Pulmonary and Invasive Fungal Infections

Nina M. Clark, MD

The incidence of serious fungal infections has been increasing, and while invasive fungal infections are less frequently encountered in patients than those due to bacteria or viruses, their impact is significant. Invasive fungal infections are typically associated with a high rate of mortality, and their diagnosis and management are often challenging. Furthermore, there are newly emerging life-threatening fungal infections such as Candida auris, and the epidemiology of some fungal infections is changing, possibly due to alterations in climate and land use, as discussed in this issue. There is also a growing population of immunocompromised hosts at risk, including those living with acquired immunodeficiency syndrome (AIDS), transplant recipients, and persons receiving one of the rapidly expanding numbers of biological agents indicated for the treatment of malignancy or inflammatory diseases of the skin, joints, or gastrointestinal tract. Therefore, clinicians need to be aware of these life-threatening infections and their most frequent manifestation, pneumonia. While advances in invasive fungal infection diagnostics have been modest, treatment has substantially changed with the introduction of less toxic and broader-spectrum antifungal medications such as the echinocandins and mold-active triazoles. This issue of Seminars in Respiratory and Critical Care Medicine reviews the epidemiology, diagnosis, treatment, and prevention of fungal infections that primarily involve the lungs.

The first chapter of this issue by Drs. Gonzalez-Lara and Ostrosky-Zeichner discusses the most frequent health care associated invasive fungal infection, candidiasis. Candida species are among the top bloodstream pathogens, particularly among critically ill hospitalized persons who have had invasive procedures or devices. Rates of nonalbicans Candida species are increasing, and some of these have reduced susceptibility to azole antifungals. While Candida is not a usual pulmonary pathogen, disseminated infection can lead to infection of sterile sites such as the pleural cavity.

The most common forms of fungal pneumonia in nonimmunocompromised hosts are the endemic fungal infections histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. The first section of this issue is devoted to these infections. Some, such as histoplasmosis and blastomycosis, appear to have expanded their geographic reach. In addition, advances in phylogenetic testing have demonstrated new species designations (e.g., Blastomyces helicus [formerly Emmonsia helica] and Paracoccidioides americana, P. restrepiensis, and P. venezuelensis). All the endemic fungi may cause disease in immunocompetent individuals, but immunosuppressed individuals often experience more severe manifestations and disseminated infection.

Drs. Monzon and Baddley provide a detailed discussion on cryptococcal disease caused by a globally distributed pathogen best known for its propensity to cause meningitis in AIDS patients. Given this predilection, the authors point out the need to search for extrapulmonary sites of infection when patients present with cryptococcal pneumonia. Management of central nervous system disease and the immune reconstitution syndrome that may be seen with cryptococcosis are reviewed, as is the emergence of Cryptococcus gattii, which, in some cases, may be associated with decreased susceptibility to azole antifungals.

Aspergillosis is the most common mold infection encountered in immunocompromised hosts, particularly those with prolonged neutropenia and/or exposure to chemotherapy, as well as recipients of hematopoietic stem cell transplantation and those receiving chimeric antigen receptor T-cell (CAR-T) therapy. As with other fungal pathogens, the taxonomy of Aspergillus has evolved, with several newly characterized species. Some of these non-fumigatus Aspergillus species may be more resistant to antifungal agents.

Three subsequent chapters of this issue discuss less common but increasingly encountered mold infections such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis. Hyalohyphomycosis is due to non-Aspergillus hyaline (nonpigmented) septate molds such as Scedosporium, Paecilomyces, and Fusarium spp. Sinopulmonary infections are common manifestations of both mucormycosis and hyalohyphomycosis, but dissemination may also occur. Mucormycosis and hyalohyphomycosis tend to occur in severely immunocompromised hosts or as a result of traumatic inoculation, and they are associated with high mortality rates. Given their uncommon nature and relative resistance to many antifungal agents, optimal treatments are not well-established for some of these mold infections. Debridement, if feasible, may be beneficial. The third group, the agents of phaeohyphomycosis, are darkly pigmented or “dematiaceous” and, like hyaline fungi, have septate hyphae. Various clinical syndromes are associated with these fungi, as outlined in the chapter by Arcobello and Revankar. These infections can be seen in persons without apparent immunosuppression, although, as the authors note, it is possible that more subtle immune deficits predisposing to this and other invasive fungal infections have yet to be identified.

Dr Fishman then provides a thorough look at Pneumocystis jiroveci, an organism previously classified as a parasite, now more properly known (through RNA sequence analysis) to be a fungus. The epidemiology of infection and infection control aspects of pneumocystosis are intriguing. While serologic testing has revealed that exposure/colonization by the organism is common in children, reactivation disease does not appear to account for all cases of infection as outbreaks in susceptible hosts have been described; the natural reservoir of the infection remains unknown.

In the final chapter, Ledoux and Herbrecht review current antifungal treatments including their mechanisms of action, treatment niches, and adverse effects. While the triazoles have added a great deal to our antifungal armamentarium in terms of broader activity and tolerability, a major drawback is their extensive drug–drug interaction profile, of which clinicians must remain acutely aware when treating patients.

This issue of Seminars in Respiratory and Critical Care Medicine is an outstanding comprehensive review of pulmonary fungal infections, and we extend our deep thanks to each of the authors. They are internationally recognized experts who have provided state-of-the-art information for clinicians treating serious fungal infections of the lung. We hope that their contributions will aid in the diagnosis, management, and prevention of these infections.