Patients with acute leukemia (AL) and hematologic stem cell transplant (HCT) recipients are at increased risk for the development of invasive fungal infections (IFI) due to prolonged neutropenia and severe immunosupression. The incidence of IFI in these patients has increased in recent years , which likely reflects changes in clinical practice including escalation of treatment intensity; more frequent use of unrelated, mismatched or alternative donors as stem cell source; rising number of multiple transplantations; and more frequent use of T-cell depleted grafts [2-3]. IFI are associated with high morbidity and mortality in the patients with AL and represent a leading cause of infectious mortality in allogeneic HCT (allo-HCT) recipients. Therefore, effective preventive strategies, accurate diagnostic techniques and optimal treatment approaches are required for an optimal management of high risk patients with AL and HCT recipients.
2. Clinical syndromes
Clinical symptoms of IFI are often non-specific, therefore a high index of suspicion in high risk patients is necessary for timely diagnosis and prompt treatment. Diagnosis of the IFI could be challenging, particularly in severely immunocompromised patients as a result of blunted inflammatory response due to profound neutropenia and altered T-cell function; hence, in such patients clinical and radiologic findings may be very subtle. In the case of clinical suspicion of IFI aggressive pursuit of a specific microbiologic diagnosis with early recognition and prompt initiation of antifungal therapy are the key components of optimizing treatment outcomes. The most common clinical signs are the symptoms of local or generalized inflammatory response, primarily persistent fever despite the use of broad spectrum antibiotics. Other symptoms significantly depend upon the involved anatomic site and causative pathogen. For example, for mold pathogens, lungs and less commonly sinuses are involved; accordingly, the most common symptomatology include dyspnea, cough, atypical chest pain, hemoptysis, rash, facial pain, nasal congestion and visual symptoms such as periorbital pain, blurred vision and proptosis.
Among numerous potential pathogens
The most common manifestation of IC is persistent and unexplained fever. In contrast to other fungal pathogens,
Despite being ubiquitous, molds are unable to effectively invade tissues in immunocompetent individuals; thus, invasive mold infections (IMI) such as Aspergillosis, Zygomycosis, and Fusariosis almost exclusively develop in high-risk patients with prolonged neutropenia or in severely immunosuppressed patients [12-13]. Nosocomial IMI among patients with AL or HCT recipients primarily develop as a result of spore transmission via inhalation or direct contact . Opportunistic molds, particularly
In the case of invasive Aspergillosis (IA), when infection spreads beyond the respiratory tract, patients often develop signs of systemic inflammation and multiorgan failure. In such cases, hematogenous dissemination can lead to involvement of the eye, sinuses and abdominal organs; however
Endocarditits is another serious complication of IA and primarily happens in patients with prosthetic heart valves or prolonged fungemia due to fungal colonolization of the central venous catheters . Symptoms are similar to those of bacterial endocarditis: persistent fever and thromboembolic complication due to septic emboli. Blood cultures are usually negative, in contrast to classical bacterial endocarditis and diagnosis is usually made by demonstration of hyphae in the embolus with a subsequent culture of the organism. Prognosis of these patients is very poor despite an intensive medical and surgical treatment with a mortality approaching 100% . Endophthalmitis and cutaneous septic lesions by
Paronychia is often caused by bacteria or yeasts; however, in severely immunocompromised recipients it can be caused by
Knowledge of the epidemiology of IFI is crucial for development of optimal prophylactic approaches and effective therapeutic strategies for patients with AL and HCT recipients. The epidemiology of IFI has changed significantly over the last two decades.
After its peak in 1980’s when
The epidemiology of
In recent years previously rare molds have been emerging as important pathogens in high risk patients. There is a rising incidence of IFI caused by
4. Risk factors
Risk factors for IFIs in patients with leukemia and HCT recipients depend on both causative pathogens and host factors. Since the most common fungal pathogens are opportunitistic, they capable of causing life-threatening infections almost exclusively in immunosuppressed host and the IFI risk directly depends on the duration of neutropenia and severity of immunosuppression. Patients with AL are considered high risk for IFI if prolonged (>7 days duration) neutropenia (absolute neutrophil count <100 cells/mm3) following cytotoxic chemotherapy is anticipated and/or significant medical co-morbid conditions such as hypotension, pneumonia, new-onset abdominal pain, or neurologic changes are present. The same criteria apply for HCT recipients alongside with additional risk factors, mainly graft versus host disease (GVHD) and prolonged immunosuppressive therapy. In ASCT recipients significant alterations of humoral and cellular immunity typically resolve within 3 months, therefore, for such patients the risk for IFI beyond that time is minimal. Immune reconstitution happens slower after allo-HCT and usually approaches normality by 1 year if GVHD does not develop. The occurrence of chronic GVHD significantly impairs immune reconstitution by requiring prolonged and often intensive immunosuppressive therapy. These patients remain at a high risk for IFI if chronic GVHD persists and requires continuing immunosuppressive therapy.
Neutropenic patients with AL and HCT recipients are at a risk for IC, particularly in the absence of antifungal prophylaxis. The risk of IC in both AL patients and HCT recipients also depends on the duration of neutropenia, severity of mucosal injury, and the presence of a central venous catheter . Patients with neutropenia are also at risk for IMI, particularly IA. The underlying disease itself and treatment intensity directly influence the risk of AI; patients with AML have the highest risk for IA with an incidence of approximately 20 times greater than that among patients with lymphoma and multiple myeloma . The precise risk for IA in AML patients varies in different published series, however in most studies it ranges between 5 and 10%, depending on the disease status, duration of neutropenia, and the types of anti-neoplastic agents used for a leukemia treatment [37-42], where patients undergoing chemotherapy for relapsed or refractory leukemia are at greatest risk, whereas patients undergoing an induction chemotherapy for a newly diagnosed leukemia are at a lower risk and those, who are receiving consolidation therapy are at lowest risk. In HCT recipients the risk for IA significantly depends on the type of transplant (ASCT versus allo-HCT); conditioning regimen (myeloablative, non-myeloablative, reduced intensity); stem cell graft source (related, unrelated, haploidentical, umbilical cord, HLA matched or mismatched, T-cell depleted); post-transplant interventions (salvage chemotherapy, prolonged treatment with glucocorticoids and anti-rejection medications); and the development of post-transplant complications, particularly GVHD [43-45]. Overall risk for IA is low in ASCT represents (1–2%) because there is only a brief period of immunosupression and neutropenia in these patients . In allo-HCT recipients, the risk for IA is substantially higher with a trimodal incidence distribution [32, 47-48]. The first peak occurs during the pre-engraftment period where the main risk factor is prolonged neutropenia which is similar to neutropenic patients with leukemia who did not receive transplantation. The second peak occurs between 2 to 3 months after the allo-HCT in patients with acute GVHD being treated with corticosteroids. The third peak occurs after one year post-transplant in patients who continue to require systemic immunosupression for extensive chronic GVHD. Late onset (41–180 days) occurrences of IA were more common in recipient of mismatched or unrelated donor HCT; in patients who received T-cell depleted or CD34-selected stem cell products; in patients receiving corticosteroids; in patients with neutropenia, lymphopenia, GVHD, CMV disease; and in patients with respiratory virus infections. Other factors such as iron overload and a toll-like receptor 4 polymorphism are recognized as independent risk factors for IA in HCT recipients [49-50].
Among less frequent IMI, Zygomycosis tends to develop relatively late, usually after 90 days post HSCT and is more commonly seen in patients with underlying MDS, chronic GVHD and patients receiving treatment of GVHD . Alternatively, severe, but rare infections with
5. Diagnostic approaches
To improve outcomes of high risk patients with AL and HCT transplant recipients it is critical to establish the diagnosis of IFI early, but currently there is no single diagnostic method that has a sufficient sensitivity and specificity to determine IFI. Therefore, timely diagnosis of IFI should be made on the basis of a constellation of clinical signs, confirmatory imaging studies and laboratory findings.
Even minor abnormalities on chest radiographs (CXR) in high risk patients should prompt further investigation, which often includes computed tomography (CT) of the chest. When suspicion of invasive pulmonary Aspergillosis is high, it is very important to pursue CT scanning of the chest, because CXR may be negative in up to 10% cases of invasive pulmonary Aspergillosis, whereas only 3% CT scans are falsely negative . If possible, images need to be compared with prior ones to exclude over interpreting persistent abnormalities, which are not related to acute infection, such as scarring or other tissue changes caused by previous radiation or administration of chemotherapy. The pulmonary infiltrates due to IMI are generally nodular. CT imaging findings that are more specific radiologic signs of IA are early on a “halo sign” when the central nodular area of fungal invasion is surrounded by a ground-glass appearing hemorrhage and a "crescent sign" may occur later as a result of necrosis and cavitation of lung tissue. In a large multicenter study, most patients with documented IA had one or more dense nodules and nearly two thirds had a halo sign . The chest CT defines the extent of the disease process with a greater accuracy than CXR and can also be used repeatedly to monitor the response to therapy. Better visualization of lung tissue on CT scan also helps to define optimal sampling sites and to select the most appropriate invasive diagnostic procedure, such as with bronchoalveolar lavage with or without transbronchial biopsy, image guided needle biopsy, video-assisted thoracoscopic or open lung biopsy. Importantly, during therapy lung infiltrates and clinical symptoms may appear or get worse with immune reconstitution and resolution of severe neutropenia when an inflammatory response develops at the site of tissue damage by an invasive fungal pathogen. It was demonstrated that initiation of therapy directed against Aspergillus when a halo sign has been identified resulted in significantly improved survival [54-55].
Detection of yeasts or fungal elements (hyphae) in the tissue by microscopic examination should be followed by a subsequent culture to identify a specific organism, since morphology is not sufficiently specific.
Because of numerous limitations related to culture techniques, adjunctive non-cultural methods such as galactomannan (GM) antigen, b-(1-3)-D glucan (BG) and PCR-based methods are now being implemented for a timely diagnosis of IFI, primarily IA, particularly when tissue sample is not obtained [60-63]. If PCR-based techniques are still considered investigational , the clinical value of serum GM and BG assays was confirmed in prospective trials. Both tests now are accepted as supplementary diagnostic tests for an early detection of common IFI in high risk patients. A positive GM test preceded the development of clinical symptoms of IFI in the majority of patients in studies . The BG has high sensitivity and specificity with a capability to detect many clinically relevant fungal pathogens including
The serum GM assay detects
GM can also be detected in other body fluids during IA infection involving those fluids or adjacent tissues, including urine, CSF and bronchoalveolar lavage (BAL) [80-82]; however, clinical utility of the assay obtained from other sources than serum is under clinical investigation. Preliminary data has suggested that detection of GM in BAL fluid  could be an reliable adjunct test with a specificity and sensitivity exceeding of those in BAL fungal culture [84-85] and some studies suggest BAL GM to be more sensitive than serum GM 
PCR assays to detect and identify fungal pathogens are being developed and ongoing clinical testing, but not yet available for a commercial use . Although development and clinical implementation of PCR assays for fungal species such as
6. Treatment and prevention
There are four common antifungal strategies used in current clinical practice to combat IFI. These include antifungal prophylaxis, empirical therapy, pre-emptive (or diagnostics-driven) therapy and treatment of proven and probable IFI.
The goal of antifungal prophylaxis is to prevent IFI with an administration of the antifungal agent(s) in high risk patients. Antifungal prophylaxis is a rapidly evolving field. Prophylaxis is considered clinically beneficial when the risk of a life-threatening IFI outweighs the risks of toxic effects and drug interactions, and the risk for emergence of drug resistance associated with the antifungal agent used. Optimally, antifungal prophylaxis should also be cost-effective. Therefore, the choice of empirical antifungal treatment is considered based on the prevalence of the most likely fungal pathogens, along with considerations about toxicities, resistance, and cost.
The most widely used agent for IFI prophylaxis in patients with AL and HCT recipients is fluconazole, an agent with activity against most (but not all)
Another widely studied agent for antifungal prophylaxis in high risk patients is itraconazole, which has activity against
Voriconazole is a well-tolerated triazole with an extended-spectrum of activity including activity against
Posaconazole is a triazole with a broad spectrum of activity against both yeasts and molds. It is active against pathogens such as the
Development of extensive chronic GVHD significantly increases the risk of late IFI (more than 100 days post-transplant), predominantly IA, with a reported incidence as high as almost 40% in one series . Therefore, anti-mold prophylaxis with posaconazole in patients with extensive chronic GVHD could be beneficial in these patients.
Amphotericin B (AmpB) is not currently used for prophylaxis of IFI due to its excessive toxicity and infusion-related events. However, recently aerosolized AmpB was prospectively tested in patients with AL and allo-HCT recipients and led to reduction in the incidence of invasive pulmonary Aspergillosis; however administration of the drug was interrupted in a substantial proportion of patients (45%) due to cough during inhalation, weakness preventing the use the aerosol delivery system and technical problem with the aerosol delivery system. Moreover, aerosol dose and delivery device have not yet been determined, therefore further study is necessary before the clinical utility of this agent can be determined .
The risk for IFI is substantially lower in the majority of ASCT recipients as compared to allo-HCT recipients. These patients usually do not require routine anti-yeast prophylaxis. However, for high risk sub-populations of ASCT recipients such as patients with underlying hematological malignancies, history of prolonged neutropenia, significant mucosal damage, and treatment within fludarabine or 2-CDA within 6 months prior ASCT ant-yeast prophylaxis is recommended .
Empirical treatment is an initiation or modification of an existing antifungal treatment in high risk patients with persistent fever of unknown source unresponsive to antibacterial agents. Although, approximately one-third of neutropenic patients with cancer receive an antifungal drug due to persistent fever, only less than 5% of these patients subsequently demonstrate the presence of IFI [102, 105-107]. Therefore, initiation of empirical antifungal therapy solely on the basis of persistent fever can be legitimately questioned.
The most common fungal pathogen in neutropenic patients is
There is not enough data for recommendations regarding a particular empirical antifungal agent for patients who are already receiving anti-mold prophylactic coverage, however changing treatment to a different class of intravenous anti-mold agent should be considered, given the possibility that breakthroughs of fungal infection could be caused by resistant organisms. Another concern is that breakthrough IFI may be due to inadequately low serum levels of voriconazole or posaconazole when these agents administered orally because of the variability of blood levels after HCT [108-109].
For more than 30 years AmpB has been used for an empirical antifungal treatment, but with development of newer agents, its therapeutic role in the current management of fungal infections is minimal, due to excessive toxicity, particularly nephrotoxicity and infusion-related events. Alternative formulations of AmpB such as liposomal AmpB, AmpB colloidal dispersion, AmpB lipid complex; azoles with anti-mold activity such as itraconazole or voriconazole, and caspofungin are widely used because of better tolerability and reduced systemic toxicity, however there are no data that have demonstrated their superior efficacy to AmpB [105, 107, 110-112].
Voriconazole is recognized by many experts as a suitable alternative to a liposomal AmpB as an empirical antifungal therapy in patients with neutropenia and persistent fever  and currently widely used for an empirical therapy for high risk patients, particularly for an empirical treatment of probable IMI.
The need for empirical antifungal therapy in febrile high risk patients have been questioned because of the very low percentage of such fevers that are actually due to IFI . The advances in our ability for early detection of fungal infections have ushered in a new strategy, pre-emptive therapy. Pre-emptive treatment refers to therapy of highly suspected IFI supported by the presence of clinical symptoms, radiological findings and/or adjunctive laboratory tests [54-55, 113].
The feasibility of preemptive antifungal therapy in high risk patients with the use of serial GM testing and early CT scans was prospectively evaluated in 131 neutropenic episodes. All patients were given fluconazole prophylaxis to eliminate
In another study PCR-based preemptive antifungal therapy was compared with an empirical treatment with liposomal amphotericin B in patients after allo-HCT . PCR-based approach led to an increased use of anti-fungal therapy and reduced 30-day mortality, but there was no difference in the incidence of IFI or 100-day survival.
These observations suggest that some of high risk neutropenic patients with persistent fever may not need an automatic empirical antifungal therapy if they receiving anti-yeast prophylaxis and closely monitored under certain specific conditions [114-117]. However, if laboratory, clinical or radiologic abnormality suggestive of probable fungal infection is identified, prompt initiation with of antifungal therapy with an agent that includes anti-mold activity is needed.
Despite being an attractive alternative, the preemptive approach is currently regarded as investigational by many and not widely accepted although its use is embraced and its promise is discussed in consensus guidelines 
Treatment of established IFI
Early recognition and treatment of invasive fungal infections in AL and HCT recipients are important clinical challenges. Early initiation is a key to optimizing treatment outcomes for both
Treatment of IC.
Candidemia is associated with a high mortality, especially in patients with delayed treatment, therefore antifungal therapy in patients with IC should be started as soon as possible . If a central venous catheter(s) is in place and suspected to be causative for IC, it should be removed. Although AmpB was historically the preferred therapy with excellent activity against most
Treatment of IMI
Voriconazole is the preferred initial agent for the treatment of IA . It is effective and well tolerated both as primary and salvage treatment . A large randomized study showed a higher response and survival rate with fewer
Although there is a very limited data regarding posaconazole activity as a first line agent in the treatment of IA as an initial agent of choice, substantial evidence supports its activity in the salvage setting after a failure of or intolerance to other antifungal treatments . There are few data regarding clinical role of caspofungin as a first-line treatment for IA, but it is effective with a response up to 50% as a salvage agent in patients with IA who failed or intolerant to standard antifungal therapy . The role of micafungin or anidulafungin for the treatment of IA has not been well studied but are active as salvage therapy.
Efficacy and safety of AmpB lipid complex (ABLC) as first-line or second-line therapy was demonstrated in large numbers of patients with hematologic malignancy or HCT recipients . Another study showed that one third of allo-HCT recipients with IA responded to ABLC, with a response of 41% and 21% when ABCL used as a first line treatment and in patients with GVHD respectively . In both studies administration of ABLC had only minimal effects on renal function in the majority of patients. Liposomal AmpB also has been shown to be effective as salvage therapy with fewer infusion related and renal toxicities. Two doses of liposomal AmpB were evaluated (10mg/day versus 3 mg/day) to determine the optimal dose for initial therapy. Both doses had comparable response rates but the 10 mg/day dose was associated with more renal toxicity 
The treatment options for Zygomycosis are more limited and less well studied. Patients with Zygomycosis showed a good response to high doses of liposomal AmpB (dose at least 5 mg/kg)  or ABLC . In the case of CNS or sinus involvement additional surgical resection of necrotic tissue in patients with Zygomycosis significantly appears to be associated with improved survival as compared to antifungal therapy alone [137-138]. Posaconazole is an effective agent with response rates of about 50–80% when uses as a salvage treatment in patients with Zygomycosis [139-140].
Therapeutic Drug Monitoring
Therapeutic drug monitoring has not been found to be useful for the polyene and echinocandin classes of antifungal drugs. However, the oral formulations of the extended spectrum triazoles have been found to have variability in blood concentrations and multiple drug interactions. Multiple studies have explored whether these variations have clinical consequences in terms of efficacy. Itraconazole oral formulations have been seen to have variable bioavailability in multiple studies [141-145]. Higher doses appear to have greater antrifungal effects in both animals and humans [141, 145-148]. Voriconazole, when taken orally also has been shown to havevariable bioavailability, especially in HCT recipients [149-151].Voriconazole is metabolized in the liver via the cytochrome P450 dependent mechanism, predominantly by CYP2C19 isoenzyme which exhibits genetic polymorphism resulting in reduced drug metabolism in 15–20% patients of Asian descent, and 3–5% of Caucasians and Blacks . Low voriconazole levels have been have been reported in patients with documented breakthrough infections, whereas super therapeutic levels may lead to hepatotoxicity and encephalopathy [150-151]. Less information is known about posaconazole, but it too has been shown to have variable bioavailability [152-156]. There is some suggestion that low levels may be associated with lower effectiveness [156-157].
Controversy remains regarding the use of routine monitoring of azole drug levels, however most experts agree that measurement of levels should be performed in patients with documented breakthrough infection or infections not responding to oral triazole therapy. A change to, or addition of, different class antifungal agent is recommended until the determination of the drug blood level. If drug level is found to be sub-therapeutic, resuming the drug at a higher dose should be considered.
Combination antifungal therapy
Combination antifungal therapy may theoretically lead to better efficacy with shorter courses of therapy, reduced toxicity and emergence of resistance. However potential drawbacks of combination therapy might include potential antagonistic effects of the antifungal drugs used in combination, potential increase in toxicity, and greater cost may offset the potential value of this approach . A randomized trial demonstrated that in non-neutropenic patients with candidemia due to species other than
Over the past two decades, significant progress has been made in the prophylaxis, diagnosis and treatment of IFI in patients with AL and HCT recipients. Introduction of newer antifungal agents, better supportive care and more effective diagnostic tools resulted to a considerable improvement of clinical outcomes for such high risk patients. However, despite advances in prevention and management of systemic fungal infections, IFI remain a significant clinical problem for AL patients and HCT recipients. Further progress should be made towards improvements in diagnostic techniques, development of novel antifungal drugs and introduction of immunotherapy approaches for high risk patients. Future efforts should also be focused on better understanding of fungal immunobiology and implementation of personalized therapy based on immunologic, metabolic and genetic profiles of high risk patients.
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