Fungal infections in lung transplantation

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3–19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.     

Fungal infections in lung transplant recipients

PURPOSE OF REVIEW: Despite numerous advances in lung transplantation, survival is still significantly compromised by a higher rate of infections. This review intends to provide an overview of the most common fungal infections afflicting lung transplant recipients, focusing on the most recent developments in diagnosis, therapy and prophylaxis. RECENT FINDINGS: Although detection of galactomannan in serum has poor sensitivity for the diagnosis of invasive aspergillosis in lung transplant recipients, detection of galactomannan in the bronchoalveolar lavage of a lung transplant recipient, with a compatible clinical illness, is highly suggestive of invasive disease. New antifungal agents, with a broader spectrum of activity and a more tolerable side effect profile, have become available for the treatment and prophylaxis of fungal infections. Evidence suggests that, at least for voriconazole, monitoring of drug concentrations may be advisable to prevent clinical failure due to underdosing and toxicity due to excessive dosing. SUMMARY: Fungal infections remain a significant cause of morbidity and mortality in lung transplant recipients; however, advances have been made in the recent years, which will allow earlier diagnosis and more effective and tolerated treatment.     

Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients

Filamentous fungal infections are associated with high morbidity and mortality in solid organ transplant patients, and prevention is warranted whenever possible. An increase in invasive aspergillosis was detected among solid organ transplant recipients in our institution during 1991–92. Rates of Aspergillus infection (18.2%) and infection or colonization (42%) were particularly high among lung transplant recipients. Epidemiologic investigation revealed cases to be both nosocomial and community‐acquired, and preventative efforts were directed at both sources. Environmental controls were implemented in the hospital, and itraconazole prophylaxis was given in the early period after lung transplantation. The rate of Aspergillus infection in solid organ transplant recipients decreased from 9.4% to 1.5%, and mortality associated with this disease decreased from 8.2% to 1.8%. The rate of Aspergillus infection or colonization among lung transplant recipients decreased from 42% to 22.5%; nosocomial Aspergillus infection decreased from 9% to 3.2%. Cases of aspergillosis in lung transplant recipients were more likely to be early infections in the pre‐intervention period. Early mortality in lung transplant recipients decreased from 15% to 3.2%. Two cases of dematiaceous fungal infection were detected, and no further cases occurred after environmental controls. The use of environmental measures that resulted in a decrease in airborne fungal spores, as well as antifungal prophylaxis, was associated with a decrease in aspergillosis and associated mortality in these patients. Ongoing surveillance and continuing intervention is needed for prevention of infection in high‐risk solid organ transplant patients.     

Phaeohyphomycotic infections in solid organ transplant patients

Phaeohyphomycoses are darkly pigmented fungi that rarely cause infection in immunocompetent persons. In the past 2 decades these fungi increasingly have been reported as pathogens that cause significant morbidity and mortality in the immunocompromised host, especially solid organ transplant recipients. Clinical manifestations range from superficial lesions to disseminated infections. Exophiala spp. and Alternaria spp. account for the great majority of these infections. Treatment should include complete surgical excision of the lesions that are accessible combined with antifungal therapy, especially when invasive or systemic infection is present. Itraconazole usually suffices if only subcutaneous lesions are present; however, if the infection is systemic or it involves the central nervous system, the addition of amphotericin B is required. New investigational azoles also should be considered in these types of infections. This is a very heterogenous group of fungi and as such the sensitivities to antifungal agents is variable. Therefore, sensitivities should be obtained on every fungal isolate.     

Fungal infections in the recipients of solid organ transplantation

The advent of effective antibacterial and antiviral prophylatic and therapeutic strategies has led to the emergence of opportunistic mycoses as a principal cause of infection-related mortality in organ transplant recipients. Candida and Aspergillus species have accounted for most invasive fungal infections in organ transplant recipients. Epidemiologic trends within the last decade, however, are notable for the emergence of mycelial fungi other than Aspergillus as increasingly important pathogens in these patients. This article reviews the epidemiology, clinical manifestations, pathogenetic basis, diagnosis, and management of invasive fungal infections after organ transplantation in context of emerging trends and new developments in these areas.     

Infectious complications following isolated lung transplantation.

STUDY OBJECTIVE: To ascertain the incidence, types, morbidity, and mortality of infectious episodes in isolated lung transplant recipients. DESIGN: Retrospective chart review of patients who have undergone transplants over a six-year period in one institution. PATIENTS: Twenty-three single and 17 double lung transplants followed up between 2 and 68 months. RESULTS: Fifty-one episodes of infection occurred in the group with a slight predominance in the double lung transplants. The 32 episodes of bacterial infection constituted the largest group of infection and more than half of these were pneumonias. Organisms identified were predominantly Gram negative. While bacterial processes made up the bulk of infections, fatalities were rare. Viral and fungal infections were less common, but more often fatal. Of six cases of viral pneumonitis, two were fatal; two of five cases of invasive fungal infection were also fatal. Overall, six patients died of infection. CONCLUSION: Our findings support previous reports from heart-lung centers documenting a high rate of infectious complications, particularly pneumonia, in recipients of lung grafts. In our experience, bacterial infections are the most common (two of three infections), but have the lowest mortality. Efforts should be directed toward establishing effective prophylaxis programs and early detection of infection.     

Prophylaxis against pulmonary viral and fungal infections in solid organ transplant recipients

Pulmonary viral and fungal infections in solid organ transplant recipients are one of the most common and potentially life-threatening infections. Understanding the strategies used for prophylaxis and prevention of these infections is critical for the health and well-being of transplant recipients. Prophylactic measures range from simple patient education to complex chemoprophylactic interventions; however, a multifaceted approach is most often required. This article focuses on strategies to prevent pulmonary viral and fungal infections in transplant recipients, with an emphasis on recent evidence that may influence practice guidelines.     

Management of bacterial and fungal infections in end stage liver disease and liver transplantation: Current options and future directions

Patients with liver cirrhosis are susceptible to infections due to various mechanisms, including abnormalities of humoral and cell-mediated immunity and occurrence of bacterial translocation from the intestine. Bacterial infections are common and represent a reason for progression to liver failure and increased mortality. Fungal infections, mainly caused by Candida spp., are often associated to delayed diagnosis and high mortality rates. High level of suspicion along with prompt diagnosis and treatment of infections are warranted. Bacterial and fungal infections negatively affect the outcomes of liver transplant candidates and recipients, causing disease progression among patients on the waiting list and increasing mortality, especially in the early posttransplant period. Abdominal, biliary tract, and bloodstream infections caused by Gram-negative bacteria [e.g., Enterobacteriaceae and Pseudomonas aeruginosa(P. aeruginosa)] and Staphylococcus spp. are commonly encountered in liver transplant recipients. Due to frequent exposure to broad-spectrum antibiotics, invasive procedures, and prolonged hospitalizations, these patients are especially at risk of developing infections caused by multidrug resistant bacteria. The increase in antimicrobial resistance hampers the choice of an adequate empiric therapy and warrants the knowledge of the local microbial epidemiology and the implementation of infection control measures. The main characteristics and the management of bacterial and fungal infections in patients with liver cirrhosis and liver transplant recipients are presented.     

Mucormycosis in organ and stem cell transplant recipients

Mucormycosis is a devastating invasive fungal disease whose incidence has increased during the past decade. Mucormycosis now represents a major threat in transplant recipients, accounting for 2% and 8% of invasive fungal infections in recent cohorts of solid-organ and allogeneic stem-cell transplant recipients, respectively. Mucormycosis most often occurs late, >3 months after transplantation, although cases occurring early have been observed, especially among liver transplant recipients and in cases of graft-transmitted infection. Recent guidelines have emphasized the direct examination of the involved fluid or tissue and culture from a sterile site as the most appropriate diagnostic strategy and the use of lipid formulations of amphotericin B and major surgery when feasible as the most appropriate first-line therapeutic strategy for mucormycosis in organ and stem cell transplant recipients.     

Prevention and treatment of fungal infections in bone marrow transplantation

There has not been as much success in the prevention and treatment of invasive fungal infections, particularly aspergillosis, compared to the prevention and treatment of cytomegalovirus infection and graft-versus-host disease in bone marrow transplant (BMT) recipients. Allogeneic BMT recipients who develop graft-versus-host disease and remain immunosuppressed for long periods are at major risk for development of these infections. Prevention of environmental exposure, antifungal chemoprophylaxis, and attempts at early diagnosis are essential for the reduction of mortality from invasive fungal infections. Chest computerized axial tomography is extremely useful in diagnosing pulmonary aspergillosis. However, microbiologic or histologic identification of infection remains essential. Unfortunately, the response to therapy in BMT recipients remains suboptimal. With the development of the lipid formulations of amphotericin B, the newer azoles, and the echinocandins, safer and more efficacious options have become available. The optimal use of antifungal agents or their combinations remains to be determined.     

Lung transplant infection

Lung transplantation has become an accepted therapeutic procedure for the treatment of end‐stage pulmonary parenchymal and vascular disease. Despite improved survival rates over the decades, lung transplant recipients have lower survival rates than other solid organ transplant recipients. The morbidity and mortality following lung transplantation is largely due to infection‐ and rejection‐related complications. This article will review the common infections that develop in the lung transplant recipient, including the general risk factors for infection in this population, and the most frequent bacterial, viral, fungal and other less frequent opportunistic infections. The epidemiology, diagnosis, prophylaxis, treatment and outcomes for the different microbial pathogens will be reviewed. The effects of infection on lung transplant rejection will also be discussed.     

Role of new antifungal agents in prophylaxis of mycoses in high risk patients

PURPOSE OF REVIEW: For pancreas, liver, and hematopoietic stem cell transplant recipients, no antifungal prophylaxis led to a high rate of and high morbidity from fungal infection. With the use of fluconazole as prophylaxis since the early 1990s, there have been shifts in the types of infecting fungal pathogens, documentation of resistance among fungal organisms, and changes in transplant practices. The aim of this article is to review recent clinical trials regarding antifungal chemoprophylaxis among several populations of high risk patients. RECENT FINDINGS: Itraconazole, micafungin, and posaconazole have been studied as alternatives to fluconazole prophylaxis. Itraconazole showed no dramatic improvement over fluconazole as prophylaxis during liver and hematopoietic stem cell transplantation, primarily due to gastrointestinal side effects. In addition, detrimental changes to cyclophosphamide metabolism were noted for hematopoietic stem cell transplant recipients. Micafungin was superior to fluconazole during the pre-engraftment period of hematopoietic stem cell transplantation, because it was able to prevent mold infections, required less switches to empirical antifungal therapy, and functioned as well as fluconazole in preventing yeast infections. Posaconazole was compared to fluconazole during a 16-week prophylaxis period during graft-versus-host disease, but results of this study are still forthcoming. Aerosolized amphotericin products appear to be safe for lung transplant recipients. SUMMARY: Fluconazole remains the standard agent for prophylaxis against invasive fungal infections for pancreas, liver, and hematopoietic stem cell transplant recipients. Micafungin is superior to fluconazole with minimal toxicity for use in the pre-engraftment period of hematopoietic stem cell transplantation. The optimal agent for prophylaxis later following transplant, if mold coverage is desired during prolonged immunosuppression, has not been determined.     

Pulmonary fungal infections

PURPOSE OF REVIEW: Invasive fungal infections of the lung have historically been associated with an extremely high mortality. This review aims to disseminate the most recent advances in the diagnosis and management of fungal infections of the lung. RECENT FINDINGS: The number and diversity of immunosuppressed populations are growing rapidly. Transplant immunosuppression is becoming more aggressive early in the posttransplant period, potentially increasing the risk of invasive fungal infections. The galactomannan antigen test and the beta-D-glucan test have emerged as methods of serially monitoring at-risk patients for invasive aspergillosis. Their utility has been established in some neutropenic populations but not in solid organ transplant recipients. In-vitro studies, animal studies, and retrospective human studies support the use of combination antifungal therapy for invasive aspergillosis. Unfortunately no randomized clinical trials exist. SUMMARY: Invasive pulmonary aspergillosis will continue to be a major problem in immunocompromised patients in the future. Immense advances in the last 2-3 years are sure to improve outcome. Well-designed multicenter evaluations are still necessary, however, to optimize management as management options widen.     

Epidemiology of fungal infections in solid organ transplant patients

The epidemiology of fungal infection in solid organ transplant patients is of concern due to the high mortality associated with this complication. Rates of fungal infections vary by type of transplant recipient. Most of these infections occur two to six months after transplantation. Liver transplant recipients are more likely to have early fungal infection which is often due to Candida species. Exogenous and endogenous Candida infection may occur in the immunosuppressed patient in the intensive care unit. Patients with chronic rejection are more likely to have late infection (after six months) which may be due to Aspergillus or endemic fungi such as Cryptococcus. Lung and heart–lung transplant recipients are more predisposed to infection with Aspergillus and other filamentous fungi, due to exposure of the transplanted organ to the external environment. Preventative measures such as environmental controls and chemoprophylaxis may be beneficial in high-risk patients. Emerging fungal pathogens such as the dematiaceous fungi may cause skin or soft tissue infection, or more serious systemic infections. Fungal infection should be ruled out in the solid organ transplant patient with early brain abscess. Characteristic risk factors in high-risk types of solid organ transplant recipients should be recognized for early diagnosis and treatment of these infections associated with high morbidity and mortality.     

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients

D. Neofytos, J.A. Fishman, D. Horn, E. Anaissie, C.‐H. Chang, A. Olyaei, M. Pfaller, W.J. Steinbach, K.M. Webster, K.A. Marr. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.
Transpl Infect Dis 2010: 12: 220–229. All rights reserved Abstract: Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received ≥2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12‐week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non‐lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.     

Impaired phagocyte respiratory burst responses to opportunistic fungal pathogens in transplant recipients: in vitro effect of r-metHuG-CSF (Filgrastim)

Abstract: Phagocyte respiratory burst capacity in response to pathogenic fungi and the in vitro effects of granulocyte colony-stimulating factor (G-CSF) were examined in 15 normal volunteers and 39 transplant recipients (4 autologous and 4 allogeneic bone marrow, 3 heart, 10 liver, 8 lung, and 10 kidney). Chemiluminescence was measured for reaction mixtures of diluted whole blood, opsonized fungi, and luminol, with and without in vitro incubation with r-metHuG-CSF (Filgrastim). Transplant patients exhibited significantly impaired respiratory burst responses to conidia and yeast compared with controls, but this was reversed with Filgrastim. Responses to hyphae were low for both groups, and G-CSF had little or no effect. There was excellent correlation between responses to fungi and responses to opsonized zymosan. In vitro respiratory burst capacity is impaired in transplant recipients. This may predict susceptibility to invasive fungal infections. G-CSF can reverse impaired phagocyte function and is of potential benefit in the prevention and/or treatment of fungal infection in transplant patients.     

Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America.

Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.     

Fungal pneumonias in transplant recipients

Fungi are ubiquitous in the environment. Opportunistic fungal pneumonias in the immunocompromised host continue to increase most commonly due to Aspergillus sp. Affected patients are usually hematopoietic stem cell and lung transplant recipients. Clinical presentation is protean, and the diagnosis is challenging. Culture of respiratory specimens has limited utility. The detection of circulating fungal antigens and DNA seems promising, but more studies are needed. Value of prophylactic strategies or preemptive therapy remains contentious. New antifungal drugs for managing invasive pulmonary aspergillosis continue to emerge, with better safety, efficacy, and pharmacologic profiles.     

Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-affiliated transplantation center. PATIENTS: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia >10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients.