Pulmonary and Invasive Fungal Infections

Carol A. Kauffman, MD

Invasive fungal infections fall into two broad categories. The endemic mycoses are true pathogens, infecting persons who are healthy as well as those who are immunosuppressed. The opportunistic fungi cause infection primarily in persons who are immunosuppressed. These infections are difficult to treat, not only because the host cannot mount an effective immune response but also because many of the opportunistic molds are resistant to antifungal agents. This update on fungal infections explores new diagnostic and therapeutic modalities for endemic mycoses and opportunistic fungi.

Three articles are devoted to invasive aspergillosis, emphasizing the importance of this opportunistic mold infection. Early detection is a key to successful outcome. CT scans give physicians a hint that an angioinvasive mold, such as Aspergillus, could be the cause of a patient's illness. Detection of cell wall antigens of Aspergillus in blood and bronchoalveolar lavage fluid provides more specific evidence for invasive aspergillosis, as reviewed by Drs. Miceli and Maertens. A major question over the past decade has been whether two drugs might be better than one to improve outcomes of treatment of invasive aspergillosis. Drs. Gregg and Kauffman review the somewhat disappointing results of the long awaited, randomized, controlled, double-blind trial that compared voriconazole alone with voriconazole plus an echinocandin (anidulafungin) for invasive aspergillosis. A nonsignificant trend toward decreased mortality was reported in patients treated with combination therapy. However, a post hoc analysis did show a significant survival advantage of combination therapy, but only in those patients who presumably had early invasive disease that was diagnosed only by a positive galactomannan test and a suggestive CT scan. It is highly unlikely that stronger evidence for combination therapy will be accrued in the future because of the enormous effort and expense involved in this sort of international clinical trial. The use of combination therapy remains a decision for the physician to make with individual patients.

Unfortunately, as diagnosis and treatment for invasive aspergillosis have improved, there is mounting evidence documenting the emergence of azole resistance among A. fumigatus strains. Azole resistance has become a special problem in the Netherlands, and has been noted in England and a few other countries, as well. As noted by Drs. Wiederhold and Patterson, there appears to be a link between resistance and the use of azole fungicides for agricultural purposes in the Netherlands, replicating similar scenarios described for agricultural use of antibiotics and bacterial resistance.

The emergence of Fusarium species as a very difficult-to-treat infection among immunosuppressed patients, especially those with hematological malignancies, is emphasized, and treatment options are discussed by Nucci et al. Fusariosis mimics aspergillosis in both clinical and radiological aspects; histopathological findings are similar, and Fusarium infections cause false-positive galactomannan tests. Fusariosis vies with mucormycosis in regard to resistance to many antifungal agents and high mortality rates in patients who are immunosuppressed. The group at the Necker Hospital and the Pasteur Institute share information on diagnosis and treatment of mucormycosis obtained from the nation-wide French registry that includes over a hundred cases of mucormycosis.

Two infections for which the pulmonary aspects are often overlooked are cryptococcosis and sporotrichosis. The usual clinical manifestation of cryptococcal infection is meningoencephalitis, but pulmonary infection is the initial pathogenetic event following environmental exposure to this organism. Chang et al present a superb overview of the pulmonary aspects of cryptococcosis and emphasize recent developments in defining the role of Cryptococcus gattii in causing pulmonary as well as extrapulmonary infection. This species, known for decades in Australia, is clearly more common in North America and elsewhere than previously realized. C. gattii more commonly causes symptomatic pulmonary infection than C. neoformans and is more likely to occur in normal hosts.

The clinical and radiological characteristics of pulmonary infection with Sporothrix schenckii are uncommon topics in reviews of sporotrichosis. Aung et al present a classification of this form of sporotrichosis, acknowledge the difficulty in making a diagnosis of pulmonary sporotrichosis, and discuss the dearth of treatment options other than amphotericin B and surgery.

Pulmonary aspects, as well as extrapulmonary manifestations, of the three major endemic mycoses in North America are reviewed and new aspects discussed. For example, coccidioidomycosis has been recently reported from Washington and Utah, and Coccidioides species have now been found in these areas. The common use of tumor necrosis factor inhibitors for many rheumatologic, dermatologic, and gastrointestinal diseases has led to an increase in severe pulmonary and disseminated histoplasmosis. Acute respiratory distress syndrome (ARDS) is reported more often than in the past. This may relate in part to increasing numbers of immunocompromised patients who acquire infection with one of the endemic mycoses, but we are reminded by Smith and Gauthier that normal hosts, as well as those who are immunocompromised, develop ARDS with pulmonary blastomycosis.

For the endemic mycoses, as well as many opportunistic fungal infections, voriconazole and posaconazole increasingly are used. With longer term use of voriconazole, troublesome adverse effects have been reported, including alopecia, periostitis from fluoride toxicity, and a variety of nervous system symptoms, such as neuropathy, trouble concentrating, and memory loss. Posaconazole appears to have fewer adverse effects than voriconazole, but similar to voriconazole, does have many drug–drug interactions that can be problematic.

In summary, this issue of Seminars will provide an up-to-date overview of infections caused by the major opportunistic fungi and the endemic mycoses that are most commonly seen in North America.