Pulmonary Fungal Infections

The respiratory tract is the portal of entry for most invasive fungal infections. Not surprisingly, the initial manifestations of invasive fungal infections are often related to the respiratory tract, and for many fungi, respiratory symptoms are the only manifestation of infection. Fungal infections have emerged as major causes of morbidity and mortality in the last decade. This emergence is clearly related to increasing numbers of immunosuppressed patients. In addition to larger numbers of patients with fungal infections, the spectrum of fungi causing infection has expanded considerably. Several articles in this issue are devoted to organisms that in previous decades were rarely reported to cause invasive infection in humans.

The clinical course of infection is highly dependent on the overall immune status of the host. For example, the endemic mycoses, histoplasmosis, coccidioidomycosis, and blastomycosis, are more likely to be disseminated in the immunosuppressed host. For some fungi, such as Fusarium and Scedosporium, invasive infection is exceedingly rare in the absence of immunosuppression. Each of the articles in this issue is devoted to a different fungal organism, with the exception of Aspergillus, which is covered in two articles. Differences between infections in immunocompetent hosts and those who are severely immunosuppressed are emphasized in each article. Each article also elaborates on the most likely clinical presentations and appropriate treatment options for each organism.

Dr. Pappas presents an overview of the current knowledge of the epidemiology, clinical manifestations, and treatment of blastomycosis. The text emphasizes that almost all infections begin with inhalation of conidia into the lungs from an environmental source and that skin lesions represent dissemination, not inoculation, disease. Problems with diagnosis remain unsolved, but treatment has been revolutionized with the use of azoles as first-line therapy for all but those individuals who are extremely ill and those who have central nervous system involvement.

Dr. Catanzaro reminds us of the importance of coccidioidomycosis in both immunocompetent and immunocompromised patients. Decisions about which patients require antifungal therapy figure prominently in the approach to the patient with coccidioidomycosis. For most patients, azoles are the antifungal agents of choice. Amphotericin B is now reserved mostly for those with life-threatening infection, pregnant women, and those in whom azoles have failed.

Histoplasmosis has protean manifestations, which are reviewed by Wheat et al. These authors focus on the pulmonary manifestations of histoplasmosis that are difficult management issues for clinicians. These include differentiating histoplasmosis from sarcoidosis, determining the appropriate management of mediastinal granuloma and fibrosing mediastinitis, for which there are no clinical trial data, and suggesting an approach to patients who have a history of histoplasmosis and who are about to be placed on immunosuppressive therapy.

During the height of the acquired immune deficiency syndrome (AIDS) epidemic in the United States, cryptococcosis was commonly seen. Although there are far fewer cases currently diagnosed in this country, cryptococcosis remains a major cause of death in persons with AIDS in Southeast Asia and Africa. Dr. Lortholary and his colleagues from Paris provide an international perspective on infections with this yeast in both immunocompetent and immunosuppressed persons. They focus on the pulmonary manifestations of infection, which have been less well characterized than meningitis. The authors note treatment regimens and discuss new data that lend support to recommendations for discontinuation of life-long suppressive therapy in AIDS patients.

The recent literature attests to the growing importance of the organisms discussed in the next three articles. Fusarium species are plant pathogens that have become increasingly important in neutropenic patients with hematological malignancies and stem cell transplant recipients. These fungi are best known as causes of localized infections, such as keratitis, in immunocompetent persons, but in the highly immunosuppressed neutropenic patient, widespread dissemination is the rule. Drs. Lionakis and Kontoyiannis discuss the clinical manifestations that should alert the clinician to fusariosis, and they describe the benefits of various diagnostic procedures. Differentiating fusariosis from aspergillosis is emphasized because Fusarium species are usually highly drug resistant and at many centers are now treated with a combination of voriconazole and a lipid formulation of amphotericin B.

Scedosporiosis is also an increasing threat to highly immunosuppressed patients. The nomenclature of the organisms in this genus is confusing for nonmycologists. Drs. Panackal and Marr define the nomenclature, epidemiology, clinical syndromes, and treatment of Scedosporium apiospermum (also known as Pseudallescheria boydii when in the sexual form) and Scedosporium prolificans, a highly drug resistant pathogen that is most commonly noted in Australia and Spain. Scedosporium species mimic Aspergillus species in tissues, but because these organisms are resistant to amphotericin B, diagnosis requires culture-based evidence in addition to the histopathological appearance to allow appropriate treatment.

The dematiaceous fungi encompass a large group of melanin-containing brown-black fungi that are common in the environment and usually cause localized infections following inoculation. However, in the immunosuppressed host, as noted by Dr. Revankar, infection is often disseminated and may be fatal. The spectrum of infections noted with these disparate fungi is reviewed and treatment options are discussed.

Although the preceding opportunistic filamentous fungi are an increasing problem, aspergillosis remains the most important filamentous fungal infection in both immunocompetent and immunosuppressed patients. Two articles are devoted to updating the approach to the diagnosis and treatment of invasive pulmonary aspergillosis (Drs. Herbrecht et al) and other forms of pulmonary aspergillosis (Dr. Judson). The most exciting developments in invasive aspergillosis are related to the use of the serum galactomannan assay for diagnosis and the role of voriconazole in the treatment of this infection. As noted by Dr. Herbrecht, in spite of a large experience with the galactomannan assay in Europe, it is still not clear what role this assay will assume in the early diagnosis of invasive aspergillosis. The role of voriconazole is more clear; it is effective therapy for invasive aspergillosis and in a randomized, multinational trial was superior to amphotericin B for this infection.

The interesting syndromes of allergic bronchopulmonary aspergillosis (ABPA) and aspergilloma, reviewed in depth by Dr. Judson, remain difficult problems in regard to treatment. ABPA is especially problematic in patients with cystic fibrosis. Corticosteroids, not antifungal agents, remain the cornerstone of therapy, but itraconazole has been shown to be steroid-sparing for some patients. Guidelines for diagnosis and treatment of both ABPA and aspergillomas are provided.

Drs. Freifeld and Iwen give their perspective on the risk factors and pathogenesis of infection with the zygomycetes, a large group of filamentous fungi that remain extremely difficult to treat. They emphasize the fact that cultures often yield no growth, even when the distinctive histopathological findings confirm the diagnosis of a zygomycotic infection. This class of fungi is known to be resistant to most antifungal agents, and surgical debridement and correction of the underlying risk factors are crucial to a successful outcome. Amphotericin B remains the agent of choice; preliminary data showing improved outcomes with an experimental azole agent, posaconazole, may increase our therapeutic options for these very serious infections.

The last article reviews the new antifungal agents, voriconazole and caspofungin, which have assumed increasing roles in treatment of the emerging filamentous and yeast fungal infections. The pharmacological properties, side effects, and drug interactions are noted for each agent, and the important clinical trials establishing their efficacy are reviewed.

This volume of Seminars in Respiratory and Critical Care Medicine gives an overview of the current status of the diagnosis and treatment of endemic mycoses and opportunistic fungi, including those filamentous fungi that have been increasingly found to cause infection in highly immunosuppressed patients. The authors have focused on the issues that are particularly problematic for both pulmonologists and infectious diseases specialists and have shared with the readers their approach to treatment of these invasive fungal infections.