Clinical and immunological features of laryngeal cryptococcosis.

The literature holds few descriptions on immune response findings for laryngeal cryptococcosis. Immunology has been more extensively described in cases involving the central nervous system and the lungs, although many of these studies were conducted in animal models. We aimed to analyze the clinical and immunological characteristics of three patients with laryngeal cryptococcosis. We observed a weak participation of the innate immune response, whereas adaptive immunity showed the predominance of a Th2-type response over a Th1-type response. Most cases occur in male older adults with immunosuppressive conditions, of which HIV infection was absent. Hoarseness configured the main symptom. We found a disease that was restricted to the larynx and possibly the lungs by contiguity. Patients with hoarseness and lesions in nasal endoscopy should be investigated for cryptococcosis by a biopsy of the larynx, including with negative serum cryptococcal antigen. The immunological aspects of our findings of laryngeal involvement resembled those in the most commonly affected systems.

A multicentre study of amphotericin B treatment for histoplasmosis: assessing mortality rates and adverse events.

BACKGROUND: Progressive disseminated histoplasmosis is a significant issue in Latin America, particularly in Brazil, contributing to high mortality rates. OBJECTIVES: Our objectives were to comprehensively describe histoplasmosis treatment with various amphotericin B (AmB) formulations, including mortality rates, adverse effects and risk factors for mortality. METHODS: This multicentre retrospective cohort study (January 2014-December 2019) evaluated medical records of patients with proven or probable histoplasmosis treated with at least two doses of AmB in seven tertiary medical centres in Brazil. We assessed risk factors associated with death during hospitalization using univariate and multivariate analyses. RESULTS: The study included 215 patients, mostly male (n = 158, 73%) with HIV infection (n = 187, 87%), and a median age of 40 years. Only 11 (5%) patients initiated treatment with liposomal amphotericin B (L-AmB). Amphotericin B deoxycholate (D-AmB) was administered to 159 (74%) patients without changes in the treatment. The overall mortality during hospitalization was 23% (50/215). Variables independently associated with mortality were use of D-AmB (OR 4.93) and hospitalization in ICU (OR 9.46). There was a high incidence of anaemia (n = 19, 90%), acute kidney injury (n = 96, 59%), hypokalaemia (n = 73, 55%) and infusion reactions (n = 44, 20%) during treatment. CONCLUSIONS: We found that D-AmB was the main formulation, which was also associated with a higher mortality rate. Lipid formulations of AmB have become more readily available in the public health system in Brazil. Further studies to evaluate the effectiveness of L-AmB will likely show improvements in the treatment outcomes for patients with disseminated histoplasmosis.

Association between neuroimaging and clinical outcomes in individuals with central nervous system cryptococcosis.

BACKGROUND: The radiological manifestations of central nervous system (CNS) cryptococcosis are diverse and often subtle. There is heterogeneity on how different neuroimaging patterns impact prognosis. This study aims to assess the association between the neuroimaging and clinical outcomes of CNS cryptococcosis. METHODS: All patients with CNS cryptococcosis between July 2017 and April 2023 who underwent brain magnetic resonance imaging (MRI) were included. The primary outcome was mortality during hospitalisation. Secondary outcomes were readmission, ventricular shunting, duration of hospitalisation and time to the first negative cerebrospinal fluid culture. We compared the outcomes for each of the five main radiological findings on the brain MRI scan. RESULTS: We included 46 proven CNS cryptococcosis cases. The two main comorbidity groups were HIV infection (20, 43%) and solid organ transplantation (10, 22%), respectively. Thirty-nine patients exhibited at least one radiological abnormality (85%), with the most common being meningeal enhancement (34, 74%). The mortality rates occurred at 11% (5/46) during hospitalisation. We found no significant disparities in mortality related to distinct radiological patterns. The presence of pseudocysts was significantly associated with the need for readmission (p = .027). The ventricular shunting was significantly associated with the presence of pseudocysts (p = .005) and hydrocephalus (p = .044). CONCLUSION: In this study, there is no association between brain MRI findings and mortality. Larger studies are needed to evaluate this important issue.

Histoplasmosis in a fingolimod-treated patient: case report and scoping review.

Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.

Paracoccidioidomycosis after eyebrow micropigmentation: Unusual reactivation or a new form of transmission by cutaneous inoculation?

We report a case of unusual paracoccidioidomycosis reactivation after eyebrow micropigmentation in a Brazilian patient. The cutaneous lesion was the only clinical manifestation. Direct cutaneous inoculation in dermal tissues with Paracoccidioides sp. is extremely rare, explaining why paracoccidioidomycosis is not classically considered a cutaneous implantation mycosis.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study.

PURPOSE: Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. METHODS: This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. FINDINGS: Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. IMPLICATIONS: ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Clinical characteristics, diagnosis, and treatment of central nervous system sporotrichosis: Systematic review and meta-analysis.

BACKGROUND: The clinical features of central nervous system (CNS) sporotrichosis are derived from case reports and a limited series of cases. Our objective was to carry out a systematic review and meta-analysis of CNS sporotrichosis. METHODS: We searched PubMed/MEDLINE, Embase, Scopus, and LILACS on 9 September 2023. Our inclusion criteria were documentation of Sporothrix and demonstrated CNS involvement. A metaproportion or metamean analysis was performed to estimate a summary proportion with 95% confidence intervals. RESULTS: We included 52 cases of CNS sporotrichosis published from 1966 to 2023. Forty-six patients were male (88%, 95% CI: 77-95), and the mean age was 39 years (95% CI: 36-43). Close contact with cats was reported in 55% of cases (95% CI: 37-72). Thirty-two (61.5%) patients were from Brazil, 18 patients from the United State of America (34.6%). Only two Sporothrix species were reported: S. schenckii (26/41, 63%), and S. brasiliensis (15/41, 37%). The most common neurological symptom was headache. Meningitis was chronic in approximately 80% of cases. A significant majority of the patients were immunocompromised. HIV infection was the primary cause of immunosuppression (85%, 95% CI: 61-95). Overall mortality was 56% (22/39). The comparison of Kaplan-Meier survival curve showed a higher mortality with a statistically significant difference in immunosuppressed patients (p = .019). CONCLUSION: CNS sporotrichosis represents a notable cause of chronic meningitis, especially in individuals living in the Americas with HIV infection and concurrent skin lesions.

Histoplasmosis in a fingolimod-treated patient: case report and scoping review

ABSTRACT Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.

Clinical and immunological features of laryngeal cryptococcosis

ABSTRACT The literature holds few descriptions on immune response findings for laryngeal cryptococcosis. Immunology has been more extensively described in cases involving the central nervous system and the lungs, although many of these studies were conducted in animal models. We aimed to analyze the clinical and immunological characteristics of three patients with laryngeal cryptococcosis. We observed a weak participation of the innate immune response, whereas adaptive immunity showed the predominance of a Th2-type response over a Th1-type response. Most cases occur in male older adults with immunosuppressive conditions, of which HIV infection was absent. Hoarseness configured the main symptom. We found a disease that was restricted to the larynx and possibly the lungs by contiguity. Patients with hoarseness and lesions in nasal endoscopy should be investigated for cryptococcosis by a biopsy of the larynx, including with negative serum cryptococcal antigen. The immunological aspects of our findings of laryngeal involvement resembled those in the most commonly affected systems.

Cutaneous Naganishia albida (Cryptococcus albidus) infection: a case report and literature review.

Naganishia albida (Cryptococcus albidus) is considered saprophytic fungi, and is rarely reported as a human pathogen. Cutaneous infections caused by non-neoformans cryptococcus are rare. We describe a case of an immunocompetent older male with cutaneous cryptococcosis caused by Naganishia albida following skin trauma, and conduct a literature review in PubMed, Lilacs, and Embase. Only six previous similar reports were found. The seven cases (including ours) were widely distributed geographically (Brazil, the US, the UK, Hungary, South Korea, and Iran), all males, and their ages varied, ranging from 14 to 86 years. Four individuals had underlying skin diseases (Sezary Syndrome, psoriasis, and skin rash without etiology) plus potentially immunosuppressive underlying conditions (diabetes mellitus, kidney transplantation, and the use of etanercept, adalimumab, and methylprednisolone). Cutaneous presentation was polymorphic, with lesions characterized as warts, ulcers, plaques, and even macules. Two patients presented disseminated disease. Serum cryptococcal antigen was negative in six patients, and diagnosis was made by fungal culture in all. There is a lack of data on optimal antifungal treatment and outcomes.

Itraconazole Serum Trough Concentrations Using Oral Capsules for the Treatment of Chronic Pulmonary Aspergillosis: What is the Target?

BACKGROUND: In regions where there is only itraconazole capsule as a therapeutic option for treatment of chronic pulmonary aspergillosis (CPA), measuring the serum concentrations becomes even more important for therapeutic success. OBJECTIVE: Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. METHODS: The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200 mg capsule every 12 h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1-4 mg/L. RESULTS: This study recruited 28 patients. The median value was 0.30 mg/L (IQR 0.01-0.70). Only 11% (n = 3) had adequate serum concentrations based on guideline recommendation. All patients with clinical deterioration had itraconazole serum levels ≤ 0.8 mg/L. CONCLUSION: The initial serum concentrations of itraconazole after capsule formulation administration were low. Increasing the dose should be considered when the itraconazole concentration is low, especially if it is ≤ 0.8 mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA.

Systematic review and meta-analysis of galactomannan antigen testing in serum and bronchoalveolar lavage for the diagnosis of chronic pulmonary aspergillosis: defining a cutoff.

BACKGROUND: A clear cutoff value of galactomannan (GM) has not been established for chronic pulmonary aspergillosis (CPA) and is frequently extrapolated from invasive pulmonary aspergillosis. We performed a systematic review and meta-analysis to evaluate the diagnostic performance of serum and bronchoalveolar lavage (BAL) GM, and to propose a cutoff. METHODS: We extracted from the studies the cutoff of serum or/and BAL GM associated with true positives, false positives, true negatives, and false negatives. We performed a multi-cutoff model and a non-parametric random effect model. We estimated the optimal cutoff and the area under the curve (AUC) for GM in serum and BAL samples. RESULTS: Nine studies from 1999 to 2021 were included. Overall, the optimal cutoff of serum GM was 0.96 with a sensitivity of 0.29 (95%CI: 0.14-0.51); specificity of 0.88 (95%CI: 0.73-0.95); and AUC of 0.529 (with a CI: [0.415-0.682] [0.307-0.713]). The AUC for the non-parametric ROC model was 0.631. For BAL GM the cutoff was 0.67 with a sensitivity of 0.68 (95%CI: 0.51-0.82), specificity of 0.84 (95%CI: 0.70-0.92), and AUC of 0.814 (with a CI: [0.696-0.895] [0.733-0.881]). The AUC for the non-parametric model was 0.789. CONCLUSION: The diagnosis of CPA requires the assessment of a combination of mycological and serological factors, as no single serum and/or BAL GM antigen test is adequate. BAL GM performed better than serum, with better sensitivity and excellent accuracy.

Characteristics, mortality, associated variables with death, and therapeutic response among HIV-positive, solid organ transplant (SOT), and non-HIV-positive/non-transplant (NHNT) patients with cryptococcosis: First multicenter cohort study in Brazil.

Cryptococcosis is traditionally associated with immunocompromised patients but is increasingly being identified in those without the human immunodeficiency virus (HIV) or other immunocompetent individuals. We aim to describe the characteristics, mortality, and associated variables with death among hospitalized patients with cryptococcosis in Brazil. This is the first multicenter retrospective cohort study conducted in seven public tertiary Brazilian hospitals. A total of 384 patients were included; the median age was 39 years and 283 (73.7%) were men. In all, 304 HIV-positive were hosts (79.2%), 16 (4.2%) solid organ transplant (SOT), and 64 (16.7%) non-HIV-positive/non-transplant (NHNT). Central nervous system (CNS) cryptococcosis had a significantly higher number across disease categories, with 313 cases (81.5%). A total of 271 (70.6%) patients were discharged and 113 (29.4%) died during hospitalization. In-hospital mortality among HIV-positive, SOT, and NHNT was 30.3% (92/304), 12.5% (2/16), and 29.7% (19/64), respectively. Induction therapy with conventional amphotericin B (AMB) mainly in combination with fluconazole (234; 84.2%) was the most used. Only 80 (22.3%) patients received an AMB lipid formulation: liposomal (n = 35) and lipid complex (n = 45). Most patients who died belong to the CNS cryptococcosis category (83/113; 73.4%) when compared with the others (P = .017). Multivariate analysis showed that age and disseminated cryptococcosis had a higher risk of death (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05; P = .008 and OR, 1.84; 95% CI, 1.01-3.53; P = .048, respectively). Understanding the epidemiology of cryptococcosis in our settings will help to recognize the burden and causes of mortality and identify strategies to improve this scenario.

This multicenter cohort study included 384 hospitalized individuals with cryptococcosis in Brazil. Most individuals were men (74%), HIV-positive (79%), had central nervous system involvement (82%), and received conventional amphotericin plus fluconazole (84%). In-hospital mortality was high (29%).

Cutaneous Naganishia albida (Cryptococcus albidus) infection: a case report and literature review

ABSTRACT Naganishia albida (Cryptococcus albidus) is considered saprophytic fungi, and is rarely reported as a human pathogen. Cutaneous infections caused by non-neoformans cryptococcus are rare. We describe a case of an immunocompetent older male with cutaneous cryptococcosis caused by Naganishia albida following skin trauma, and conduct a literature review in PubMed, Lilacs, and Embase. Only six previous similar reports were found. The seven cases (including ours) were widely distributed geographically (Brazil, the US, the UK, Hungary, South Korea, and Iran), all males, and their ages varied, ranging from 14 to 86 years. Four individuals had underlying skin diseases (Sezary Syndrome, psoriasis, and skin rash without etiology) plus potentially immunosuppressive underlying conditions (diabetes mellitus, kidney transplantation, and the use of etanercept, adalimumab, and methylprednisolone). Cutaneous presentation was polymorphic, with lesions characterized as warts, ulcers, plaques, and even macules. Two patients presented disseminated disease. Serum cryptococcal antigen was negative in six patients, and diagnosis was made by fungal culture in all. There is a lack of data on optimal antifungal treatment and outcomes.

Understanding Sabiá virus infections (Brazilian mammarenavirus).

BACKGROUND: Only two naturally occurring human Sabiá virus (SABV) infections have been reported, and those occurred over 20 years ago. METHODS: We diagnosed two new cases of SABV infection using metagenomics in patients thought to have severe yellow fever and described new features of histopathological findings. RESULTS: We characterized clinical manifestations, histopathology and analyzed possible nosocomial transmission. Patients presented with hepatitis, bleeding, neurological alterations and died. We traced twenty-nine hospital contacts and evaluated them clinically and by RT-PCR and neutralizing antibodies. Autopsies uncovered unique features on electron microscopy, such as hepatocyte "pinewood knot" lesions. Although previous reports with similar New-World arenavirus had nosocomial transmission, our data did not find any case in contact tracing. CONCLUSIONS: Although an apparent by rare, Brazilian mammarenavirus infection is an etiology for acute hemorrhagic fever syndrome. The two fatal cases had peculiar histopathological findings not previously described. The virological diagnosis was possible only by contemporary techniques such as metagenomic assays. We found no subsequent infections when we used serological and molecular tests to evaluate close contacts.

A Case-Control Study of Paracoccidioidomycosis in Women: The Hormonal Protection Revisited.

Clinical observations have long suggested that women are protected against paracoccidioidomycosis. 17ß-estradiol, the main female estrogen, inhibits conidia-to-yeast transformation (C-to-Y), which is required for the infection establishment. However, experiments in murine models have yielded conflicting results, suggesting that C-to-Y inhibition, alone, fails to explain the female-associated protection and that sexual hormones may also act by modulating the host's immune responses. Therefore, this issue remains unsolved. Strikingly, no studies have compared the severity of paracoccidioidomycosis between men and women. This retrospective case-control study compared 36 women with 72 age-matched men for clinical-demographic, laboratory, and chest imaging findings. Overall, paracoccidioidomycosis in women presented the main features described in the acute/subacute and chronic forms seen in men. Women also showed similar demographic features and clinical-laboratory and imaging severity scores as men. We additionally reviewed 58 paracoccidioidin skin test surveys undertaken by volunteers from endemic areas. Data accumulated from 10.873 tests showed that females and males are infected with similar magnitudes (21.9% vs. 25.2%) and that reactivity steadily increased with age, peaking after the age of 60. We discuss the paradox of similar infection rates but much lower disease prevalence in women, considering the current pathogenetic views of paracoccidioidomycosis, and we raise alternative hypotheses to account for this paradox.