Medical Care
Treatment of chronic necrotizing pulmonary aspergillosis (CNPA) and invasive aspergillosis differs significantly from treatment of allergic bronchopulmonary aspergillosis (ABPA) and aspergilloma.
Allergic bronchopulmonary aspergillosis
ABPA is a hypersensitivity reaction that requires treatment with oral corticosteroids. Inhaled steroids are not effective.
Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful. [8, 9, 10, 11] This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the needed maintenance corticosteroid dosage. In CF patients with ABPA, the concomitant use of itraconazole and inhaled corticosteroids may increase the risk of adrenal insufficiency.
Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy. Nasal washes with amphotericin or itraconazole have also been employed.
Case reports have described the beneficial use of the anti-immunoglobulin E (IgE) monoclonal antibody omalizumab (Xolair) in patients with ABPA. [38]
Aspergilloma
Treatment of aspergilloma is considered when patients become symptomatic, usually with hemoptysis. Surgical resection is curative but may not be possible in patients with limited pulmonary function. Oral itraconazole may provide partial or complete resolution of aspergillomas in 60% of patients. Successful intracavitary treatment using computed tomography (CT)-guided, percutaneously placed catheters to instill amphotericin (alone or with other drugs, including acetylcysteine and aminocaproic acid) has been reported in small numbers of patients. [12]
Bronchial artery embolization may be used for life-threatening hemoptysis in patients thought to have insufficient pulmonary reserve to tolerate surgery or in patients with recurrent hemoptysis (eg, patients with CF in whom hemoptysis may be related to underlying bronchiectasis with or without aspergilloma). [13] Bronchial artery embolization requires a skilled and experienced radiologist because localizing the abnormal vessel(s) may be challenging. Because the anterior spinal arteries may originate from the bronchial vessels, serious neurologic complications, although rare, may occur.
Chronic necrotizing pulmonary aspergillosis
Treatment of CNPA consists of administration of voriconazole, or, in some cases, itraconazole (if expense is an issue), caspofungin, or amphotericin B or amphotericin lipid formulation. A prolonged course of therapy with the goal of radiographic resolution is required. In addition, reduction or elimination of immunosuppression should be attempted, if possible.
Surgical resection may be considered when localized disease fails to respond to antifungal therapy.
Invasive aspergillosis
Invasive aspergillosis [39, 40] is often rapidly progressive and has a high mortality. Therefore, preventive therapy and rapid institution of therapy in patients in whom invasive aspergillosis is suggested may be lifesaving.
Prophylactic antifungal therapy and the use of laminar airflow (LAF) or high-efficiency particulate air (HEPA) filtration of patient rooms in patients who receive bone marrow transplants and other high-risk patients may prevent invasive aspergillosis. In patients with solid organ transplants, especially lung, in whom Aspergillus is cultured from sputum without evidence of pneumonia (colonization), inhaled amphotericin B may be administered.
When high-risk patients develop a compatible clinical picture, empiric treatment for aspergillosis should be initiated as diagnostic testing is undertaken. Voriconazole is now considered the drug of choice for invasive aspergillosis because of better tolerance and improved survival in comparison with amphotericin. [14]
Posaconazole, amphotericin B, or amphotericin B lipid formulations may be considered as empiric therapy in critically ill patients if the clinical picture, particularly the presence of sinusitis, could be compatible with mucormycosis, because voriconazole is ineffective for Zygomycetes infection. Caspofungin has also been approved for treatment of invasive aspergillosis in patients who are unable to tolerate or are resistant to other therapies. [15] Initial combination therapy is usually not indicated and should generally be reserved for treatment failures. [41, 42]
If possible, the level of immunosuppression should be decreased. For example, patients who are neutropenic may receive growth factors (ie, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor), and patients with certain types of transplants, in which transplanted organ dysfunction will not be life threatening (eg, renal transplant), may have immunosuppressive medications, including corticosteroids, reduced or discontinued.
Combination antifungal therapy is sometimes used for patients whose disease progresses while on single-drug therapy. Concomitant therapy with azole antifungals and amphotericin is controversial because the azole antifungals decrease amphotericin-binding sites and may therefore diminish its effectiveness. Be alert to the possibility of diminished effectiveness of amphotericin in any patient who has received prior treatment with an azole antifungal, including voriconazole, itraconazole, fluconazole, or ketoconazole. Newer antifungal azoles are under study (eg, ravuconazole) and may be available for compassionate use in patients in whom other therapies have failed.
The 100-mg delayed-release formulation of the triazole antifungal posaconazole (Noxafil) is indicated for the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients aged 13 years and older who are at high risk of developing these infections. The tablets are administered as a loading dose of 300 mg twice daily on day 1, followed by a once-daily maintenance dose of 300 mg. [43]
The FDA has approved an intravenous formulation of posaconazole (Noxafil), which is indicated for the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised adults who are at high risk of developing these infections. Posaconazole injection is administered as a loading dose of 300 mg twice on the first day of treatment, followed by 300 mg once daily thereafter. Posaconazole is also available as a 100-mg delayed-release tablet and in a 40 mg/mL oral suspension. [44]
In March 2015, the FDA approved isavuconazole (Cresemba) for invasive aspergillosis. It has activity against most strains of the following microorganisms, both in vitro and in clinical infection: Aspergillus flavus, Aspergillus fumigatus, and Aspergillus niger. Approval was based on the SECURE study (n = 516) that demonstrated isavuconazole was noninferior voriconazole on the primary endpoint of all-cause mortality at day 42 for the treatment of adult patients with invasive aspergillosis or other filamentous fungi (isavuconazole 18.6% vs voriconazole 20.2%). [45]
Further inpatient care and transfer
Further inpatient care
For invasive aspergillosis, monitor the patient for resolution of fever, hypoxemia, and pulmonary infiltrates. Patients who do not respond to therapy with voriconazole or combination therapy with voriconazole and caspofungin should be seen in consultation by an infectious disease specialist. Monitoring of serum voriconazole levels may be considered in nonresponders. [46] Consider reducing immunosuppression if possible based on the underlying disease. Other considerations include surgical resection for localized disease and the addition of other antifungal agents.
Transfer
Transfer to a tertiary care center may be warranted in patients with aspergilloma or invasive aspergillosis with massive hemoptysis if bronchial artery embolization or surgical resection is considered. Patients with invasive aspergillosis who do not respond to initial antifungal therapy may also benefit from transfer to a center where infectious disease expertise in the management of fungal infections is available.
Surgical Care
Allergic bronchopulmonary aspergillosis
Areas of mucoid impaction in ABPA may have a masslike appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred. Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage.
Aspergilloma
Surgical resection may be considered for massive hemoptysis in patients with aspergilloma if pulmonary function is sufficient for this sort of intervention. Assessment of operative risk necessitates obtaining pulmonary function studies, arterial blood gas determinations, and, possibly, split lung function studies (eg, quantitative perfusion lung scanning). Because aspergilloma occurs in cavitary areas, the affected lung may not be functional. Surgical resection may be difficult because of scarring, pleural adhesion, and the presence of abnormal vasculature.
Chronic necrotizing pulmonary aspergillosis and invasive aspergillosis
Surgical resection is a consideration for localized CNPA that has failed to respond to prolonged antifungal therapy. [47] Aspergillomas may occasionally form in areas of necrotizing pneumonia. These necrotic areas may bleed, sometimes massively, necessitating consideration of surgical resection. Patients may be high-risk surgical candidates because of underlying disease, coagulopathy, or thrombocytopenia and limited pulmonary reserve. [26] Age is also a factor. [48] The UK National Aspergillosis Centre noted the need to raise awareness of this disease to encourage drug trials and studies that will result in more effective treatment. [49]
Consultations
Consultation with a pulmonologist may be helpful for patients suggested to have invasive aspergillosis or chronic necrotizing Aspergillus pneumonia in order to establish a definitive diagnosis. Once the diagnosis is established, consultation with an infectious diseases specialist is usually helpful in management, especially if patients do not respond to initial fungal therapy.
Patients with ABPA or allergic fungal sinusitis should be treated by a pulmonologist or allergist familiar with the management of these conditions. Consultation with a pulmonologist is also indicated in patients with aspergilloma. Input from a thoracic surgeon may also be needed if surgical resection is feasible. In selected patients, consultation with an invasive radiologist may be indicated for CT-directed catheter placement to allow intracavitary therapy or bronchial artery embolization.
Prevention
Invasive aspergillosis is frequently fatal, and prevention is the best way to decrease its associated morbidity and mortality. The use of LAF rooms or HEPA filters decreases the concentration of fungi and bacteria in hospital rooms. Use of LAF rooms has been shown to decrease the incidence of invasive Aspergillus infection in patients undergoing bone marrow transplantation.
Prophylactic antifungal therapy indications in high-risk patients
Although fluconazole is not effective against Aspergillus, it significantly decreases the incidence of fungal infections after bone marrow transplantation and is the most frequently used oral prophylactic antifungal therapy [50]
Oral itraconazole has been found to be less effective than fluconazole, probably because of poor bioavailability of the drug in capsule form
Voriconazole is effective as secondary prophylaxis in patients who have been successfully treated for Aspergillus infection and who again require chemotherapy for consolidation or relapse [51] ; however, the use of voriconazole may increase the risk of the patient developing zygomycosis [52]
Posaconazole has been shown to be more effective than fluconazole for preventing invasive Aspergillus infection in patients with graft-versus-host disease (GVHD), though the overall incidence of fungal infections is similar for the two drugs. [30] ; posaconazole is approved for prophylaxis of invasive Aspergillus and Candida infections in high-risk patients, including those with GVHD and prolonged neutropenia from chemotherapy; because posaconazole is a broad-spectrum antifungal agent and widespread use would promote resistance, posaconazole prophylaxis should be limited to patients at highest risk or those with known resistance to other antifungals [53]
Inhaled amphotericin has also been used for prophylaxis, particularly in lung transplant recipients colonized with Aspergillus [54] ; however, results are variable, and concerns have been raised about its effect on lung function [55]
Oral itraconazole appears to be a safe and effective prophylactic antifungal for children with chronic granulomatous disease
Long-Term Monitoring
ABPA is usually managed in an outpatient setting. Serial measurement of the serum IgE level is a useful way to monitor response to therapy and to predict relapse after initial management. Levels are measured every 1-2 months during an exacerbation and every 3 months during remission. The rationale for repeat measurements of IgE levels during clinical remission is that 35% of exacerbations are asymptomatic but may result in lung damage. Elevated IgE levels should be evaluated further with a chest radiograph and institution of therapy with prednisone and possibly itraconazole.
Patients with invasive aspergillosis or CNPA who respond to initial inpatient treatment may require several weeks of antifungal therapy. Oral voriconazole or itraconazole (sometimes chosen because of cost) is administered until clinical and radiographic resolution.
