Approach

The two key elements for successful therapy in patients with invasive aspergillosis (IA) are:

  1. Reversal of the underlying immune deficiency

  2. Early introduction of antifungal therapy.

Antifungal therapy may be definitive, empiric, or preemptive.

  • Definitive treatment is provided in a setting of confirmed/probable diagnosis.

  • Empiric treatment is given in a suspected diagnosis in a high-risk patient with clinical features suggestive of the infection without further confirmation (e.g., radiology, serology).

  • Preemptive therapy is provided in cases of strongly suspected IA in a high-risk patient with suggestive clinical features plus the presence of additional evidence (e.g., suggestive computed tomography [CT] scan and/or positive biomarkers).

In occasional cases, a surgical approach in removing infected tissue may play a critical role for a successful outcome.

Treatment of chronic pulmonary aspergillosis (CPA) depends on the type. Chronic cavitary pulmonary aspergillosis (CCPA) may require antifungal therapy to stabilize progression and improve symptoms. Treatment of simple aspergilloma in asymptomatic patients is not warranted. Good-quality evidence-based data to support the use of antifungal therapy are lacking.[2] In symptomatic patients with severe hemoptysis surgical treatment should be considered.

Suspected invasive aspergillosis (possible diagnosis)

In high-risk patients, empiric therapy may be used when the diagnosis of IA is suspected (e.g., in neutropenic patients with fever unresponsive to broad-spectrum antibacterial agents without an obvious focus of infection).[2] Fever may be due to nonfungal etiology. However, since the diagnosis is difficult to confirm, antifungals are frequently employed. Liposomal amphotericin B or an echinocandin are the drugs used in this context.[97][98] The Infectious Diseases Society of America (IDSA) guidelines also recommend voriconazole.[2]

Invasive aspergillosis (confirmed/probable diagnosis)

1. Reversal of the underlying immune deficiency

The use of colony-stimulating factors may reduce the duration of neutropenia. Discontinuing or reducing the dose of corticosteroids may help restore immune function. However, in many situations the underlying immunological deficiency may not be correctable (e.g., in presence of severe graft-versus-host disease [GVHD]). In such cases, the prognosis is generally poor. Early diagnosis followed by early initiation of therapy with antifungal agents improves outcome.[99]

2. Antifungal therapy

Classes of antifungal drugs with good in vitro/in vivo activity against Aspergillus species include:

  • Polyenes (e.g., amphotericin B)

  • Azoles (e.g., voriconazole, posaconazole, isavuconazonium)

  • Echinocandins (e.g., caspofungin, micafungin).

Isavuconazonium and voriconazole are the drugs of choice in the treatment of confirmed/probable IA.[2][98][100] Although efficacies of isavuconazonium and voriconazole are similar, the former appears to have a better safety profile.[16] Isavuconazonium is a prodrug of isavuconazole, a broad-spectrum antifungal agent with activity against both Aspergillus and Mucor. It is indicated for the treatment of adults with IA.[101] Isavuconazole is only available as isavuconazonium in the US.

Voriconazole has shown to be safer and more effective than conventional amphotericin B deoxycholate.[102] However, it has not been compared with any lipid formulation of amphotericin B.

There is a well established link between voriconazole and cutaneous reactions. This includes phototoxicity and importantly, cutaneous squamous cell carcinoma, which has been described as aggressive and multifocal, in multiple case reports.[103] Such reactions have been widely described in 1% to 2% of patients receiving >12 weeks of therapy.[104][105] Photosensitivity induced by voriconazole results in a sunburn-like erythema that is limited to sun-exposed sites.[103] The underlying mechanisms for this are unclear and establishing a definitive causative link between voriconazole and squamous cell carcinoma will require further studies. In patients requiring longer duration treatment with voriconazole, patient education and careful examination of skin should be regularly performed alongside advice to avoid excess sun exposure and to use ultraviolet protection liberally.

Alternative options to isavuconazonium or voriconazole are posaconazole or a lipid formulation of amphotericin B, either amphotericin B lipid complex or liposomal amphotericin B.[106][107][108] Posaconazole demonstrated noninferiority to voriconazole in the treatment of invasive aspergillosis in one randomized controlled trial; posaconazole was also associated with fewer treatment-related adverse events.[109] In areas of known and increasing azole-resistance, a lipid formulation of amphotericin B should be considered the first-line agent until the results of resistance testing are available.[16] In view of the nephrotoxic potential, conventional amphotericin B is no longer favored.[101] IA due to Aspergillus terreus may not respond to amphotericin B.[19][20] Patients generally show clinical/radiologic improvement in 5 to 7 days. Improvement is enhanced if the underlying immune deficiency is corrected - typically, the return of neutrophils. If the immune system remains impaired, the outcome is generally poor.

Therapeutic drug monitoring (TDM) is useful in the management of IA with voriconazole, isavuconazonium, and posaconazole where available. In case of failure of therapy with voriconazole, isavuconazonium, or lipid formulations of amphotericin B, clinical deterioration is apparent in 7 to 10 days. Additional measures include checking serum concentrations of voriconazole, switching from voriconazole to lipid formulations of amphotericin B and/or an echinocandin, or adding an echinocandin to therapy with voriconazole for potential synergy. Combination therapy (an azole antifungal plus an echinocandin) may be more effective than monotherapy with an azole.[110][111] In critically ill patients, combination therapy may be attempted. For salvage therapy, multiple drugs have been used simultaneously as a desperate measure with a success rate of about 40%.[112][113]

Patients at high risk for invasive fungal infection with a suggestive CT scan and/or positive biomarkers (e.g., serum galactomannan) are candidates for preemptive therapy with voriconazole. Invasive procedures may not yield positive results or may be difficult to perform, so voriconazole is employed on the basis of a presumptive diagnosis.[114]

Surgical intervention may be indicated in patients with IA lesions contiguous with the great vessels or the pericardium or in severe hemoptysis from a single cavity or invasion of the chest wall. A single pulmonary lesion prior to intensive chemotherapy or stem cell transplantation is another relative indication for surgical resection.[2][115][Figure caption and citation for the preceding image starts]: Treatment approach for invasive aspergillosisCreated by authors [Citation ends].com.bmj.content.model.Caption@725ca4dc

Chronic pulmonary aspergillosis

Aspergilloma:

Patients with stable, simple aspergilloma who have minimal or no symptoms require no treatment.[2][116]

There is insufficient evidence that aspergilloma responds to antifungal agents. Therapy with intravenous amphotericin B has failed to show benefit in these patients. Penetration of amphotericin B within the lung cavities is suboptimal, and inhaled, intracavitary, and endobronchial instillation of amphotericin B have not shown consistent benefit.[2] There are only anecdotal reports that treatment with intravenous itraconazole or voriconazole may be effective. In asymptomatic patients with aspergilloma, periodic monitoring with chest x-ray is appropriate.

Bronchial artery embolization may be helpful as a temporizing measure in symptomatic patients with severe hemoptysis, although the presence of massive collateral blood vessels makes the procedure suboptimal.[3][117] Surgical resection may be necessary in life-threatening hemoptysis; however, the postoperative morbidity/mortality remains a major concern. Complications include bleeding, bronchopulmonary fistula, empyema, and respiratory failure.[118][119] Peri- and postoperative antifungal therapy is not routinely required, but guidelines suggest that if there is a moderate risk of surgical spillage of the aspergilloma, antifungal therapy with an azole or an echinocandin may be used to prevent Aspergillus empyema.[2][3]

Chronic cavitary pulmonary aspergillosis (CCPA):

Patients with CCPA are treated with antifungal therapy to halt progression, improve symptoms, and minimize hemoptysis.[116] Oral itraconazole and oral voriconazole are the preferred options.[2][116] Oral posaconazole may also be considered as an alternative option if the preferred options cannot be used. Treatment is for a minimum of 6 months and may be extended in some patients. Treatment requires therapeutic drug monitoring and monitoring for drug-related side effects or toxicity.[2][3] Patients should be managed by physicians with experience of antifungal therapy. Intravenous antifungal therapy may be considered in patients with progressive disease, or who are intolerant to azoles or develop resistance. An initial course of intravenous antifungal therapy may also be considered for some acutely ill patients.[2][3] Options include amphotericin B deoxycholate, liposomal amphotericin B, or a echinocandin (e.g., micafungin, caspofungin).

Chronic fibrosing pulmonary aspergillosis (CFPA):

CFPA generally results from untreated CCPA, though may represent treatment failure and disease progression. Antifungal treatment is the same as for CCPA, and may be continued indefinitely.[3][4]

Subacute invasive aspergillosis (SAIA):

SAIA should be treated in the same way as acute IA above.[3]

Aspergillus nodule:

Aspergillus nodules are diagnosed after excision biopsy, usually following suspicion for malignancy. Single nodules that are completely excised may not need antifungal therapy, unless the patient is immunocompromised.[3][4] Single nodules that are not completely resected should be closely monitored.

Antifungal therapy may also be considered in patients with multiple nodules.[3]

Use of this content is subject to our disclaimer