INTRODUCTION — Chronic pulmonary aspergillosis includes several disease manifestations, including aspergilloma, Aspergillus nodules, chronic cavitary pulmonary aspergillosis, and chronic fibrosing pulmonary aspergillosis. Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing pulmonary aspergillosis) is on the spectrum between chronic and acute forms of pulmonary aspergillosis (see 'Definitions' below). A duration of disease longer than three months distinguishes chronic pulmonary aspergillosis from acute and subacute invasive pulmonary aspergillosis.
The treatment of chronic pulmonary aspergillosis will be reviewed here. The pathophysiology, clinical manifestations, and diagnosis of chronic pulmonary aspergillosis are discussed separately; the treatment of allergic bronchopulmonary aspergillosis and invasive aspergillosis are also reviewed elsewhere. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Treatment and prevention of invasive aspergillosis".)
DEFINITIONS — Chronic pulmonary aspergillosis describes several patterns of disease. However, the terminology that has been developed can be difficult to apply to a spectrum of disease entities that have considerable overlap and variation in severity. The following terminology will be used to describe the spectrum of disease; each entity is characterized by specific radiographic findings [1].
Aspergilloma — An aspergilloma is a fungus ball composed of Aspergillus hyphae, fibrin, mucus, and cellular debris found within a pulmonary cavity [2]. Aspergillomas arise in preexisting pulmonary cavities that have become colonized with Aspergillus spp or develop in chronic cavitary pulmonary aspergillosis [1].
If the aspergilloma is single, the cavity stable over months, and the patient has few symptoms (ie, a mild cough only) and little evidence of systemic inflammation, a simple aspergilloma may be diagnosed. We will use the term "simple aspergilloma" to distinguish this entity from the more complex forms of chronic pulmonary aspergillosis. (See "Diagnosis of invasive aspergillosis", section on 'Diagnostic modalities'.)
Aspergillus nodule — Aspergillus nodules occur in immunocompetent hosts, may be single or multiple, and may or may not have cavitation within them [3]. The differential diagnosis includes lung cancer and coccidioidal nodules. Patients are usually asymptomatic or have a new minor pulmonary symptom such as cough or may have an incidental chest infection or an exacerbation of asthma or chronic obstructive pulmonary disease. Using positron emission tomography (PET) scanning, Aspergillus nodules are fluorodeoxyglucose avid to variable degrees [4] and are usually accompanied by a raised Aspergillus immunoglobulin (Ig)G titer. On histopathology, necrosis is surrounded by granulomatous inflammation with occasional multinucleate giant cells [5]. The center of the necrotic material contains fungal hyphae.
Chronic cavitary pulmonary aspergillosis — The term "chronic cavitary pulmonary aspergillosis" describes a pattern of disease in immunocompetent patients in whom there is formation and expansion of one or more pulmonary cavities over months (image 1 and image 2 and image 3 and image 4) [1]. This term is preferred over the older term "complex aspergilloma" because more than 70 percent of such patients don't have an aspergilloma visible radiographically. Approximately 90 percent of patients with chronic cavitary pulmonary aspergillosis have Aspergillus IgG antibodies in the blood. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Radiographic features' and "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Laboratory findings'.)
Chronic fibrosing pulmonary aspergillosis — Chronic fibrosing pulmonary aspergillosis is a late-stage manifestation of chronic cavitary pulmonary aspergillosis in which progression to marked and extensive lung fibrosis has occurred, sometimes called "destroyed lung" [1,6].
Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis) — Patients with some degree of immunocompromise who present with progressive features over one to three months have subacute invasive pulmonary aspergillosis. Hyphal invasion of tissue is observed histologically or can be inferred based upon radiographic findings, including cavitation [1]. Such patients usually have a single thin-walled cavity or area of cavitating pneumonia/consolidation and may have detectable Aspergillus antigen (galactomannan) or Aspergillus IgG antibodies (precipitins) in blood.
APPROACH TO THERAPY — Since chronic pulmonary aspergillosis represents a spectrum of disease, and the risks and benefits of medical and surgical therapy vary with the manifestations of disease and the patient's pulmonary status, the approach to therapy must be individualized. These recommendations generally follow those of the 2016 European Society of Clinical Microbiology and Infectious Diseases and European Respiratory Society guidelines on chronic pulmonary aspergillosis and the 2016 Infectious Diseases Society of America aspergillosis guidelines [7,8].
Aspergilloma — Data regarding the treatment of a simple aspergilloma are limited to extensive case series over decades and case reports [7-10]. Surgical resection is offered in order to prevent or treat potentially life-threatening hemoptysis and is usually curative [11]. In patients with good respiratory function, no other significant contraindications to thoracotomy, and disease limited to one lobe, the 30-day operative mortality is <5 percent and, in recent series, <1 percent at centers that have substantial experience with this disease. Recurrent infection, inability to take azole therapy, azole resistance, and concurrent infection or tumor represent additional indications for surgical resection but carry greater risk. Bronchial artery embolization for significant hemoptysis may be used before surgery to stabilize the patient. Pre- and postoperative antifungal therapy (usually voriconazole) is appropriate in some patients to minimize the risk of postoperative pleural aspergillosis (in case the cavity is opened inadvertently during surgery, leading to spillage) and also reduces the risk of relapse [12]. (See 'Surgery' below and 'Embolization' below.)
Antifungal therapy provides some benefit for the treatment of a simple aspergilloma [13-16]. As an example, in a study that included 14 patients with aspergilloma who were treated with oral itraconazole for an average of 7 months (range 2 to 13 months), two patients were considered to be cured based upon the absence of symptoms and the development of scarring of the initial radiographic abnormalities; eight patients had significant clinical improvement despite a lack of radiographic improvement [13]. However, two patients had no clinical or radiographic response, and two patients had clinical and radiographic worsening. Instillation of amphotericin B into a cavity has sometimes been effective. (See 'Investigational approaches' below.)
Many patients, such as those who are asymptomatic and have stable radiographic findings over many months, require no therapy. However, progression to chronic cavitary pulmonary aspergillosis, sometimes with extensive fibrosis, is common and can occur silently, so continued observation is required. Spontaneous resolution of the aspergilloma occurs in fewer than 10 percent of patients [17,18]. Antifungal therapy for a single aspergilloma is reserved for patients who are unable to undergo surgery but require therapy for symptoms or radiologic progression or because they are immunocompromised. The choice of antifungal agent is similar to that for chronic cavitary pulmonary aspergillosis, which is discussed below.
Low-dose computed tomography is the imaging mode of choice and has the benefit of minimizing the radiation dose. There is no agreed-upon frequency of repeat imaging, but every 6 to 12 months is reasonable in immunocompromised patients and less often in immunocompetent patients. New symptoms, especially hemoptysis, are an indication for additional imaging and a search for other infectious agents. A persistently rising Aspergillus immunoglobulin (Ig)G titer suggests treatment failure.
Aspergillus nodule — Patients with incidentally resected Aspergillus nodules, initially thought to be carcinoma of the lung [3], should not receive antifungal therapy unless symptomatic but should be followed up with appropriate imaging and Aspergillus antibody titers for months or years to detect relapse of active infection. Patients with nodules that develop in the context of allergic bronchopulmonary aspergillosis (ABPA) or severe asthma may derive improvement of their asthma control with antifungal therapy. (See "Treatment of allergic bronchopulmonary aspergillosis", section on 'Antifungal therapy'.)
Chronic cavitary pulmonary aspergillosis — In contrast with patients with a simple aspergilloma, the vast majority of patients with chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis require antifungal therapy. Only asymptomatic patients with radiographically and serologically stable disease, as determined over many months, do not require therapy. Embolization is indicated to prevent or treat hemoptysis. Surgical outcomes are not as good as those for single aspergillomas. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis" and 'Surgery' below and 'Embolization' below.)
The evidence regarding the efficacy of long-term antifungal therapy for chronic cavitary pulmonary aspergillosis is based upon retrospective case series, open-label non-comparative studies, and one randomized controlled trial [1,19-28]. Itraconazole and voriconazole are the preferred oral agents for the treatment of chronic pulmonary aspergillosis [1,7,8,19-21,29,30], with posaconazole being substituted for failure, toxicity, or emergence of resistance [22]. (See 'Choice of agent' below.)
Itraconazole has been used most commonly for the treatment of chronic pulmonary aspergillosis. Among 17 patients with chronic pulmonary aspergillosis, the majority of whom had chronic cavitary pulmonary aspergillosis, initial therapy with itraconazole resulted in improvement or stabilization of disease in 12 patients (71 percent) [1]. The duration of therapy ranged from 12 days to over 10 years. In a three-center prospective series of 29 patients, 44 percent responded [31]. In a trial that included 31 patients with chronic cavitary pulmonary aspergillosis, patients were randomly assigned to receive either itraconazole 400 mg daily plus supportive therapy or supportive therapy alone for six months [24]. Compared with patients who received supportive care only, patients who received itraconazole plus supportive care had a greater likelihood of clinical improvement (35 versus 7 percent) or stabilization (41 versus 29 percent) and a lower likelihood of clinical worsening (24 versus 64 percent). Using the St George's Respiratory Questionnaire, quality of life in patients with chronic cavitary pulmonary aspergillosis receiving itraconazole was improved in 56 percent at 3 months but in only 40 percent by 12 months [23].
In a large series from India, 106 of 123 patients (84.1 percent) had a clinical response to itraconazole at 6 months [28]. In another study, outcomes at 12 months were similar in those treated with itraconazole compared with voriconazole, although only 47 percent of 105 patients remained on itraconazole therapy at 12 months; discontinuation followed development of adverse events or azole resistance (in 8 percent) [26]. Following initial intravenous therapy, the response to itraconazole was lower than the response to voriconazole (18 versus 40 percent) and there were more hospital admissions over about two years with itraconazole, but overall mortality was the same [27].
Voriconazole has been studied in three prospective studies [32-34], involving a total of 165 patients, as well as in other collected series [19-21,23,25-27,30]. In a trial in France, 5 of 41 patients died on therapy, and 7 (17 percent) were intolerant of voriconazole [33]. The overall response rate at six months was 32 percent, with better responses in patients with subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing pulmonary aspergillosis) than in those with chronic cavitary pulmonary aspergillosis. In a multicenter study in Japan, 61 percent responded well, with only two patients stopping therapy [34]. In another study of over 12 months of observation, quality of life in patients treated with voriconazole was improved in 30 percent at 3 months and in 43 percent by 12 months [23]. In a study in Italy, 6 of 21 patients could not tolerate voriconazole, and 9 (42.9 percent) had improved significantly at 12 months [30]. Intravenous (IV) voriconazole can be used in severely ill patients who are not suspected of having azole-resistant Aspergillus infections [32]. Over 12 months of therapy in 27 patients initiated on voriconazole, 14 (52 percent) remained on therapy at 12 months, with the remainder switching or discontinuing therapy because of adverse events or development of resistance (in 4 percent) [26].
Posaconazole was evaluated in a retrospective study of 67 patients with chronic pulmonary aspergillosis who were treated for at least six months [22] and in a study that prospectively assessed quality of life quarterly for a year [23]. Clinical and/or radiographic response to or stabilization of disease with posaconazole was observed in 61 percent of patients at 6 months and 46 percent of patients at 12 months. Over 12 months of observation, quality of life with posaconazole was improved in 45 percent of patients at 3 months and in 60 percent by 12 months [23]. Prospective trials should be performed to compare the various azole agents to determine which azole is most effective. All 36 patients switched from itraconazole or voriconazole were able to take posaconazole for many months; patients in the study were followed for 12 months [26].
There are no data on isavuconazole for the treatment of chronic pulmonary aspergillosis. The resistance profile for isavuconazole cannot be extrapolated from data for other azoles.
Amphotericin B or an echinocandin, such as micafungin, should be used in severely ill patients who are failing azole therapy [1,32]. Almost all reported studies with an echinocandin used micafungin. Overall response was 61 percent in a meta-analysis of 12-case series evaluating 380 patients, with little difference in response rates between amphotericin B or micafungin [35]. One study compared micafungin with IV voriconazole as initial therapy of chronic pulmonary aspergillosis in a randomized open-label trial and noted similar response rates [32]. A later prospective study of micafungin in 38 patients with chronic pulmonary aspergillosis suggested that the maximum useful dose of micafungin is 150 mg once daily [36]. Another small study compared caspofungin with micafungin with similar results [37]. Our own experience indicates that amphotericin B can also be effective for initial therapy [1]. Residual impairment of renal function was noted in 25 percent of those receiving amphotericin B [35].
Administration of micafungin as outpatient parenteral antimicrobial therapy (OPAT) is feasible. In one study of micafungin used for OPAT, 6 of 20 patients (33 percent) had improvement in symptoms (as measured by quality of life) and 3 patients (17 percent) had stability of symptoms [38].
Chronic fibrosing pulmonary aspergillosis — Other than antifungal therapy as discussed above, there are no specific additional treatments for chronic fibrosing pulmonary aspergillosis. Symptomatic remedies, rapid institution of antibiotics for intercurrent bacterial infections, oxygen, and adequate nutrition are all indicated [6].
Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis) — Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing pulmonary aspergillosis) is treated with antifungal agents, preferably voriconazole [21,33]. The approach to antifungal therapy is similar to the approach to acute invasive aspergillosis. Embolization may be indicated for certain patients to treat hemoptysis. Surgical resection is not usually contemplated because of the patient's general state of health and poor respiratory reserve. (See 'Surgery' below and 'Embolization' below.)
The older literature regarding the efficacy of antifungal agents for subacute invasive pulmonary aspergillosis is composed of small non-randomized open-label studies and case series [7,8,13,19,21,39]. In one study, 14 patients were treated with oral itraconazole and a complete or partial response was noted in 13 patients (93 percent) [13]. However, three patients experienced relapse after discontinuation of therapy.
In a prospective open-label study of oral voriconazole in 21 patients with subacute invasive pulmonary aspergillosis, a complete or partial response was observed in 9 patients (43 percent) [21]. A subsequent retrospective study found that 10 of 15 patients (67 percent) who had subacute invasive pulmonary aspergillosis and who received voriconazole had radiographic and clinical improvement, and 8 of 13 (62 percent) were considered to have control of disease after a median of 10 months (range 6 to 36 months) of therapy [19]. In another study, 10 of 19 patients (54 percent) with subacute invasive pulmonary aspergillosis responded to voriconazole at 6 months [33]. Finally, an open-label study of micafungin included nine patients with subacute invasive pulmonary aspergillosis, of whom six had a favorable clinical response [40].
ANTIFUNGAL THERAPY — The azoles, particularly itraconazole and voriconazole, are the mainstays of antifungal therapy for chronic pulmonary aspergillosis [7,8]. The efficacy of and indications for antifungal therapy are discussed above. (See 'Approach to therapy' above.)
It is important to be aware that significant adverse effects and drug interactions commonly occur with the azoles and that monitoring of serum concentrations is necessary [41]. Potential drug interactions, especially those related to cytochrome P450, are important since many patients who require long-term therapy for chronic pulmonary aspergillosis are receiving other agents that may cause significant interactions. These issues are discussed in detail separately. (See "Pharmacology of azoles".)
Choice of agent
Oral therapy — When oral antifungal therapy is indicated, we would recommend either itraconazole (200 mg twice daily) or voriconazole (200 mg twice daily; may increase to 300 mg twice daily based on therapeutic drug monitoring) as first-line agents [7,8]. Some experts start at a lower dose in older patients (eg, >70 years) with lower body weights. The apparently higher rate of azole resistance emerging on itraconazole therapy compared with voriconazole [26] has shifted the choice in favor of voriconazole for patients with extensive disease, particularly those with aspergillomas. Voriconazole is more often fungicidal for Aspergillus spp and is better tolerated in some but not all patients. Another study showed better initial improvement rates and reduced hospitalization rates and need to switch antifungal agent with voriconazole compared with itraconazole, but no difference in overall mortality [27]. Overall, many patients need to change initial therapy (approximately 50 percent) because of intolerance, poor response, or development of azole resistance [26].
Potential drug interactions are another important consideration in agent selection; in those on rifampin or other cytochrome-inducing agents, delayed-release posaconazole (ie, 300 mg twice daily) with early therapeutic drug monitoring may be the best oral choice. In those with a prolonged QT interval, isavuconazole may be the best choice as it shortens the QT interval. Care should be taken when using voriconazole in older patients as loss of balance due to the drug may lead to falls. The efficacy of these agents is discussed above. It is important to check for azole susceptibility in the infecting isolate if a culture is positive [42]. Switching between itraconazole preparations, especially some generic preparations, can lead to loss of disease control because of inadequate bioavailability of some generic preparations in some patients [43,44]. (See 'Approach to therapy' above.)
There is increasing experience with posaconazole for chronic pulmonary aspergillosis. It is used in patients who have experienced failure, toxicity, or emergence of resistance with another regimen. Posaconazole delayed-release tablets are preferred; the dosing is 300 mg every 12 hours on the first day, then 300 mg once daily, which is adjusted based upon therapeutic drug monitoring. (See "Pharmacology of azoles", section on 'Posaconazole'.)
There are limited data on the efficacy and tolerability of isavuconazole for chronic pulmonary aspergillosis. In one cases series evaluating the tolerability of voriconazole and isavuconazole in 41 patients with chronic pulmonary aspergillosis, who had received other azole therapy in the past, adverse event rates were lower with isavuconazole compared with voriconazole (86 versus 60 percent; p = 0.02). Drug discontinuation rates were similar. Five patients who were intolerant of voriconazole were able to tolerate isavuconazole [45].
Intravenous therapy — In severely ill patients or those infected with pan-azole-resistant isolates, intravenous (IV) therapy is indicated. The choices are voriconazole (unless resistance is present), posaconazole, an echinocandin such as micafungin, and amphotericin B [32]. Voriconazole (4 mg/kg twice daily), posaconazole (300 mg IV once daily), micafungin (150 mg IV daily), or amphotericin B can be used. The amphotericin B deoxycholate dosage is 1 mg/kg IV daily, but we prefer to use a less nephrotoxic lipid formulation (liposomal amphotericin B at 3 mg/kg IV daily or amphotericin B lipid complex at 5 mg/kg IV daily). Significant temporary nephrotoxicity is common with amphotericin B and residual nephrotoxicity occurs in a minority of patients [35]; some physicians prefer an echinocandin for this reason [46].
Echinocandins appear to be useful in patients with chronic pulmonary aspergillosis who are failing therapy due to azole resistance or who are intolerant of other drugs. Micafungin has been studied most extensively for this indication [32,36,37,40], but there is at least one trial that evaluated caspofungin [37]. There are no data for anidulafungin. (See 'Chronic cavitary pulmonary aspergillosis' above and 'Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis)' above and 'Clinical failure' below and "Treatment and prevention of invasive aspergillosis".)
Duration — The Infectious Diseases Society of America guidelines recommend that patients with chronic cavitary pulmonary aspergillosis and either pulmonary or generalized symptoms or progressive loss of lung function or radiographic progression receive a minimum of six months of antifungal therapy [8]. The guidelines also state that, in those with progressive disease, long-term, even lifelong, antifungal therapy may be necessary. In our experience, many patients with chronic cavitary or chronic fibrosing pulmonary aspergillosis require lifelong antifungal therapy, whereas Aspergillus nodules may or may not need to be treated indefinitely. Six months of antifungal therapy is often adequate for patients with subacute invasive pulmonary aspergillosis, but a longer duration is necessary in those with ongoing immunosuppression or a poor response to therapy [7].
Data are limited, but relapse is common if treatment is discontinued in patients with chronic cavitary or chronic fibrosing pulmonary aspergillosis [1,47]; 14 of 39 (36 percent) patients relapsed in one series [47] and 30 percent relapsed in another [24]. Recurrence is more likely in younger patients, those with more than one lobe affected, those with a slower response to therapy, and those treated for longer periods (probably signifying difficulty in controlling disease) [47]. Discontinuation of therapy is usually associated with gradual return of symptoms, worsening of findings by chest radiography, and rising Aspergillus antibody titers.
Quality of life is significantly worse in patients who cannot continue therapy because of intolerance, toxicity, or azole resistance [23,26]. A reason for curtailing therapy with an azole is peripheral neuropathy, which may be motor or sensory, and doesn’t always resolve even with stopping therapy promptly [48]. It is most common with itraconazole when there are high serum concentrations and with voriconazole when elevated doses are required to achieve adequate serum concentrations. It may or may not recur with therapy with another azole, after a period of recovery off treatment.
The duration of antifungal therapy in patients who undergo surgical resection is discussed below. (See 'Surgery' below.)
Assessing treatment response — Response to antifungal therapy can be assessed by reviewing pulmonary symptoms (cough, sputum production, dyspnea), systemic symptoms, and change in weight [1,19,20]. Symptoms usually improve during the first 6 to 8 weeks of therapy, and a lack of improvement by 12 weeks can be classified as a failure. Assessment of response is more complex in those with multiple pulmonary pathologies and requires experience and clinical judgment. We have found the St. George's Respiratory Questionnaire to be superior to the general health survey, SF36, in assessing severity of disease [49] and in assessing therapeutic response [23].
Aspergillus antibody titer is the most useful laboratory parameter to follow but takes months to fall in responders [26]. Those with only slightly elevated titers respond less well than those with very high titers [50], and change in titer is a helpful, but imperfect, guide to response and relapse [28]. Inflammatory markers, such as C-reactive protein and/or erythrocyte sedimentation rate, fall when therapy is successful but slowly and incompletely. The frequency with which laboratory and radiographic tests should be monitored during therapy is discussed separately. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Monitoring during therapy'.)
On chest imaging, pericavitary infiltrates and pleural thickening adjacent to cavities appear to be indicative of disease activity; these abnormalities may improve with appropriate antifungal therapy, leaving residual thin-walled empty cavities. Reduction in pleural thickening is the most reliable parameter of response [25]. The cavities themselves usually stabilize in size in response to therapy but may even enlarge in responding patients [1]. Disappearance of a fungus ball and minimization of intracavitary material are signs of a good response to therapy. In a carefully performed study that compared maximum cavity wall and pleural wall thickness by computed tomography at diagnosis and six months later in 36 patients with chronic pulmonary aspergillosis, reduced cavity wall thickness and pleural wall thickness were associated with clinical improvement [25]. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Radiographic features'.)
Lack of resolution of hemoptysis may reflect either antifungal failure or persistence of a large vascular network that would not be expected to resolve with antifungal control of the fungal infection alone. Recurrence of hemoptysis may be a sign of antifungal failure.
Clinical failure — Oral azole therapy is associated with response rates of approximately 60 to 80 percent, depending on the azole, drug concentrations, susceptibility of the organism, and probably some immune parameters that are not well understood [1,13,19-24,32,51]. Continuing weight loss is a common feature of failure, although with voriconazole it may reflect either chronic toxicity or clinical failure [26].
Patients who fail oral therapy or who are very ill with extensive disease may require a two- to four-week course of intravenous amphotericin B or micafungin therapy [35,40]. Maintenance of improved health on oral azoles is then often achievable, even if therapeutic failure with initial azole therapy was documented.
Glucocorticoids at modest doses should be used with caution in patients with chronic pulmonary aspergillosis, especially early in the treatment course before antifungal response can be assessed, but may have a place in management for some patients who remain chronically ill but have evidence of control of Aspergillus [52]. Occasional patients appear to decompensate with markedly increased breathlessness and reduced diffusing capacity of the lungs for carbon monoxide (DLCO) early after starting antifungal therapy; oral glucocorticoids may be useful in such patients.
Glucocorticoids should be avoided in patients with concurrent chronic pulmonary aspergillosis and pulmonary nontuberculous mycobacterial infection due increased risk of mortality [53].
There are at least four well-recognized reasons for clinical failure of therapy:
●Low serum concentration of azole – The variable bioavailability of itraconazole, voriconazole, and posaconazole present a challenge to clinicians that is best resolved by therapeutic drug monitoring [41]. Low serum concentrations may be the result of poor absorption, inappropriate timing of medication with food, rapid metabolism due to drug-drug interactions, a switch in capsule formulation to a generic variety, or poor adherence.
In most circumstances in which low plasma itraconazole levels occur, altering the formulation, improving the timing of the dose with food, and removing interacting drugs allows adequate serum concentrations to be achieved. A completely new formulation of itraconazole (SUBA-itraconazole) is better absorbed than many older formulations [54]. If this strategy is not successful, raising the itraconazole dose to 200 mg three times daily is usually successful. Generic preparations of itraconazole, available in some countries, have variable bioavailability [43].
With voriconazole, care should be taken with dose escalation, since resulting changes in plasma level may be disproportionately higher than dosage increments due to nonlinear pharmacokinetics. (See 'Choice of agent' above and "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
With posaconazole delayed-release tablets, very few patients have sub-therapeutic levels (<1 mcg/mL). Isavuconazole levels are more predictable, but occasional patients have very high or low levels [45].
●Antifungal resistance – Resistance to one or more azoles may occur during long-term treatment and may even occur in the absence of antifungal therapy [55]. Low concentrations of itraconazole probably predispose to itraconazole resistance and possibly to azole cross-resistance [56]. A positive culture while on antifungal therapy is an indication for susceptibility testing or, if not possible, then a switch of therapy. Itraconazole resistance is considerably more common than voriconazole and/or posaconazole resistance [26]. Itraconazole-resistant Aspergillus isolates obtained after itraconazole treatment may be cross-resistant to voriconazole but usually are not. Itraconazole-resistant isolates are usually resistant to posaconazole. Any azole resistance is usually associated with isavuconazole resistance, which is therefore likely to be ineffective in therapy.
In patients who are failing azole therapy, treatment decisions should be guided by in vitro susceptibility results. Isolates with minimum inhibitory concentrations (MICs) ≥4 mcg/mL to either itraconazole or voriconazole are very unlikely to respond to either of these agents. Isolates with a posaconazole MIC ≥1 mcg/mL are very unlikely to respond to posaconazole [22,57]. These MIC values are higher than those generally used as breakpoints. Some isolates resistant to all azoles require a switch to long-term amphotericin B (usually a lipid formulation) or an echinocandin, since azole-resistant isolates do not manifest cross resistance with other antifungal classes. Antifungal resistance among Aspergillus species is discussed in detail separately. (See "Antifungal susceptibility testing" and "Treatment and prevention of invasive aspergillosis".)
●Coinfection with another pathogen – Nontuberculous mycobacterial (NTM) infections may precede or follow chronic cavitary pulmonary aspergillosis. In those with NTM infection and chronic pulmonary aspergillosis, the driver for a worse outcome is the chronic cavitary pulmonary aspergillosis, not the NTM infection [58], especially if the C-reactive protein is elevated [53]. Therefore, optimizing antifungal therapy is important. It is not possible to coadminister itraconazole, voriconazole, or isavuconazole with a rifamycin and achieve therapeutic azole concentrations because rifamycin enzyme induction is so profound. High doses of posaconazole delayed-release tablets (ie, 300 mg twice daily) may achieve therapeutic concentrations. Rifampin and rifabutin should be avoided as part of the NTM regimen if possible, but if a rifamycin is used, the patient should be given an echinocandin to treat chronic cavitary pulmonary aspergillosis. Combinations of an azole, a fluoroquinolone, and/or a macrolide may prolong the QT interval, which should be monitored. (See 'Intravenous therapy' above and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Pharmacology of azoles", section on 'Drug interactions' and "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events'.)
Many patients with chronic cavitary pulmonary aspergillosis have bronchiectasis, producing voluminous amounts of purulent sputum, which may be the result of the fungal infection itself or a superimposed bacterial infection. Antibiotic therapy against this pathogen is indicated. When a cavity becomes superinfected with bacteria, such as Pseudomonas aeruginosa, a fluid level may appear. If sputum cultures do not yield a pathogen, percutaneous aspiration and drainage of such a cavity may be required, accompanied by antibiotic therapy. (See "Lung abscess in adults".)
●Interferon-gamma production defect – Numerous relatively subtle immune defects are seen in chronic cavitary pulmonary aspergillosis patients [59], but the remediable ones are interferon-gamma or interleukin-12 deficiency [60]. Testing in some patients shows defective production to standard stimuli [61]. A replacement dose of interferon-gamma results in modest improvement in some patients and reduced admissions to the hospital. Three patients without known defects in interferon-gamma production had stable or improved disease when interferon-gamma was given in combination with itraconazole [1]. Likewise, two patients with poor interferon-gamma production also benefited [61]. Further studies are needed to establish the role of interferon-gamma treatment in such individuals and the optimal dose and frequency, although a reduction in hospital admissions was seen in one cohort of deficient patients treated for many months [62]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'IFN-gamma receptor deficiencies' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'IL-12 receptor beta 1 deficiency' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'IL-12 p40 deficiency'.)
MANAGEMENT OF HEMOPTYSIS
Surgery — Surgery is the mainstay of treatment for symptomatic patients with simple aspergillomas in order to prevent or treat life-threatening hemoptysis [7,8,11] or to remove disease and try to effect a cure. Surgery is generally well-tolerated in patients with a single aspergilloma, with a mortality rate of <1 percent in multiple contemporary studies [5,9,10,63-66]. However, patients with more complicated disease, such as those with chronic cavitary pulmonary aspergillosis or pleural-based aspergillomas, are more likely to have complications, and usually surgery is avoided. As an example, among 89 patients who underwent surgical resection for aspergilloma, no deaths or complications occurred in patients with asymptomatic disease, but five postoperative deaths occurred in patients with complicated disease, all of whom had undergone lobectomy [63]. Surgical and anesthetic advances have improved outcomes [9]. Preoperative preparation with adequate nutrition (including tube feeding if necessary) probably improves surgical outcomes in malnourished, underweight patients.
In patients with chronic cavitary pulmonary aspergillosis, surgical removal of aspergillomas is fraught with difficulty because of the very vascular, adherent pleura and because the residual pleural space may become infected with Aspergillus spp, leading to Aspergillus empyema and/or a bronchopleural fistula [67]. Surgical removal of pleural-based aspergillomas, in particular, is prone to many complications and should be avoided if possible [68]. Many patients have underlying respiratory insufficiency, and removal of a lobe of the lung would leave them with inadequate pulmonary reserve. However, several series describe acceptable outcomes with 2 to 5 percent mortality and an overall complication rate of approximately 25 percent [64,65,69-72].
In unilateral chronic cavitary pulmonary aspergillosis, with or without an aspergilloma, surgery may be preferable to long-term antifungal therapy for some patients with limited disease, azole resistance, and/or drug intolerance. Pneumonectomy, and in particular completion pneumonectomy, is associated with higher morbidity and mortality, especially if it is performed as an emergency procedure [73].
Although not prospectively studied, antifungal therapy administered before surgery and during the perioperative period reduces the risk of relapse [5,12]. Relapse is more frequent in those not given antifungal therapy, whatever the manifestation of aspergillosis [12,74]. The optimal agent is voriconazole because of its intrinsic activity and the availability of both oral and intravenous (IV) formulations. Voriconazole interferes with some anesthetic and sedative agents. Voriconazole should be given orally as 400 mg twice daily for the first day followed by 200 mg twice daily one or two weeks prior to surgery, if possible. If the aspergilloma was fully resected without spillage of the contents of the cavity into the pleura, then a four-week course of voriconazole postoperatively is reasonable. If there is spillage, then a minimum of 12 weeks therapy is recommended in an attempt to prevent pleural aspergillosis/empyema. Fungal cultures should be obtained during surgery and susceptibility testing performed on isolates [12]. (See "Antifungal susceptibility testing".)
Spillage of the contents of a cavity containing Aspergillus is a risk factor for development of an Aspergillus empyema; local washout of the pleura with amphotericin B or taurolidine 2% may be useful when this occurs, although the efficacy of this approach remains unproven [5].
Embolization — In patients with moderate or severe hemoptysis who are too ill to undergo surgery or who have extensive disease, embolization may be appropriate. Most instances of hemoptysis are caused by abnormal and novel vascular connections to the systemic circulation in proximity to the affected area (image 1). Usually this is the bronchial circulation, but it may be any of the other arteries supplying the chest (eg, intercostal, subclavian, or internal mammary arteries). Otherwise, asymptomatic patients with aspergillomas may have an extensive network of small vessels and can develop hemoptysis. Several abnormal connections may exist in a single patient. The objective of embolization is to permanently occlude these vessels.
Patients with a communication between an intercostal and the anterior spinal artery can undergo embolization safely only if the catheter is introduced well past the anterior spinal artery. These patients require a skilled interventional radiologist, and the patient has to lie supine for two to four hours during the procedure.
Depending on the radiologist, approximately 50 to 90 percent of embolization procedures are successful [75-77]. However, rebleeding occurs in 30 to 50 percent of patients over three years [78,79]; relapse can be minimized with successful long-term antifungal therapy. Complications include local pain, stroke, and chest wall or spinal cord infarction as well as reactions to the contrast dye.
Investigational approaches — Temporary relief of hemoptysis may be gained with tranexamic acid (typically 500 mg orally three times daily), although it is not licensed for this indication. It is widely used throughout the United Kingdom for hemoptysis. Tranexamic acid slightly increases infarction potential, and a low rate of strokes has been reported after its use. It is sometimes not well tolerated, with gastrointestinal upset being the most common adverse effect.
The use of computed tomography–guided intracavitary instillation of amphotericin B has been attempted in some patients with inoperable aspergillomas. In one report, this procedure was performed in 40 inoperable cases of hemoptysis due to aspergilloma; the aspergilloma disappeared in 23 cases, and the cavity also disappeared in three [80]. Daily instillation of amphotericin B (50 mg in 20 mL dextrose) into a cavity through a catheter benefited some patients [81]. Spillage of amphotericin B into the bronchial tree can be problematic for patients with poor respiratory reserve. Repeated installations are often required [82], and efficacy has not been proven in randomized trials.
SUPPORTIVE CARE — Some patients are not able to take antifungal therapy because of adverse events, antifungal resistance, or personal preference. In such patients, adequate nutrition to maintain weight, avoidance or treatment of depression, and oxygen for hypoxic patients are helpful. In those with recurrent or continuous infection (bronchiectasis), intermittent or long-term antibiotic therapy is often helpful.
Glucocorticoids — Patients who are not doing well may benefit from glucocorticoids. There are no data on dose or duration for this indication. If used, adequate antifungal therapy must also be given, otherwise temporary improvement will be replaced by rapidly progressive and ultimately fatal disease, as demonstrated in this with nontuberculous mycobacterial infection [53] (see "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis"). Some patients with inflammatory disorders (such as sarcoidosis and rheumatoid arthritis) require long-term glucocorticoids, and antifungal therapy is especially important in these patients. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Role of glucocorticoids'.)
PROGNOSIS — There are no useful natural history data on patients who have simple aspergillomas, separated from those who have undergone surgical resection and those with other forms of chronic pulmonary aspergillosis, such as Aspergillus nodules. Among patients with tuberculosis (TB) who developed aspergillosis over four years of observation following the end of TB therapy, 6 percent of patients died each year [83].
Poor prognostic features include older age, lower body mass index, prior or concurrent nontuberculous mycobacterial infection, chronic obstructive pulmonary disease, presence of an aspergilloma, worse breathlessness, lower albumin, and lower activity scores [84]. Development of azole resistance may be a poor prognostic marker as well, but the number of cases in the study was too small to reach statistical significance.
The natural history of chronic cavitary pulmonary aspergillosis with and without antifungal therapy can be summarized as follows [84-87]:
●High initial mortality of 30 percent over 3 to 6 months in older patients
●Approximately 20 to 40 percent mortality at 3 years
●Approximately 50 to 80 percent mortality at 7 to 10 years
Few data are available with regard to the prognosis of chronic fibrosing pulmonary aspergillosis, but it is almost certainly worse than chronic cavitary pulmonary aspergillosis, with most deaths occurring from sepsis and/or bacterial pneumonia with respiratory failure. In a series of 10 patients, 50 percent had died within 3 years [6].
One small series noted a much worse outcome in patients with sarcoidosis with chronic pulmonary aspergillosis than those with prior tuberculosis for unclear reasons, but possibly related to glucocorticoid use in the former group [86]. However, more recent reports do not suggest the same poor outcomes [84,88].
Subacute invasive pulmonary aspergillosis is associated with high mortality, as demonstrated by a 20 percent short-term mortality rate despite treatment [89], a 33 percent 3-month mortality rate, and a 51 percent mortality rate over a median of 15 months, also despite treatment [90].
The impact of antifungal therapy on longevity has not been documented, but our own experience is more favorable than that published before orally active agents for aspergillosis became available in 1991. Current estimates are an annual mortality rate of 10 to 12 percent in patients receiving antifungal therapy, mostly as a result of pneumonia leading to acute on chronic respiratory failure.
Occasional patients develop carcinoma of the lung in immediate proximity to the infected area, which is problematic for both diagnosis and treatment and is usually inoperable and ultimately fatal.
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" and "Society guideline links: Hemoptysis".)
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 e-mail 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: Chronic pulmonary aspergillosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Chronic pulmonary aspergillosis includes several disease manifestations, including aspergilloma, Aspergillus nodules, chronic cavitary pulmonary aspergillosis, and chronic fibrosing pulmonary aspergillosis. Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing aspergillosis) is on the spectrum between chronic and acute forms of pulmonary aspergillosis. A duration of disease longer than three months distinguishes chronic pulmonary aspergillosis from acute and subacute pulmonary aspergillosis. (See 'Introduction' above and 'Definitions' above.)
●Chronic pulmonary aspergillosis represents a spectrum of disease; the risks and benefits of medical and surgical therapy vary with the manifestations of disease and the patient's pulmonary status, and, thus, the approach to therapy must be individualized. (See 'Approach to therapy' above.)
●For patients with a simple aspergilloma, we suggest surgical resection for patients who are symptomatic, particularly for those with hemoptysis, in order to prevent or treat potentially life-threatening hemoptysis (Grade 2C). We suggest antifungal therapy for patients who have progressive radiographic findings and/or symptoms and who are unable to undergo surgery (Grade 2C). We also suggest antifungal agents for adjunctive therapy following surgical resection, particularly if there is concern about concomitant tissue invasion by Aspergillus spp (Grade 2C). (See 'Approach to therapy' above and 'Surgery' above.)
●In patients with moderate or severe hemoptysis who are too ill to undergo surgery or have extensive disease, embolization may be appropriate. (See 'Embolization' above.)
●We suggest not treating asymptomatic patients who have either a simple aspergilloma or an Aspergillus nodule that is radiographically stable (Grade 2C). (See 'Aspergilloma' above.)
●For patients with chronic cavitary pulmonary aspergillosis or chronic fibrosing pulmonary aspergillosis, we suggest voriconazole or itraconazole initially, with a slight preference for voriconazole (Grade 2C). Voriconazole should be administered as 200 mg twice daily (may be increased to 300 mg twice daily based on drug monitoring). Itraconazole should be administered as 200 mg orally twice daily. Serum drug concentrations should be monitored initially to optimize dose and preparation. For those who are severely ill, intravenous therapy may be needed initially. Voriconazole (4 mg/kg twice daily), micafungin (150 mg daily), or amphotericin B (3 to 5 mg/kg daily for a lipid formulation or 1 mg/kg daily for the deoxycholate formulation) can be used. (See 'Approach to therapy' above.)
●For patients with subacute invasive pulmonary aspergillosis, which is more aggressive in its course than chronic cavitary pulmonary aspergillosis, we recommend voriconazole (200 mg twice daily) (Grade 1B). Posaconazole (300 mg once daily), amphotericin B, or isavuconazole can be used as alternatives if the patient cannot take voriconazole. (See 'Approach to therapy' above.)
●Patients with chronic cavitary pulmonary aspergillosis and either pulmonary or generalized symptoms or progressive loss of lung function or radiographic progression should be given a minimum of six months of antifungal therapy. For those with progressive disease, long-term, even lifelong, antifungal therapy may be necessary. In our experience, many patients with chronic cavitary or chronic fibrosing pulmonary aspergillosis require lifelong antifungal therapy, whereas Aspergillus nodules and subacute invasive pulmonary aspergillosis may or may not need to be treated indefinitely. Six months of antifungal therapy is often adequate for patients with subacute invasive pulmonary aspergillosis, but a longer duration is necessary in those with ongoing immunosuppression or progression of disease. (See 'Duration' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Denning, MBBS, FRCP, FRCPath, FMedSci, who contributed to an earlier version of this topic review.
