Aspergillosis in Critically Ill Patients with and Without COVID-19 in a Tertiary Hospital in Southern Brazil.

The impact of invasive pulmonary aspergillosis (IPA) on non-neutropenic critically ill patients in intensive care units (ICU) has been demonstrated in recent decades. Furthermore, after the start of the COVID-19 pandemic, COVID-19 associated with pulmonary aspergillosis (CAPA) has become a major concern in ICUs. However, epidemiological data from different regions are scarce. We evaluated the prevalence and clinical-epidemiological data of IPA in patients with COVID-19 requiring mechanical ventilation (MV) in the ICU ("severe COVID-19") and non-COVID ICU patients in MV of a tertiary hospital in the southern region of Brazil. Eighty-seven patients admitted between June 2020 and August 2022 were included; 31 with severe COVID-19. For the diagnosis of IPA or CAPA, algorithms including host factors and mycological criteria (positive culture for Aspergillus spp., immunoassay for galactomannan detection, and/or qPCR) were utilized. The overall incidence of IPA and CAPA in our ICU was 73 cases/1000 ICU hospitalizations. Aspergillosis occurred in 13% (4/31) of the COVID-19 patients, and in 16% (9/56) of the critically ill patients without COVID-19, with mortality rates of 75% (3/4) and 67% (6/9), respectively. Our results highlight the need for physicians enrolled in ICU care to be aware of aspergillosis and for more access of the patients to sensitive and robust diagnostic tests by biomarkers detection.

Sporothrix brasiliensis Causing Atypical Sporotrichosis in Brazil: A Systematic Review.

Zoonotic sporotrichosis, a subcutaneous mycosis caused by Sporothrix brasiliensis, has become hyperendemic and a serious public health issue in Brazil and an emerging disease throughout the world. Typical sporotrichosis is defined as fixed or lymphocutaneous lesion development, however, reports of atypical presentations have been described in hyperendemic areas, which may result in a worse prognosis. Thus, considering an increase in atypical cases and in more severe extracutaneous cases and hospitalizations reported in Brazil, we aimed to perform a systematic review to search for hypersensitivity reactions (HRs) and extracutaneous presentations associated with zoonotic sporotrichosis. A systematic review was performed, following the PRISMA guidelines to search for atypical/extracutaneous cases (mucosal, osteoarthritis, HRs, pulmonary, meningeal) of zoonotic sporotrichosis. A total of 791 published cases over 26 years (1998-2023) in eleven Brazilian states were reviewed. Most cases corresponded to a HR (47%; n = 370), followed by mucosal (32%; n = 256), multifocal (8%; n = 60), osteoarthritis (7%; n = 59), meningeal (4%; n = 32), and pulmonary (2%; n = 14) infections. When available (n = 607), the outcome was death in 7% (n = 43) of cases. Here, we show a frequent and worrisome scenario of zoonotic sporotrichosis in Brazil, with a high and dispersed incidence of atypical/extracutaneous cases throughout the Brazilian territory. Therefore, educational measures are necessary to make health professionals and the overall population aware of this fungal pathogen in Brazil as well as in other countries in the Americas.

Septic arthritis caused by Candida dubliniensis following arthroscopic surgery.

A 37-year-old immunocompetent man was admitted to the emergency department due to recurrent pain and oedema of his right knee. Two months earlier, he had undergone surgery to repair his meniscus. Arthroscopic joint lavage was performed and Candida dubliniensis was recovered in culture. The authors describe the first case of septic arthritis caused by Candida dubliniensis.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Screening with urine Histoplasma antigen test in asymptomatic patients starting TNF-alpha inhibitor therapy: a cohort study.

Background: Histoplasmosis is the second most frequent granulomatous disease in patients treated with tumor necrosis factor (TNF)-α inhibitors, second only to tuberculosis. However, there is limited information about pre-therapy screening procedures and the need for preventive treatments for patients who will start immunobiologicals. Methods: This is a cohort study that evaluated the prevalence of histoplasmosis in asymptomatic HIV-negative patients before initiation of TNF-α inhibitors by testing for Histoplasma antigen in urine samples. The patients included completed a 180-day follow-up after the initiation of the biologics to assess the onset of symptoms suggestive of histoplasmosis. Results: From January 2021 to December 2022, 54 patients who were prescribed a TNF-α inhibitor agent for treating autoimmune diseases in centers in southern Brazil were included. In the screening before therapy, the prevalence of a positive urinary Histoplasma antigen test was 14.8%. None of the 54 patients developed histoplasmosis after 6 months of immunobiological therapy, including the eight patients who tested positive. Conclusion: The prevalence of Histoplasma capsulatum infection in chronic patients may be higher than expected, but the impact of latent infection in asymptomatic patients is still uncertain, including those starting treatment with immunobiological drugs such as TNF-α inhibitors. Our study did not identify risk factors for the diagnosis of disseminated histoplasmosis in this group, including a positive result in an antigen test performed before immunobiological therapy. To date, there is no evidence to recommend routine antigen-based screening or preventive therapy for histoplasmosis before initiating a TNF-α inhibitor.

Using a urine test for fungal infection to screen people without symptoms who are about to start taking immunobiologic medications This study looked at the prevalence of histoplasmosis, a fungal infection, in asymptomatic patients who were about to start treatment with TNF-α inhibitors, which are medications used for autoimmune diseases. The researchers tested urine samples for Histoplasma antigen before the patients started the treatment and followed them for 180 days after starting the medication to see if they developed any symptoms of histoplasmosis. The study included 54 patients in southern Brazil, and they found that 14.8% of the patients tested positive for the Histoplasma antigen before starting the treatment. However, none of the patients, including those who tested positive, developed histoplasmosis during the 6-month follow-up. The researchers concluded that histoplasmosis infection may be more common in these patients than previously thought, but it's still not clear if asymptomatic patients with a positive antigen test will develop the infection when starting TNF-α inhibitor treatment. The study did not find any specific risk factors for developing histoplasmosis in this group of patients, and based on their findings, they did not recommend routine screening or preventive therapy for histoplasmosis before starting TNF-α inhibitor treatment.

Incidence of histoplasmosis in patients receiving TNF-alpha inhibitors: A systematic review and meta-analysis.

BACKGROUND: Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy. METHODS: This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate. RESULTS: We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies. CONCLUSION: The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.

Safety of Single High-Dose Liposomal Amphotericin B for Induction Treatment of Cryptococcal Meningitis and Histoplasmosis in People With HIV: A Systematic Review and Meta-analysis.

Background: Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. Methods: We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Results: Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Conclusions: Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

Cyanotic Raynaud's phenomenon induced by amphotericin B deoxycholate: A case report.

A 59-year-old male patient with chronic headache was admitted to the emergency department due to cryptococcal meningitis. His past medical history was marked by liver transplant 18 months prior to admission. Induction therapy with amphotericin B deoxycholate was initiated and the patient developed cyanotic Raynaud's phenomenon related to the infusion. The antifungal treatment was switched to liposomal amphotericin B, with complete resolution of the phenomenon.

The Current and Future States of Diagnostic Tests for Histoplasmosis with a Focus on People with HIV and Disseminated Histoplasmosis.

Histoplasmosis is caused by Histoplasma capsulatum and, although endemic in large parts of the world, is often underrecognized in many locations. In addition to underrecognition, inadequate availability of diagnostic tests is a major contributor to poor outcomes in disseminated disease in people with HIV. For those with advanced HIV and disseminated disease, antibody testing is less useful. Culture and histopathology can be useful in this situation, but each has limitations, including variable sensitivity by site and, in the case of culture, the need for a biosafety level three laboratory and a long period of growth. Antigen testing has proven useful for disseminated histoplasmosis due to the excellent sensitivity of urine. Yet, turnaround is slower than ideal due to use in a limited number of centers. The development of lateral flow assays has the potential to make for true rapid point-of-care assays for histoplasmosis, but in order to meet that promise, the tests must be widely available and affordable.

Cost-effectiveness evaluation of routine histoplasmosis screening among people living with advanced HIV disease in Latin America and the Caribbean.

Histoplasma antigen can be detected in people with advanced HIV disease (AHD), allowing for early and accurate diagnosis of histoplasmosis. The aim of this analysis was to assess the cost-effectiveness of routine histoplasmosis screening using antigen detection, among people with AHD. We developed a decision analytic model to evaluate Histoplasma antigen screening among people with AHD. The model estimated the costs, effectiveness, and cost-effectiveness of routine screening for Histoplasma antigen compared to the current practice of no routine Histoplasma antigen screening. The model includes stratification by symptoms of histoplasmosis, severity of presentation, and estimates of 30-day mortality. Data sources were taken from the Pan American Health Organization (PAHO) Strategic Fund databases on public purchases of medicines, and published literature on treatment outcomes. Outcome measures are life years saved (LYS), costs (US dollars), and incremental cost-effectiveness ratios (ICERs). Routine Histoplasma antigen screening avoids an estimated 17% of deaths in persons with advanced HIV disease, and is cost-effective compared to no histoplasmosis screening, with an ICER of $26/LYS. In sensitivity analysis assuming treatment for histoplasmosis with liposomal amphotericin, Histoplasma antigen screening remains cost-effective with an ICER of $607/LYS. Histoplasma antigen screening among people with AHD is a cost-effective strategy and could potentially avert 17% of AIDS-related deaths. Prospective evaluation of histoplasmosis screening is warranted to determine effectiveness and treatment outcomes with this strategy.

Imaging Findings in Aspergillosis: From Head to Toe.

Aspergillosis is a mycotic infection induced by airborne fungi that are ubiquitous. Inhalation of Aspergillus conidia results in transmission through the respiratory tract. The clinical presentation is dependent on organism and host specifics, with immunodeficiency, allergies, and preexisting pulmonary disease constituting the most important risk factors. In recent decades, the incidence of fungal infections has increased dramatically, due in part to the increased number of transplants and the pervasive use of chemotherapy and immunosuppressive drugs. The spectrum of clinical manifestations can range from an asymptomatic or mild infection to a swiftly progressive, life-threatening illness. Additionally, invasive infections can migrate to extrapulmonary sites, causing infections in distant organs. Recognition and familiarity with the various radiological findings in the appropriate clinical context are essential for patient management and the prompt initiation of life-saving treatment. We discuss the radiological characteristics of chronic and invasive pulmonary aspergillosis, as well as some of the typically unexpected extrapulmonary manifestations of disseminated disease.

COVID-19 PCR: frequency of internal control inhibition in clinical practice.

Introduction: Diagnosis of COVID-19 (coronavirus disease 2019) is best performed with real-time (quantitative) PCR (qPCR), the most sensitive method for detection and quantification of viral RNA. Using the Centers for Disease Control and Prevention (CDC) protocol, for each sample tested for the virus, three qPCR tests are performed, targeting the viral genes N1 and N2, in addition to the internal control gene RNase P. Samples in which internal control fails to amplify should be labelled 'invalid'. Methods: This study aims to determine the frequency of inhibition of the RNase P gene used as an internal control in qPCR tests for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in a reference hospital in Southern Brazil during the COVID-19 pandemic (1 February 2021 to 31 March 2021). Results: A total 10, 311 samples were available for analysis. The mean cycle threshold (Ct) value for the RNAse P gene was 26.65 and the standard deviation was 3.18. A total of 252 samples were inhibited (2.4%) during the study period: amongst these, 77 (30.5%) showed late amplifications (beyond 2 standard deviations from the mean Ct value), and 175 (69.4%) revealed no fluorescence at all for the RNase P gene. Conclusions: This study showed a low percentage of inhibition using RNase P as an internal control in COVID-19 PCRs using the CDC protocol, thus proving the effectiveness of this protocol for identification of SARS-CoV-2 in clinical samples. Re-extraction was efficacious for samples that showed little or no fluorescence for the RNase P gene.

Single High Dose of Liposomal Amphotericin B in Human Immunodeficiency Virus/AIDS-Related Disseminated Histoplasmosis: A Randomized Trial.

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

A contemporary investigation of burden and natural history of aspergillosis in people living with HIV/AIDS.

BACKGROUND: Untreated HIV infection can lead to profound immunosuppression and increase susceptibility of people living with HIV/AIDS (PLHA) to aspergillosis. OBJECTIVES: Reporting the burden and natural history of aspergillosis documented in PLHA admitted in five medical centres in Brazil. PATIENTS AND METHODS: Clinical, epidemiological and laboratory data were collected in all sequential cases of proven or probable aspergillosis documented in PLHA hospitalised in five medical centres between 2012 and 2020. RESULTS: We enrolled 25 patients ageing between 23 and 58 years (mean = 39) including 11 patients with invasive aspergillosis (IA) and 14 with chronic pulmonary aspergillosis (CPA). The prevalence rate of aspergillosis was 0.1% of 19.616 PLHA. Overall, 72.7% of patients with IA exhibited CD4 < 100 cells/mL and 42.8% of patients with CPA exhibited CD4 count >200 cells/mL. Most patients had a history of tuberculosis, especially those with CPA (85.7%). IA was documented after a mean of 16.5 days of hospitalisation, mainly in critically ill patients exposed to corticosteroids and broad-spectrum antibiotics. In the CPA group, a positive culture (71.4%) and radiological alterations were the most frequent findings supporting their diagnosis. Episodes of IA were mostly documented by tissue biopsies. Crude mortality rates were 72.7% and 42.8% in patients with IA and CPA, respectively. CONCLUSIONS: Despite being considered an unusual complication in PLHA (0.1%), IA should be considered in patients with profound immunosuppression and pneumonia refractory to conventional therapy. CPA should be investigated in PLHA with chronic deterioration of pulmonary function and previous diagnosis of tuberculosis.

Optimization of a commercial Histoplasma galactomannan EIA test in a population from an endemic area of histoplasmosis in southern Brazil.

BACKGROUND: Since 2020 the World Health Organization (WHO) recommends Histoplasma antigen detection for the diagnosis of disseminated histoplasmosis (DH) in people living with HIV (PLHIV). OBJECTIVE: Here we aimed to optimise the IMMY's Clarus® Histoplasma GM enzyme immunoassay (EIA), evaluating the best cut-off in the semi-quantitative (SQ-HGM EIA), also known as 'calibrator cut-off procedure'. METHODS: The optimization was done using the quantitative standard procedure (Q-HGM EIA), also known as 'standard curve procedure', as reference test. A retrospective study from an endemic area of DH in southern Brazil was carried out including 264 patients investigated for DH using the test. Receiver Operator Characteristic curve was plotted, and sensitivity and specificity of the SQ-HGM EIA were calculated. RESULTS: The study included 24 positive (values ≥ 0.20 ng/ml) and 240 negative patients by the Q-HGM EIA. According to the manufacturer SQ-HGM EIA protocol, the new SQ-HGM EIA cut-off of 0.8 EIA units was validated, resulting in sensitivity and specificity of 88% and 98.7%, respectively. CONCLUSION: Our study pioneers and brings important data about the optimization of the Histoplasma antigen testing for the diagnosis of DH in a population from Southern Brazil. This optimization also reduced the amount of reagents used, lowering the cost associated with testing.

Dynamics of nosocomial SARS-CoV-2 transmissions: Facing the challenge of variants of concern in a Brazilian reference hospital.

The hospital environment can be considered a high risk for the occurrence of SARS-CoV-2 transmission outbreaks, either for health professionals who are directly involved in the care of suspected or confirmed cases of the disease, or for patients, for being in an environment more vulnerable to the acquisition of nosocomial infections. In this molecular epidemiology study, we aimed to analyze the occurrence and transmission dynamics of SARS-CoV-2 in outbreaks and local chains of transmission in a large tertiary teaching hospital in southern Brazil, in addition to verifying circulating strains and their epidemiological relation in the local context, from September 21, 2020 to October 5, 2021. Positive samples involved in COVID-19 clusters or outbreaks were analyzed using clinical, epidemiological and genomic data. Different lineages and sublineages among patients in the same room were observed. Most patients had their first clinical manifestation, evidence of suspicion, and diagnostic confirmation within 7-14 days or >14 days after hospital admission. The patients who have contact with confirmed cases of COVID-19 spent, on average, 6.28 days in the same environment until the positive test. There was a significant association between the outcome and the number of vaccine doses (p < 0.05), where those who received two doses presented a lower occurrence of death. There was a total replacement of variant of concern (VOC) Gamma by VOC Delta from August 2021 at the study site. Although the epidemiological analysis indicates nosocomial infections, through genomic sequencing, it was established that most of the hospital outbreaks had different origins. These findings highlight the utility of integrating epidemiological and genomic data to identify possible routes of viral entry and dissemination.

Invasive Aspergillosis in Patients with Acute Leukemia: Comparison Between Acute Myeloid and Acute Lymphoid Leukemia.

BACKGROUND: The epidemiology of invasive aspergillosis (IA) in patients with acute lymphoid leukemia (ALL) has not been well characterized. OBJECTIVES: To identify potential peculiarities in the natural history, treatment response and outcome of IA diagnosed in patients with ALL and AML. METHODS: This is a retrospective cohort study conducted in seven tertiary-care hospitals between 2009 and 2017 of all consecutive episodes of IA occurring in adult patients with acute leukemia. Demographic characteristics, underlying disease and recent treatment, antifungal prophylaxis, neutropenia, receipt of corticosteroids, clinical and radiological findings, mycological results, antifungal therapy, and 6-week and 12-week survival were recorded. RESULTS: We identified 77 cases of IA in 54 patients with AML and 23 patients with ALL. The majority of patients developed IA in the context of induction chemotherapy for newly diagnosed (48.0%) or relapsed (41.6%) leukemia, with no differences between ALL and AML. Lung involvement was more frequent in AML (96.3% vs. 82.6%, p = 0.06) and rhinosinusitis was more common in ALL (43.5% vs. 24.1%, p = 0.09). Galactomannan was the microbiologic documentation of IA in 76.6%, with similar patterns of positivity in AML and ALL. The 6-week survival of IA in patients with AML and ALL was 63.0% and 56.5%, respectively (p = 0.60). CONCLUSIONS: The epidemiology, clinical presentation, diagnosis and outcome of IA in ALL patients are similar to patients with AML.

Chest Imaging in Systemic Endemic Mycoses.

Endemic fungal infections are responsible for high rates of morbidity and mortality in certain regions of the world. The diagnosis and management remain a challenge, and the reason could be explained by the lack of disease awareness, variability of symptoms, and insidious and often overlooked clinical presentation. Imaging findings are nonspecific and frequently misinterpreted as other more common infectious or malignant diseases. Patient demographics and clinical and travel history are important clues that may lead to a proper diagnosis. The purpose of this paper is to review the presentation and differential diagnosis of endemic mycoses based on the most common chest imaging findings.

Endemic Mycoses: Novel Findings for the Clinician.

Endemic mycoses are difficult-to-diagnose conditions that may mimic several other diseases, particularly tuberculosis, community-acquired pneumonia, and cancer [...].