Approach to the diagnosis of invasive fungal infections of the respiratory tract in the immunocompromised host

Publication summary

Diagnosis of fungal infections in the respiratory tract can be challenging, especially for immunocompromised patients who may be too unstable for invasive specimen collection or have complex case histories that make assessment of fungal colonization and infection difficult. As climate change and immunocompromising conditions, such as those caused by cancer chemotherapy and immunosuppressive use for chronic conditions, increase the risk for invasive respiratory infections caused by fungal pathogens, diagnostic algorithms designed for vulnerable and complex patients are urgently needed. Fungal disease causes 1.6 million deaths globally per year, and rapid diagnosis and treatment are essential to saving lives. This review examines the intersecting patient characteristics, clinical and imaging signs and pathways, and diagnostic tests available and in development to aid in rapid assessment of invasive fungal respiratory infections in immunocompromised people.

Who this is for

• Fungal diagnostic test and clinical trial developers
• Clinicians who work with immunocompromised people
• Medical mycologists

Key findings

Because of the difficulty in diagnosing invasive fungal infections in the respiratory tract, the authors outline host factors, clinical and imaging signs, and tests that aid in making a confirmed or probable diagnosis in immunocompromised people.

Patient characteristics

Immunosuppressive use. Risk for invasive fungal respiratory infection may rise with the use of glucocorticosteroids, dexamethasone, neutropenia following cytotoxic chemotherapy, lymphocyte-depleting antibodies, mycophenolic acid, and small molecule inhibitors and small molecule kinase inhibitors.

Solid organ transplantation. Much of the risk for invasive fungal respiratory infection following solid organ transplantation depends on the transplant site, the types of immunosuppressive agents used to prevent organ rejection, and whether or not fungal colonization is present in the respiratory tract. Invasive aspergillosis and cryptococcosis may be more likely to occur as a late complication of solid organ transplantation, and risk for invasive aspergillosis also rises in conjunction with renal transplantation or when iron overload is present in an explanted liver. Pneumocystis jirovecii pneumonia is more typically associated with the post-transplant prophylaxis period.

Hematopoietic stem cell transplantation (HSCT). Invasive mold infection in HSCT recipients is associated with a mortality rate as high as 60%, and great care must be taken to quickly identify suspected infections in these patients. Risk factors following allogenic HSCT include mucosal damage and neutropenia following T-cell suppression, cytotoxic chemotherapy, and irradiation. Autologous HSCT, which typically does not require significant immunomodulation following chemotherapy, is associated with a far lower risk of invasive fungal respiratory infection, yet the use of immunosuppressive agents to address any complications should raise clinical suspicion of the possibility for Pneumocystis jirovecii pneumonia and invasive aspergillosis.

Clinical and imaging findings

Nose and paranasal sinuses. Infections caused by Mucorales, which increased significantly during the COVID-19 pandemic, are associated with a death rate of about 50%, and risk for Mucorales infections rises in association with blood cancers, solid organ transplantation and HSCT, corticosteroid use, and uncontrolled diabetes. Infection is associated with pain, nasal ulceration, and necrotic tissue. Tracheobronchial fungal infections, often caused by Aspergillus, may accompany the post-lung-transplant period and present with ulcers, pseudomembranes, plaques, eschars, and occasionally nodules.

Distal respiratory tract (thorax). High-resolution computed tomography (CT) typically provides a significant amount of information about possible fungal infection in the lower respiratory tract. Because disseminated fungal infection is more likely in immunocompromised patients, a travel history to ascertain exposure to Histoplasma, Cryptococcus, or Talaromyces is important. Angioinvasive pulmonary molds may be associated with hemoptysis and nodules that may or may not display a halo sign on CT (i.e., ground-glass opacities surrounding the nodule). Pneumocystis pneumonia typically presents with dyspnea, malaise, cough, low oxygen saturation or partial pressure with exertion, and sometimes radiological evidence of ground-glass opacities and bilateral interstitial pneumonia. Pulmonary cryptococcosis may be associated with respiratory failure and radiological evidence of cavitation or bilateral bronchopneumonia. Pulmonary candidiasis is often associated with neutropenia and radiological evidence of nodules and ground-glass or tree-in-bud opacities.

Diagnostic and susceptibility testing

Fungal culture and microscopy. Though slow and associated with low sensitivity, fungal culture remains the gold standard for diagnosing invasive fungal respiratory infections. Guidelines from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) also permit a diagnosis of proven infection to be made via histopathology, cytology, or direct microscopy of needle aspiration or biopsy from a normally sterile site. Pneumocystis jirovecii, which cannot be cultured in diagnostic laboratories, is typically identified in bronchoalveolar lavage fluid, expectorated sputum, or via an immunofluorescence assay. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), when available, may aid in fungal species identification.

Antigen testing. A serum or bronchoalveolar lavage fluid galactomannan antigen enzyme-linked immunosorbent assay (ELISA) may aid in the diagnosis of infections caused by Aspergillus, Histoplasma, Fusarium, and Talaromyces, although galactomannan test sensitivity may be lowered for patients receiving antimold prophylaxis. Beta-1, 3-D-glucan antigen testing may help to identify Pneumocystis pneumonia or aspergillosis, yet may also be associated with a high rate of false positives. Lateral flow assay is often used to detect Cryptococcus, yet may be associated with a high rate of false negatives in non-disseminated pulmonary cryptococcal infections. Urine lateral flow assays for Histoplasma antigen and a point-of-care serum antigen test for Coccidioides have shown significant promise.

Molecular testing. Polymerase chain reaction may characterize fungi in the respiratory tract, yet determining whether the presence of fungi in immunocompromised patients represents infection or colonization remains challenging, and molecular test results should be interpreted alongside other clinical, imaging, and test data.

Recommendations

In light of the difficulties involved in diagnosing invasive fungal respiratory infections in immunocompromised patients and the urgency in ensuring that these patients are treated rapidly, the authors advocate for the following:

• Designing implementation studies that assess new diagnostic tests within established or innovative clinical pathways, especially those that are designed with complex patients and multidisciplinary decision-making in mind; and
• Continuing to design novel and non- or minimally invasive diagnostic tests, such as metagenomic next-generation sequencing, microbial cell-free DNA sequencing in plasma, tests that assess volatile organic compounds in exhaled breath, artificial intelligence used in imaging, and tests that incorporate antifungal susceptibility testing alongside species identification.