as well as a complete physical examination, periodic visits, and appropriate diagnostic procedures., Results: Increasing dryness of the skin and seborrheic dermatitis are early findings in a large percentage of patients in WR stage 1; the occurrence and severity of both conditions increase with disease progression. Tinea infections, condylomata acuminata, and verrucae are seen early, but with disease progression, although there is no clear increase in occurrence, these infections become more diffuse and resistant to treatment. Flares in acne vulgaris and folliculitis show a peak occurrence in early and mid-stage disease with a decreased occurrence in late-stage disease. Herpes simplex infections, oral candidiasis, molluscum contagiosum, Staphylococcus aureus infections, and oral hairy leukoplakia show a marked increase in occurrence with advanced disease. Conditions that have a statistically significant association with disease progression as measured by a change in a stage include drug eruptions, seborrheic dermatitis, oral candidiasis, oral hairy leukoplakia, molluscum contagiosum, herpes zoster, and hyperpigmentation (nail, oral, skin)., Conclusion: The most frequent and persistent cutaneous disorders were asteatosis (with or without asteatotic eczema) and seborrheic dermatitis. Conditions that were associated with a change in WR stage include drug eruptions, seborrheic dermatitis, oral candidiasis, oral hairy leukoplakia, molluscum contagiosum, herpes zoster, and hyperpigmentation. In addition to Kaposi's sarcoma, patients with HIV-1 disease have an increased potential for the development of both cutaneous epithelial and probably melanocytic malignancies. Epithelial tumors were seen in patients in all stages of disease.