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Chronic pulmonary aspergillosis: Treatment

Chronic pulmonary aspergillosis: Treatment
Literature review current through: Jan 2024.
This topic last updated: Sep 07, 2023.

INTRODUCTION — Chronic pulmonary aspergillosis (CPA) encompasses a spectrum of disorders caused by local proliferation of Aspergillus hyphae in patients with underlying structural lung disease.

This topic will discuss the management of each of the five clinical forms of CPA. The epidemiology, pathophysiology, clinical manifestations, and diagnosis of CPA are discussed separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis".)

The treatment of other disorders associated with Aspergillus are also discussed separately. (See "Treatment and prevention of invasive aspergillosis" and "Treatment of allergic bronchopulmonary aspergillosis".)

SIMPLE ASPERGILLOMA — A simple aspergilloma is a single aspergilloma that is stable on serial imaging obtained several months apart. Most patients have minimal to no symptoms, although hemoptysis can be a serious complication (algorithm 1).

Further information about manifestations and diagnosis of simple aspergillomas is found separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Aspergilloma' and "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Imaging suspicious for aspergilloma'.)

Patients without hemoptysis — For patients with minimal to no symptoms and no hemoptysis, we do not treat with antifungal therapy or any other therapeutic intervention (algorithm 1). Most patients do not progress on imaging and have no symptoms. Antifungal therapy for asymptomatic simple aspergillomas has not been systematically studied [1].

We obtain annual imaging (with x-ray or low-dose computed tomography [CT], depending on diagnostic certainty) to confirm stability or improvement; typically, annual imaging continues indefinitely because these patients have underlying chronic lung disease that warrants annual screening. Most aspergillomas do not spontaneously resolve.

Enlargement or development of surrounding parenchymal disease suggests evolution to chronic cavitary pulmonary aspergillosis (CCPA) or a concomitant process (eg, mycobacterial infection, cavitary lung cancer), as discussed separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Chronic cavitary pulmonary aspergillosis (CCPA)' and "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

Patients with hemoptysis — Hemoptysis is not uncommon in patients with CPA, including those with simple aspergilloma. Life-threatening hemoptysis is the most feared complication of simple aspergilloma.

Low-grade hemoptysis – For patients with simple aspergilloma whose hemoptysis is low grade (ie, blood-streaked sputum only) or infrequent, we typically follow these patients in the same manner as patients without hemoptysis, as described above (algorithm 1). (See 'Patients without hemoptysis' above.)

Hemoptysis that worsens over time or occurs more often may indicate progression to CCPA or need for more aggressive intervention, as discussed below (algorithm 1) (see 'Management of hemoptysis' below). Antifungal treatment may be considered if other approaches for management of hemoptysis are not possible or ineffective, although this has not been studied in patients with simple aspergilloma.

Severe hemoptysis – Patients with simple aspergilloma who have severe hemoptysis are managed with surgical intervention or bronchial artery embolization, as described in detail below. (See 'Severe hemoptysis' below.)

Surgery – For patients with simple aspergilloma undergoing surgery, we typically do not provide preoperative antifungal therapy. However, if spillage of fungal contents is anticipated during surgery because of pleural involvement or surgical complexity, we prescribe oral antifungal therapy with an azole for two to three weeks prior to surgery, if possible; if surgery is imminent or there is concern for azole resistance, we give an echinocandin (eg, micafungin) on the day of surgery. Antifungal options are the same as for other forms of CPA. (See 'Azoles as the preferred antifungal' below and 'Alternative antifungals' below.)

Postoperative antifungal therapy is usually unnecessary in patients whose simple aspergilloma has been removed [1]. However, for patients who meet one of the following criteria, we provide three months of postoperative antifungal therapy (see 'Azoles as the preferred antifungal' below and 'Alternative antifungals' below):

-Intraoperative spillage of fungal contents into the pleural space

-Incomplete resection

-Intraoperative difficulty that may have caused extension of infection to adjacent lung tissue or pleura

-Histopathologic visualization of hyphae invading the excised lung tissue (hyphae are to be expected inside the cavity and the fungus ball)

In all post-surgical patients, we perform follow-up CT scan 6 to 12 months after surgery to evaluate for relapse of the aspergilloma or evidence of new disease elsewhere.

In our experience, surgery results in resolution of hemoptysis in most patients with simple aspergilloma. However, relapse of fungal disease is not uncommon, occurring in 12 (43 percent) of 28 patients with surgically treated simple aspergilloma in one observational study; relapse usually occurred within three years [2].

Nonsurgical intervention – For patients at high risk for adverse outcome from surgery, bronchial artery embolization is an option, either as a temporizing measure before surgery or as definitive treatment, as discussed below [1]. (See 'Severe hemoptysis' below.)

We typically do not provide pre- or post-procedure antifungal therapy to patients with simple aspergillomas treated with bronchial artery embolization.

ASPERGILLUS NODULE — Most Aspergillus nodules are diagnosed via biopsy or surgical resection performed for suspicion of malignancy. Management depends on whether the nodule(s) are completely resected and the immune status of the patient. Below we offer suggested treatment strategies. However, as evidence is limited, treatment should be individualized and a specialist with expertise in the management of aspergillosis should be consulted.

Single nodules — Patients who have only one nodule, and the nodule has been confirmed to be an Aspergillus nodule, are managed based on their immune status.

Immunocompetent patients — Immunocompetent patients are those with no immunocompromising conditions whatsoever. By our definition, even patients with mildly immunocompromising conditions (eg, poorly controlled diabetes mellitus) should be managed as immunocompromised, as described below. (See 'Immunocompromised patients' below.)

For immunocompetent patients with a single Aspergillus nodule, our management approach depends on whether the nodule has been resected (algorithm 2):

Resected nodule – We do not provide postoperative antifungal therapy or do any follow-up imaging in immunocompetent patients with a single Aspergillus nodule that has been completely resected (algorithm 2) [1]. In a series of 73 patients whose Aspergillus nodule was resected, no relapses occurred after a median follow-up of three years, and antifungal therapy was not prescribed in 58 (79 percent) [3].

Unresected nodule – In immunocompetent patients with a single unresected Aspergillus nodule, we typically do not treat with antifungals (algorithm 2). We recommend this approach as there are limited data on the natural history of unresected Aspergillus nodules as well as on the effect of antifungals on Aspergillus nodules.

We obtain a follow-up CT scan six months after diagnosis and again one year later (ie, 18 months after diagnosis). If the nodule is stable, improved, or resolved on both scans, we stop further imaging. If the nodule enlarges, we risk-assess for lung cancer, and we treat with antifungal therapy for three months and repeat a CT-scan. If the nodule has resolved or is unchanged, we stop antifungal therapy and repeat a CT scan in one year. If the nodule is reduced, we continue antifungal therapy and repeat a CT scan in three to six months. If the nodule has enlarged, we typically pursue biopsy or resection.

There are minimal data on the role of antifungal therapy for unresected Aspergillus nodules. In a series of seven patients with biopsy-confirmed Aspergillus nodules, no patients had progression of nodular disease at one year of follow-up; nodular size decreased in the five patients who received an antifungal, and the nodules were unchanged in the two who received no antifungal [3].

Immunocompromised patients — Immunocompromised patients are divided into those who are mildly immunocompromised and those with severe immunocompromise.

Mildly immunocompromised – Mildly immunocompromising conditions include poorly controlled diabetes mellitus, prolonged low-dose corticosteroid therapy (eg, < equivalent of prednisone 0.3 mg/kg/day or any dosage given for <3 weeks), HIV disease with CD4 count ≥200 cells/microL, and malnutrition, among other conditions.

Resected nodule – For mildly immunocompromised patients with a completely resected Aspergillus nodule, we typically do not offer antifungal therapy or do follow-up imaging (algorithm 2).

Unresected nodule – For mildly immunocompromised patients with a single unresected Aspergillus nodule, we typically treat with oral antifungal therapy and get a CT scan once patients have received three months of therapy (algorithm 2). However, we sometimes defer treatment if we believe the risk of antifungal toxicity outweighs the potential benefit of treatment; for example, we may use this approach in frail or elderly patients with low levels of immunosuppression. Antifungal options are the same as those used for other forms of CPA, as described below. (See 'Azoles as the preferred antifungal' below and 'Alternative antifungals' below.)

Imaging results determine our next steps (algorithm 2):

-Complete resolution – For patients whose nodule has completely resolved, we stop antifungal therapy and repeat a CT scan one year later.

-Stabilized or improved – For patients whose nodule has stabilized or improved but is still present, we provide an additional three months of antifungal therapy and then get another CT scan. If the nodule is unchanged at that point, we stop therapy. If it has improved, we continue therapy and imaging for an additional three to six months; we stop therapy at that point if it has not enlarged. We get a follow-up CT scan one year after antifungal therapy is completed.

-Enlarged – Enlarging nodules often require repeat tissue sampling, as described below. (See 'Recurrent or worsening disease' below.)

Severely immunocompromised patients – Patients with severe immunocompromise (eg, neutropenia, medications that chronically suppress cellular immune response [eg, transplant recipients, high-dose corticosteroids (eg, ≥ equivalent of prednisone 0.3 mg/kg/day for >3 weeks)], graft-versus-host disease, HIV disease with CD4 <200 cells/mL) should be managed as if they have invasive aspergillosis, as discussed separately (algorithm 2). (See "Treatment and prevention of invasive aspergillosis".)

Recurrent or worsening disease — For patients who have not received antifungal therapy and their imaging reveals an enlarging or changing nodule, progression to CCPA should be considered, particularly with compatible radiological features, such as progression to a cavitating nodule with or without intracavitary material.

Patients whose imaging shows recurrent or worsening disease despite antifungal therapy often require repeat tissue sampling. Potential diagnoses include malignancy, a concomitant process (eg, mycobacterial infection), progression to CCPA, antifungal resistance, and suboptimal drug levels. Tissue sampling (via biopsy or excision) allows diagnosis of many of these conditions; all samples should undergo histopathologic examination as well as fungal, mycobacterial, and bacterial cultures with susceptibility testing. Recurrence of nodules after resection or resolution should not be assumed to be due to Aspergillus [3].

Imaging that reveals new or worsening cavitation in a nodule without evidence of nodule enlargement can be difficult to interpret. Cavitation can be an inconsequential finding in an Aspergillus nodule. However, it can also be indicative of evolution to CCPA or a concomitant process (eg, cavitary lung cancer, mycobacterial infection). We typically increase the frequency of imaging in these patients and have a low threshold for tissue sampling.

Multiple nodules — Often patients have multiple nodules, one of which is confirmed to be an Aspergillus nodule. These patients should also be followed with serial imaging, but we have a lower threshold to treat with antifungals, especially in patients with any degree of immunocompromise. It cannot be assumed that all nodules are Aspergillus-related, although this is presumed to be more likely in immunocompromised individuals. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' below.)

If the nodules do not decrease in size on therapy or findings suggest another diagnosis, such as primary or metastatic malignancy, further workup should be performed. Management of lung nodules is discussed in detail separately [1]. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Multiple nodules, solid or subsolid'.)

CHRONIC CAVITARY PULMONARY ASPERGILLOSIS (CCPA) — Most patients with CCPA have symptoms (eg, cough, shortness of breath, weight loss), and all have characteristic radiographic findings, as discussed separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Chronic cavitary pulmonary aspergillosis (CCPA)'.)

Goals of treatment — CCPA is a chronically progressive disease that is challenging to treat. Although cure of the disease is sometimes possible, in many cases the goals of treatment are to achieve clinical and radiographic stability or improvement and to prevent hemoptysis. Although improvement is the primary aim, stability is often what is achieved and may be considered a satisfactory outcome in patients who had been significantly deteriorating before treatment and/or have high burden of disease. Clinical and radiological improvement may take several months to achieve.

Available data suggest that 60 to 80 percent of patients with CCPA achieve stability or improvement on therapy [4-12]. One small randomized trial of 31 patients found a higher response rate in patients treated with itraconazole versus controls (76.5 versus 35.7 percent) [11].

Antifungal therapy — Treatment with antifungals is the cornerstone of management of CCPA.

Indications for treatment — For most patients with CCPA, we suggest treatment with antifungals starting at the time of diagnosis.

Therapy may be deferred in a select group of patients, specifically those who have no or very mild symptoms and have no evidence of progression on recent radiologic assessments. Untreated patients need frequent clinical and radiographic assessments, since untreated CCPA typically progresses over time. We typically clinically assess untreated patients with CCPA every three months and obtain CT scans every 6 to 12 months.

CCPA is best managed using a multidisciplinary approach, involving infectious diseases physicians, pulmonologists, thoracic surgeons, and interventional radiologists.

Azoles as the preferred antifungal — Most patients with CCPA are treated as outpatients with oral azoles. The azoles are the only oral class of antifungal with reliable activity against Aspergillus spp.

Preferred azoles – We initiate therapy with either voriconazole or itraconazole. We use the following dosing regimens:

Voriconazole: 200 mg orally every 12 hours in most patients. We use 150 mg orally every 12 hours in the elderly, in frail patients, and in patients with a low body weight (body mass index <18.5).

Itraconazole: 200 mg orally every 12 hours in most patients. We use 300 mg total daily dose (eg, 200 mg in the morning and 100 mg in the evening) in the elderly, in frail patients, and in patients with a low body weight (body mass index <18.5).

We prefer these agents because we have more experience with them, and they are typically less expensive than alternatives. In general, we favor voriconazole in patients with high burden of disease (eg, bilateral disease, large aspergillomas) because of voriconazole's greater activity against Aspergillus species and data suggesting improved clinical outcomes and tolerability compared to itraconazole (see below) [4,13]. However, there are no prospective comparative studies of the two agents.

Other azole options – If voriconazole and itraconazole are not options, we treat with posaconazole or isavuconazole. We use the following dosing regimens:

Posaconazole: Delayed-release tablets 300 mg orally once daily in most patients. We use 200 mg orally once daily in the elderly, in frail patients, and in patients with a low body weight.

Isavuconazole: 200 mg orally once daily.

For patients who are ill enough to require hospitalization for their CCPA, intravenous formulations of azoles can be given as initial therapy. Step-down to oral therapy is indicated once the patient improves. Because oral azoles have excellent bioavailability and can often be monitored with drug levels, there are minimal intrinsic advantages to intravenous therapy. The pharmacology of azoles is discussed in detail separately. (See "Pharmacology of azoles".)

Prior to starting azole therapy, patients' other medications should be reviewed to assess for drug interactions. In addition, drug levels of azoles should be monitored during therapy, as dose changes may be indicated. These issues are further discussed separately and below. (See "Pharmacology of azoles", section on 'Drug interactions' and 'Laboratory monitoring' below.)

There are no randomized trials comparing different azoles for treatment of CPA. In a meta-analysis of observational data, no difference was found in outcomes comparing itraconazole, voriconazole, or posaconazole [14]. No data are available for isavuconazole.

In the largest retrospective study (160 patients) comparing itraconazole and voriconazole, more patients had clinical improvement with voriconazole (40 versus 18 percent), although the difference was not statistically significant [13]. In another retrospective study, 12 months of voriconazole or posaconazole had a higher rate of clinical improvement (50 percent and 62 percent, respectively) than itraconazole (43 percent), but statistical analysis was not performed to assess the significance of this finding [4].

Fluconazole has no role in the treatment of Aspergillus infections because it has limited activity against the fungus.

Alternative antifungals — Besides azoles, echinocandins and amphotericin B are active against Aspergillus spp, but they are not available in oral formulations.

We reserve these agents for individuals who cannot tolerate azoles, are suspected to have azole resistance, or are failing azole therapy.

Echinocandins – For patients in whom an azole is not an option, we suggest micafungin (150 mg once daily). If micafungin is not available, caspofungin (70 mg on day 1, then 50 mg once daily) or anidulafungin can be used.

A randomized trial of micafungin versus intravenous voriconazole in 107 patients with CCPA showed no difference in overall favorable response (60 percent for micafungin versus 53 percent for voriconazole), and micafungin had less adverse events [5]. In another randomized study that included 70 patients with CPA, micafungin and caspofungin had comparable favorable response rates (42 percent and 47 percent, respectively) [15].

Administration of micafungin via outpatient parenteral antimicrobial therapy (OPAT) programs may be preferable and has been shown to be safe in patients with CPA [16].

The pharmacology of echinocandins is discussed in detail separately. (See "Pharmacology of echinocandins and other glucan synthesis inhibitors".)

Amphotericin B – For patients in whom azoles and echinocandins are not options due to intolerance, drug interactions, or suspected resistance, we administer liposomal amphotericin B (typical dosage is 3 mg/kg intravenously once daily). We use liposomal amphotericin B instead of amphotericin B deoxycholate because of the lower risk of toxicity (eg, kidney failure) with the liposomal formulation.

Intermittent dosing of liposomal amphotericin B for OPAT has been described for other fungal infections but not for CPA [17,18].

Details regarding dosing and side effects of liposomal amphotericin B is found separately. (See "Pharmacology of amphotericin B", section on 'Dosing'.)

There are less data available for amphotericin than for azoles and echinocandins in patients with CCPA.

Management of hemoptysis — Hemoptysis is not uncommon in patients with CCPA.

Low-grade hemoptysis — For patients with CCPA whose hemoptysis is low grade (ie, blood-streaked sputum only) or infrequent, we typically treat with antifungals and follow them clinically.

Hemoptysis that worsens over time or occurs more often may indicate the need for more aggressive management. Bronchial artery embolization or surgical resection should be considered in these patients, as discussed below. (See 'Severe hemoptysis' below.)

Low-grade hemoptysis that is not life threatening is further discussed separately. (See "Evaluation of nonlife-threatening hemoptysis in adults".)

Severe hemoptysis — Severe hemoptysis is defined as life-threatening hemoptysis or large-volume hemoptysis (≥ approximately 150 mL of expectorated blood in a 24-hour period).

For patients with ongoing life-threatening hemoptysis, initial stabilization procedures (eg, airway management, intubation) should be performed, as described separately. (See "Evaluation and management of life-threatening hemoptysis".)

While awaiting definitive treatment, we usually prescribe tranexamic acid (1 g orally or intravenously every eight hours), a fibrinolysis inhibitor that has been shown to decrease bleeding in other patient populations [1,19]. Efficacy data for hemoptysis are limited and inconclusive, and the rate of adverse effects has not been definitively established [19,20].

Once patients have been stabilized, surgery and/or embolization should be performed as definitive therapy:

Surgical intervention (preferred) – For patients who present with severe hemoptysis, surgical resection is the preferred approach [1].

Surgical options – Lobectomy is the most common procedure; other surgical options include pneumonectomy, sublobar resection, bullectomy, wedge resection, and use of video-assisted thoracic surgery (VATS).

Preoperative preparation – Before surgery, we advise surgeons to obtain intraoperative fungal cultures for susceptibility testing (along with bacterial and mycobacterial cultures). We also advise the surgeon to instill 2% taurolidine into the pleural space during surgery if intrapleural spillage occurs. However, this agent is not widely available, and evidence supporting its use are derived from small case series with no comparator groups [21].

Postoperative management – In most patients with CCPA, we provide three months of postoperative antifungal therapy and repeat imaging. We stop antifungals if no residual disease is found. (See 'Monitoring response to treatment' below.)

In our experience, surgery results in resolution of hemoptysis in most patients. In a study of 24 patients with CPA who underwent surgery for hemoptysis, 20 (83 percent) had resolution of hemoptysis [2].

Main complications of surgical intervention include prolonged air leak and empyema due to spillage of fungal elements into the pleural space. In a retrospective study of 30 patients with CPA treated with surgical intervention, prolonged air leak occurred in seven (23 percent) and fungal empyema occurred in six (20 percent) [21].

Nonsurgical intervention – For patients who are deemed too high risk for surgery due to comorbidities or suboptimal pulmonary function, bronchial artery embolization is an option, either as a temporizing measure before surgery or as definitive treatment [1]. Bronchial artery embolization has variable success rates, and recurrences of hemoptysis are common, affecting more than half of patients [22,23].

If bronchial artery embolization is performed on a patient who is receiving intravenous amphotericin B, we withhold the amphotericin doses for 24 to 48 hours after the procedure to avoid additive toxicity, in accordance with expert guidelines [1].

Some experts treat hemoptysis with installation of amphotericin B into an aspergilloma cavity [24]. Data for this practice are scarce, and we do not advise this intervention, except in select patients at institutions with extensive experience performing the procedure.

Monitoring response to treatment — The clinical response to antifungal therapy in the absence of curative surgery is slow, and the radiographic response is even slower.

While patients are on antifungal therapy, we monitor them closely:

Clinical and radiographic assessments — Four weeks after initiating antifungal therapy, we see patients in clinic for their first follow-up visit. The visit allows us to evaluate clinical status and identify adverse effects from the antifungal medication. We do not anticipate significant improvement in the patient's clinical status by this time; in fact, some patients will appear to be worsening because it sometimes takes weeks for antifungals to reverse the underlying disease process.

For most patients, we evaluate clinical and radiographic response (with CT scan) six months after initiation of therapy. Clinical improvement manifests as weight gain, improvement in constitutional symptoms such as fatigue and anorexia, and reduction in respiratory symptoms such as productive cough or hemoptysis. To assess clinical response, some experts utilize the St. George's Respiratory Questionnaire [25]; others use the Respiratory Symptom Score (RSS), which assesses cough, sputum production, dyspnea, hemoptysis, chest tightness, and nocturnal awakening on a visual 10-point analog scale [26]. An improvement of at least 25 percent on the RSS score is indicative of a positive response to treatment according to a consensus statement [26].

A favorable response on a CT scan is a reduction in pleural thickening, consolidation, cavity size, thickness of the cavity wall, and size and number of aspergillomas and nodules (image 1). According to a detailed study of CT scan-related changes, decrease in cavity wall thickness, decrease in pleural thickening, and fungal ball disappearance were the changes most closely associated with clinical improvement, whereas cavity size did not correlate with clinical response [27].

Among patients who respond to therapy, clinical improvement in respiratory and systemic symptoms usually becomes apparent after several weeks of treatment. Most patients will have radiographic improvement within six months [1]. Clinical failure is typically defined as lack of clinical and radiographic stabilization or improvement by the end of six months [26,28].

For patients who are clinically stable or improved after six months of therapy, we typically see them in clinic regularly every three months and eventually decrease the frequency of visits to every six months.

For patients with treatment failure at six months, we change the treatment plan, as discussed elsewhere. (See 'Refractory disease' below.)

Laboratory monitoring

Drug levels – Therapeutic drug monitoring of azoles should be performed after initiation of therapy, after every dosage change, and whenever toxicity, clinical failure, or alterations in interacting medications occur. Although isavuconazole drug level monitoring is usually not recommended, we check isavuconazole levels in patients with adverse effects to assess whether a dose reduction is necessary [29]. Data suggest that lower dosages of posaconazole (200 mg orally once daily) and isavuconazole (100 mg orally once daily) can still achieve adequate drug levels and decrease long-term side effects in patients with CPA [29,30].

In general, we aim for the same target levels as those favored for treatment of invasive aspergillosis, as described separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Dosing and drug effects'.)

Once patients have achieved an appropriate and stable drug level, we do not follow serial drug levels unless circumstances change.

Drug-related adverse effects – Antifungal agents can have serious adverse effects, some of which can be detected via bloodwork. For example, azoles can cause elevated liver transaminases, and amphotericin B can cause kidney and electrolyte dysfunction. Depending on the specific antifungal, appropriate lab tests should be regularly performed, as described elsewhere. (See "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of echinocandins and other glucan synthesis inhibitors", section on 'Adverse effects' and "Pharmacology of amphotericin B".)

Aspergillus serology and inflammatory markers – We monitor Aspergillus immunoglobulin (Ig)G levels during treatment of CCPA; IgG often improves with treatment, but improvement of levels has not been conclusively linked to a favorable clinical response [31,32]. We also monitor markers of disease activity, such as C-reactive protein and albumin.

Duration of therapy — The duration of therapy for patients with CCPA depends on their clinical and radiographic response to treatment, as described above. (See 'Monitoring response to treatment' above.)

Patients on oral azole therapy – Most patients require extended courses of therapy. We assess for response after six months but usually continue treatment for at least 12 months. We discontinue therapy if clinical improvement has occurred and imaging reveals no evidence of active disease. Active disease on imaging is manifest as continued aspergilloma, thick walls on cavities, consolidation, or pleural thickening. We tend to recommend indefinite antifungal therapy in patients with a history of significant hemoptysis who have persistent disease such as aspergillomas. Patients with extensive and/or bilateral disease often remain on antifungals for years or for the rest of their lives (image 2).

In some cases, radiologic findings persist over long periods on antifungal therapy without appreciable change over serial imaging and with minimal symptoms. In those cases, the decision to stop should be individualized considering tolerability of antifungals, patient preference, and risk of relapse. (See 'Relapses' below.)

As long as patients remain on antifungal therapy, we reassess them clinically and radiographically every six months. If treatment is discontinued, we typically follow patients clinically and with CT scans; frequency of monitoring depends on the risk of relapse. (See 'Relapses' below.)

Patients whose disease continues to worsen while on therapy are defined as having refractory disease, as discussed below. (See 'Refractory disease' below.)

Patients on intravenous antifungal therapy – For the subset of patients on intravenous therapy because oral antifungals are not an option, determining the appropriate duration can be challenging. Our approach is to provide intravenous therapy, preferably via an OPAT service, for three to six weeks, after which we assess clinical and radiographic response. For patients who have a favorable response and subsequently deteriorate, we repeat intravenous courses as needed. Patients with unfavorable responses are discussed below. (See 'Refractory disease' below.)

Limited data are available to inform decisions about duration of therapy. In a randomized trial of 164 patients with CPA treated with itraconazole, 8 of 83 patients (10 percent) who received 12 months of therapy relapsed at two years compared with 31 of 81 (38 percent) who received six months of therapy (absolute risk reduction 0.29; 95% CI, 0.16 to 0.40) [33].

Refractory disease — In clinical studies, up to 40 percent of patients with CCPA fail to improve while on azole therapy [4-12]. Large cavity size at the time of diagnosis may be a predictor of poor clinical response [34].

For patients with refractory disease, we systematically evaluate for possible etiologies:

Review dosages of antifungal agents – For patients on an oral azole, ensure that drug levels are within the therapeutic range and adjust dosages if necessary. Low drug levels may be due to noncompliance, drug interactions, malabsorption, or altered drug metabolism unique to the patient. In some cases, change to a different agent or class may be necessary to ensure adequate blood levels.

Assess for antifungal resistance – We obtain high-volume fungal cultures of sputum or bronchoscopic specimens to assess for resistant isolates [35]. All prior fungal cultures and susceptibilities should be reviewed as well. An azole-resistant strain isolated during treatment suggests treatment failure, particularly if found repeatedly.

Sensitivity of sputum cultures is suboptimal, as discussed separately (see "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Diagnostic evaluation'). Molecular methods (eg, polymerase chain reaction [PCR], pyrosequencing) have been used to detect resistant organisms in patients with CPA [36].

Risk factors for development of resistance while on therapy include high disease burden and subtherapeutic drug levels [37-39]. Mechanisms of resistance vary geographically and may cause resistance to some or all azoles, as discussed separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Microbiology'.)

For patients in whom resistance to available oral agents is confirmed, we initiate intravenous therapy and consult surgery for potential debulking of disease, as described below.

Evaluate for concomitant or alternative diagnosis – Failure to respond to antifungal therapy may be due to the presence of a process unrelated to Aspergillus (eg, malignancy, another infection).

We obtain sputum for bacterial and mycobacterial stains and cultures and often perform bronchoscopy to increase yield for these organisms; bronchoscopic biopsy may detect underlying malignancy or other noninfectious etiologies.

Example coinfections include mycobacteria (eg, tuberculosis, nontuberculous mycobacteria) and common causes of bacterial pneumonia (pneumococcus, Pseudomonas spp). The presence of air-fluid levels inside cavities may indicate a secondary bacterial infection or bleeding. Management of coinfections is discussed below. (See 'Treatment of co-infections' below.)

Assess the burden of disease – In some patients, antifungals are unable to overcome high burden of disease. For these individuals, we sometimes give a course of intravenous antifungal therapy; in our experience, a brief course of intravenous therapy may lead to clinical improvement that can be maintained with subsequent oral azole therapy, even if failure of initial azole therapy was documented [40,41].

For patients with unilateral localized disease failing to respond to antifungal therapy, we sometimes offer surgical consultation to debulk the infection. In this subset of patients, surgery is performed with a curative intent (ie, by removing all affected lung tissue). In the weeks leading up to surgery, we try to optimize patients' surgical outcome by maximizing nutritional and cardiopulmonary status. Even without cure, surgery may debulk the infection enough to allow antifungal therapy to be effective against residual disease.

Patients with bilateral disease or extensive fibrosis and adhesions are unlikely to have a good outcome with surgery, primarily because they often have too little functional reserve to withstand extent of surgery and its complications. In such patients, we only offer surgery if no other options are available and only after extensive discussion with the patient and members of the treatment team.

Evaluate for progression of disease to the CFPA form – A subset of patients with CCPA transition to chronic fibrosing pulmonary aspergillosis (CFPA), which is more refractory to treatment than CCPA, as discussed below. (See 'Chronic fibrosing pulmonary aspergillosis (CFPA)' below.)

Clinical criteria for diagnosing CFPA are discussed separately, and management is discussed below. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Diagnosis' and 'Chronic fibrosing pulmonary aspergillosis (CFPA)' below.)

Consider interferon-gamma deficiency – In vitro data suggest that patients with genetic defects in the interferon-gamma inflammatory cascade are at increased risk of CPA, as discussed separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Pathology'.)

In case reports, patients with CPA who have inadequate production of interferon-gamma have been successfully treated with subcutaneous injections of interferon-gamma given as salvage therapy [42,43]. Patients should be evaluated for interferon-gamma deficiency before being treated with the agent, ideally with support from a Clinical Immunologist. Duration of interferon-gamma treatment is not defined.

Relapses — Relapses occur in approximately 20 percent of patients within one year after treatment is stopped [28,44]. Risk factors for relapse include bilateral or more extensive disease and presence of aspergillomas [32,44].

The definition of relapse is not uniform in various studies; we suspect relapse in a patient with clinical and radiological deterioration after initial clinical and radiographic improvement. The suspicion for relapse is supported by a newly positive sputum culture or increasing Aspergillus IgG.

In patients whose relapse occurs after discontinuation of antifungal therapy, we typically restart the antifungal that was most effective and well tolerated. In these patients, antifungal therapy may have to continue indefinitely.

Mortality — CCPA is associated with high all-cause mortality rates. In a cohort of 387 patients with CCPA, all-cause mortality was 14 percent at one year and 38 percent at five years [45]. Older age, lower serum albumin, a worse score on the St George's Respiratory Questionnaire activity domain, chronic obstructive pulmonary disease (COPD) diagnosis, and presence of non-tuberculous mycobacteria (NTM) lung infection were associated with mortality. In a nationwide study of patients admitted with CPA in France, mortality was 32 percent at one year and 45 percent at five years [46]. In a more recent study, mortality was 7 percent at one year. A higher Aspergillus IgG, a lower albumin, and a higher C-Reactive protein at baseline were associated with mortality [47].

CHRONIC FIBROSING PULMONARY ASPERGILLOSIS (CFPA) — CFPA represents an advanced form of CCPA; therefore, these patients may have already received antifungal treatment and may have developed toxicity or resistance [48].

For patients who have progressed from CCPA to CFPA while on antifungal therapy, non-azole agents are often required. For patients whose initial diagnosis is CFPA, treatment is the same as CCPA. Antifungal regimens are outlined above. (See 'Antifungal therapy' above.)

Because of the refractory nature of CFPA, lifelong therapy is usually necessary. These patients should be managed in conjunction with CPA specialists, if possible.

The prognosis for CFPA has not been adequately studied, but it is worse than that of CCPA based on our experience. (See 'Mortality' above.)

SUBACUTE INVASIVE PULMONARY ASPERGILLOSIS (SAIA) — Unlike other forms of CPA, SAIA is characterized by invasion of lung tissue by Aspergillus hyphae. For this reason, antifungal selections for SAIA are the same as for invasive aspergillosis. (See "Treatment and prevention of invasive aspergillosis".)

However, the duration of treatment for SAIA is usually longer than the 6- to 12-week duration usually recommended for invasive aspergillosis. Often, a six-month course is provided [1]. In some cases, SAIA progresses into cavities with aspergillomas, at which point it is treated as CCPA.

SAIA is treated with the intention to cure more often than CCPA [1]. While SAIA responds slower than invasive aspergillosis, response is usually faster and more complete than CCPA. The more rapid response of SAIA is thought to be due to its shorter onset and lack of pre-existing cavities as well as the capability of reducing immunosuppression in some patients [49].

TREATMENT OF CO-INFECTIONS — A small subset of patients may simultaneously have CPA and other infections, usually non-tuberculous mycobacteria (NTM).

Although many of these patients have significant comorbidities, the main challenge is the drug interaction between azoles and rifamycins that often causes subtherapeutic or undetectable azole levels. However, therapeutic levels of posaconazole have been achieved at a dose of 300 mg twice daily in the form of delayed-release tablets in patients on rifampicin [50].

If we are unable to treat both infections simultaneously, our approach is to prioritize the treatment of the condition felt to contribute most to the patient's disease. For example, we may prioritize NTM treatment in patients with smear-positive disease whereas CPA treatment may be prioritized in patients with large aspergillomas.

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".)

SUMMARY AND RECOMMENDATIONS

Simple aspergilloma – For patients with simple aspergilloma who have no or minimal hemoptysis, we suggest not administering antifungal therapy (algorithm 1) (Grade 2C). We typically follow these patients with annual imaging. (See 'Patients without hemoptysis' above and 'Patients with hemoptysis' above.)

For patients with severe hemoptysis, we suggest surgical resection rather than antifungal therapy or bronchial artery embolization (algorithm 1) (Grade 2C). For patients in whom surgery is not an option, brachial artery embolization is an alternative. Some patients will require pre- or postoperative antifungal agents as discussed above. (See 'Patients with hemoptysis' above.)

Aspergillus nodule – Most Aspergillus nodules are diagnosed via biopsy or surgical resection performed for suspicion of malignancy. (See 'Aspergillus nodule' above.)

Immunocompetent patients – For such patients, we suggest not administering antifungal therapy (algorithm 2) (Grade 2C). If the nodule has not been completely resected, we follow the patient with serial imaging for evidence of worsening. (See 'Immunocompetent patients' above.)

Immunocompromised patients – Management of immunocompromised patients with an Aspergillus nodule depends on the level of immunosuppression.

-Mild immunocompromise (eg, diabetes mellitus, low-dose corticosteroids) – Antifungal therapy is not required if the nodule is completely resected (algorithm 2). (See 'Immunocompromised patients' above.)

If the nodule has not been completely resected, we suggest antifungal therapy (Grade 2C). We give three months of antifungals, with further therapy depending on the results of follow-up imaging.

-Severe immunocompromise (eg, neutropenia, high-dose corticosteroids) – We manage these patients as if they have invasive aspergillosis. (See "Treatment and prevention of invasive aspergillosis".)

Chronic cavitary pulmonary aspergillosis (CCPA) – Patients with CCPA usually require antifungal therapy; CCPA is otherwise a chronic progressive disease. The available evidence (mostly uncontrolled observational reports) suggests that 60 to 80 percent of patients stabilize or improve on treatment. We administer a minimum of six months of antifungal therapy and often provide longer or lifelong therapy due to persistent residual disease while on therapy. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' above.)

Chronic fibrosing pulmonary aspergillosis (CFPA) – This disease is typically treated in the same way as CCPA. Lifelong therapy is almost always necessary due to the refractory nature of CFPA. (See 'Chronic fibrosing pulmonary aspergillosis (CFPA)' above.)

Subacute invasive aspergillosis (SAIA) – This disease is characterized by tissue invasion by fungal hyphae and usually occurs in mildly immunocompromised patients. As such, it is treated in the same manner as invasive aspergillosis, except duration of therapy is often longer for SAIA. (See 'Subacute invasive pulmonary aspergillosis (SAIA)' above.)

Antifungal selection – With the exception of SAIA, antifungal options are the same for any form of CPA. (See 'Antifungal therapy' above.)

Azoles (preferred) – We suggest initiating therapy with either voriconazole (200 mg orally every 12 hours) or itraconazole (200 mg orally every 12 hours) rather than other antifungals (Grade 2C). Other azole alternatives include posaconazole and isavuconazole. Oral therapy is usually adequate, but azoles can be initially given intravenously for patients with severe illness. (See 'Azoles as the preferred antifungal' above.)

Alternative antifungals – Echinocandins (eg, micafungin) and liposomal amphotericin B are alternatives to azoles. When azole therapy is not an option, we suggest echinocandin therapy (eg, micafungin) rather than liposomal amphotericin B (Grade 2C). (See 'Alternative antifungals' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Denning, MBBS, FRCP, FRCPath, FMedSci, who contributed to an earlier version of this topic review.

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References

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