10 Fungal Infections Abida K. Haque and Michael R. McGinnis The incidence of invasive fungal infections has increased Thus, fungi can elicit similar tissue reactions as bacteria, dramatically over the past two decades, mostly due to including acute exudative, necrotizing, and granulomatous an increase in the number of immunocompromised reactions. Pathogenicity of fungi depends on the virulence l patients. -4 Patients who undergo chemotherapy for a of the particular fungus, the infecting dose, the route of variety of diseases, patients with organ transplants, and infection, and the immune status of the host. Other factors patients with the acquired immune deficiency syndrome that influence the pathogenicity include the coexistence have contributed most to the increase in fungal infec­ of other infections in the host, the organs affected, and tions.s The actual incidence of invasive fungal infections other underlying diseases. There is no clear-cut evidence in transplant patients ranges from 15% to 25% in bone that fungal infections are contagious, with the exception marrow transplant recipients to 5% to 42% in solid organ of dermatophytoses, pityriasis versicolor, and candidiasis 6 transplant recipients. ,7 The most frequently encountered of the newborn. However, accidental inoculation or direct are Aspergillus species, followed by Cryptococcus and contamination of an open wound can result in transmis­ Candida species. Fungal infections are also associated sion of the etiologic agent of infection.13 Hence care with a higher mortality than either bacterial or viral infec­ should be taken to avoid direct contact when handling tions in these patient popUlations. This is because of the contaminated bodily discharges and tissues. limited number of available therapies, dose-limiting tox­ Most pulmonary infections begin in the lungs following 12 icities of the antifungal drugs, fewer symptoms due to inhalation of aerosolized fungi from the environment. ,14 lack of inflammatory response, and the lack of sensitive Once the fungi reach the lungs, the infection can remain tests to aid in the diagnosis of invasive fungal infections. I localized, or it can disseminate to produce severe sys­ A study of patients with fungal infections admitted to a temic disease that is often fatal. Rarely, the gastrointesti­ university-affiliated hospital indicated that community­ nal tract and skin may be the primary focus of systemic acquired infections are becoming a serious problem; 67% infection with secondary involvement of the lungs, espe­ of the 140 patients had community-acquired fungal pneu­ cially in immunocompromised patients. monia.8 There is also an increase in nosocomial fungal The discussion of fungi in this chapter is confined to infections.9 invasive pulmonary infections. Fungi that cause invasive Fungi are eukaryotic, unicellular to multicellular organ­ pulmonary infection can be divided in two main groups: isms that have chitinous cell walls, and reproduce asexu­ (1) primary or true pathogens, and (2) opportunistic ally, sexually, or both ways. Fungal cells are larger and pathogens. The primary or true pathogenic fungi (also genomically more complex than bacteria. Their cell wall referred to as endemic fungi) infect healthy, immunologi­ 15 contains polysaccharides, proteins, and sugars, and their cally competent individuals. ,16 These fungi can be very antigens are rich in complex polysaccharides and glyco­ aggressive, and produce severe disseminated and fatal proteins. Plasma membranes of fungi contain ergosterol, infections in immunocompromised patients. While which is the primary target for antifungals such as ampho­ endemic fungi such as Histoplasma capsulatum and Coc­ tericin B. Although there are more than 1.3 million fungal cidioides immitis are the most common, a number of species in the environment, only about 150 are known to other fungi have emerged as important, though less be pathogenic to humans. For detailed taxonomy of the common pathogens. Penicillium marneffei, Fusarium fungi, several texts are available. W-12 The virulence factors species, Scedosporium species, and Malassezia species are of fungi resemble those of bacteria, such as possession of increasing in incidence as opportunistic infections in a capsule, adhesion molecules, toxins, free radicals, etc. immunocompromised hosts, especially in those with 349 350 A.K. Haque and M,R. McGinnis 17 8 AIDS. ,1 Each of these fungi can cause systemic life (3) molecular diagnostic techniques. A combination of threatening infections. In contrast, the opportunistic fungi these approaches is recommended, but is not always cause infections in critically ill or immunosuppressed possible.25 patients. Almost all opportunistic fungi gain entry through the lungs, except endogenous Candida spp. The most Isolation of Fungi by Culture common opportunistic mycoses include candidiasis, aspergillosis, cryptococcosis, zygomycosis, pseudallesche­ Most of the fungi that cause invasive infection can be riasis, fusariosis, and trichosporonosis. cultured on standard laboratory media. One of the major The dramatic increase in opportunistic fungal infection advancements over the past two decades has been in the in the latter half of the 20th century is related to several culture and recovery of fungi from blood.1.26 Biphasic 17 factors. .l9.20 The important factors include immunosup­ systems were the first advancement in the broth-based pression of transplant patients, chemotherapy for malig­ culture system, This was followed by the development of nancies, broad-spectrum therapy for bacterial infections, lysis centrifugation, involving the incorporation of a tube and the long-term placements of catheters for various containing an anticoagulant and a lytic agent, centrifuga­ therapies. Other conditions that predispose to opportu­ tion, and placement of the pellet on solid media. Although nistic infections include malignancies, especially leuke­ labor intensive and relatively expensive, this method has mia and lymphomas, chronic lung diseases, abdominal become the "gold standard" for recovery of fungi from surgery, burns, diabetes mellitus, Cushing's syndrome, blood.27.28 Automated blood culture systems have been malnutrition, uremia, alcohol abuse with cirrhosis, drug developed, that are superior in their recovery of yeast abuse, congenital immunodeficiency syndromes, and from blood.29 Despite these advances in technology, isola­ AIDS.5,18.21 Epidemiologic factors such as an increasing tion of fungi from blood cultures is an insensitive marker aging population and migration of susceptible persons for invasive fungal infections, and often takes several into highly endemic areas also contribute to the increase days to weeks for growth, resulting in delays in treatment. in opportunistic infections,22 Fungemia was found in only 28% of patients with autopsy­ Host factors responsible for increased susceptibility to proven invasive candidiasis in one series, and only 58% fungal infections include (1) a decrease in the number or of patients with two or more visceral infections had functional impairment of mature granulocytes and mono­ fungemia. 30 Most of the fungi that cause invasive pulmo­ nuclearphagocytes, (2) depressed B-Iymphocyte (humoral) nary infections can be cultured on standard media; immunity resulting in decreased production of immuno­ however, culture and characterization may take up to 2 globulins and impaired opsonization, (3) depressed T­ to 4 weeks. lymphocyte (cell-mediated) immunity, (4) abnormal host When a fungus is isolated, the question may still remain immune-regulation,20.23.24 and (5) neutropenia. Other whether the isolate is an invasive pathogen, normal flora factors include disruption of mucosal and skin barriers, not causing infection, or an environmental contaminant. disorders of complement system, and hereditary immune Often the specimen may not be sent to the laboratory dysfunctions.23.24 for culture and entirely submitted for histologic evalua­ Fungal infections in severely immunocompromised tion. Pathologists therefore have to rely on their ability patients present with clinical features that are often dif­ to recognize and identify fungi in smears and tissue sec­ ferent from immunocompetent patients. The tissue tions. The presence of a fungus growing in tissue provides response is also different. There may be little or no inflam­ indisputable evidence of invasive infection. Histologic matory response with even massive infection, and there studies can also confirm the presence of other concomi­ may not be granuloma formation. Additionally, coexist­ tant infections by bacteria, viruses, protozoa, and para­ ing infections are very common; therefore, the possibility sites. Finally, no other diagnostic test can determine of multiple infectious agents should never be overlooked. whether the host response signifies invasion or allergic Special stains or immunostains for fungi and other organ­ reaction. Although certain patterns of host reaction isms should be routinely used for demonstrating fungi suggest that mycosis exists, there are no absolute criteria and other infectious agents in severely immunocompro­ that permit an etiologic diagnosis with as much certainty mised patients. as tissue diagnosis. Currently Available Histologic Diagnosis of Fungal Infections Diagnostic Methods Although different methods of diagnosis are available for fungal infections, the presence of a fungus in the tissue Currently available laboratory methods for diagnosing sections provides indisputable