Clinical Pearls & Morning Reports
Aspergillus conidia (spores) are ubiquitous in the environment and thus unavoidable. After inhalation of airborne fungal conidia, clinical manifestations of disease are largely dependent on the host immune response. Read the NEJM Review Article here.
Q: Describe some of the different manifestations of aspergillus infection.
A: A wide range of clinical syndromes can be observed. Hypersensitivity to inhaled airborne conidia causes allergic bronchopulmonary aspergillosis or asthma with fungal sensitization, whereas an aspergillus fungus ball (aspergilloma) or chronic pulmonary aspergillosis develops more frequently in persons with structural lung disease. Invasive infection is the most devastating form of disease and is primarily observed in persons with clinically significant immunosuppression.
Q: What are the so-called “cryptic species” of aspergillus?
A: Invasive infection of humans is most frequently caused by members of the Aspergillus fumigatus complex, followed by A. flavus, A. niger, and A. terreus. A. fumigatus is most common in the lung, whereas A. flavus more commonly causes infection of the larger passageways and sinuses. In contrast, burn wounds are commonly colonized by A. niger and A. flavus. These organisms were previously identified solely by phenotypic methods; however, molecular methods have revealed a substantial number of new species. Phenotypically similar to more well-known pathogens, these organisms are termed “cryptic” species. In multicenter surveillance investigations of fungal disease in populations in the United States and Spain, 11 to 15% of all aspergillus isolates were identified as cryptic species. These species are frequently resistant to antifungal agents, underscoring the importance of accurate identification.
A: An increased risk of aspergillosis has been recognized for decades among patients who have undergone hematopoietic-cell transplantation, particularly in the early period of neutropenia and during treatment of graft-versus-host disease, and among solid-organ transplant recipients treated with systemic glucocorticoids or other immunosuppressive agents. More recently, nontraditional risk factors for invasive aspergillosis have been identified. Patients in the ICU frequently have a multitude of overlapping risk factors conferring a predisposition to invasive aspergillosis. Patients with severe respiratory viral infections are also at increased risk for the development of invasive aspergillosis. Bruton’s tyrosine kinase inhibitors, such as ibrutinib, have emerged as risk factors, not only for invasive aspergillosis but also for the development of disseminated or central nervous system disease. CAR-T therapy has also emerged as a risk factor for invasive aspergillosis.
A: A number of professional societies have published guidelines for treatment, with voriconazole or isavuconazole recommended as first-line therapy. A trial reported in 2021 supports the use of posaconazole as first-line therapy. Amphotericin B was previously the mainstay of treatment but was supplanted by voriconazole on the basis of a randomized study, reported in 2002, comparing voriconazole with amphotericin B deoxycholate as primary therapy. Itraconazole should not be used as first-line therapy for invasive aspergillosis, although it is a potential treatment option in patients with other forms of disease. Despite the extensive work done in this field and advances in antifungal therapy, outcomes for patients with invasive infections must be improved, since mortality rates at 6 weeks remain close to 20%. Drug–drug interactions during clinical care are a serious problem, and adverse events limit current therapeutic regimens. The search for alternative agents has prompted interest in agents with improved pharmacokinetic characteristics and novel mechanisms of action.