Virulence and resistance factors of Nakaseomyces glabratus (formerly known as Candida glabrata) in Europe: A systematic review.

BACKGROUND: Nakaseomyces glabratus (N. glabratus) formerly known as Candida glabrata (C. glabrata), is an endogenous opportunistic pathogen, which is generally located in the gastrointestinal tract but can spread in immunocompromised patients. N. glabratus is the second most common pathogen that causes candidemia in several countries. N. glabratus virulence factors may increase antifungal resistance and reduce the number of available treatment options. High resistance to azoles and increasing resistance to echinocandins have been previously reported in N. glabratus. OBJECTIVE: To establish the distribution of N. glabratus isolates in Europe and its drug susceptibility/resistance in each country over the last 7 years. METHODS: The search was performed across three databases: PubMed, Scopus and Scielo, using the MeSH terms: "Candida glabrata", "Nakaseomyces glabratus", "Europe", "resistance" and "Epidemiology" exclusively in English. All available information from January 2002 to December 2022 was included, excluding reviews, meta-analyses and book chapters. RESULTS: Fifty-seven articles with information on antifungal susceptibility in Europe were retrieved and analysed with a total of 15,400 reported C. glabrata isolates. Remarkably, nations that presented the maximum number of cases during the study period included the United Kingdom (n = 7241, 47.02%), France (n = 3190, 20.71%), Spain (n = 900, 5.84%), Hungary (n = 745, 4.84%) and Italy (n = 486, 3.16%). C. glabrata isolates presented resistance to azoles [voriconazole (n = 2225, 14.45%), fluconazole (n = 1612, 10.47%), itraconazole (n = 337, 2.19%) and clotrimazole (n = 89, 0.58%)], increased resistance to echinocandins, especially to anidulafungin (n = 138, 0.89%), and high sensitivity to amphotericin B. CONCLUSION: The number of candidemia cases associated with triazole-resistant N. glabratus isolates have been increasing in Europe. Therefore, echinocandins and amphotericin B can be considered optional empirical treatments; however, antifungal susceptibility testing is required to determine the best therapeutic options.

PAPA Syndrome: Challenges in Achieving Long-Term Remission.

For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) gene and clinically characterized by the presence of pyogenic arthritis, pyoderma gangrenosum (PG), and acne (1,2). Due to the involvement of the PSTPIP1 gene in the regulation of innate immunity, mutations of this gene cause abnormal activation of inflammasomes, complexes of NLRP3/ASC/caspase-1 proteins. As a result, production of interleukin-1ß, a key molecule that triggers synthesis of cytokines necessary for the recruitment of neutrophils, is significantly increased (2,3). Additionally, the levels of other pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin 17 (IL-7) are also elevated, which further disrupts inflammatory mechanisms in the microenvironment (4). Since hyperproduction of IL-1 and other involved cytokines is the predominant event in the pathogenesis, these molecules are promising targets in the treatment of PAPA syndrome. Corticosteroids and biologics are currently the most commonly used agents for inducing and hastening remission of symptoms (5). A substantial step forward in the treatment of PAPA syndrome has been the introduction of medications blocking the cytokines crucial in the pathogenesis of this disorder, with TNF-α and IL-1 inhibitors being the most frequent choice of such biological therapy (6). We report the case of a 22-year-old male patient with PAPA syndrome who was referred to our department 18 months ago due to exacerbation of skin changes. Initial presentation and subsequent evolution of disease in this patient matched the typical clinical pattern of PAPA syndrome. The first symptoms occurred at the age of two in the form of unspecific joint disease that was diagnosed as juvenile idiopathic arthritis. Subsequently, in the early adolescence the patient presented with new skin changes manifesting as severe acne and persistent pyoderma gangrenosum-like ulcers. At the same time, severity of joint involvement gradually decreased. After the characteristic phenotype of the disease had fully developed, suspicion of possible syndromic origin of symptoms arose. For this reason, genetic analysis was performed as requested by attending pediatricians at the University Clinical Center in Sarajevo, and E250Q mutation of the PSTPIP1 gene was detected. Thus, the diagnosis of PAPA syndrome was confirmed. Throughout the duration of the disease, several types of medication had been introduced in the treatment with varying success. Earliest joint symptoms were alleviated with non-steroidal anti-inflammatory drugs, while repeated courses of corticosteroids were the mainstay of the therapy during a decade-long period. As a consequence of prolonged steroid therapy, growth disorder, among various other side-effects, had been especially pronounced. Acting as a classic steroid-sparing immunosuppressive agent, methotrexate had also been part of the patient's treatment regimen. Lastly, biologics, including both TNF-α and IL-a inhibitors, had been separately administered as the remaining treatment options. However, adalimumab expressed a predominant effect on joint symptoms, whereas re-activation of previously undetected Hepatitis-B infection occurred during the subsequent therapy with anakinra. Due to this adverse reaction, anakinra treatment was discontinued. At the initial examination, the patient presented with multiple erythematous, partially excoriated papules and nodules, along with residual post-inflammatory hyperpigmented patches and scars on the skin of the whole back, chest, shoulders, and upper arms (Figure 1, Figure 2). The presence of postoperative scars on the elbows, resulting from previously performed surgical procedures of persistently affected joints with the goal of achieving pain relief and functional improvement, was also observed. Several smaller ulcers with undermined edges (Figure 3), as well as residual hyperpigmentation and cicatrices (Figure 4) were visible on the lower extremities. Additionally, the patient reported appearance of pustules and non-healing ulcers after minor trauma, which corresponds to the pathergy phenomenon, a common feature of PAPA syndrome. In contrast to the severity of cutaneous changes, the joint symptoms were mild. After thorough assessment of the patient's medical history and current condition, a multi-agent regimen was initiated, consisting of adalimumab, isotretinoin, and prednisone. Regular check-ups during the 12 months of treatment showed that the applied agents stabilized the patient's condition, alleviated more severe and acute skin changes, and slowed down further exacerbation of symptoms. Due to the rarity of PAPA syndrome, data on its treatment is scarce. Official guidelines are non-existing, and available information is based on case reports, case series, and a few smaller retrospective studies (5,7). In general, response to therapy remains inconsistent between patients, despite introduction of novel drugs. Furthermore, single treatment regimens are often not equally effective for all manifestations of the disease, which in a number of cases results in the administration of multi-agent treatment (2). As described in our case report, we opted for a multi-agent regimen not only due to specific individual role of each drug in the treatment of PAPA syndrome but also because of the possible augmented effect of combined therapy. Initially, a short course of systemic corticosteroid (prednisone 30 mg/day for 3 weeks) was introduced in order to alleviate acute symptoms until other agents started showing their effects. The initial dose of administered corticosteroid was gradually tapered by 5 mg every week and soon discontinued. Adalimumab (40 mg every 2 weeks for 12 months) was chosen since its previous administration was without significant adverse effects and with more acceptable end results, unlike therapy with anakinra (8). In addition, TNF-α inhibitors, such as adalimumab, etanercept, and infliximab, have been generally regarded as a more effective treatment option for cutaneous changes, while anakinra, an anti-IL-1 agent, has been more beneficial in alleviating joint symptoms (9-11). Since the skin of our patient was significantly more affected than the joints, adalimumab was a preferred option for biological treatment. Finally, isotretinoin (0.5 mg/kg/day for 6 months) also found a place in our multi-agent therapy plan as a specific, supportive treatment agent for acne (12). Due to the fact that our national health insurance system covered the costs of treatment with TNF-α inhibitors for only 12 months, adalimumab had to be discontinued after the end of this period. Episodes of acute exacerbation that the patient experienced after the cessation of multi-agent regimen were addressed with systemic corticosteroids and symptomatic therapy. Based on case reports, corticosteroids are usually one of the first agents to be administered in patients diagnosed with PAPA syndrome. They are frequently effective in alleviating joint symptoms, but, on the other hand, high doses of corticosteroids can worsen acne lesions (6). Moreover, due to the multiple side-effects of corticosteroids, such as electrolyte abnormalities, hypertension, hyperglycemia, osteoporosis, growth suppression, and adrenal insufficiency (13), a steroid-sparing agent is typically introduced into treatment together with or after corticosteroid therapy. A substantial step forward in the treatment of PAPA syndrome has been achieved with the introduction of medications targeting cytokines crucial in the pathogenesis of this disorder. The two most commonly used groups of such biological drugs have been those that block TNF-α and IL-1. A longer lasting improvement of symptoms has been achieved in a number of cases with both types of agents. Since other medications have often failed to establish long-term control of PAPA syndrome, such effects can be seen as a valuable accomplishment (6,14). Regardless of this observation, the response to treatment still differs between patients. More variable effects have been documented for IL-1 inhibitors, such as anakinra, while TNF-α inhibitors, such as adalimumab, infliximab, and etanercept, have been associated with more steady responses (4,6,10). The inconsistent effect of biologic therapies could be explained by the fact that PSTPIP1 protein is involved in various biochemical processes in different cells of the immune system. Thuse, none of the medications has an adequate spectrum of activity to control all involved immunological pathways (5,15). Overall, due to scarcity of valid information and guidelines, there is an increasing need for multicentric randomized controlled trials that would provide evidence-based data on effective treatment options for PAPA syndrome. Despite the rarity of this disorder, extensive research should be performed in order to discover therapies that could successfully manage all different manifestations of PAPA syndrome. Consequently, such efforts and breakthroughs would lead to decreased mortality and improved quality of life for patients suffering from this debilitating disease. The case described herein shows that PAPA syndrome can remain undiagnosed for longer periods of time, resulting in delayed treatment. Furthermore, the available therapeutic options are not sufficient to achieve long-term remission in many patients. Thus, continuous and comprehensive research is vital for ensuring adequate care of patients with PAPA syndrome.

Erythema Ab Igne with Histological Features of Keratosis Lichenoides Chronica.

Erythema ab igne (EAI) is a localized, hyperpigmented and reticulated dermatosis at sites of chronic heat exposure. Within longstanding skin lesions of EAI, hyperkeratotic lesions may emerge and can potentially transform into pre-malignant or malignant skin lesions. A 55-year-old woman presented for the evaluation of multiple hyperkeratotic lesions along with a reticular patterned hyperpigmentation on her right knee, an area that had repeated and prolonged exposure to a heat source over a period of several months. Based on her clinical history and the physical examination of her lesions, she was diagnosed as having a hyperkeratotic form of EAI. A skin biopsy was performed to rule out malignant alteration, but the histopathological findings were supportive of keratosis lichenoides chronica.

Sister Mary Joseph Nodule in an Ovary Adenocarcinoma.

INTRODUCTION: Sister Mary Joseph Nodule (SMJN) is a metastatic umbilical lesion secondary to a primary malignancy of any viscera, stomach and colon being most common in men, and ovary in women. CASE REPORT: In this article, we present the case of SMJN in a 54-year old female patient. An urgent diagnostic workup was performed with a computerized tomography of abdominal cavity and pelvis showing an expansive tumorous formation covering uterus with a carcinomatosis of peritoneum. After biopsy, immunohistochemical profile suggested adenocarcinoma of the ovarian origin. The patient was then referred to the Oncology Consilier of Gynecology Department and further continued followed by the Oncology team.

Distribution of Malassezia Species in Patients with Different Dermatological Disorders and Healthy Individuals.

There are differences with respect to the commonly isolated Malassezia species, not only between healthy individuals and the patients with various skin diseases, but also between different countries. We investigated the species composition of Malassezia microflora on the skin of patients with Malassezia-associated diseases and of healthy subjects (HS). Two hundred and fifty skin scrapings from patients with pityriasis versicolor (PV), seborrheic dermatitis (SD), atopic dermatitis (AD), psoriasis (PS), and healthy subjects (HS), fifty each, were inoculated into Sabouraud dextrose agar and into modified Dixon agar and identified using conventional culture-based methods. In PV and PS lesions, the most common species was M. globosa (62% and 52%, respectively), while M. restricta was predominant in SD lesions (28%). M. sympodialis was the most common species recovered from AD (52%) and healthy trunk skin (30%). Fewer cultures were positive for Malassezia growth in patients with AD than in patients with other skin conditions, and even in controls. Our data are in agreement with other studies and suggest that the pathogenic species of PV is M. globosa. The evidence that any given species is clinically important in the pathogenicity of SD, AD and PS is still lacking.

Malassezia species in healthy skin and in dermatological conditions.

The genus Malassezia comprises lipophilic species, the natural habitat of which is the skin of humans and other warm-blooded animals. However, these species have been associated with a diversity of dermatological disorders and even systemic infections. Pityriasis versicolor is the only cutaneous disease etiologically connected to Malassezia yeasts. In the other dermatoses, such as Malassezia folliculitis, seborrheic dermatitis, atopic dermatitis, and psoriasis, these yeasts have been suggested to play pathogenic roles either as direct agents of infection or as trigger factors because there is no evidence that the organisms invade the skin. Malassezia yeasts have been classified into at least 14 species, of which eight have been isolated from human skin, including Malassezia furfur, Malassezia pachydermatis, Malassezia sympodialis, Malassezia slooffiae, Malassezia globosa, Malassezia obtusa, Malassezia restricta, Malassezia dermatis, Malassezia japonica, and Malassezia yamatoensis. Distributions of Malassezia species in the healthy body and in skin diseases have been investigated using culture-based and molecular techniques, and variable results have been reported from different geographical regions. This article reviews and discusses the latest available data on the pathogenicity of Malassezia spp., their distributions in dermatological conditions and in healthy skin, discrepancies in the two methods of identification, and the susceptibility of Malassezia spp. to antifungals.

The Prevalence and Species Composition of Malassezia yeasts in Patients with Clinically Suspected Onychomycosis.

INTRODUCTION: There are limited numbers of studies which focused on the identification of Malassezia yeasts to a species level in onychomycosis. Therefore, the aim of our study was to determine the prevalence and species composition of Malassezia yeasts in patients with clinically suspected onychomycosis and to examine if the range of species varies with patient gender, age, site of involvement and clinical pattern of onychomycosis. METHODS: Specimens were taken from 785 patients presenting signs of onychomycosis and then incubated on Sabouraud dextrose agar and modified Dixon agar. The yeasts isolated were identified according to their macroscopic and microscopic features and physiological characteristics. RESULTS: Malassezia species were diagnosed both by microscopy and culture in fourteen (1.8%) patients. M. globosa was the predominant, if not only, species identified from nail samples. Mixed cultures were observed in five cases: in 4 cases Malassezia was co-isolated with Candida albicans and in one case with dermatophyte. Fingernails were affected more frequently than toenails (85.7%) and distolateral subungual onychomycosis was the most common clinical type (78.6%). CONCLUSION: No significant differences were found in the distribution of Malassezia species isolated according to demographic parameters.

Incidence and etiological agents of genital dermatophytosis in males.

AIM: To determine the incidence and etiological agents of dermatophytosis of male genitalia in Sarajevo area, Bosnia and Herzegovina, during a 5-year period (2009-2013). METHODS: A total of 313 male patients with confirmed dermatophyte infection elsewhere in the body was analyzed. All samples (skin scrapings and hairs) were treated with lactophenol to detect a possible presence of fungal elements and then cultured on Sabouraud glucose agar. Dermatophytes species were identified based on macroscopic and microscopic morphology. RESULTS: Dermatopyte infection of penis and/or scrotum was confirmed by positive cultures in 17 (5.4%) patients, of which four had lesions on the penis alone, five had lesions on scrotum and eight patients had lesions on both penis and scrotum. Majority of patients, 12 (70.0%) belonged to the age group 21-40. Fifteen patients (88.2%) had associated foci of dermatophyte infection, but the inguinal area was most frequently affected, in 10 (66.6%) patients. Microsporum canis was the most frequent dermatophyte found on culture, in 10 (58.8%) patients. CONCLUSION: Dermatophytosis of male genitalia is a rare entity, occurring more often in young males and the main causative species is Microsporum canis.

Aplasia Cutis Congenita in a Newborn Child Associated with Two Fetus Papyraceous.

Aplasia cutis congenita (ACC) is a rare inborn lesion, presenting with absence of skin. The etiology is unknown and is probably not attributable to a single cause but to a combination of genetic factors. Multiple causes have been suggested for ACC: syndromes and teratogens, intrauterine infection--varicella zoster virus, herpes simplex virus--fetal exposure to cocaine, heroin, alcohol, or antithyroid drugs. The most common site is the scalp. We report a case with multiple lesions on the trunk, resembling an instance with ACC group 5. This form of ACC occurs in association with the in utero death of a twin or more (in this case triple) fetus. Histological findings are available in very few reports. Therapy options depend on the characteristics of the lesion, but conservative treatment is usually chosen.

Distribution of Malassezia species on healthy human skin in Bosnia and Herzegovina: correlation with body part, age and gender.

BACKGROUND AND OBJECTIVES: The genus Malasezia currently includes fourteen species that have been isolated from healthy and diseased human and animal skin. However, there were differences with respect to the species most commonly isolated, not only in patients with various skin diseases but also between healthy individuals. The aim of this study was to analyze the prevalence of Malassezia species from clinically normal skin of the scalp and trunk of healthy individuals and to examine if the range of species varies according to body site, gender and age. MATERIALS AND METHODS: The study was conducted at the Department of Dermatovenerology, University Clinical Center in Sarajevo, Bosnia and Herzegovina from December 2012 to May 2013. One hundred healthy men and women with no skin diseases and aged from <1 to 82 years were studied. The samples were obtained by scraping the skin surface from the upper and middle part of trunk and from scalps of all subjects and then incubated on modified Dixon agar. The yeasts isolated were identified by their morphological and physiological properties according to Guillot et al. method. RESULTS: M. sympodialis was the predominant species on trunk skin in older subjects, M. restricta on scalp skin in age groups 21-35 years, while M. globosa was identified as common species in adults (36-50 years), both from scalp skin and trunk skin. From the trunk skin M. furfur was the most frequent in children. CONCLUSION: This study confirmed that cutaneous Malassezia microbiota in healthy subjects varies by body part and age but not by gender.