A comprehensive narrative review of the cutaneous manifestations associated with COVID-19.

The systemic and respiratory clinical manifestations of coronavirus disease 2019 (COVID-19) include fever, coughing, sneezing, sore throat, rhinitis, dyspnea, chest pain, malaise, fatigue, anorexia and headache. Moreover, cutaneous manifestations have been reported in 0.2% to 20.4% of cases. Early diagnosis of COVID-19 leads to a better prognosis; knowledge of its cutaneous manifestations is one way that may help fulfil this goal. In this review, PubMed and Medline were searched with the terms "dermatology", "skin" and "cutaneous", each in combination with "SARS-CoV-2" or "COVID-19". All articles, including original articles, case reports, case series and review articles published from the emergence of the disease to the time of submission, were included. In this comprehensive narrative review, we tried to provide an analysis of the cutaneous manifestations associated with COVID-19, including maculopapular rash, urticaria, Chilblain-like, vesicular lesions, livedo reticularis and petechiae in asymptomatic/symptomatic COVID-19 patients that might be the first complication of infection after respiratory symptoms. Immune dysregulation, cytokine storms, side effects of antiviral drugs, environmental conditions and high-dose intravenous immunoglobulin (IVIG) therapy might be involved in the pathogenesis of the cutaneous manifestations in COVID-19 patients. Therefore, knowledge of cutaneous COVID-19 manifestations might be vital in achieving a quick diagnosis in some COVID-19 patients, which would help control the pandemic. Further research is very much warranted to clarify this issue.

Immunopathology of anthroponotic cutaneous leishmaniasis and incidental diagnostic tool of metastatic granuloma: A case-control study.

BACKGROUND: Cutaneous leishmaniasis (CL) is a neglected disease with important public health concerns in many parts of the world including Iran. OBJECTIVES: We aimed to explore the histological changes and immunohistochemical quantification of inflammatory cells and their role in the immunopathology of acute, chronic non-lupoid, and chronic lupoid skin lesions in anthroponotic CL (ACL). METHODS: In this study, skin biopsies of 53 patients with ACL were taken. Samples were studied by light microscopy and immunohistochemistry to quantify the immune and inflammatory cells. RESULTS: Of the 53 skin lesions, 38 were acute, nine chronic non-lupoid and six chronic lupoid. CD68+ macrophages were the most common cells. CD3+ T-lymphocytes were present as diffuse and focal dermal infiltrates and CD8+ cytotoxic T-lymphocytes were the dominant lymphocyte type, constituting more than 50% of the lymphocyte population. CD4+ T-lymphocytes in chronic non-lupoid (10.57 ± 2.37%) and chronic lupoid (14.40 ± 1.28%) lesions were more than those observed in the acute form (8.61 ± 1.31%), but the differences were not statistically significant. CD20+ B-lymphocytes constituted a small percentage of inflammatory cell infiltrates. CD1a + Langerhans cells showed progressively higher percentages from acute to chronic non-lupoid to chronic lupoid lesions. The differences were statistically significant (P < 0.05) between acute and chronic lupoid lesions. CD68+ macrophages were the most common cells and CD8+ T lymphocytes remained the predominant T-lymphocytes in acute, chronic non-lupoid, and chronic lupoid lesions, suggesting their central role in the pathogenesis and possible healing of CL. CONCLUSION: Focusing on the deep dermis, periadnexal and/or peripheral margins or even papillary tip of inflammatory sites of sandfly bites, we sometimes find granuloma inside lymphatic vessels (lymphangiectatic metastatic granuloma) or even infected macrophages with engulfed Leishman bodies faraway. Knowledge of the histopathological and immunohistochemical findings for various forms of ACL is essential in improving clinical and medical strategies and crucial for proper prophylactic and therapeutic plans.

Assessing effectiveness of adding niosomal atorvastatin 1% ointment to topical calcineurin inhibitor treatment in non-segmental vitiligo.

BACKGROUND: Treatment of vitiligo is still a big challenge for dermatologists. The efficacy of statins in the treatment of vitiligo is controversial. AIM AND OBJECTIVE: We studied possible therapeutic effect of topical 1% niosomal atorvastatin ointment combined with topical 0.1% tacrolimus in treatment of non-segmental vitiligo. METHODS: This is a triple blind, pilot, randomized placebo-controlled trial (RCT) that was performed in dermatology clinic. All the patients used topical 0.1% tacrolimus cream twice daily (BD). Moreover, the intervention group participants used topical 1% niosomal atorvastatin ointment, and control group participants were prescribed placebo ointment, BD. Patients were evaluated using vitiligo area surface index (VASI) score and patients' satisfaction at baseline and after 3 months treatment. RESULTS: The mean patient satisfaction in the intervention and control groups were 5 ± 1.4 and 3.5 ± 1.9; the difference between groups was not statistically significant (p = 0.9). We found statistically significant difference in VASI score before and after treatment in both intervention and control groups (p = 0.01 and p = 0.03, respectively). However, comparison of the VASI score between groups was not statistically significant (p = 0.62). We also found no significant correlation between VASI score and other variables. CONCLUSION: The result of this study indicates that adding of niosomal atorvastatin 1% ointment to topical calcineurin inhibitor has no additional effect on non-segmental type of vitiligo. Further large studies with different combinations are recommended before any conclusive result can be concluded on efficacy of statins in vitiligo.

Efficacy of topical cysteamine hydrochloride in treating melasma: a systematic review.

INTRODUCTION: Melasma remains a recurrent, chronic, therapeutically challenging, and psychologically burdening condition. Several different modalities and approaches have been utilized, and some with notable success to experimentally manage the condition. Cysteamines, with their depigmentation properties, have only recently been intensely studied. One such formulation is the topical 5% cysteamine hydrochloride, the structure of which is notably more stable and with a less foul odor than its prior counterparts. We, therefore, aimed to assess the efficacy of the mentioned formulation in the treatment of melasma. METHODS: The PubMed, SCOPUS, ISI Web of Science, and Embase, Cochrane, and Proquest databases were thoroughly searched for English studies evaluating the effects of the topical agent mentioned. RESULTS: Eight studies (five RCTs, two case reports, and one case series) were included after three rounds of screening, most of which were carried out in Iran. Statistical significance was noted when assessing decreased melanin content and satisfaction rates. CONCLUSIONS: It appears that the cysteamine cream could be comparably efficient in treating melasma while accompanied only by minor and transient adverse events. However, current evidence is limited by insufficient sample size, long-term follow-up, and only to epidermal melasma, highlighting the need for appropriately designed randomized controlled clinical trials to draw a conclusive image of the cysteamine's role in treating this recalcitrant condition.

Major risk factors and histopathological profile of treatment failure, relapse and chronic patients with anthroponotic cutaneous leishmaniasis: A prospective case-control study on treatment outcome and their medical importance.

Over the last years, there has been a remarkable increase in the number of unresponsive patients with anthroponotic cutaneous leishmaniasis (ACL) reported worldwide. The primary objective of this study was to explore the role of demographic, clinical and environmental risk related-factors in the development of treatment failure, relapse and chronic cases compared to responsive patients with ACL. Moreover, molecular, histopathological and immunohistochemical (IHC) findings between these forms were explored. This work was undertaken as a prospective and case-control study in southeastern Iran. Culture media and nested PCR were used to identify the causative agent. Univariate multinomial and multiple multinomial logistic regression models and the backward elimination stepwise method were applied to analyze the data. A P<0.05 was defined as significant. Also, for different groups, skin punch biopsies were used to study the histopathological and immunohistochemical (IHC) profile. All samples showed that L. tropica was the only etiological agent in all unresponsive and responsive patients with ACL. Data analysis represented that 8 major risk factors including nationality, age groups, occupation, marital status, history of chronic diseases, duration of the lesion, the lesion on face and presence of domestic animals in the house were significantly associated with the induction of unresponsive forms. The histopathological and immunohistochemical findings were different from one form to another. The present findings clearly demonstrated a positive relation between ACL and distinct demographic, clinical and environmental risk determinants. Knowledge of the main risk factors for ACL infection is crucial in improving clinical and public health strategies and monitor such perplexing factors.

Pathogenesis of COVID-19; Acute Auto-inflammatory Disease (Endotheliopathica & Leukocytoclastica COVIDicus).

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.

In vitro and in vivo therapeutic potentials of 6-gingerol in combination with amphotericin B for treatment of Leishmania major infection: Powerful synergistic and multifunctional effects.

The ongoing conventional drugs for leishmaniasis treatment are insufficient. The present study aimed to assess 6-gingerol alone and in combination with amphotericin B on Leishmania major stages using experimental and in vivo murine models. Here, arrays of experimental approaches were designed to monitor and evaluate the 6-gingerol potential therapeutic outcomes. The binding affinity of 6-gingerol and IFN-γ was the basis for docking conformations. 6-Gingerol combined with amphotericin B represented a safe mixture, extremely leishmanicidal, a potent antioxidant, induced a remarkable apoptotic index, significantly increased the expression of the Th1-related cytokines (IL-12p40, IFN-γ, and TNF- α), iNOS, and transcription factors (STAT1, c-Fos, and Elk-1). In contrast, the expression of the Th2-related cytokines was significantly downregulated (p < 0.001). This combination was also potent when the lesion appearance was evaluated following three weeks of treatment. The histopathological and immunohistochemical patterns of the murine model represented clusters of CD4+ and CD8+ T lymphocytes which compressed and deteriorated the macrophages harboring Leishman bodies. The primary mode of action of 6-gingerol and amphotericin B involved broad mechanistic insights providing a coherent basis for further clinical study as a potential drug candidate for CL. In conclusion, 6-gingerol with amphotericin B synergistically exerted anti-leishmanial activity in vitro and in vivo and potentiated macrophages' leishmanicidal activity, modulated Th1- and Th2-related phenotypes improved the histopathological changes in the BALB/c mice infected with L. major. They elevated the leukocyte infiltration into the lesions. Therefore, this combination should be considered for treating volunteer patients with CL in clinical studies.

Efficacy of microneedling plus topical 4% tranexamic acid solution vs 4% hydroquinone in the treatment of melasma: A single-blind randomized clinical trial.

BACKGROUND: There are various treatment modalities for melasma, but none of them are effective on dermal component of melasma. AIMS: In this study, we decided to evaluate the efficacy of microneedling plus tranexamic acid in comparison with 4% hydroquinone in the treatment of melasma. METHODS: This is a single-blind randomized clinical trial on 70 participants with 14% dropout, and therefore, 60 patients with melasma completed the study. Patients were randomized based on simple randomization in 2 groups of A (microneedling plus topical 4% tranexamic acid, monthly) and B (topical 4% hydroquinone, nightly). Evaluation of mean MASI score, patient and physician assessments was performed at 4th, 8th and12th weeks of the treatment. Statistical analysis was performed by paired t test, chi-square test and Fisher's exact test, respectively. RESULTS: Sixty women (30 patients in each group) were completed the study. Mean MASI score in group A was significantly lower at the end of the treatment (6.84 ± 4.31) than at the baseline (12.89 ± 5.16) (P < .01). Mean MASI score in group B was significantly lower at the end of the treatment (7.16 ± 4.38) than at the baseline (13.56 ± 4.88) (P < .01). There was no statistical difference between 2 groups regarding MASI score, physician and patient assessments during the treatment. Percentage of patient satisfaction was significantly higher than physician satisfaction in both treatment groups (P < .01). CONCLUSION: In our study, the combination of microneedling with tranexamic acid did not differ from 4% hydroquinone in the treatment of melasma.

Ability of real-time PCR for differential diagnosis of various forms of cutaneous leishmaniasis: a comparative study with histopathology.

OBJECTIVE: Histopathological studies suggest that parasite load is different between acute and chronic forms of cutaneous leishmaniasis (CL). However, highly sensitive detection methods are still needed to distinguish different forms of leishmaniasis. In the present study, we developed a quantitative real-time polymerase chain reaction (PCR) to detect and quantify Leishmania tropica parasites in paraffin-embedded tissue samples. RESULTS: The ability of real-time PCR for leishmania detection was higher than histopathological evaluation. The quantitative real-time PCR (qPCR) quantified parasite loads were highly correlated with microscopic results (r = 0.598; P < 0.001). Among patients, the parasite load was inversely correlated with disease duration (acute CL lesions had very higher parasite load than chronic CL lesions), but there was no difference in the parasite load according to the patients' age and sex as well as location of the lesions. In contrast to Ridley scoring system (P < 0.001), there were no statistically significant differences in the relative number of parasites among the lupoid and non-lupoid forms of chronic lesions in real-time PCR (P = 0.549), which indicates the superiority of histopathological evaluation for chronic forms differentiation.

A History of Leishmaniasis in Iran from 19th Century Onward.

The history of leishmaniasis dates back to the distant past; however, its etiologic agent was unidentified until the mid-19th century. Here is an overview of some historical aspects of leishmaniasis in Iran mainly focused on the cutaneous form, from the mid-19th century onwards. In addition, short biographies of several contemporary researchers and experts of leishmaniasis and their achievements in the past decades are presented.

Topical terbinafine in the treatment of cutaneous leishmaniasis: triple blind randomized clinical trial.

Leishmaniasis is a spectrum of disease condition with considerable health impacts, caused by different species of Leishmania. This disease is currently endemic in 98 countries and territories in the world. There are many treatment modalities for cutaneous leishmaniasis. The use of topical terbinafine in the treatment of cutaneous leishmaniasis has recently been considered. Eighty-eight participants more than two years old with proven acute CL by a positive direct smear were randomly allocated to one of the two study arms: first group received meglumine antimoniate (Glucantime) 20 mg/kg/day intramuscular injection (IM) plus a placebo ointment (Mahan Vaseline) for 20 days. The second group received meglumine antimoniate (Glucantime) 20 mg/kg/day IM plus topical terbinafine, for 20 days and were monitored closely by dermatologist during the course of the study. Crude regression analysis showed that there was no significant difference between placebo and intervention group regarding partial or complete treatment (partial treatment: HRcrude = 1.1, CI 95 % = 0.7-1.7; complete treatment: HRcrude = 1.1, CI 95 % = 0.8-1.7). Although, there was no statistically significant different between the two treatment groups, but clinically it seems that the treatment rate in those who receive glucantime plus terbinafine was more effective than the other group. However this rate depended on the type of lesions. As data indicated ulcerated nodules, papules and plaque in experimental group have been completely improved two times faster than placebo group. Ulcerated nodules, nodules and plaque were partially improved faster in those used tebinafine than placebo ointment.

Studying intense pulsed light method along with corticosteroid injection in treating keloid scars.

BACKGROUND: Results of various studies suggest that the hypertrophic and keloid scars are highly prevalent in the general population and are irritating both physically and mentally. OBJECTIVE: Considering the variety of existing therapies, intense pulsed light (IPL) method along with corticosteroid injection was evaluated in treating these scars. MATERIALS AND METHODS: 86 subjects were included in this clinical trial. Eight sessions of therapeutic intervention were done with IPL along with corticosteroid intralesional injection using 450 to 1200 NM filter, Fluence 30-40 J/cm2, pulse duration of 2.1-10 ms and palsed delay 10-40 ms with an interval of three weeks. To specify the recovery consequences and complication rate and to determine features of the lesion, the criteria specified in the study of Eroll and Vancouver scar scale were used. RESULTS: The level of clinical improvement, color improvement and scar height was 89.1%, 88.8% and 89.1% respectively. The incidence of complications (1 telangiectasia case, 7 hyperpigmentation cases and 2 atrophy cases) following treatment with IPL was 11.6%. Moreover, the participants' satisfaction with IPL method was 88.8%. CONCLUSIONS: This study revealed that a combined therapy (intralesional corticosteroid injection + IPL) increases the recovery level of hypertrophic and keloid scars. It was also demonstrated that this method had no significant side effect and patients were highly satisfied with this method.

Molecular pathology and histopathological findings in localized leishmania lymphadenitis.

BACKGROUND: A rare variant of Leishmaniasis is Localized Leishmania Lymphadenitis which has been occasionally reported from south-eastern parts of Iran. So far, no molecular assay has been performed for diagnosing this variety of Leishmaniasis. METHODS: Nineteen lymph node paraffin blocks were collected from 1994 to 2007. Parasite load count and histopathological patterns reported on Hematoxylin-Eosin and Giemsa stained slides.DNA extraction was carried out just on the remaining available 7 lymph node paraffin blocks according to QIAamp DNA FFPE kit instructions. A pair of primers and a probe were designed for rRNA ITS region with Allele ID 6.0 software, followed by real time PCR amplification. RESULT: The most common histopathological pattern was necrotizing granuloma with few Leishman bodies. Parasite load was the highest in submental lymph node (3 ± 1.41 per oil field) which was significantly higher compared to cervical and inguinal nodes (P < 0.05). Absolute load of parasite DNA was detectable in all 7 cases. The positive cases revealed a 201 bpamplicon after electrophoresis of end product which was confirmative for Leishmania tropica. CONCLUSION: Real time PCR revealed Leishmania tropica as the etiologic agent of Localized Leishmania Lymphadenitis. Although this molecular method is a sensitive diagnostic tool, histopathological findings are still important.

Quality of life in patients with cutaneous leishmaniasis.

BACKGROUND: Leishmaniasis is a zoonotic infection caused by a protozoa belonging to the genus Leishmania. Its clinical manifestations range from a self-healing cutaneous leishmaniasis (CL) to lethal visceral leishmaniasis. We aim to examine the quality of life of patients with CL in Kerman, Iran.  METHODS: In this cross-sectional study we evaluated 124 patients with CL. The Dermatology Life Quality Index (DLQI) questionnaire was used for measuring quality of life. Data on demographics and characteristics of the lesions also were collected. Mann-Whitney U-test and Kruskal-Wallis were used for data analyses. RESULTS: The mean DLQI score was 5.87 ± 5.96. We observed the highest effect in the symptoms and feelings domains; the lowest effect was seen in the treatment domain of the DLQI. There was no significant difference in DLQI scores between men and women. Patients with ulcerated lesions had lower quality of life (P < 0.05).  CONCLUSION: CL significantly affects the quality of life of patients. Further studies are suggested to examine the effect of its treatment on the quality of life in these patients.

Comparative histological and immunohistochemical changes of dry type cutaneous leishmaniasis after administration of meglumine antimoniate, imiquimod or combination therapy.

BACKGROUND: This study compared histological and immunohistochemical changes of cutaneous leishmaniasis treated with meglumine antimoniate, imiquimod, and the combination of both therapies. METHODS: Single blind clinicopathological studies of fifteen patients with old world cutaneous leishmaniasis in Kerman, Iran were included. A total of four patients received a combination of imiquimod (5% cream) and intra-lesional meglumine antimoniate weekly for four weeks. Monotherapy with imiquimod was given to seven patients and four patients were treated with meglumine antimoniate intralesionally. Histological confirmation was performed before and during therapy. Semi-quantitative histological parameters such as numbers of mixed inflammatory cells (cells/mm(2)) and percentages of Langerhans cells (CD1a+), T-cells (CD3+), B-cells (CD20+), and macrophages (CD68+) were calculated immunohistochemically in the dermis and adjacent epidermis. RESULTS: Topical imiquimod significantly reduced mean histiocytic cellular aggregation size (P<0.05). Meglumine antimoniate reduced parasite load and infected activated histiocytes in the dermis (P<0.05). Meglumine antimoniate therapy decreased epidermal CD3+ lymphocytes but increased them in the dermis, within the granulomas (P<0.05). During topical application of imiquimod a depletion of CD1a+ dendritic cells in the epidermis (P<0.05) and slight predominance of dendritic cells in the dermis were observed. Combined therapy and imiquimod monotherapy decreased CD68+ macrophages in the dermis (P<0.05). CONCLUSION: Meglumine antimoniate decreases parasite load with considerable effect on up-regulation of T-cells, which demonstrates that meglumine antimoniate works as parasitocidal and immunomodulator, which could be a first line of treatment. Imiquimod accentuates the host immune response and reduces granuloma size which could be effective immunomodulator for combination therapy. Monotherapy of imiquimod is less effective than the two other regimens in decreasing parasite load, inflammation and congestion at the inoculated site.