INTRODUCTION — Invasive aspergillosis is the most common mold infection in immunocompromised hosts. This infection is caused by Aspergillus, a hyaline mold that is ubiquitous. Exposure to Aspergillus conidia is frequent, but invasive disease is uncommon because of control by host immunity in nonimmunosuppressed hosts. The most common risk factors for infection include neutropenia and glucocorticoid use, but other risk factors include hematopoietic cell transplantation, solid organ transplantation (particularly lung transplantation), the use of biologic agents, pulmonary diseases, and critical illness. The most common infecting species is Aspergillus fumigatus complex, but other species complexes that are common causes of disease include A. flavus, A. terreus, and A. niger. Less common species, such as A. nidulans, A. calidoustus, A. lentulus, and many others, have been reported to cause infection in highly immunosuppressed patients. Many of these unusual or "cryptic" species, which are often difficult to identify, are clinically important due to varying susceptibility to antifungal agents. The effective management of invasive aspergillosis includes strategies to optimize prevention, prompt diagnosis, early antifungal treatment, and, in some cases, immunomodulation and surgery. An increasing number of cases of invasive aspergillosis have also been reported as complications of coronavirus disease 2019 infection.
The treatment and prevention of invasive aspergillosis are reviewed here. The clinical features and diagnosis of invasive aspergillosis are discussed separately; treatment of the other manifestations of Aspergillus infection is also presented elsewhere. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Diagnosis of invasive aspergillosis" and "Fungal rhinosinusitis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Chronic pulmonary aspergillosis: Treatment".)
The epidemiology and prophylaxis of invasive fungal infections in patients with hematologic malignancies and hematopoietic cell transplant recipients are also discussed in greater detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)
GENERAL PRINCIPLES — The general approach to management presented in this topic review is intended to apply to the various clinical manifestations of invasive aspergillosis. The most common clinical manifestation of invasive aspergillosis is pulmonary disease, but other manifestations include central nervous system infection, rhinosinusitis, endocarditis, gastrointestinal disease, and others. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Clinical features'.)
Expert guidelines — Optimal management involves early and definitive diagnosis as well as early initiation of antifungal therapy . In addition to antifungal therapy, surgery should be considered for patients with certain manifestations. Reduction of immunosuppression, when feasible, is another important component of management. Surgery and reduction of immunosuppression are discussed in detail below. (See 'Role of surgery' below and 'Reduction of immunosuppression' below.)
Guidelines for the treatment and prevention of aspergillosis have been published by several organizations, including the Infectious Diseases Society of America (IDSA), which published updated guidelines for the treatment of aspergillosis in 2016 . Guidelines also have been published by the European Conference on Infections in Leukemia in 2017  and the European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology, and the European Respiratory Society in 2018 . These guidelines for the management of invasive aspergillosis are generally similar and reflect increasing experience with and evidence supporting newer antifungal agents and management strategies [1-3]. Links to guidelines are provided separately. (See 'Society guideline links' below.)
Our recommendations agree with the recommendations in the IDSA and other guidelines regarding voriconazole or isavuconazole being an essential element of therapy for most patients. The IDSA guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in select patients. Many experts would consider combination therapy for severe disease, particularly in patients with hematologic malignancy and/or in those with profound and persistent neutropenia . Our approach and the data regarding combination therapy are discussed in detail below. (See 'Choice of regimen' below and 'Voriconazole' below and 'Voriconazole and an echinocandin' below.)
Expert recommendations have also been developed on the clinical management of pulmonary aspergillosis associated with coronavirus disease 2019 (COVID-19) infection . Maintaining a high degree of suspicion is critical to diagnosing pulmonary aspergillosis in the setting of COVID-19, but management recommendation are the same as for other forms of invasive aspergillosis.
Consideration of antifungal resistance — It is important to consider the likelihood of resistance when choosing initial therapy. Antifungal resistance is being detected with increasing frequency in some geographic regions and is more likely to occur with certain Aspergillus species.
Antifungal susceptibility testing may help guide choices of antifungal agents. (See "Antifungal susceptibility testing".)
A. fumigatus — Among A. fumigatus isolates, resistance patterns vary geographically.
●United States – In the US, in vitro resistance among A. fumigatus is uncommon. A study of over 2000 Aspergillus isolates (97 percent of which were A. fumigatus) collected throughout the US from 2015 to 2020 found that 99 percent of isolates were susceptible to amphotericin B . Azoles exhibited good activity as well, with susceptibility rates ranging from 91 to 95 percent. Although echinocandin results were not specifically reported, the study stated that "very few" isolates were resistant to the echinocandin class.
However, there may be higher resistance rates within certain patient groups. Reports have emerged of increased MICs for triazoles among patients with hematologic malignancies or hematopoietic stem cell transplant recipients who have had prior exposure to azoles, but the clinical implications of this finding remain unknown .
●Countries other than the United States – Globally, isolates of A. fumigatus with resistance to multiple azoles are increasing in prevalence [7-17].
In the Netherlands and Western Europe, triazole resistance rates over 25 percent have been reported in some centers and are associated with increased treatment failure and mortality [11,15,18-20]. In the Netherlands, a clone with a resistance mutation (TR34/L98H) that causes pan-azole resistance has emerged, with an annual prevalence of seven percent of Aspergillus isolates between 2012 and 2016 . Another less common mutation (TR46/Y121F/T289A) has been discovered in the Netherlands that confers high-level resistance to voriconazole and isavuconazole and increased MICs to posaconazole; these isolates have been found in indoor and outdoor environments and appear to be associated with widespread use of triazole fungicides in the Netherlands and elsewhere [18,21]. Transfer of these isolates from one locale to another has been documented, including a report of plant bulbs imported from the Netherlands to Ireland that harbored triazole-resistant A. fumigatus .
Outside Europe and the United States, epidemiology of A. fumigatus resistance has not been as thoroughly evaluated. Nonetheless, surveillance studies and case series have reported azole-resistant A. fumigatus in the Middle East, Africa, Australia, and North and South America [15,23,24].
Species other than A. fumigatus — Certain species of Aspergillus are known to have variable susceptibilities to different antifungal drugs.
A. terreus is intrinsically less susceptible to amphotericin B in vitro and in animal models, and clinical reports suggest that outcomes are better with use of alternative drugs such as voriconazole or isavuconazole . (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".)
Other species, such as A. calidoustus, A. lentulus, and Neosartorya udagawae, generally exhibit innately high-level resistance to multiple antifungal agents, including amphotericin B and voriconazole. The clinical significance of this resistance is not well defined, although case series suggest poor outcomes in patients with documented infection [26-28]. (See 'Initial therapy' below and 'Salvage therapy' below.)
Choice of regimen — Three classes of antifungal agents are available for the treatment of aspergillosis: polyenes, azoles, and echinocandins. Appropriate therapy for aspergillosis depends upon the host's immune status, organ function (kidney and liver), prior therapies, and risk of a resistant pathogen.
Initial therapy — As noted above, the recommendations in this topic review are intended to apply to the various clinical manifestations of invasive aspergillosis, the most common of which is invasive pulmonary aspergillosis. An exception is Aspergillus endophthalmitis, which is discussed in detail separately. (See "Treatment of endophthalmitis due to molds".)
Patients with established diagnosis of invasive aspergillosis
●For initial therapy of invasive aspergillosis, we recommend voriconazole if a resistant pathogen is not suspected. We use monotherapy for most patients, but for severe disease, we use combination therapy with voriconazole and an echinocandin .
However, some experts prefer monotherapy with voriconazole even for severe cases. The routine use of combination therapy is not recommended in most guidelines because of the lack of definitive randomized clinical trial data to support its use. The decision of whether to give combination therapy should be weighed against the risk of toxicities and the feasibility of intravenous therapy. (See 'Voriconazole and an echinocandin' below.)
Regimen selection for cases when azole resistance is suspected is discussed elsewhere. (See 'When azole resistance is suspected' below.)
●For patients who cannot tolerate voriconazole or when it is advisable to avoid its side effects, posaconazole and isavuconazole are the preferred alternatives. Both have been shown to be as effective as voriconazole and to be better tolerated in randomized trials [29,30]. However, because clinical experience with these agents is limited, we prefer voriconazole when possible, particularly in patients with severe disease. Liposomal amphotericin B (AmBisome) or amphotericin B lipid complex (Abelcet) are additional alternatives but these agents carry the risk of nephrotoxicity and are only available intravenously.
The decision of which azole to choose depends on organ dysfunction, toxicities, tolerability, and need for initial intravenous therapy. As examples, we consider using posaconazole over voriconazole in patients who have sustained visual disturbances, other neurologic disturbances, or dermatologic toxicity with voriconazole. Isavuconazole is a potential alternative for patients with a prolonged QTc or for patients who require intravenous therapy but cannot receive intravenous voriconazole due to its cyclodextrin vehicle. (See 'Voriconazole' below and 'Isavuconazole' below and 'Posaconazole' below.)
Azoles sometimes interact with chemotherapy agents used in conditioning regimens, potentially increasing toxicities (eg, neurotoxicity from vincristine) or reducing the efficacy of certain cytotoxic drugs. If a patient is receiving interacting chemotherapeutic agents, then a noninteracting mold-active antifungal agent should be given.
●We generally reserve amphotericin B for patients at risk for drug interactions with azoles, severe hepatotoxicity, or isolates suspected to be triazole-resistant. We favor lipid formulations of amphotericin B over amphotericin B deoxycholate. (See 'When azole resistance is suspected' below.)
Patients with suspected invasive mold infection without confirmation of Aspergillus — For patients in whom an invasive mold infection is suspected but the diagnosis of invasive aspergillosis has not been established, we suggest treating empirically with a lipid formulation of amphotericin B, particularly in those who have recently received voriconazole or another azole. In this situation, the use of amphotericin B provides antifungal activity against both Aspergillus spp and other molds such as Mucorales. This is particularly important when patients have received voriconazole previously, because Mucorales are intrinsically resistant to this drug [31,32]. When the diagnosis is uncertain, further diagnostic studies should be pursued aggressively even after empiric therapy has been initiated. If the diagnosis of aspergillosis is established, we suggest changing to a voriconazole-based regimen, with consideration of addition of an echinocandin for those with severe disease. For patients in whom Aspergillus seems most likely but mucormycosis remains a possibility, de-escalating to isavuconazole or posaconazole, rather than voriconazole, is appropriate once the patient experiences clinical improvement after two weeks of therapy with a lipid formulation of amphotericin B. (See "Diagnosis of invasive aspergillosis" and "Mucormycosis (zygomycosis)" and 'Lipid formulations' below.)
When azole resistance is suspected — Our approach to antifungal therapy when azole resistance is suspected depends on the likelihood of resistance and is generally consistent with recommendations from an international expert panel on treatment of azole-resistant A. fumigatus infections :
●When local prevalence of azole resistance among Aspergillus species is ≥10 percent, we favor empiric treatment with liposomal amphotericin B while awaiting susceptibility results. Another option would be to initiate combination therapy with voriconazole plus an echinocandin. The rationale for the latter regimen is that voriconazole treatment of susceptible isolates is associated with improved outcomes, including mortality, compared with amphotericin B; echinocandins have some in vitro activity against Aspergillus spp and might control the infection if the isolate is subsequently found to be azole resistant. One study showed that mortality was higher when empiric voriconazole monotherapy was initiated for infections ultimately determined to be voriconazole resistant .
●When the local prevalence of azole resistance is between 5 and 10 percent, appropriate options include monotherapy with either voriconazole or a lipid formulation of amphotericin B or combination therapy with voriconazole plus an echinocandin while awaiting susceptibility results. In seriously ill patients, we prefer to use a lipid formulation of amphotericin B.
●For individuals with invasive aspergillosis in areas with high rates of Aspergillus resistance who are diagnosed by nonculture-based methods (such as galactomannan or PCR), we favor initial therapy with a lipid formulation of amphotericin B.
If susceptibility results become known, directed therapy can be based on those results.
Salvage therapy — In patients with refractory or progressive invasive aspergillosis and in patients in whom infection has emerged or progressed despite antifungal prophylaxis, an individualized approach should be taken that considers the rapidity and severity of infection as well as the local epidemiology of Aspergillus infection . In these patients, an aggressive and prompt attempt to establish a specific mycologic diagnosis should be pursued, usually with bronchoscopy and bronchoalveolar lavage or, for peripheral lung lesions, a computed tomography (CT)-directed biopsy, if feasible in patients who have thrombocytopenia. Measurement of antifungal serum concentration is appropriate for patients receiving azole therapy who have refractory or progressive disease. If an isolate is available, susceptibility testing should be performed.
In most cases, antifungal therapy should be empirically changed to another drug class (usually to liposomal amphotericin B) pending a definitive diagnosis. Combination therapy with voriconazole or another mold-active azole such as isavuconazole or posaconazole plus an echinocandin can be given if Aspergillus is confirmed to be the pathogen, particularly if susceptibility results are available. In addition to antifungal therapy, immunosuppression should be reduced, if feasible.
We do not use other combinations such as amphotericin B with a triazole as there are no clinical data to support their use. In many cases of progressive disease, factors such as uncontrolled underlying disease lead to clinical failure rather than drug resistance or drug failure.
Several different members of the A. fumigatus species complex exhibit high MICs to azoles (eg, "cryptic" Aspergillus spp such as A. lentulus that are slow to form conidia and are often difficult to identify). Additionally, A. fumigatus can acquire resistance to azoles by mutations in the drug target; these organisms have emerged globally, likely due to environmental use of agricultural fungicides. These isolates frequently demonstrate cross-resistance to all azoles and have caused infections in patients who had not received prior azole therapy. In patients with documented infection who do not respond to initial therapy, antifungal susceptibility testing should be performed. (See 'Consideration of antifungal resistance' above.)
Dosing and drug effects
●Voriconazole – Voriconazole is available in both intravenous and oral formulations [31,34,35]. The recommended dosing regimen is 6 mg/kg IV every 12 hours on day 1 followed by 4 mg/kg IV every 12 hours thereafter. When the patient is able to take oral medications, one can consider switching to the oral form. Optimal oral dosing is a matter of controversy. The currently recommended dose of 200 mg orally every 12 hours has been noted to result in low or even unmeasurable serum concentrations in a substantial proportion of patients, and high concentrations may be associated with excessive toxicities . The dose of oral voriconazole can be increased to 4 mg/kg orally every 12 hours (or 300 mg orally every 12 hours) in patients with disease progression. Higher doses may be required to achieve appropriate serum concentrations, but therapy should be carefully monitored by serial measurement of serum concentrations.
We monitor serum voriconazole trough concentrations in all patients receiving voriconazole for treatment or prevention of invasive aspergillosis. We check a trough concentration four to seven days into therapy and after every dosage change; we also measure levels whenever toxicity occurs or new medications are added that may alter absorption. For most patients, we aim for a target serum trough concentration between 1 and 5.5 mcg/mL, but for those with severe infection (eg, multifocal or disseminated disease, central nervous system infections), we favor a serum trough concentration between 2 and 6 mcg/mL . Trough concentrations below 1 mcg/mL warrant an increase in the voriconazole dose and appropriate subsequent monitoring . On the other hand, elevated serum drug concentrations warrant a reduction in the voriconazole dose because they have been associated with an increased risk of toxicity, particularly neurotoxicity, including hallucinations, delirium, and delusions [36,38]. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
Voriconazole is associated with a number of drug interactions, which the clinician should carefully check for when prescribing this medication. The drug has also been reported to cause visual changes, hallucinations, a prolonged QTc interval, neuropathy, central nervous system alterations (eg, memory loss, difficulty concentrating), alopecia, and a photosensitivity skin rash that has been linked to squamous cell carcinoma. (See "Pharmacology of azoles", section on 'Voriconazole'.)
Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate. An overview of the drug interactions associated with the azoles is presented separately. (See "Pharmacology of azoles", section on 'Drug interactions'.)
●Isavuconazole – Loading doses of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole base) every 8 hours for 6 doses (48 hours) via oral (2 capsules) or IV administration, followed by 372 mg once daily (equivalent to 200 mg of isavuconazole base) orally or IV starting 12 to 24 hours after the last loading dose . Isavuconazole is formulated as the prodrug, isavuconazonium sulfate. How the dose is expressed (ie, isavuconazonium sulfate salt, isavuconazole base, or both) can differ between countries. As an example, the available product in the United States is expressed primarily in milligrams of isavuconazonium sulfate salt, whereas the product in Canada, European countries, and the United Kingdom is expressed primarily in equivalent amount of isavuconazole base. To avoid confusion, clinicians should consult local labeling before prescribing.
Data from clinical trials show consistent isavuconazole levels in most patients receiving the drug, and clinical experience has supported these findings . Routine measurement of serum isavuconazole levels may therefore not be necessary. However, we suggest measurement of serum isavuconazole levels in patients with severe or progressive disease, breakthrough infection, signs of toxicity, or in patients with potential drug interactions that could alter isavuconazole levels. Optimal drug concentrations have not been established, but most patients achieve levels >1 mcg/mL with standard dosing regimens; an upper limit associated with toxicity has not been established.
The most common adverse reactions associated with isavuconazole are nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, and peripheral edema . Isavuconazole may also cause serious side effects including hepatotoxicity and infusion reactions. Isavuconazole is associated with shortening of the QT interval, the clinical significance of which remains unclear. It is contraindicated in patients with familial short QT syndrome but is preferred in patients who already have long QTc intervals. (See "Pharmacology of azoles", section on 'Isavuconazole'.)
●Posaconazole – Intravenous or delayed-release formulations are preferred for the treatment of aspergillosis. Both formulations require a loading dose of 300 mg twice daily on the first day followed by a 300 mg daily dose thereafter. Switching between intravenous and delayed-release tablets is acceptable and does not require an additional loading dose . For prophylaxis of invasive aspergillosis in high-risk patients, the intravenous and delayed-release formulations are also recommended at those same doses. An oral suspension at a dose of 200 mg three times a day is approved by the US Food and Drug Administration (FDA) for prophylaxis of invasive aspergillosis but we do not recommended its use due to limited absorption of the drug. A delayed-release oral suspension is available but not for use in adults.
We typically measure drug levels of posaconazole for patients who receive the agent for treatment or prophylaxis. For treatment of serious infections, we target posaconazole concentrations of 1.5 to 3.75 mg/L. For prophylaxis, we target levels of 0.7 to 3.75 mg/L. Most patients on standard dosages do not have levels above 3.75 mg/L, a level at which risk of toxicity (eg, posaconazole-induced pseudohyperaldosteroinsm [PIPH]) may be elevated [42,43] (see "Pharmacology of azoles", section on 'Posaconazole'). We measure levels approximately four to five days after initiating the agent and after every dosage change; we also measure levels whenever toxicity occurs or new medications are added that may alter absorption. While use of the delayed-release tablets or intravenous formulations substantially increases the likelihood of achieving target drug levels (>0.7 mg/L for prophylaxis and >1.5 for treatment), we measure drug levels in most patients in order to document absorption and to evaluate for potential supratherapeutic levels .
Patients with gastrointestinal disorders and limited absorption may have lower concentrations. Among patients with graft versus host disease (GHVD), 56 percent of patients receiving prophylaxis and 30 percent of patients receiving treatment had subtherapeutic concentrations in one study . Conversely, >10 percent of patients are reported to have supratherapeutic levels. Thus, monitoring levels is particularly important in patients with GHVD, those with impaired gastrointestinal absorption, and when there is clinical concern for toxicity.
In a randomized trial comparing posaconazole with voriconazole, the most frequently reported treatment-related adverse events (incidence >3 percent) were increased aspartate aminotransferase or alanine aminotransferase, nausea, hypokalemia, and vomiting in the posaconazole group. The overall incidence of treatment-related adverse event rates was 30 percent for posaconazole and 40 percent for voriconazole but was not statistically different (treatment difference -10·2%; 95% CI -17·9 to -2·4) .
A syndrome of posaconazole-induced pseudohyperaldosteronism occurs with elevated posaconazole serum concentrations. When this occurs, dosage reduction or changing to another antifungal may be required [46,47]. This syndrome is associated with hypertension and hypokalemia and is more common in patients who are older and those who have baseline hypertension . While the overall incidence is not known, it was detected in 23.2 percent of patients in one small study . The diagnosis is made by laboratory testing that shows an elevated 11-deoxycortisol, undetectable plasma aldosterone, and low to low-normal renin activity in the absence of other conditions or medications that may cause similar laboratory values.
●Echinocandins – The echinocandins are available as intravenous formulations only. Dose adjustment is not required in patients with renal insufficiency, including patients who are receiving hemodialysis or continuous renal replacement therapy (continuous venovenous hemofiltration or continuous venovenous hemodialysis). The recommended dosing of each echinocandin is:
•Micafungin – 100 to 150 mg IV dose daily; no loading dose is required.
•Anidulafungin – 200 mg IV loading dose on day 1, followed by 100 mg IV daily.
Echinocandins are well tolerated, and all three members of the class have similar types of adverse effects. Serious adverse effects requiring drug discontinuation occur less frequently with the echinocandins than with other classes of systemic antifungals. Modest asymptomatic elevations of aminotransferases and alkaline phosphatase are the most frequently reported laboratory abnormalities in healthy volunteers and patients treated with echinocandins. Clinically relevant drug interactions are uncommon. The pharmacology of the echinocandins is discussed in detail separately. (See "Pharmacology of echinocandins".)
●Amphotericin B lipid formulations – The dosing of lipid formulations of amphotericin B is:
•Amphotericin B lipid complex (Abelcet) – 5 mg/kg IV daily. This drug has not been evaluated for aspergillosis in large randomized trials but is approved for use in the setting of salvage therapy.
Lipid formulations of amphotericin B are less likely to cause nephrotoxicity than amphotericin B deoxycholate. Other adverse effects of amphotericin B formulations include infusion-related reactions and electrolyte abnormalities. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".)
Duration — The duration of antifungal therapy is dependent upon the location of the infection, the patient's underlying disease, the need for further immunosuppression, and the response to therapy. Antifungal therapy is generally continued until all signs and symptoms of the infection have resolved and often longer in patients with persistent immune defects. Radiographic abnormalities should have stabilized and signs of active infection should have disappeared before treatment is discontinued. The minimum duration of therapy is 6 to 12 weeks , but, for most immunosuppressed patients, antifungal therapy will continue for months or even years in some cases.
When combination therapy with an azole and an echinocandin is used, we suggest continuing both medications for two weeks before transitioning to monotherapy. Adjustments in duration of combination therapy can be made based on clinical response. There are no data on the optimal duration of combination therapy. In one trial of combination therapy, the echinocandin was given for a planned two to four weeks (median actual duration was 14 days) before step-down to voriconazole monotherapy .
For patients with endocarditis or other severe forms of infection such as brain abscess, we give lifelong suppressive antifungal therapy with an oral triazole (eg, voriconazole, isavuconazole, posaconazole) at the same doses as those used for treatment .
Efficacy and safety
Triazoles — Triazole antifungal agents include voriconazole, posaconazole, itraconazole, and fluconazole. Fluconazole has no activity against Aspergillus spp, and itraconazole has become a second-line agent for aspergillosis.
Voriconazole — Voriconazole should be included in the antifungal regimen in most patients with invasive aspergillosis [1,49-54]. The best efficacy data come from the Global Comparative Aspergillus Study, an international multicenter randomized open-label trial in which voriconazole was compared with amphotericin B deoxycholate followed by other licensed antifungal therapy as initial therapy in 277 patients with confirmed or probable invasive aspergillosis . Patients with multiple underlying diseases were enrolled, although the majority had hematologic malignancies and many had undergone hematopoietic cell transplantation (HCT). Primary therapy with voriconazole (administered at 6 mg/kg IV twice a day on day 1, followed by 4 mg/kg twice daily for at least seven days, with the option to switch to oral dosing at 200 mg orally twice daily thereafter) was compared with amphotericin B deoxycholate (1 to 1.5 mg/kg IV daily). The treating clinician had the opportunity to switch the patient to another antifungal agent for drug intolerance or clinical failure. Most of the changes in therapy were in the amphotericin B deoxycholate arm; patients were most often switched to a lipid formulation of amphotericin B because of intolerance.
●A greater likelihood of a complete or partial response (53 versus 32 percent)
●A lower mortality rate (29 versus 42 percent)
●A lesser likelihood of the clinician changing the patient to another antifungal agent because of intolerance or poor response (36 versus 80 percent)
●A lower rate of severe adverse reactions, although 45 percent of patients receiving voriconazole reported transient visual disturbances
These findings suggest that voriconazole is superior to amphotericin B deoxycholate in patients with invasive aspergillosis. The relative efficacy of voriconazole compared with a lipid formulation of amphotericin B is unknown since no comparative studies have been published.
Because predefined definitions used for the Global Comparative Aspergillus Study were different from the consensus definition proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group , the data from this trial were reanalyzed after recategorizing patients according to the consensus definition . After recategorization, response rates still favored voriconazole over amphotericin B.
Voriconazole may also have a role in the setting of central nervous system disease, for which the mortality rate historically has approached 100 percent. In a retrospective study of 48 patients with definite and 33 patients with probable central nervous system aspergillosis, 31 percent of patients who received voriconazole survived for a median observation time of 390 days . The vast majority of patients had received antifungal agents other than voriconazole for a median of 31 days prior to receiving voriconazole.
Isavuconazole — Isavuconazole was approved by the FDA for the treatment of invasive aspergillosis in 2015 . Its approval was based on a phase III noninferiority trial that involved 527 patients who had suspected invasive fungal disease caused by Aspergillus spp or another filamentous fungus and who were randomly assigned to receive either isavuconazole or voriconazole . All-cause mortality through day 42 in the overall intention-to-treat population was 19 percent in the isavuconazole group and 20 percent in the voriconazole group. Similar results were seen in patients with proven or probable invasive aspergillosis . Drug-related adverse effects were reported in 42 percent of patients receiving isavuconazole and 60 percent of patients receiving voriconazole. Patients receiving isavuconazole had a lower frequency of hepatobiliary disorders (9 versus 16 percent), eye disorders (15 versus 27 percent), and skin or subcutaneous disorders (33 versus 42 percent). Drug interactions associated with isavuconazole may be less significant than those seen with voriconazole, although interactions with drugs metabolized through cytochrome 3A4 occur.
Posaconazole — Posaconazole is a broad-spectrum triazole. Posaconazole injection and delayed-release tablets are FDA approved for the treatment of invasive aspergillosis in patients ≥13 years; the delayed-release tablets are also approved for the prevention of aspergillosis . An oral suspension of posaconazole is also available but its absorption is less reliable than the delayed-release tablets. Thus, delayed-release tablets are preferred. (See "Pharmacology of azoles", section on 'Posaconazole'.)
The efficacy and safety of the oral suspension of posaconazole as monotherapy was investigated in an open-label multicenter trial in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy . Data from external control cases were collected retrospectively as a comparative reference group. The overall success rate was 42 percent for 107 posaconazole recipients and 26 percent for 86 controls. The differences in treatment outcomes were maintained across several prespecified patient subsets (eg, site of infection, underlying disease, and indication for enrollment, refractory disease versus intolerance of therapy). Patients with the highest quartile of serum posaconazole levels (mean 1250 mcg/mL) were more likely to have favorable responses than those in the lowest quartile of drug levels (mean 124 mcg/mL; favorable responses: 12 of 16 [75 percent] in the highest quartile group versus 4 of 17 [24 percent] in the lowest quartile group). Drug levels with the extended-release tablet formulation and with the intravenous formulation are significantly increased compared with the oral suspension, so that most patients will have levels >1 mcg/mL and approximately 10 percent will have levels >3.5 mcg/mL [44,61].
In a randomized trial comparing posaconazole versus voriconazole for the treatment of invasive aspergillosis in 575 patients, all-cause mortality at day 42 was lower in the posaconazole group (15 versus 21 percent, p<0.0001) in the intention to treat analysis . When analysis was limited to patients with proven or probable invasive aspergillosis, all-cause mortality was similar between groups (19 percent [31/163] in the posaconazole group versus 19 percent [32/171] in voriconazole group). Clinical response rates (both complete and partial response to therapy) and day 84 all-cause mortality were also similar between groups. Treatment-related adverse effects were lower in the posaconazole group and fewer patients stopped the study drug due to adverse effects in the posaconazole group, though these results were not statistically significant.
The posaconazole extended-tablet formulation is generally well tolerated; the most common side effect of posaconazole is gastrointestinal upset . A syndrome of apparent mineralocorticoid excess associated with hypertension, hypokalemia, and alkalosis due to posaconazole has also been described . (See "Pharmacology of azoles", section on 'Posaconazole'.)
Itraconazole — Itraconazole is not a first-line agent for the treatment of invasive aspergillosis, and it should not be used in immunocompromised patients with invasive disease. Oral itraconazole has been used in selected patients with mild immunosuppression and nonlife-threatening Aspergillus infection or in patients who had already been stabilized with amphotericin B. In a multicenter open-label study of 76 evaluable patients who were treated with itraconazole, only 39 percent had a complete or partial response . Other drawbacks associated with use of itraconazole include the requirement of an acid environment for absorption, poor bioavailability, and important drug interactions. Adverse events include substantial hepatotoxicity as well as its propensity for causing or exacerbating heart failure, which has resulted in an FDA boxed warning. (See "Pharmacology of azoles", section on 'Drug interactions'.)
When used for the treatment of aspergillosis, the serum itraconazole concentration should be measured two weeks into therapy. If there is a change in clinical condition, serum concentrations of itraconazole should be rechecked. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
Amphotericin B deoxycholate — Administration of amphotericin B deoxycholate is associated with severe nephrotoxicity, and treatment outcomes have been poor. Unless lipid formulations of amphotericin B or other mold-active antifungals are unavailable, amphotericin B deoxycholate is not recommended for use in invasive aspergillosis.
Lipid formulations — There are two currently marketed lipid formulations of amphotericin B:
●Liposomal amphotericin B (AmBisome)
●Amphotericin B lipid complex (Abelcet)
The main advantage of the lipid formulations is the ability to administer larger doses of amphotericin B with fewer toxicities. Amphotericin B lipid complex and liposomal amphotericin B have fewer infusion-related side effects than amphotericin B deoxycholate . The lipid formulations, although less toxic, have not been definitively shown to result in better outcomes compared with conventional amphotericin B.
When using a lipid formulation of amphotericin B for the treatment of invasive aspergillosis, we prefer liposomal amphotericin B (AmBisome) at an initial dose of 3 to 5 mg/kg IV per day [1,3,67]; amphotericin B lipid complex (Abelcet) at a dose of 5 mg/kg IV per day is an appropriate alternative .
A small observational study suggested that using higher doses of lipid formulations of amphotericin B results in better response rates . However, a randomized trial in 201 patients with confirmed invasive pulmonary aspergillosis compared the efficacy of 10 mg/kg per day versus 3 mg/kg per day dosing for the first 14 days of treatment, followed by receipt of 3 mg/kg per day . The vast majority of patients had underlying hematologic malignancies and neutropenia. Patients assigned to the higher dosing arm had a higher rate of nephrotoxicity without any additional clinical benefits. Based on these data and our clinical experience as well as that of other experts, we feel that 3 to 5 mg/kg IV once daily is the appropriate dose of AmBisome and 5 mg/kg once daily is the appropriate dose of amphotericin B lipid complex for treating invasive pulmonary aspergillosis, although higher doses may be appropriate for less susceptible isolates, progressive infection, or disseminated or central nervous system disease.
Echinocandins — The echinocandins include caspofungin, micafungin, and anidulafungin. Caspofungin has been approved by the FDA for the treatment of invasive aspergillosis in patients who cannot tolerate or who are refractory to standard therapy . The other echinocandins, micafungin and anidulafungin, are not FDA approved for the treatment of invasive aspergillosis. However, these agents have activity against Aspergillus spp, and all three echinocandins are considered to have equivalent efficacy.
The echinocandins should not be utilized for initial monotherapy of invasive aspergillosis. Echinocandins are sometimes used for initial therapy and salvage therapy, in combination with another antifungal drug [28,70-72]. (See 'Combination therapy' below.)
In a compassionate salvage treatment trial for proven or probable invasive aspergillosis, caspofungin was administered to 83 patients who were intolerant of standard therapy (15 percent of patients) or whose infection was refractory to standard therapy (85 percent of patients) . Almost all had previously received an amphotericin B formulation. The overall complete and partial success rate was 45 percent; as expected, the response rates were higher for the patients who were intolerant of standard therapy compared with those who were refractory (75 versus 40 percent) .
Combination therapy — Combination antifungal therapy has been evaluated both as initial therapy and as salvage therapy in patients who have not responded to their initial regimen .
Voriconazole and an echinocandin — The strongest evidence for combination therapy with voriconazole and an echinocandin comes from a large randomized trial that assessed the safety and efficacy of six weeks of voriconazole with or without two to four weeks of anidulafungin for the treatment of invasive aspergillosis in patients with hematologic malignancies and/or HCT . Results showed a trend toward improved six-week survival (the primary endpoint) with the combination of voriconazole and anidulafungin compared with voriconazole monotherapy but did not reach statistical significance. Among the 277 patients with documented proven or probable invasive aspergillosis, six-week mortality was 19.3 percent for combination therapy and 27.5 percent for monotherapy, suggesting a trend toward improved survival with combination therapy (95% CI -19.0 to 1.5). In a post-hoc analysis of 222 patients who had probable invasive aspergillosis defined by radiographic abnormalities and a positive serum or bronchoalveolar lavage fluid galactomannan antigen, a statistically significant difference in mortality was observed (16 percent with combination therapy versus 27 percent with voriconazole monotherapy; 95% CI -22.7 to -0.4).
The following observations illustrate the range of findings of combination antifungal therapy in other clinical studies:
●One study evaluated 47 patients with evidence of progressive infection after seven or more days of treatment with an amphotericin B preparation . Thirty-one patients were treated with voriconazole alone; the next 16 patients were given voriconazole plus caspofungin. Using a multivariate model, at three months, patients who received combination therapy had a significantly lower rate of mortality compared with those who received voriconazole monotherapy (odds ratio [OR] 0.28, 95% CI 0.28-0.92).
●In a retrospective analysis of 405 HCT recipients with probable or proven aspergillosis, there was no difference in clinical outcomes in the 33 patients treated with voriconazole and caspofungin as primary antifungal therapy compared with those who were treated with voriconazole monotherapy .
●In another study, 40 solid organ transplant patients who received voriconazole and caspofungin as primary therapy were compared with a historical control group of 47 patients who received liposomal amphotericin B . Combination therapy was associated with reduced mortality in the subset of patients with A. fumigatus infection (adjusted hazard ratio [HR] 0.37, 95% CI 0.16-0.84) and in those with renal failure (adjusted HR 0.32, 95% CI 0.12-0.85).
Despite the suggestion of benefit of combination therapy with voriconazole and caspofungin in some studies, there are major limitations to study designs, limiting conclusions. Without clearly documented, replicable evidence of superiority, the clinician must weigh the risks and benefits of giving two drugs based upon an individual assessment of potential toxicities, severity of disease, and degree of immunosuppression, as well as practical considerations including cost and the feasibility of IV therapy. Historical controls are of limited utility because improvements in early diagnosis and therapy of the underlying condition will impact outcomes in the cohort treated during a later time period . (See "Diagnosis of invasive aspergillosis".)
Experimental models of aspergillosis have also suggested benefit of a variety of antifungal combinations, but results have varied [78-80].
Liposomal amphotericin B and an echinocandin — Prior to the availability of voriconazole, there was substantial interest in combination regimens of liposomal amphotericin B (AmBisome) and caspofungin for invasive aspergillosis. This combination has shown some benefit compared with liposomal amphotericin monotherapy but has not been studied in randomized trials nor has it been compared with voriconazole-based regimens.
In a small prospective open-label study of 30 patients with hematologic malignancies with probable or, in a few cases, proven invasive aspergillosis, a combination of liposomal amphotericin B (3 mg/kg IV daily) and caspofungin was compared with monotherapy with high-dose liposomal amphotericin B (10 mg/kg IV daily) for initial therapy . There were significantly more favorable responses (partial or complete) in the combination therapy group (10 of 15 patients versus 4 of 15 patients with liposomal amphotericin B). At 12 weeks, survival rates were 100 percent in the combination therapy group compared with 80 percent in the amphotericin B monotherapy group.
The combination of liposomal amphotericin B and caspofungin has also been studied in small retrospective studies as a salvage regimen [70,71]. One of these studies evaluated 48 patients with hematologic malignancy and invasive aspergillosis (23 probable, 25 possible); in two-thirds of patients, caspofungin was added after failure to respond to at least seven days of liposomal amphotericin . Only 18 percent of these patients responded to combination therapy.
Amphotericin B and triazoles — There are no clinical data to support the use of amphotericin B with a triazole for combination therapy [82,83]. Animal models of aspergillosis suggest that triazoles may be antagonistic when given concomitantly or sequentially with amphotericin B [82-85]. One proposed mechanism to explain these observations includes the reduction of amphotericin B binding to fungal membranes due to azole inhibition of the ergosterol biosynthetic pathway . An alternative mechanism may be the accumulation of azole in the cell membrane, which competitively inhibits the binding of amphotericin B to ergosterol.
Reduction of immunosuppression — Whenever possible, the degree of immunosuppression should be decreased as an adjunct to antifungal therapy for the treatment of invasive aspergillosis . The worst outcomes occur in patients with persistent, severe immune dysfunction and in those with organ impairment that limits administration of antifungals. Although the relative contribution of these prognostic indicators is unclear, it is generally accepted that decreasing immune suppression will result in improved outcomes. Invasive aspergillosis occurs most commonly in the setting of immunosuppression, particularly chemotherapy-induced neutropenia or glucocorticoid administration for graft-versus-host disease (GVHD). In neutropenic patients, recovery of bone marrow function is critical to the control of aspergillosis ; in the hematopoietic cell transplant (HCT) recipient with aspergillosis, for example, failure to engraft will result in death due to this infection.
The high mortality observed in invasive aspergillosis reflects the influence of the underlying disease on outcome and the frequent inability to improve immunosuppression . In a detailed review of 405 patients who had aspergillosis in the setting of HCT or treatment of hematologic malignancy, the most important prognostic factors included clinical variables that dictated overall immune impairment (GVHD severity and human leukocyte antigen mismatch), relative paucity of multiple cell types (neutropenia, monocytopenia, and lymphocytopenia), and kidney and liver impairment .
Colony-stimulating factors — At present, we do not recommend routine use of colony-stimulating factors in neutropenic patients with invasive aspergillosis [1,88]. Consideration of the risks and benefits should be made on a case-by-case basis.
Colony-stimulating growth factors enhance neutrophil chemotaxis and phagocytosis and attract neutrophils to the site of inflammation. In clinical studies, granulocyte colony-stimulating factor (G-CSF) shortens the period of neutropenia following myelosuppressive chemotherapy, leading to shorter hospitalizations, fewer documented infections, and fewer days of antimicrobial therapy. Despite these positive effects, there is currently no definitive proof that hematopoietic growth factors decrease mortality from infection, improve the response rate to antibiotics, or improve overall survival. Furthermore, there is no evidence to support the role of colony-stimulating factors to increase innate neutrophil fungicidal capacity.
Granulocyte transfusions — There are few data to support the use of donor granulocyte transfusions for the management of patients with neutropenia and invasive aspergillosis. Experience has been limited to situations in which severe disease warranted drastic measures. A randomized trial that assessed granulocyte transfusion from G-CSF-dexamethasone-treated donors enrolled few patients with invasive mold infections and did not show any evidence of benefit . The use of granulocyte transfusions is discussed in detail separately. (See "Granulocyte transfusions".)
ROLE OF SURGERY — In addition to antifungal therapy, surgical management to debride necrotic tissue may be appropriate as adjunctive therapy in some complex cases with chronic necrotizing disease . The decision of whether to perform surgery depends on many factors, including the extent and location of the lesion(s), the degree of resection required, comorbidities, performance status, the ability of the patient to tolerate surgery, and the underlying disease . Patients with hematologic malignancies and hematopoietic cell transplant (HCT) recipients are rarely appropriate candidates for surgery; surgical complications in this setting are frequent and include bleeding (due to thrombocytopenia), secondary infections including empyema, and nonhealing wounds.
Surgery is recommended for localized infections that are easily accessible for debridement (eg, invasive rhinosinusitis, localized cutaneous disease) . Our approach to surgical management for specific clinical manifestations includes the following:
●Rhinosinusitis – Emergent debridement of Aspergillus rhinosinusitis can limit extension to the orbit and brain and can be lifesaving . Debridement appears to be a useful adjunct to antifungal therapy for Aspergillus rhinosinusitis, according to at least one case series . Radical surgical debridement is required in some cases to achieve cure and sometimes requires multiple surgeries. The need for surgery may depend on the degree of fungal bone invasion at diagnosis and anticipated risks in the setting of severe thrombocytopenia; we have treated some patients successfully with medical therapy alone. (See "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)
●Primary cutaneous infection – Debridement is recommended for primary cutaneous infection associated with burns or massive soft tissue wounds .
●Pulmonary infection – Surgical excision of a pulmonary cavity has been performed in patients with a single pulmonary lesion and recurrent hemoptysis or bacterial superinfection . Surgery may be useful in patients with lesions contiguous to the great vessels or pericardium with a high risk for invasion and bleeding, for uncontrolled bleeding, or with invasion of the chest wall or pleural space . It can be considered in patients with a single pulmonary lesion prior to intensive chemotherapy or HCT and in patients with localized pulmonary disease refractory to antifungal therapy; however, risks are substantial and utility is not clear as availability of current antifungals alone may be effective . Risks include persistent pneumothorax as well as spillage of viable fungus into the pleural cavity. We recommend initial medical therapy of pulmonary aspergillosis with sequential follow-up to determine whether surgery is necessary, except in cases of impending major bleeding. Most patients with invasive pulmonary aspergillosis do not require surgery. One retrospective series evaluated 41 patients with hematologic disease complicated by neutropenia and invasive pulmonary aspergillosis . Patients underwent lobectomy (23 patients), wedge resection (16 patients), or enucleation of a mass lesion (2 patients); complication rate and 30-day mortality were both estimated to be 10 percent. Outcomes were generally good (response rate 80 percent) and were associated with successful treatment of the underlying hematologic malignancy. In this study, it was not possible to identify which patients benefited most from a surgical approach. The surgical management of chronic pulmonary aspergillosis is discussed in detail separately. (See "Chronic pulmonary aspergillosis: Treatment".)
●Endocarditis – Early valve replacement should be performed in patients with Aspergillus endocarditis in an attempt to prevent embolic complications and valvular decompensation . (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)
●Central nervous system disease – While a mortality benefit to surgery for the management of cerebral lesions in combination with antifungal therapy with voriconazole has been suggested in small studies , many patients resolve residual central nervous system disease with current antifungal management and do not require surgical management.
●Osteomyelitis and septic arthritis – Surgical intervention should be performed in patients with Aspergillus osteomyelitis and/or septic arthritis, when feasible .
●Other – Surgery may also be indicated for settings in which a large degree of necrosis limits antifungal activity (especially in those who have not responded to initial antifungal therapy) and/or there is an imminent threat to the great vessels or uncontrolled bleeding, pericardial involvement, pulmonary lesions contiguous with the heart, or invasion of the pleural space and/or chest wall .
PREVENTION AND EARLY TREATMENT — Studies performed in the 1990s and early 2000s reported very poor outcomes for invasive aspergillosis. Mortality rates ranged from 60 to 90 percent and were largely dependent upon the underlying disease . Overall survival has improved but varies depending upon factors such as duration of neutropenia, dosage of glucocorticoids, liver and kidney function, and site and extent of infection [49,95]. A great deal of effort has been put into preventing infections by utilizing prophylactic strategies and into treating invasive aspergillosis as early as possible by either empiric treatment of febrile patients with neutropenia or pre-emptive treatment based upon results of screening assays (eg, galactomannan, beta-D-glucan, and polymerase chain reaction [PCR]) for infection [96,97].
When prophylactic azole therapy is administered, we typically follow drug levels in the same way we do for treatment dosages, as described above. (See 'Dosing and drug effects' above.)
These issues are briefly reviewed here; more extensive discussions are provided separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent' and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis' and "Fungal infections following lung transplantation", section on 'Invasive fungal infections'.)
Primary prophylaxis — Providing prophylaxis with mold-active drugs can prevent invasive aspergillosis. Which specific patients will benefit from prophylactic strategies remains ill-defined and is partly dependent upon patient characteristics and the epidemiology of invasive fungal infections at individual institutions.
Results of several randomized trials are summarized as follows:
●Posaconazole was more effective than fluconazole or itraconazole for preventing aspergillosis in patients receiving therapy for acute myeloid leukemia (absolute reduction in the posaconazole group -6 percent, 95% CI -9.7 to -2.5 percent) and was associated with improved survival . It was also more effective than fluconazole in allogeneic hematopoietic cell transplant (HCT) recipients with severe graft-versus-host disease (odds ratio [OR] 0.31, 95% CI 0.13-0.75) .
●Voriconazole was associated with fewer cases of documented infections caused by Aspergillus species compared with fluconazole (both with galactomannan antigen monitoring), although these results failed to reach statistical superiority in a study endpoint that included measurement of survival .
●Itraconazole may be more effective than fluconazole in preventing aspergillosis in patients with leukemia and in HCT recipients but is generally not recommended due to lack of bioavailability, drug interactions, and toxicity [101-103].
●Inhaled administration of amphotericin B formulations reduced the incidence of aspergillosis in patients with hematologic malignancies who had prolonged neutropenia (OR 0.26, 95% CI 0.09-0.72) .
●Based upon observational data, inhaled amphotericin B is often used in lung transplant recipients during the early posttransplant period. (See "Fungal infections following lung transplantation", section on 'Invasive fungal infections'.)
Positive results from each of these studies are balanced with the potential drawbacks of prophylaxis, including possible toxicities and drug interactions, costs of the drugs, and the potential generation of microbial resistance. Oral drugs often are poorly absorbed in the setting of gastrointestinal tract mucositis and/or graft-versus-host disease .
The use of anti-mold prophylaxis is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)
Empiric therapy — Empiric therapy involves antifungal treatment of febrile patients during periods of neutropenia. This strategy was first introduced as a means to prevent invasive fungal infections in the 1980s after it was noted that many patients with fevers had underlying, otherwise undiagnosed, fungal infections, particularly invasive candidiasis . Such infections were especially common in patients with a long duration of neutropenia who were not receiving azole prophylaxis.
Empiric antifungal treatment after a defined duration of persistent fever has become standard practice, and multiple drugs have been studied and approved for this indication. It is important to note that placebo-controlled trials have not been performed to prove the benefit in the era of widespread azole prophylaxis, and the drugs have potential negative effects (eg, toxicity, cost). In high-risk patients with prolonged neutropenia and/or severe immunosuppression (eg, graft-versus-host disease, receipt of biologic agents, high-dose glucocorticoids, etc) who have pulmonary nodules, invasive mold infection should be highly suspected and treated while a diagnosis is aggressively pursued. This subject is reviewed in more depth elsewhere. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.)
Pre-emptive therapy — Pre-emptive therapy is an early treatment strategy that has been proposed as an alternative to empiric therapy . Pre-emptive therapy involves initiating antifungal therapy based upon the results of serial screening for aspergillosis with galactomannan, beta-D-glucan assays, or PCR if available. Results of studies that have compared pre-emptive therapy to empiric therapy in allogeneic HCT recipients and/or patients with hematologic malignancies have shown:
●A significant reduction in the use of empiric antifungal therapy (32 versus 15 percent) who were assigned to serial galactomannan and PCR testing compared with those who were assigned to standard diagnosis. There was an increase in the diagnosis of proven or probable invasive aspergillosis, but no difference in mortality among patients was seen .
●No overall clinical or survival benefit to a pre-emptive strategy that involved serial PCR testing .
●No survival benefit of a pre-emptive strategy that used the serum galactomannan assay in combination with other clinical indicators . Probable or proven invasive fungal infections were significantly more common among those who received pre-emptive therapy (9 versus 4 percent), but some of these infections were due to Candida spp rather than molds. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)
Although the results of these studies suggest benefit of a pre-emptive strategy particularly in limiting antifungal use, none of the trials provides definitive conclusions due to study design issues.
Secondary prophylaxis for prevention of relapse — Patients who complete antifungal therapy are at risk for reactivation of aspergillosis if neutropenia recurs. Individuals who are at high risk of relapse, such as those who receive chemotherapy or HCT, require secondary prophylaxis. Secondary prophylaxis involves the continuation or reinitiation of antifungal therapy during periods of increased risk of relapse, such as following chemotherapy or HCT. Voriconazole has been evaluated as secondary prophylaxis to prevent relapsed aspergillosis . In patients at increased risk of relapse following the completion of primary treatment, we recommend reinitiation of antifungal therapy with voriconazole or another mold-active antifungal that the patient responded to and tolerated. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Secondary prophylaxis' and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section on 'Secondary prophylaxis'.)
The pathogenesis of relapsed invasive aspergillosis is thought to be due to reactivation of a latent subclinical infection that had not been fully eradicated. This may be secondary to the angioinvasive nature of the organism or due to lack of sterilization secondary to poor drug penetration (eg, foreign bodies, vegetations, or lung or bone sequestra) . Factors that predispose patients to relapsing invasive aspergillosis include site of infection (eg, sinuses), use of systemic glucocorticoids, lack of remission of underlying hematologic malignancy, duration of neutropenia, and receipt of an unrelated HCT . The recognition that certain variations in innate immunity increase the risk of invasive aspergillosis suggest that at least some of these infections may represent reinfection due to ongoing high risk of disease; examples include polymorphisms in the genes encoding toll-like receptor-4, dectin-1, and mannose-binding lectin. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Risk factors'.)
PROGNOSTIC FACTORS — Invasive aspergillosis is a major cause of death in immunosuppressed patients, particularly following hematopoietic cell transplantation (HCT) . Historically, the one-year mortality rate after onset of invasive aspergillosis in this population was as high as 80 percent . However, results of more recent studies demonstrate improved outcomes, both with regard to estimated attributable and overall mortality [49,95].
In a United States–based multicenter surveillance study that enrolled patients from 2001 to 2005, the 12-week all-cause mortality among HCT recipients with invasive aspergillosis was 58 percent . Lower mortality rates have been observed in trials that included patients other than HCT recipients. As an example, in one trial in which only 29 percent of patients were HCT recipients, the 12-week mortality in patients who received voriconazole was 29 versus 42 percent in those who received amphotericin B deoxycholate . (See 'Voriconazole' above.)
Studies evaluating more homogeneous patient populations, such as those done only in HCT recipients, have shown a measurable increase in survival after the diagnosis of invasive aspergillosis in recent years [49,113]. However, variables that influence outcome include a complex combination of host factors, including the underlying disease, as well as the therapies used. Factors predictive of death include disseminated disease, cerebral involvement, persistent and severe neutropenia, administration of glucocorticoids, receipt of human leukocyte antigen-mismatched stem cells, and uncontrolled graft-versus-host disease [49,95,114,115]. Multiple host factors, such as pulmonary function prior to transplant, and underlying organ (kidney and liver) function also impact outcomes. There is some indication that recipients of nonmyeloablative (or reduced intensity) conditioning regimens have relatively better outcomes after infection compared with patients who received myeloablative therapies .
As noted above, glucocorticoid use has been associated with higher mortality rates among HCT recipients in several studies [49,111-115], but, in one study of solid organ transplant recipients, glucocorticoid use resulted in a decreased risk of death .
Among patients with COVID-19 coinfection, it is unclear whether mortality rates are higher than in patients who only have COVID-19 infection [116-119]. A European multicenter case-control study of 823 intensive care unit (ICU) patients found an overall mortality rate for coinfected patients of 52 percent, but coinfection did not increase mortality when compared to patients with only COVID-19 in multivariate analysis . In contrast, a prospective study of 108 COVID-19 ICU patients found increased mortality among coinfected patients (odds ratio [OR] for death 4.3; 95% CI 1.5-12.1) .
In a study of allogeneic HCT recipients, those with poorly controlled invasive aspergillosis had lower reactive oxygen species production (which is important for neutrophil-mediated fungal killing) and NK cell counts than patients with well-controlled disease .
A delay in diagnosis and in the initiation of appropriate therapy may lead to worse outcomes. In a retrospective study, mortality in patients who received appropriate initial therapy with voriconazole was 24 percent compared with 47 percent in those who received inappropriate initial therapy with voriconazole (ie, in the setting of voriconazole resistance), despite switching to appropriate antifungal therapy after a median of 10 days . The association between antifungal resistance and poor outcomes is discussed in greater detail above. (See 'Consideration of antifungal resistance' above.)
Serial monitoring with galactomannan or other assays — The serum galactomannan assay has diagnostic value, and serial monitoring may have prognostic value [121-126], as illustrated by the following studies:
●In a review of 27 studies of patients with hematologic malignancies and proven or probable aspergillosis, patients with persistently positive galactomannan results were significantly more likely to die and to have autopsy-proven aspergillosis than those with a test that normalized in value .
●Another study demonstrated that both the serum galactomannan value at the time of diagnosis of invasive aspergillosis and the one-week galactomannan decay were predictive of all-cause mortality . Each enzyme immunoassay (EIA) unit increase in galactomannan at the time of diagnosis increased the hazard of time to all-cause mortality at six weeks by 25 percent, whereas each galactomannan EIA unit decline during the week following the initial test decreased the risk of time to all-cause mortality at six weeks by 22 percent. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)
In contrast, in bronchoalveolar lavage fluid samples, neither the detection of galactomannan nor the magnitude of the results correlated with mortality in allogeneic cell transplant recipients with invasive pulmonary aspergillosis . (See "Diagnosis of invasive aspergillosis", section on 'Bronchoalveolar lavage fluid'.)
There are limited data regarding the use of other assays such as beta-D-glucan or PCR for monitoring response to therapy [127,128].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aspergillosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Invasive aspergillosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●High prevalence in immunocompromised hosts − Aspergillus species are ubiquitous, but invasive aspergillosis occurs primarily in immunocompromised hosts. Neutropenia and glucocorticoid use are the most common predisposing factors. It is a major cause of death in immunosuppressed patients, particularly following hematopoietic cell transplantation (HCT). (See 'Introduction' above and 'Prognostic factors' above.)
●Importance of early diagnosis and treatment − Optimal management involves early diagnosis and early initiation of antifungal therapy. Surgery and reduction of immunosuppression are important adjunctive components of management in selected patients. (See 'General principles' above and 'Role of surgery' above and 'Reduction of immunosuppression' above.)
●Antifungal resistance − Antifungal resistance should be considered in patients with Aspergillus fumigatus in areas of high rates of resistance or who do not respond to voriconazole and in patients infected with certain Aspergillus species that have reduced antifungal susceptibility profiles (eg, A. terreus, A. calidoustus, A. lentulus, Neosartorya udagawae). The approach to antifungal therapy when azole resistance is a concern is discussed in the text. (See 'Voriconazole' above and 'Consideration of antifungal resistance' above.)
●Initial antifungal therapy − For initial therapy of patients with invasive aspergillosis (ie, diagnosed by culture, galactomannan antigen, or histopathology), we suggest voriconazole rather than other antifungal agents (Grade 2C). For patients with severe or progressive disease, we suggest adding two weeks of echinocandin therapy to voriconazole before transitioning to voriconazole monotherapy (Grade 2C). However, some experts prefer monotherapy with voriconazole for these patients. (See 'Choice of regimen' above and 'Voriconazole' above and 'Voriconazole and an echinocandin' above and 'Dosing and drug effects' above.)
•Alternatives to voriconazole − For patients who cannot receive voriconazole, posaconazole or isavuconazole are preferred alternatives. Both have been shown to be as effective as voriconazole and to be better tolerated in randomized trials but clinical experience with each is limited. Liposomal formulations of amphotericin B are additional alternatives, but these agents carry the risk of nephrotoxicity and must be administered intravenously. The decision of which agent to choose depends on organ dysfunction, toxicities, tolerability, severity of illness, need for intravenous therapy, and the likelihood of resistance. (See 'Initial therapy' above.)
•Concurrent concern for mucormycosis − If an invasive mold infection is suspected and the likelihood of mucormycosis is increased due to recent receipt of voriconazole or clinical factors, we use a lipid formulation of amphotericin B (AmBisome or Abelcet) rather than voriconazole in order to provide antifungal activity against both aspergillosis and mucormycosis. A definitive diagnosis should be pursued aggressively, and if the diagnosis of invasive aspergillosis is established, the regimen should be switched to a voriconazole-based regimen, with addition of an echinocandin for those with severe disease. (See 'Choice of regimen' above.)
●Salvage therapy − For salvage therapy in patients who do not respond to initial therapy, we favor an individualized approach. An aggressive and prompt attempt should be undertaken to establish a specific mycologic diagnosis if it was not done previously. Azole drug levels should be measured and if an isolate is available, susceptibility testing performed. For most patients, an empiric change of antifungal therapy to another drug class (usually liposomal amphotericin B) pending a definitive diagnosis is appropriate. For those with confirmed aspergillosis who initially received azole monotherapy or liposomal amphotericin B, we typically give combination therapy with either voriconazole or another azole (isavuconazole or posaconazole) plus an echinocandin. When use of a triazole for salvage therapy is being considered, prior therapeutic regimens, pharmacokinetic factors, and possible antifungal resistance should be taken into account. (See 'Salvage therapy' above and 'Echinocandins' above and 'Voriconazole and an echinocandin' above.)
●Therapeutic drug monitoring − All patients receiving voriconazole for the treatment of invasive aspergillosis, particularly those receiving oral therapy, should undergo monitoring of serum voriconazole trough concentrations (see 'Voriconazole' above). We also monitor concentrations for patients on posaconazole. (See 'Dosing and drug effects' above and 'Posaconazole' above.)
●Duration of therapy − The duration of antifungal therapy depends on the location of the infection, the patient's underlying disease and immunosuppression, and the response to therapy. For most immunosuppressed patients, antifungal therapy will continue for months or even years in some cases. (See 'Duration' above.)
●Adjunctive surgical management − In addition to antifungal therapy, surgical management to debride necrotic tissue may be appropriate as adjunctive therapy in some complex cases with chronic necrotizing disease. The decision of whether to perform surgery depends on many factors, including the extent and location of the lesion(s), the degree of resection required, comorbidities, performance status, the ability of the patient to tolerate surgery, the potential impact of delay of chemotherapy, and the underlying disease. (See 'Role of surgery' above.)
●Preventing recurrence − Patients who complete antifungal therapy are at risk for relapse of aspergillosis during periods of immunosuppression, particularly if neutropenia recurs. We recommend continuing or reinitiating antifungal therapy if chemotherapy is planned and the patient is expected to become neutropenic or if immunosuppression is intensified (Grade 1B). (See 'Secondary prophylaxis for prevention of relapse' above.)
●Primary prophylaxis − Strategies to prevent advanced disease include prophylactic therapy with a mold-active drug and antigen-based screening (eg, galactomannan) in high-risk patients. The most effective approach has not been determined and is likely to vary depending on patient characteristics and logistics (eg, ability to monitor assays serially). (See 'Prevention and early treatment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.
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