ESSENTIALS OF DIAGNOSIS
Most common cause of non-candidal invasive fungal infection in transplant recipients and in patients with hematologic malignancies.
Predisposing factors for invasive disease: leukemia, bone marrow or organ transplantation, corticosteroid use, advanced AIDS.
Pulmonary, sinus, and CNS are most common disease sites.
Detection of galactomannan in serum or other body fluids is useful for early diagnosis in at-risk patients.
Aspergillus fumigatus is the usual cause of aspergillosis, though many species of Aspergillus may cause a wide spectrum of disease. The lungs, sinuses, and brain are the organs most often involved. Clinical illness results either from an aberrant immunologic response or tissue invasion.
1. Allergic forms of aspergillosis—
Allergic bronchopulmonary aspergillosis (ABPA) occurs in patients with preexisting asthma or cystic fibrosis. Patients develop worsening bronchospasm and fleeting pulmonary infiltrates accompanied by eosinophilia, high levels of IgE, and IgG Aspergillus precipitins in the blood. Allergic aspergillus sinusitis produces a chronic sinus inflammation characterized by eosinophilic mucus and noninvasive hyphal elements.
2. Chronic aspergillosis—
Chronic pulmonary aspergillosis produces a spectrum of disease that usually occurs when there is preexisting lung damage but not significant immunocompromise. Disease manifestations range from aspergillomas that develop in a lung cavity to chronic fibrosing pulmonary aspergillosis in which the majority of lung tissue is replaced with fibrosis. Long-standing (longer than 3 months) pulmonary and systemic symptoms such as cough, shortness of breath, weight loss, and malaise are common.
3. Invasive aspergillosis—
Invasive aspergillosis most commonly occurs in profoundly immunodeficient patients, such as those who have undergone hematopoietic stem cell transplantation or have prolonged, severe neutropenia, but it can occur among critically ill immunocompetent patients as well. Specific risk factors in patients who have undergone a hematopoietic stem cell transplant include cytopenias, corticosteroid use, iron overload, cytomegalovirus disease, and graft-versus-host disease. Pulmonary disease is most common, with patchy infiltration leading to a severe necrotizing pneumonia. Invasive sinus disease also occurs. There is often tissue infarction as the organism grows into blood vessels; clues to this are the development of pleuritic chest pain and elevation of serum LD. At any time, there may be hematogenous dissemination to the CNS, skin, and other organs. Early diagnosis and reversal of any correctable immunosuppression are essential.
There is eosinophilia, high levels of total IgE, and IgE and IgG specific for Aspergillus in the blood of patients with ABPA.
For invasive aspergillosis, definitive diagnosis requires demonstration of Aspergillus in tissue or culture from a sterile site; however, given the morbidity of the disease and the low yield of culture, clinicians must maintain a high index of suspicion and use a combination of host, radiologic, and mycologic criteria to yield a probable diagnosis of invasive aspergillosis in at-risk patients. Indirect diagnostic assays include detection of galactomannan in bronchoalveolar lavage fluid or serum or serum assays for (1,3)-beta-D-glucan (though the latter is not specific for Aspergillus); the diagnostic utility of Aspergillus DNA by PCR is debated. To improve the reliability of galactomannan testing, multiple determinations should be done, though sensitivity is decreased in patients receiving anti-mold prophylaxis (ie, voriconazole or posaconazole). Galactomannan levels and Aspergillus DNA PCR can be tested in serum or in bronchoalveolar lavage fluid, which may be more sensitive than serum. Higher galactomannan levels are correlated with increased mortality, and failure of galactomannan levels to fall in response to therapy portends a worse outcome. Isolation of Aspergillus from pulmonary secretions does not necessarily imply invasive disease, although its positive predictive value increases with more advanced immunosuppression. Clinical suspicion for invasive aspergillosis should prompt CT scanning of the chest, which may aid in early detection and help direct additional diagnostic procedures. Common radiologic findings include nodules; wedge-shaped infarcts; or a characteristic “halo sign,” a zone of diminution of ground glass around a consolidation.
The high mortality rate and difficulty in diagnosis of invasive aspergillosis often lead clinicians to institute prophylactic therapy for patients with profound immunosuppression. The best-studied agents include posaconazole (300 mg orally daily) and voriconazole (200 mg orally twice daily), although patient and agent selection criteria remain undefined. A 2019 retrospective study suggested lower efficacy for isavuconazole (versus voriconazole or posaconazole) in preventing invasive aspergillosis; further study is warranted regarding the use of isavuconazole for antifungal prophylaxis in at-risk patients. Widespread use of broad-spectrum azoles raises concern for development of breakthrough invasive disease by highly resistant fungi.
1. Allergic forms of aspergillosis—
Itraconazole is the best studied agent for the treatment of allergic aspergillus sinusitis with topical corticosteroids being the cornerstone of therapy for ongoing care. For acute exacerbations of ABPA, oral prednisone is begun at a dose of 0.5 mg/kg/day and then tapered slowly over several months. Itraconazole at a dose of 200 mg orally daily for 16 weeks appears to improve pulmonary function and decrease corticosteroid requirements in these patients; voriconazole is an alternative agent.
2. Chronic aspergillosis—
The most effective therapy for symptomatic aspergilloma is surgical resection. Other forms of chronic aspergillosis are generally treated with at least 4–6 months of oral azole therapy (itraconazole 200 mg twice daily, voriconazole 200 mg twice daily, or posaconazole 300 mg daily); observational data suggests voriconazole may be superior to itraconazole for maintenance therapy.
3. Invasive aspergillosis—
The 2016 Infectious Diseases Society of America guidelines consider voriconazole (6 mg/kg intravenously twice on day 1 and then 4 mg/kg every 12 hours thereafter) as optimal therapy for invasive aspergillosis. However, the 2017 European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology, and the European Respiratory Society (ESCMID-ECMM-ERS) joint clinical guidelines indicate either isavuconazole (200 mg intravenously every 8 hours for six doses, then 200 mg daily) or voriconazole as first-line therapy. These guidelines are based on data from a randomized controlled trial demonstrating noninferiority of isavuconazole in terms of treatment outcomes and fewer adverse events. Another randomized controlled trial did not find an overall benefit of adding anidulafungin (200 mg on day 1, then 100 mg daily) to voriconazole, but among patients in whom galactomannan was detected, those who received combination therapy had better outcomes. Other alternatives include a lipid formulation of amphotericin B (3–5 mg/kg/day), caspofungin (70 mg intravenously on day 1, then 50 mg/day thereafter), micafungin (100–150 mg intravenously daily), and posaconazole oral tablets (300 mg twice daily on day 1 then 300 mg daily thereafter). Oral dosing of voriconazole at 4 mg/kg twice daily can be used for less serious infections or as a step-down strategy after intravenous therapy. Antifungal susceptibility testing of Aspergillus isolates is recommended in patients who are unresponsive to therapy or with clinical suspicion for azole-resistance. Therapeutic drug monitoring should be considered for both voriconazole and posaconazole given variations in metabolism and absorption.
Surgical debridement is generally done for sinusitis, and can be useful for focal pulmonary lesions, especially for treatment of life-threatening hemoptysis and infections recalcitrant to medical therapy. The mortality rate of pulmonary or disseminated disease in the immunocompromised patient remains high, particularly in patients with refractory neutropenia.
et al. Microbiological laboratory testing in the diagnosis of fungal infections in pulmonary and critical care practice. An Official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2019 Sep 1;200(5):535–50.
et al. Treatment of aspergillosis. J Fungi (Basel). 2018 Aug 19;4(3):E98.
et al. Isavuconazole versus voriconazole
for primary treatment of invasive mould disease caused by Aspergillus
and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016 Feb 20;387(10020):760–9.
et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20;162(2):81–9.
et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol. 2018 Feb;97(2):197–207.
et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63(4):e1–60.
et al. Selection of oral antifungals for initial maintenance therapy in chronic pulmonary aspergillosis: a longitudinal analysis. Clin Infect Dis. 2020 Feb 14;70(5):835–42.
et al. Diagnosis and management of Aspergillus
diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018 May;24(Suppl 1):e1–38.