American Society for Transplantation and Cellular Therapy Series, #6: Management of Invasive Candidiasis in Hematopoietic Cell Transplantation Recipients.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transplant Infectious Disease Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and then answered FAQs and finalized topics with harmonized recommendations made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This sixth guideline in the series focuses on invasive candidiasis (IC) with FAQs to address epidemiology, clinical diagnosis, prophylaxis, and treatment of IC, plus special considerations for pediatric, cord blood, haploidentical, and T cell-depleted HCT recipients and chimeric antigen receptor T cell recipients, as well as future research directions.

Invasive candidiasis in a Brazilian neonatal intensive care unit / Candidíase invasiva em uma Unidade de Terapia Intensiva Neonatal brasileira

Abstract Objectives: to describe the epidemiology of invasive candidiasis in a neonatal intensive care unit. Methods: cross-sectional study that included all neonates with invasive candidiasis confirmed by blood culture from April 2015 to June 2018. Demographic, clinical and microbiological data were analyzed, comparing neonates with extreme low birth weight (ELBW) with neonates ≥ 1000g birth weight, considering a p <0.05 as statistically significant. Results: there were 38 cases of invasive candidiasis, resulting in an overall incidence of 2.5%. Twelve (32%) were ELBW neonates and 26 (68%) neonates ≥ 1000g birth weight, an incidence of 4.4% and 2.0%, respectively. Abdominal surgery was more frequent among neonates with birth weight ≥ 1000g compared to ELBW neonates (85% vs. 17%; p <0.01), as well as the median in days of antibiotics use (18 vs. 10.5; p = 0.04). The median in days of mechanical ventilation was more frequent among ELBW neonates (10 vs. 5.5; p = 0.04). The majority of Candida species were non-albicans (64%). Fatality rate was 32%. Conclusions: the incidence of invasive candidiasis among neonates with birth weight ≥ 1000g was higher than that found in the literature. This group has a higher proportion of gastrointestinal malformations that require surgery. Thus, fluconazole prophylaxis may be necessary for a broader group of neonates.

Resumo Objetivos: descrever a epidemiologia de candidíase invasiva em uma unidade de terapia intensiva neonatal. Métodos: estudo transversal que incluiu todos recém-nascidos com candidíase invasiva confirmada por hemocultura de abril de 2015 a junho de 2018. Foi analisado dados demográficos, clínicos e microbiológicos, comparando recém-nascidos de extremo baixo peso ao nascer (EBPN) com os recém-nascidos com peso ao nascer ≥1000g, considerando um valor de p<0,05 como estatisticamente significativo. Resultados: houve 38 casos de candidíase invasiva, resultando em uma incidência global de 2,5%. Doze (32%) eram neonatos de EBPN e 26 (68%) neonatos com peso ao nascer ≥1000g, resultando em uma incidência de 4,4% e 2,0%, respectivamente. A realização de cirurgia abdominal foi mais frequente nos neonatos com peso ao nascer ≥1000g em comparação com os neonatos de EBPN (85% vs. 17%; p<0,01), assim como a mediana dos dias de uso de antibióticos (18 vs. 10,5; p =0,04). Já o a mediana dos dias de ventilação mecânica foi mais frequente entre recém-nascido de EBPN (10 vs. 5,5; p = 0,04). A maioria das espécies de Candida eram não-albicans (64%). A letalidade foi de 32%. Conclusões: a incidência de candidíase invasiva entre os recém-nascidos ≥1000g ao nascer foi superior ao encontrado na literatura. Este grupo tem uma maior proporção de malformações gastrointestinais que requerem cirurgia. Assim, a profilaxia com fluconazol pode ser necessária para um grupo mais amplo de recém-nascidos.

[Invasive fungal infections in ICU patients - What's New?] / Invasive Pilzinfektionen bei Intensivpatienten ­ Was gibt es Neues?

Invasive fungal infections are gaining increasing importance in intensive care medicine. The aim of this article is to present an update on recent developments in the field of invasive fungal infection in critically ill patients. Particular emphasis is placed on the recently described invasive mold infections in patients with acute respiratory distress syndrome due to influenza or COVID-19. Detecting high-risk patients and the optimal diagnostic and therapeutic strategies play a decisive role to improve outcome.

Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been sweeping across the globe. Based on a retrospective analysis of SARS and influenza data from China and worldwide, we surmise that the fungal co-infections associated with global COVID-19 might be missed or misdiagnosed. Although there are few publications, COVID-19 patients, especially severely ill or immunocompromised, have a higher probability of suffering from invasive mycoses. Aspergillus and Candida infections in COVID-19 patients will require early detection by a comprehensive diagnostic intervention (histopathology, direct microscopic examination, culture, (1,3)-ß-D-glucan, galactomannan, and PCR-based assays) to ensure effective treatments. We suggest it is prudent to assess the risk factors, the types of invasive mycosis, the strengths and limitations of diagnostic methods, clinical settings, and the need for standard or individualized treatment in COVID-19 patients. We provide a clinical flow diagram to assist the clinicians and laboratory experts in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as co-morbidities in COVID-19 patients.

Clinicians' challenges in managing patients with invasive fungal diseases in seven Asian countries: An Asia Fungal Working Group (AFWG) Survey.

BACKGROUND: Invasive fungal diseases (IFD) are a serious threat, but physicians in Asia lack access to many advanced diagnostics in mycology. It is likely that they face other impediments in the management of IFD. A gap analysis was performed to understand the challenges Asian physicians faced in medical mycology. METHODS: The Asia Fungal Working Group (AFWG) conducted a web-based survey on management practices for IFD among clinicians in China, India, Indonesia, Philippines, Singapore, Taiwan and Thailand. FINDINGS: Among 292 respondents, 51.7% were infectious disease (ID) specialists. Only 37% of respondents had received formal training in medical mycology. They handled only around 2-4 proven cases of each fungal infection monthly, with invasive candidiasis the most common. For laboratory support, the majority had access to direct microscopy (96%) and histopathology (87%), but galactomannan and azole levels were available to 60% and 25% of respondents, respectively. The majority (84%) used clinical parameters for treatment response monitoring, and 77% followed the Infectious Diseases Society of America guidelines. The majority (84%) did not use the services of an ID physician. Where febrile neutropenia was concerned, 74% of respondents used the empirical approach. Only 30% had an antifungal stewardship program in their hospital. Eighty percent could not use preferred antifungals because of cost. INTERPRETATION: The survey identified inadequacies in medical mycology training, non-culture diagnostics, access to antifungal drugs, and local guidelines as the major gaps in the management of IFDs in Asian countries. These gaps are targets for improvement.

The Economic Burden of Candidemia and Invasive Candidiasis: A Systematic Review.

BACKGROUND: Candidemia or invasive candidiasis (IC) is an increasingly common fungal infection and has been associated with high mortality, particularly among the immunocompromised and critically ill. Although several studies have been conducted to estimate the cost of managing candidemia and IC, quality assessment on the methodological aspects of these cost studies was not performed. To date, no systematic review focusing on the economic burden of candidemia and IC has ever been conducted. OBJECTIVES: The aim of this study was to systematically review the available evidence on the economic burden of candidemia and IC worldwide. METHODS: Databases (ie, PubMed, Scopus, EconLit, HEORO, and Ovid/Embase) were searched through June 2018. Two researchers independently assessed the quality of the eligible studies. Costs reported in the included studies were converted to 2016 USD using Campbell and Cochrane Economics Methods Group-the Evidence for Policy and Practice Information (CCEMG-EPPI)-Centre Cost Converter software. RESULTS: Eight articles were included in this systematic review. The mean total cost per patient with candidemia and IC ranged from $48 487 to $157 574, whereas the mean cost per hospitalization associated with candidemia and IC was from $10 216 to $37 715. All studies were from developed Western countries and reported only direct costs of candidemia and IC. Hospitalization was the main cost driver, contributing to more than half of the total costs. CONCLUSION: Quality cost studies on candidemia and IC based on standardized methods to provide informed decision making among healthcare authorities in implementing appropriate strategies is anticipated, in particular in developing countries.

ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients.

INTRODUCTION: The term invasive candidiasis (IC) refers to both bloodstream and deep-seated invasive infections, such as peritonitis, caused by Candida species. Several guidelines on the management of candidemia and invasive infection due to Candida species have recently been published, but none of them focuses specifically on critically ill patients admitted to intensive care units (ICUs). MATERIAL AND METHODS: In the absence of available scientific evidence, the resulting recommendations are based solely on epidemiological and clinical evidence in conjunction with expert opinion. The task force used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the recommendations and assign levels of evidence. The recommendations and their strength were decided by consensus and, if necessary, by vote (modified Delphi process). Descriptive statistics were used to analyze the results of the Delphi process. Statements obtaining > 80% agreement were considered to have achieved consensus. CONCLUSIONS: The heterogeneity of this patient population necessitated the creation of a mixed working group comprising experts in clinical microbiology, infectious diseases and intensive care medicine, all chosen on the basis of their expertise in the management of IC and/or research methodology. The working group's main goal was to provide clinicians with clear and practical recommendations to optimize microbiological diagnosis and treatment of IC. The Systemic Inflammation and Sepsis and Infection sections of the European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) therefore decided to develop a set of recommendations for application in non-immunocompromised critically ill patients.

Invasive candidiasis in the neutropenic patient.

There are major differences in the epidemiology and prognosis of invasive candidiasis and candidemia in the neutropenic patient; however, a recent study performed in Spanish hospitals (Candipop) confirmed that mortality at 1 month is 30%, which is similar to that observed in the general population. Although Candida albicans is the most frequently isolated species, C. tropicalis, C. glabrata, and C. krusei are more prevalent than in non-neutropenic patients. The benefit of neutrophil transfusion is unclear, and catheter withdrawal must be tailored and based on confirmation of the diagnosis. Echinocandins are the first-line option for therapy and have a better safety profile than other agents.

Early-Onset Invasive Candidiasis in Extremely Low Birth Weight Infants: Perinatal Acquisition Predicts Poor Outcome.

BACKGROUND: Neonatal invasive candidiasis (IC) presenting in the first week of life is less common and less well described than later-onset IC. Risk factors, clinical features, and disease outcomes have not been studied in early-onset disease (EOD, ≤7 days) or compared to late-onset disease (LOD, >7 days). METHODS: All extremely low birth weight (ELBW, <1000 g) cases with IC and controls from a multicenter study of neonatal candidiasis enrolled from 2001 to 2003 were included in this study. Factors associated with occurrence and outcome of EOD in ELBW infants were determined. RESULTS: Forty-five ELBW infants and their 84 matched controls were included. Fourteen (31%) ELBW infants had EOD. Birth weight <750 g, gestation <25 weeks, chorioamnionitis, and vaginal delivery were all strongly associated with EOD. Infection with Candida albicans, disseminated disease, pneumonia, and cardiovascular disease were significantly more common in EOD than in LOD. The EOD case fatality rate (71%) was higher than in LOD (32%) or controls (15%) (P = .0001). The rate of neurodevelopmental impairment and mortality combined was similar in EOD (86%) and LOD (72%), but higher than in controls (32%; P = .007). CONCLUSIONS: ELBW infants with EOD have a very poor prognosis compared to those with LOD. The role of perinatal transmission in EOD is supported by its association with chorioamnionitis, vaginal delivery, and pneumonia. Dissemination and cardiovascular involvement are common, and affected infants often die. Empiric treatment should be considered for ELBW infants delivered vaginally who have pneumonia and whose mothers have chorioamnionitis or an intrauterine foreign body.

ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients.

The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first-line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. Aspergillus guidelines now recommend the use of either voriconazole or isavuconazole for first-line treatment of invasive aspergillosis, while first-line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were made to mucormycosis recommendations.

Invasive fungal sinusitis in the pediatric population: Systematic review with quantitative synthesis of the literature.

BACKGROUND: Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we performed a systematic review. METHODS: We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series including 3 or more patients were included. Demographics, treatment and outcomes were analyzed using R Gui statistical software. RESULTS: Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5% with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor of overall mortality (OR 0.296, 95% CI: 0.104-0.843, p < 0.05). CONCLUSION: Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however, approximately one seventh presented with only nasal findings and half overall had nasal involvement.

Invasive candidiasis: from mycobiome to infection, therapy, and prevention.

Candida spp. are commonly found in humans, colonizing most healthy individuals. A high prevalence of invasive candidiasis has been reported in recent years. Here, we assess the relation between Candida spp. as part of the human mycobiome, the host defense mechanisms, and the pathophysiology of invasive disease in critically ill patients. Many hypotheses have been proposed to explain the different immune responses to the process where Candida goes through healthy mycobiome to colonization to invasion; the involvement of other microbiota inhabitants, changes in temperature, low nitrogen levels, and the caspase system activation have been described. Patients admitted to an intensive care unit (ICU) are at the highest risk for invasive candidiasis, mostly due to the severity of their disease, immune-suppressive states, prolonged length of stay, broad-spectrum antibiotics, septic shock, and Candida colonization. The first approach should be using predictive scores as screening, followed by the determination of biomarkers (when available), and, in the near future, probably immune-genomics and analysis of the clinical background in order to initiate prompt and correct treatment. Regarding treatment, the initiation with an echinocandin is strongly recommended in critically ill patients. In conclusion, prompt treatment and adequate source control in the more severe patients remains the ultimate goal, as well as restoration of a healthy microbiota.

Common invasive fungal diseases: an overview of invasive candidiasis, aspergillosis, cryptococcosis, and Pneumocystis pneumonia.

Every year, Candida, Aspergillus, Cryptococcus and Pneumocystis infect an estimated two million individuals worldwide. Most are immunocompromised or critically ill. Candida is the most common fungal pathogen of the critically ill and of recipients of transplanted abdominal organs. In high-risk haemato-oncological patients, in contrast, the introduction of antifungal prophylaxis with fluconazole and later with mould-active posaconazole has led to a remarkable reduction of invasive candidiasis and is likely to have a similar effect on invasive aspergillosis. Invasive aspergillosis remains the dominant invasive fungal disease (IFD) of haemato-oncological patients and solid-organ transplant recipients and is increasingly found in individuals with exacerbated chronic obstructive pulmonary disease on corticosteroids. In the developed world, owing to antiretroviral therapy Pneumocystis pneumonia and cryptococcosis have become rare in patients with human immunodeficiency virus (HIV) and are mainly found in solid-organ transplant recipients or immunocompromised patients. In the developing world, cryptococcosis remains a common and highly lethal disease of HIV positive individuals. With invasive candidiasis and invasive aspergillosis, timely diagnosis is the principal challenge. The clinical presentation is nonspecific and current diagnostic tests lack sensitivity and specificity. The combination of several tests improves sensitivity, but not specificity. Standardised polymerase chain-reaction-based assays may be promising tools for more rapid and specific diagnosis of candidiasis and invasive aspergillosis. Nevertheless, initiation of treatment is often based solely on clinical suspicion. Empirical therapy, however, may lead to over-treatment of patients without IFD or it may miss its target in the case of resistance. Despite the success of antifungal prophylaxis in reducing the incidence of IFDs in haemato-oncological patients, there are a considerable number of breakthrough infections demonstrating not only fungal resistance but also the emergence of rare and often lethal fungal pathogens. Knowledge of the local epidemiology and antifungal resistance is therefore pivotal. Current trial-based guidelines leave major gaps in identifying those most at risk, who may benefit from prophylaxis. Ongoing searches for disease-associated genetic polymorphisms may contribute to the establishment of individual risk profiles and targeted prophylaxis.

Invasive Candidiasis.

Invasive candidiasis is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 5 of which cause most cases. Candidemia is the most commonly recognized syndrome associated with invasive candidiasis. Certain conditions may influence the likelihood for one species versus another in a specific clinical scenario, and this can have important implications for selection of antifungal therapy and the duration of treatment. Molecular diagnostic technology plays an ever-increasing role as an adjunct to traditional culture-based diagnostics, offering significant potential toward improvement in patient care.

Influence of IgG Subclass on Human Antimannan Antibody-Mediated Resistance to Hematogenously Disseminated Candidiasis in Mice.

Candida albicans is a yeast-like pathogen and can cause life-threatening systemic candidiasis. Its cell surface is enriched with mannan that is resistant to complement activation. Previously, we developed the recombinant human IgG1 antimannan antibody M1g1. M1g1 was found to promote complement activation and phagocytosis and protect mice from systemic candidiasis. Here, we evaluate the influence of IgG subclass on antimannan antibody-mediated protection. Three IgG subclass variants of M1g1 were constructed: M1g2, M1g3, and M1g4. The IgG subclass identity for each variant was confirmed with DNA sequence and subclass-specific antibodies. These variants contain identical M1 Fabs and exhibited similar binding affinities for C. albicans yeast and purified mannan. Yeast cells and hyphae recovered from the kidney of antibody-treated mice with systemic candidiasis showed uniform binding of each variant, indicating constitutive expression of the M1 epitope and antibody opsonization in the kidney. All variants promoted deposition of both murine and human C3 onto the yeast cell surface, with M1g4 showing delayed activation, as determined by flow cytometry and immunofluorescence microscopy. M1g4-mediated complement activation was found to be associated with its M1 Fab that activates the alternative pathway in an Fc-independent manner. Treatment with each subclass variant extended the survival of mice with systemic candidiasis (P < 0.001). However, treatment with M1g1, M1g3, or M1g4, but not with M1g2, also reduced the kidney fungal burden (P < 0.001). Thus, the role of human antimannan antibody in host resistance to systemic candidiasis is influenced by its IgG subclass.

Candidiasis: a fungal infection--current challenges and progress in prevention and treatment.

Despite therapeutic advances candidiasis remains a common fungal infection most frequently caused by C. albicans and may occur as vulvovaginal candidiasis or thrush, a mucocutaneous candidiasis. Candidiasis frequently occurs in newborns, in immune-deficient people like AIDS patients, and in people being treated with broad spectrum antibiotics. It is mainly due to C. albicans while other species such as C. tropicalis, C. glabrata, C. parapsilosis and C. krusei are increasingly isolated. OTC antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis. Present review summarizes the diagnosis, current status and challenges in the treatment and prevention of candidiasis with prime focus on host defense against candidiasis, advancements in diagnosis, probiotics role and recent progress in the development of vaccines against candidiasis.