Practice Guidelines for Diseases Caused by Aspergillus

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1–1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be ∼0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). Although the frequency of these diseases is on the rise, there is a paucity of randomized comparative trials involving these entities; therefore, the recommendations represent a compromise and consensus among students of these diseases (i.e., the authors). They have synthesized the recommendations from published and personal experience, including case series, open trials, and any comparative trials, as indicated. Aspergillus species are saprophytic molds found worldwide. Diseases caused by Aspergillus species are most commonly caused by Aspergillus fumigatus, with Aspergillus flavus the second most frequently isolated pathogen. Other species reported to cause disease include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus candidus, Aspergillus carneus, Aspergillus caesiellus, Aspergillus clavatus, Aspergillus glaucus, Aspergillus granulosus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Aspergillus quadrilineatus, Aspergillus restrictus, Aspergillus sydowi, Aspergillus terreus, Aspergillus ustus, and Aspergillus versicolor. The frequency and relative importance of these infections are on the rise in all developed countries, which is possibly related to increased numbers of immunocompromised patients, owing to improved survival from AIDS, malignancies and more intensive cytotoxic therapy, more transplantation (with immunosuppression) for organ dysfunctions, and better therapy and prophylaxis for candidal infections. These guidelines are drafted to ensure appropriate and successful therapy for 3 main diseases caused by Aspergillus species. They include invasive aspergillosis, ABPA, and aspergilloma. The guidelines proposed initially are general and are followed by modifications for individual clinical settings. The guidelines are based on scientific publications and peer-reviewed information (this documentation is provided), and are largely concerned with therapy. The guidelines are not intended to be a comprehensive treatise on pathogenesis or diagnosis. The categories of ranking of the strength of the recommendation and the quality of the evidence are given in tables 1 and 2. Guidelines for prophylaxis and empirical therapy for invasive aspergillosis in neutropenic hosts have recently been published [1] and will not be discussed here. Categories reflecting the strength of each recommendation for or against the use of therapy for diseases caused by Aspergillus species. Categories indicating the quality of evidence for recommendations for antifungal therapy in diseases caused by Aspergillus species. General and specific commentary on antifungal drugs has been provided in a previous guideline in this series. The drugs available to treat aspergillosis presently include amphotericin B in deoxycholate [2–4], a familiar drug with 40 years' clinical experience; 3 lipid-based preparations of amphotericin B [5–12]; and itraconazole, an oral and iv triazole [13–18]. In general, the largest databases for therapy in aspergillosis concern amphotericin B deoxycholate and various surgical modalities. There is thus some concern about the efficacy of the newer in patients with rapidly invasive Itraconazole has drug which are in patients at of aspergillosis, because such patients are receiving other drugs for a variety of These patients also have as a of these therefore, oral itraconazole is serum should be to ensure adequate (BII). should be given to the oral of itraconazole in such patients, because is to that with itraconazole iv has been but there is information available about that any drug used for invasive disease be given at for 1–1.5 mg/kg/d of amphotericin B deoxycholate, mg/kg/d of formulations of and of itraconazole (BIII). in serum creatinine level with amphotericin B deoxycholate is and with amphotericin use are to the dose because of a modest of and have against Aspergillus species and are or clinical oral triazole and 3 and are also in of clinical Invasive aspergillosis is a that patients with or cytotoxic chemotherapy, corticosteroid therapy, or organ or or in patients at and prompt of antifungal therapy may be for patient survival (BIII). The are the most of invasive disease it in frequency in some The is the most of invasive most of the in this are on invasive pulmonary The of this disease and to therapy in to the and to to for clinical trials have and will to as clinical trials such as the of and Diseases the for and of and and to of previous trials and the and to a evidence of in and Aspergillus species from by from the from a and rarely Aspergillus species. The of Aspergillus are by and and it would be to include these in the initial invasive disease is Aspergillus are to from those of of and some other Aspergillus species from of the (e.g., and are a of in the but may invasive disease in the immunocompromised The may be as as in patients with or studies may include such as or on on include the of a lung initially by or an the the of a lung caused by of These studies may and the of in neutropenic patients, but the are not because other infections and may The have been in neutropenic commonly chest the more specific and chest should be considered in patients with a infection. resolution or may an with of the by has and for invasive aspergillosis in immunocompromised patients (BII). or are (CIII). of have been useful such are Because of the of the a definitive of disease caused by Aspergillus is The use of against Aspergillus to invasive aspergillosis has in are frequently or more isolated but specific recommendations about frequency of have not been have been developed to Aspergillus in and by and These more and with an available in for of Aspergillus reported of and of largely among in in some studies with that case to be has been in some studies with In some more among the and more in are for use in the In that use have been reported to the of Aspergillus species the in the of Aspergillus species and a in the of and may more of these have been with in trials of invasive aspergillosis, and must be There is also in such as or for of invasive are with some but not evidence of invasive pulmonary and treatment may need to be initiated at that in the more immunocompromised or to or the should in such an empirical treatment The optimal duration of therapy is and on the of invasive aspergillosis, the to therapy, and the underlying or course would be to therapy to treat clinical and are can be are and reversible underlying predispositions have (BIII). of therapy should be by clinical any of antifungal therapy chemotherapy, or of antifungal therapy in patients with who are about to chemotherapy, is of The of these patients to antifungal therapy is largely related to such as the resolution of and the of and the of function from a or organ as as the of aspergillosis Intravenous therapy may be at in patients who are because drug is certain (BIII). B has been the of treatment in invasive aspergillosis, for life-threatening and infections. In patients, the has been to all because of underlying of resolution of or underlying of duration of and other with in made in other a is more likely with in The lipid-based formulations are indicated for patients with invasive aspergillosis who nephrotoxicity while receiving amphotericin B (AII). The lipid-based preparations may be as initial therapy in patients with renal function or in patients receiving other The studies on the preparations have been or with amphotericin B comparative clinical trials amphotericin B and a specific lipid-based for invasive aspergillosis, or specific doses of to be or have been thus Although most studies have that doses of the preparations are to therapeutic to deoxycholate a has the doses are Itraconazole has been as therapy for invasive aspergillosis in studies which found of and These are of has been reported in may be among the immunocompromised The oral is an alternative to amphotericin in patients who are likely to to therapy, to have with and who are not receiving drugs that with itraconazole or which be and attractive would be to use iv therapy (e.g., amphotericin at disease is and with oral therapy for prolonged treatment (CIII). has been used in an of invasive aspergillosis with in studies has been that a triazole with any amphotericin B for invasive aspergillosis. therapy that amphotericin B with or has in and in has also been in and in has with limited in case but the of or efficacy of such has not been in invasive aspergillosis. In may in patients with and levels may be amphotericin is owing to the to function of the of may have significant drug owing to in who are receiving or and this also the of itraconazole use for Surgical has been successful for some of pulmonary prompt surgery as a for the the because of the of pulmonary such as such as or are for prophylaxis or therapy, in the neutropenic or immunocompromised host, but are not for therapeutic use (CIII). of increased survival has not been demonstrated with any of these modalities. to Aspergillus species at other are pulmonary and treatment trials are with most reported treatment In this the therapeutic recommendations are based on of or series, in to from the of infections at more such as lung infections. Aspergillus infections may or may not be invasive and can a or an course The disease manifestations and the subsequent treatment may also depending on the of of the invasive is the of aspergillosis that in the immunocompromised These infections are by with and of in to is from in patients with in who are therapy, to to in patients with or those transplantation of suspicion is in immunocompromised patients. Although are of or limited should be considered in these patients. is and the of new such as a in a host, or an should to including of the and subsequent of are not to but also to Aspergillus infections from those caused by other such as those to or species of by corticosteroid or resolution of the most that should with surgical (BIII). Although surgical alone may be in it may mortality among patients with surgery has been used for in which an is in an to with as as is more extensive surgery is indicated there is of the or or or is (BIII). amphotericin B or has been used by some invasive infections occur in hosts in with levels of such as the and other or and in patients with in other flavus is the most agent of these in to the of from of in immunocompromised These infections have a clinical course to with of the the and subsequent and with acute invasive infections in treatment of surgical and which is in the majority of (BIII). The of antifungal therapy is (CIII). this are Aspergillus infections may also as a or These to a for to with and no invasive surgical removal of the to ensure adequate antifungal therapy has no in these infections (CIII). The is Aspergillus species are a cause of allergic which in with a of allergic from is in of in the of the and is surgical with as for (BIII). antifungal therapy is not used there is evidence of or (CIII). corticosteroids and may be used for There may be a potential for corticosteroids with allergic in to surgery and in the there is a in corticosteroid use is because of corticosteroid of and of the and The of of Aspergillus of the have been reported in immunocompromised such as patients with or AIDS, organ or patients receiving chronic corticosteroid therapy that has commonly been limited to the has been in and lung or have been in patients who with and to this has rarely been reported antifungal therapy has been the of treatment in these Although amphotericin B may have a as therapy In the several reported of surgical or has been for a successful in to antifungal therapy. in the of Aspergillus with the of a in the removal of the by procedure may be given the of antifungals the infections. invasive and infections have been Aspergillus species may the in the with no infection. invasive of the has been in patients with and in patients with acute Aspergillus may Aspergillus In immunocompromised patients, antifungal therapy appears (BIII). infections of or those that occur in patients may be with including removal (BIII). variety of such therapeutic has been which amphotericin B and In these prolonged therapy may be infections. Aspergillus may occur by several including by surgical such as or by which is most commonly in immunocompromised patients, drug or patients with Aspergillus in these and of of amphotericin B and itraconazole the and is inadequate and treatment is Because of amphotericin B may be of in are that of serum experience with this agent in infections is may be for the and of these in with amphotericin B or amphotericin B (BIII). Other manifestations of Aspergillus infections are may be with surgery and amphotericin B it is not antifungal therapy is in these have been used for including the of with amphotericin B amphotericin B amphotericin B or Oral itraconazole may also a in these more since this agent the is there is while the patient is receiving therapy or there is a of Surgical include of a a to the from or or to or may be infections. Aspergillus infections of the may as or an or a The published that mortality in occur as a of with subsequent of and of these is to Aspergillus infections from those caused by other such as or which may of antifungal therapy has been reported to be in some surgical for of the agent with removal of which may not be by antifungals for have also been used Although surgery alone may be in the of in immunocompromised patients, antifungal therapy is also used in the majority of (BIII). in with amphotericin may have a because of There are of with itraconazole, or may be Aspergillus is are reported in drug or or patients on prolonged corticosteroid therapy. may as an of as a of therapy or in the surgery and rarely in patients with no underlying Aspergillus may be in the and may be used for of the course of therapy and (e.g., an amphotericin B has been used for the treatment of these infections as has itraconazole and of may be caused by Aspergillus are to a of such as in a Surgical with therapy is indicated for these infections (BIII). infections. The for Aspergillus infections is by by a surgical or in patients with the those with chronic or drug or is the most caused by Aspergillus with infections Surgical is for these infections. Although an case may be by surgical antifungal therapy is used in B levels in are which may the of drugs that have such as or Itraconazole and has also been used infections. infections caused by Aspergillus species are commonly a of from a of most the which in highly immunocompromised patients. These may be or may not be and occur most commonly on the They as and a with an that is by a Although this is of Aspergillus the is not and a with is indicated to other infections that may in a The majority of infections are caused by fumigatus, or terreus, more Aspergillus has been reported to cause which and in invasive infections to Aspergillus species have been reported in with for which are with Aspergillus These to of of may may also by Aspergillus species. may be caused by Aspergillus species. The of of for a definitive has been antifungal therapy is the of therapy and the are Surgical may be the be in the neutropenic In removal of the in to antifungal therapy is indicated aspergillosis and infections are by surgical in to therapy. Oral itraconazole, with or without therapy, such as is used for infections and Aspergillus species have been reported as a cause of and which is a of aspergillosis. The is rarely isolated from The are and and a of Because of the of amphotericin B the in to the of surgical with is in the of amphotericin B appears case has been with amphotericin B and alone is a of may from of a or from the with or of the may useful in diagnosis. of patients with or have been of antifungal therapy and including appropriate may be as an isolated or with infections. infections are a of that the renal are more in immunocompromised such as patients with or chronic or drug and patients with are at for infections that the renal The of a renal with or without a also occur antifungal therapy is used for of and surgical removal may be indicated. Therapy is by the in by itraconazole or or disease has been with amphotericin B or preparations the of may be since this agent in the with amphotericin B has also been used for and renal infections. infections. antifungal therapy is for aspergillosis The of this with amphotericin B therapy has been this amphotericin or itraconazole, of which in should be Aspergillus has as a of chronic removal is for these infections therapy should be used in and amphotericin B have been as has itraconazole organ with Aspergillus species most in the of infection. The is the most of in the the and in these may in or therapy is but the is infections. Aspergillus species may cause of In to antifungal therapy, surgical of the may be to the infection. aspergilloma. aspergilloma can be as a a pulmonary or of Aspergillus with and have underlying pulmonary disease such as sarcoidosis, or or lung disease The of aspergilloma is made without a lung and the chest are of importance in the diagnosis. pulmonary aspergilloma appears as a of a or and from the of the by an of and is The of an aspergilloma is made the are found in a patient with serum that are for an Aspergillus a with for aspergilloma some patients who corticosteroids may be Although aspergillomas are of as saprophytic of the lung with the manifestations of Aspergillus lung disease with a and Invasive pulmonary aspergillosis may from an aspergilloma and is chronic of Aspergillus has been in which symptoms (e.g., and are an aspergilloma is on chest radiograph, and evidence of is found on of lung is a of aspergilloma and may in is the cause of in to of patients with aspergilloma that aspergilloma on preventing life-threatening hemoptysis, patients with symptoms are candidates for therapy. have been that suggest a with aspergilloma. These include the of the underlying lung increasing or of aspergillomas on chest increasing Aspergillus-specific IgG titers underlying and Although not it that patients who have an of would be at of a life-threatening There is no consensus the treatment of aspergilloma. or randomized trials have been treatment have been from trials and case The decision in the of aspergilloma is therapy is Since life-threatening in a of patients, it may be to all patients with aspergilloma to therapy, since therapy is with significant morbidity and treatment for aspergilloma is surgical surgery has been with a morbidity and mortality is owing to the of and the of of the mortality is and such as and are that to the surgical of is that aspergillomas to in with pulmonary function in patients, surgery is because of underlying pulmonary has been that surgical of aspergilloma be to patients with and adequate pulmonary function and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). The course of the in the of surgery about surgical Bronchial artery embolization has been used to the that the in patients from aspergilloma other are in and can be is or and a patient who can for from the pulmonary and to the will not be successful should be considered as a temporizing procedure in a patient with life-threatening hemoptysis, who be for more definitive therapy the (BIII). for aspergillomas have therapy intracavitary or instillation of antifungal antifungals and antifungals symptoms (e.g., or are may be related in to with agent or to allergic has been in patients with evidence of (e.g., IgE and given corticosteroid therapy such therapy the of to invasive or disease of an infection. of these studies Intravenous amphotericin B for aspergilloma provided no pulmonary that used or intracavitary instillation of amphotericin B for aspergilloma of patients resolution or clinical is more in the patient with pulmonary The use of itraconazole for aspergilloma has been reported in several studies of these studies and not a the dose and duration of itraconazole therapy not the of these studies suggest that itraconazole may be in the treatment of aspergilloma (BIII). is a disease of the caused by initially as a disease by pulmonary and and or for ABPA proposed to Aspergillus to Aspergillus serum of pulmonary or and The of ABPA likely the and the of all made the certain of Aspergillus in by use of a of of or specific IgE directed against Aspergillus to Aspergillus and on with ABPA has been reported to be in of patients with in the patients with have with Aspergillus and ABPA these patients may be at for invasive aspergillosis lung transplantation is the chest in ABPA of that in the and may be These are commonly caused by with The with may a or a These are a of the disease and may be by a or may be on chest The of ABPA should be considered in a asthmatic or an asthmatic with any of the ABPA may clinical of acute to to lung disease with lung Therapy in ABPA is directed at acute asthmatic exacerbations and of Although corticosteroid therapy is the of therapy for ABPA, there is a paucity of data The studies of corticosteroids for ABPA have numbers of patients and have been nor and the corticosteroid dose has despite these data support the of corticosteroids in the of acute ABPA (AII). ABPA patients with mg/kg/d of for 1 followed by other made to The symptoms of and rapidly with this the dose of most patients developed symptoms of that with corticosteroids in most IgE levels with disease since with a clinical to corticosteroids and increased exacerbations of There have been studies that the treatment of chronic ABPA with and all have been ABPA patients for and found that patients a chronic course by pulmonary with in lung not a to as several asymptomatic patients developed and lung that in chronic lung doses in episodes of patients with pulmonary of ABPA patients given chronic corticosteroid therapy likely to those given These found that of for an to the of pulmonary the clinical course of patients with ABPA a of of with at a dose of There no significant in spirometry the These data are since pulmonary function not the a would be to the by a in a Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids are (BII). Multiple asthmatic exacerbations in an ABPA patient suggest that corticosteroid therapy should be at a dose of of (BIII). The decision to the of corticosteroids should be made on an individual basis, depending on the clinical course (BIII). to the treatment of ABPA is to Aspergillus species from the and oral are not in preventing In a Aspergillus-specific IgG and symptoms in ABPA patients. subsequent of an that not randomized no from trials have indicated that itraconazole is useful as therapy in ABPA, because the corticosteroid dose can be pulmonary function is and IgE levels recently for ABPA that itraconazole, for in significant in to as by the in corticosteroid dose and IgE and the in and in pulmonary Itraconazole may be useful as a agent (BII). corticosteroids not to be for ABPA some this may be a useful in some patients and suggest doses may be in to with exacerbations of ABPA there have been no studies of to ABPA, and the of such therapy therapy or of in the have not been