Pulmonary Aspergillosis in Immunocompromised Critically Ill Patients: Prevalence, Risk Factors, Clinical Features and Diagnosis-A Narrative Review

Abstract

Aspergillosis in immunocompromised individuals is a serious and potentially life-threatening infection, as the weakened immune system cannot effectively fight the Aspergillus fungus. This review provides an in-depth examination of aspergillosis in patients with various conditions that compromise immunity, including hematological disorders, HIV, SARS-CoV-2 pneumonia, influenza, and those who have undergone solid organ transplants. The clinical manifestations of aspergillosis are influenced by factors such as the host's underlying comorbidities, immune response, and immune suppression due to medications or treatments. The review delves into the epidemiology of aspergillosis, exploring various risk factors that predispose individuals to infection. It also discusses the wide range of clinical symptoms, highlighting the challenges in diagnosis and the importance of early detection. The review contrasts traditional diagnostic approaches with emerging molecular techniques, emphasizing the role of advanced diagnostics in improving outcomes. A proposed clinical decision-making flowchart is provided to assist healthcare professionals in managing suspected cases of aspergillosis. In addition to diagnostic challenges, the review addresses antifungal prophylaxis, pre-emptive therapy, and the growing concern of pharmacological resistance to antifungal agents. It concludes with a discussion of future research directions, underscoring the need for improved therapeutic strategies and preventative measures in immunocompromised patients to reduce the burden of this severe fungal infection.

Keywords: Aspergillus; antifungal treatment; immunocompromised patients; invasive aspergillosis; pulmonary aspergillosis.

Figure 1

Spectrum of disease due to interaction between Aspergillus and the human host. The inhalation of Aspergillus spp. airborne conidia can cause different categories of human disease depending on the immunological status of the infected host. Among immunocompetent individuals, diseases such as aspergilloma, tracheobronchitis, or chronic cavitary pulmonary aspergillosis (CCPA) are typically caused by A. fumigatus, but other species such as A. niger, A. flavus, and A. terreus may also be involved. In immunocompromised patients, IA is predominantly associated with A. fumigatus, but emerging pathogens like A. terreus, A. nidulans, A. flavus, and cryptic species in the A. fumigatus complex (e.g., A. lentulus, A. udagawae) have increasingly been reported, often associated with intrinsic antifungal resistance. Conversely, patients with immune system hyperactivation may develop allergic manifestations such as severe asthma with fungal sensitization (SAFS), allergic bronchopulmonary aspergillosis (ABPA), and allergic fungal rhinosinusitis (AFRS), mostly related to A. fumigatus and occasionally A. niger.

Figure 2

Criteria for probable aspergillosis diagnosis in patients admitted in ICU. Various criteria have been proposed for diagnosing probable aspergillosis in different patient populations. Modified AspICU criteria 2021 and FUNDICU criteria 2024 are applied to non-immunocompromised individuals. The EORTC/MSGERC criteria are used for immunocompromised patients and rely on a combination of host factors, clinical and radiological evidence, and microbiological and histopathological findings to achieve a rapid and accurate diagnosis. For a proven diagnosis of aspergillosis, identification of Aspergillus is required through microscopic analysis of sterile material, histopathological or cytopathological examination, or direct microscopic examination of a specimen obtained via needle aspiration or biopsy. Possible aspergillosis requires at least 1 host factor and 1 clinical criterion without any mycological criteria. CSF: Cerebrospinal fluid.

Figure 3

Direct microscopic diagnosis of IA in three immunocompromised patients. (a) Patient n. 1 HSCT recipient presenting IA and a granulomatous reaction with giant cells (black arrow) surrounding Aspergillus hyphae on the surface of the pleura. (a1) Splendor Hoeppli phenomenon (black circle) around the hyphae. This phenomenon consists of radiating eosinophilic material at the lesion’s periphery and is typical of chronic granulomatous lesions. (a2) Detail of (a1): Splendor Hoeppli phenomenon with septated hyphae and conidial heads. (a3) Cardiac dissemination of Aspergillus hyphae dissecting myocardial fibers with neutrophilic inflammation (myocarditis). (a4) Hyphae of Aspergillus highlighted by histochemical reaction of Grocott-Gomori methenamine silver (GMS). (a5,a6): (a5) hematogenous spread of Aspergillus in IA. (a6) Hyphae within a vascular lumen highlighted by GMS. (b) Patient n. 2 with AIDS presenting necrotizing pseudomembranous bronchitis with pseudomembrane of Aspergillus in bronchial wall eroding the epithelium (black circle; exudate of necrotic tissue, inflammatory cells, fungal hyphae and conidial heads). Figure (b1,b2) show an enlargement of figure (b) of the typical branching at acute angle shape (45°) of the Aspergillus hyphae with conidial heads. Hyphae of Aspergillus are branching (b1) and septated (b2). (c) Patient n. 3 positive to SARS-CoV-2 with necrotizing pseudomembranous bronchitis. The fungus plug (black arrow) completely occludes the airway lumen. Post-mortem artifacts are present. (c1) Enlargement of pseudomembrane of Aspergillus growing along the surface of the bronchial mucosa and eroding the epithelium (black arrow; exudate of necrotic tissue, inflammatory cells, fungal hyphae and conidial heads). (c2) Detail of (c1): fungal hyphae and conidial heads (red arrow) eroding the mucosa (black arrows). Images were taken from the hospital archive.