Review of Medical Microbiology and Immunology, 13th Edition

50. Opportunistic Mycoses

CHAPTER CONTENTS

Introduction

Candida

Cryptococcus

Aspergillus

Mucor & Rhizopus

Pneumocystis

FUNGI OF MINOR IMPORTANCE

Penicillium marneffei

Pseudallescheria boydii

Fusarium solani

Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations

INTRODUCTION

Opportunistic fungi fail to induce disease in most immunocompetent persons but can do so in those with impaired host defenses. There are five genera of medically important fungi: Candida, Cryptococcus, Aspergillus, Mucor, and Rhizopus. Important features of the opportunistic fungal diseases are described in Table 50–1.

TABLE 50–1 Important Features of Opportunistic Fungal Diseases

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CANDIDA

Diseases

Candida albicans, the most important species of Candida, causes thrush, vaginitis, esophagitis, diaper rash, and chronic mucocutaneous candidiasis. It also causes disseminated infections such as right-sided endocarditis (especially in intravenous drug users), bloodstream infections (candidemia), and endophthalmitis. Infections related to indwelling intravenous and urinary catheters are also important.

Properties

C. albicans is an oval yeast with a single bud (Figures 50–1 and 50–2). It is part of the normal flora of mucous membranes of the upper respiratory, gastrointestinal, and female genital tracts. In tissues it may appear as yeasts or as pseudohyphae (Figures 50–1 and 50–3). Pseudohyphae are elongated yeasts that visually resemble hyphae but are not true hyphae. True hyphae are also formed when C. albicans invades tissues.

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FIGURE 50–1 Candida albicansA: Budding yeasts and pseudohyphae in tissues or exudate. B: Pseudohyphae and chlamydospores in culture at 20°C. C: Germ tubes at 37°C. (Reproduced with permission from Brooks GF et al. Medical Microbiology. 20th ed. Originally published by Appleton & Lange. Copyright 1995 McGraw-Hill.)

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FIGURE 50–2 Candida albicans—yeast. Long arrow points to a budding yeast. Short arrow points to the outer membrane of a vaginal epithelial cell. In this Gram-stained specimen, various bacteria that are part of the normal flora of the vagina can be seen. (Figure courtesy of Dr. S. Brown, Public Health Image Library, Centers for Disease Control and Prevention.)

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FIGURE 50–3 Candida albicans—pseudohyphae. Two arrows point to pseudohyphae of Candida albicans. (Figure courtesy of Dr. S. Brown, Public Health Image Library, Centers for Disease Control and Prevention.)

Carbohydrate fermentation reactions differentiate it from other species (e.g., Candida tropicalis, Candida parapsilosis, Candida krusei, and Candida glabrata).

Transmission

As a member of the normal flora, C. albicans is already present on the skin and mucous membranes. The presence of C. albicans on the skin predisposes to infections involving instruments that penetrate the skin, such as needles (intravenous drug use) and indwelling catheters.

Pathogenesis & Clinical Findings

When local or systemic host defenses are impaired, disease may result. Overgrowth of C. albicans in the mouth produces white patches called thrush (Figure 50–4). (Note that thrush is a pseudomembrane, a term that is defined in Chapter 7 on page 39.) Vaginitis with itching and discharge is favored by high pH, diabetes, or use of antibiotics. Antibiotics suppress the normal flora Lactobacillus, which keep the pH low. As a result, the pH rises, which favors the growth of Candida.

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FIGURE 50–4 Candida albicans—thrush in mouth. Note whitish plaques on tongue. (Courtesy of Richard P. Usatine, MD, and The Color Atlas of Family Medicine.)

Skin invasion occurs in warm, moist areas, which become red and weeping. Fingers and nails become involved when repeatedly immersed in water; persons employed as dishwashers in restaurants are commonly affected. Thickening or loss of the nail can occur. Diaper rash in infants occurs when wet diapers are not changed promptly (Figure 50–5).

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FIGURE 50–5 Candida albicans—diaper rash. Note extensive area of inflammation in perineal region. (Reproduced with permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

In immunosuppressed individuals, Candida may disseminate to many organs or cause chronic mucocutaneous candidiasis (CMC). CMC is a prolonged infection of the skin, oral and genital mucosa, and nails that occurs in individuals deficient in T-cell immunity. Patients with mutations in the gene encoding interleukin-17 (IL-17) and the receptor for IL-17 are predisposed to CMC. After organ transplantation, patients receiving immunosuppressive drugs to prevent rejection are predisposed to invasive Candida infections.

Intravenous drug abuse, indwelling intravenous catheters, and hyperalimentation also predispose to disseminated candidiasis, especially right-sided endocarditis and endophthalmitis (infection within the eye). Candida esophagitis, often accompanied by involvement of the stomach and small intestine, is seen in patients with leukemia and lymphoma. Subcutaneous nodules are often seen in neutropenic patients with disseminated disease. C. albicans is the most common species to cause disseminated disease in these patients, but C. tropicalis and C. parapsilosis are important pathogens also.

Laboratory Diagnosis

In exudates or tissues, budding yeasts and pseudohyphae appear gram-positive and can be visualized by using calcofluor-white staining. In culture, typical yeast colonies are formed that resemble large staphylococcal colonies. Germ tubes form in serum at 37°C, which serves to distinguish C. albicans from most other Candida species (Figure 50–1). Chlamydospores are typically formed by C. albicans but not by other species of Candida. Serologic testing is rarely helpful.

Skin tests with Candida antigens are uniformly positive in immunocompetent adults and are used as an indicator that the person can mount a cellular immune response. A person who does not respond to Candida antigens in the skin test is presumed to have deficient cell-mediated immunity. Such a person is anergic, and other skin tests cannot be interpreted. Thus if a person has a negative Candida skin test, a negative purified protein derivative (PPD) skin test for tuberculosis could be a false-negative result.

Treatment & Prevention

The drug of choice for oropharyngeal or esophageal thrush is fluconazole. Itraconazole and voriconazole are also effective. Caspofungin or micafungin can also be used for esophageal candidiasis. Treatment of skin infections consists of topical antifungal drugs (e.g., clotrimazole or nystatin). Candida vaginitis is treated either with topical (intravaginal) azole drugs, such as clotrimazole or miconazole, or with oral fluconazole. Mucocutaneous candidiasis can be controlled by ketoconazole.

Treatment of disseminated candidiasis consists of either amphotericin B or fluconazole. Liposomal amphotericin B should be used in patients with preexisting kidney damage.

These two drugs can be used with or without flucytosine. Treatment of candidal infections with antifungal drugs should be supplemented by reduction of predisposing factors. Strains of C. albicans resistant to azole drugs have emerged in patients with acquired immunodeficiency syndrome (AIDS) receiving long-term prophylaxis with fluconazole.

Certain candidal infections (e.g., thrush) can be prevented by oral clotrimazole troches, buccal miconazole tablets, or nystatin “swish and swallow.” Fluconazole is useful in preventing candidal infections in high-risk patients, such as those undergoing bone marrow transplantation and premature infants. Micafungin can also be used. There is no vaccine.

CRYPTOCOCCUS

Disease

Cryptococcus neoformans causes cryptococcosis, especially cryptococcal meningitis. Cryptococcosis is the most common, life-threatening invasive fungal disease worldwide. It is especially important in AIDS patients. Another species, Cryptococcus gattii, causes human disease less frequently than C. neoformans.

Properties

C. neoformans is an oval, budding yeast surrounded by a wide polysaccharide capsule (Figures 50–6 and 50–7). It is not dimorphic. Note that this organism forms a narrow-based bud, whereas the yeast form of Blastomyces dermatitidis forms a broad-based bud.

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FIGURE 50–6 Cryptococcus neoformans. India ink preparation shows budding yeasts with a wide capsule. India ink forms a dark background; it does not stain the yeast itself. (Reproduced with permission from Brooks GF et al. Medical Microbiology. 20th ed. Originally published by Appleton & Lange. Copyright 1995 McGraw-Hill.)

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FIGURE 50–7 Cryptococcus neoformans—India ink preparation. Arrow points to a budding yeast of Cryptococcus neoformans. Note the thick, translucent polysaccharide capsule outlined by the dark India ink particles. (Figure courtesy of Dr. L. Haley, Public Health Image Library, Centers for Disease Control and Prevention.)

Transmission

C. neoformans occurs widely in nature and grows abundantly in soil containing bird (especially pigeon) droppings. The birds are not infected. Human infection results from inhalation of the organism. There is no human-to-human transmission. C. gattii is associated with eucalyptus trees, most often in the northwestern states of the United States. It is also found in subtropical and tropical areas of many countries.

Pathogenesis & Clinical Findings

Lung infection is often asymptomatic or may produce pneumonia. Disease caused by C. neoformans occurs mainly in patients with reduced cell-mediated immunity, especially AIDS patients, in whom the organism disseminates to the central nervous system (meningitis) and other organs. Subcutaneous nodules are often seen in disseminated disease. Note, however, that roughly half the patients with cryptococcal meningitis fail to show evidence of immunosuppression.

In some patients with AIDS who are infected with Cryptococcus, treating the patient with highly active antiretroviral therapy (HAART) causes an exacerbation of symptoms. This phenomenon is called immune reconstitution inflammatory syndrome (IRIS). The explanation of the exacerbation of symptoms is that HAART increases the number of CD4 cells, which increases the inflammatory response. Some patients have died as a result of cryptococcal IRIS. To prevent IRIS, patients should be treated for the underlying infection before starting HAART.

C. gattii causes human disease less frequently but is more capable of causing disease in an immunocompetent person than C. neoformansC. gattii is more likely to cause cryptococcomas (granulomas), especially in the brain, than C. neoformans.

Laboratory Diagnosis

In spinal fluid mixed with India ink, the yeast cell is seen microscopically surrounded by a wide, unstained capsule. Appearance of the organism in Gram stain is unreliable, but stains such as methenamine silver, periodic acid–Schiff, and mucicarmine will allow the organism to be visualized. The organism can be cultured from spinal fluid and other specimens. The colonies are highly mucoid—a reflection of the large amount of capsular polysaccharide produced by the organism.

Serologic tests can be done for both antibody and antigen. In infected spinal fluid, capsular antigen occurs in high titer and can be detected by the latex particle agglutination test. This test is called the cryptococcal antigen test, often abbreviated as “crag.”

Distinguishing between C. neoformans and C. gattii in the laboratory requires specialized media not generally available, so many C. gattii infections may go undiagnosed.

Treatment & Prevention

Combined treatment with amphotericin B and flucytosine is used in meningitis and other disseminated disease. Liposomal amphotericin B should be used in patients with preexisting kidney damage. There are no specific means of prevention. Fluconazole is used in AIDS patients for long-term suppression of cryptococcal meningitis. C. gattii is less responsive to antifungal drugs than is C. neoformans.

ASPERGILLUS

Disease

Aspergillus species, especially Aspergillus fumigatus, cause infections of the skin, eyes, ears, and other organs; “fungus ball” in the lungs; and allergic bronchopulmonary aspergillosis.

Properties

Aspergillus species exist only as molds; they are not dimorphic. They have septate hyphae that form V-shaped (dichotomous) branches (Figures 50–8 and 50–9). The walls are more or less parallel, in contrast to Mucor and Rhizopus walls, which are irregular (Figures 50–8 and 50–10). The conidia of Aspergillus form radiating chains, in contrast to those of Mucor and Rhizopus, which are enclosed within a sporangium (Figure 50–11).

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FIGURE 50–8 Aspergillus and Mucor in tissue. A: Aspergillus has septate hyphae with V-shaped branching. B: Mucor has nonseptate hyphae with right-angle branching.

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FIGURE 50–9 Aspergillus fumigatus—septate hyphae. Long arrow points to the septate hyphae of Aspergillus. Note the straight parallel cell walls of this mold. Short arrow points to the typical low-angle, Y-shaped branching. (Used with permission of Prof. Henry Sanchez, University of California, San Francisco School of Medicine.)

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FIGURE 50–10 Mucor species—nonseptate hyphae. Arrow points to irregular-shaped, nonseptate hyphae of Mucor. (Figure courtesy of Dr. L. Ajello, Public Health Image Library, Centers for Disease Control and Prevention.)

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FIGURE 50–11 Aspergillus and Mucor in culture. A: Aspergillus spores form in radiating columns. B: Mucor spores are contained within a sporangium.

Transmission

These molds are widely distributed in nature. They grow on decaying vegetation, producing chains of conidia. Transmission is by airborne conidia.

Pathogenesis & Clinical Findings

A. fumigatus can colonize and later invade abraded skin, wounds, burns, the cornea, the external ear, or paranasal sinuses. It is the most common cause of fungal sinusitis. In immunocompromised persons, especially those with neutropenia, it can invade the lungs and other organs, producing hemoptysis and granulomas. Neutropenic patients are also predisposed to intravenous catheter infections caused by this organism. In 2012, an outbreak of A. fumigatus infections, especially meningitis, occurred caused by injectable corticosteroid solutions that were contaminated with the fungus.

Aspergilli are well-known for their ability to grow in cavities within the lungs, especially cavities caused by tuberculosis. Within the cavities, they produce an aspergilloma (fungus ball), which can be seen on chest X-ray as a radiopaque structure that changes its position when the patient is moved from an erect to a supine position.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the presence of Aspergillus in the bronchi. Patients with ABPA have asthmatic symptoms and a high IgE titer against Aspergillus antigens, and they expectorate brownish bronchial plugs containing hyphae. Asthma caused by the inhalation of airborne conidia, especially in certain occupational settings, also occurs. Aspergillus flavus growing on cereals or nuts produces aflatoxins that may be carcinogenic or acutely toxic.

Laboratory Diagnosis

Biopsy specimens show septate, branching hyphae invading tissue (Figure 50–9). Cultures show colonies with characteristic radiating chains of conidia (Figure 50–11). However, positive cultures do not prove disease because colonization is common. In persons with invasive aspergillosis, there may be high titers of galactomannan antigen in serum. Patients with ABPA have high levels of IgE specific for Aspergillus antigens and prominent eosinophilia. IgG precipitins are also present.

Treatment & Prevention

Invasive aspergillosis is treated with voriconazole or amphotericin B. Liposomal amphotericin B should be used in patients with preexisting kidney damage. Caspofungin may be effective in cases of invasive aspergillosis that do not respond to amphotericin B. A fungus ball growing in a sinus or in a pulmonary cavity can be surgically removed. Patients with ABPA can be treated with corticosteroids and antifungal agents, such as itraconazole. There are no specific means of prevention.

MUCOR & RHIZOPUS

Mucormycosis (zygomycosis, phycomycosis) is a disease caused by saprophytic molds (e.g., Mucor, Rhizopus, and Absidia) found widely in the environment. They are not dimorphic. These organisms are transmitted by airborne asexual spores and invade tissues of patients with reduced host defenses. They proliferate in the walls of blood vessels, particularly of the paranasal sinuses, lungs, or gut, and cause infarction and necrosis of tissue distal to the blocked vessel (Figure 50–12).

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FIGURE 50–12 Mucor species—mucormycosis. Note necrotic area involving the nose and face. (Reproduced with permission from Lichtman MA et al, eds. Lichtman’s Atlas of Hematology. New York: McGraw-Hill, 2007. Copyright © 2007 by The McGraw-Hill Companies, Inc.)

Patients with diabetic ketoacidosis, burns, bone marrow transplants, or leukemia are particularly susceptible. Diabetic patients are particularly susceptible to rhinocerebral mucormycosis, in which mold spores in the sinuses germinate to form hyphae that invade blood vessels that supply the brain. One species, Rhizopus oryzae, causes about 60% of cases of mucormycosis.

In biopsy specimens, organisms are seen microscopically as nonseptate hyphae with broad, irregular walls and branches that form more or less at right angles (Figures 50–8 and 50–10). Cultures show colonies with spores contained within a sporangium (Figure 50–11). These organisms are difficult to culture because they are a single, very long cell, and damage to any part of the cell can limit its ability to grow.

If diagnosis is made early, treatment of the underlying disorder, plus administration of amphotericin B and surgical removal of necrotic infected tissue, has resulted in some remissions and cures. Liposomal amphotericin B should be used in patients with preexisting kidney damage. Posaconazole can also be used.

PNEUMOCYSTIS

Pneumocystis jiroveci is classified as a yeast on the basis of molecular analysis, but medically many still think of it as a protozoan or as an “unclassified” organism. It is therefore discussed in Chapter 52 with the blood and tissue protozoa. In 2002, taxonomists renamed the human species of Pneumocystis as P. jiroveci and recommended that P. carinii be used only to describe the rat species of Pneumocystis.

FUNGI OF MINOR IMPORTANCE

PENICILLIUM MARNEFFEI

Penicillium marneffei is a dimorphic fungus that causes tuberculosis-like disease in AIDS patients, particularly in Southeast Asian countries such as Thailand. It grows as a mold that produces a rose-colored pigment at 25±C but at 37±C grows as a small yeast that resembles Histoplasma capsulatum. Bamboo rats are the only other known hosts. The diagnosis is made either by growing the organism in culture or by using fluorescent antibody staining of affected tissue. The treatment of choice consists of amphotericin B for 2 weeks followed by oral itraconazole for 10 weeks. Relapses can be prevented with prolonged administration of oral itraconazole.

PSEUDALLESCHERIA BOYDII

Pseudallescheria boydii is a mold that causes disease primarily in immunocompromised patients. The clinical findings and the microscopic appearance of the septate hyphae in tissue closely resemble those of Aspergillus. In culture, the appearance of the conidia (pear-shaped) and the color of the mycelium (brownish-gray) of P. boydii are different from those of Aspergillus. The drug of choice is either ketoconazole or itraconazole because the response to amphotericin B is poor. Debridement of necrotic tissue is important as well.

FUSARIUM SOLANI

Fusarium solani is a mold that causes disease primarily in neutropenic patients. Fever and skin lesions are the most common clinical features. The organism is similar to Aspergillus in that it is a mold with septate hyphae that tends to invade blood vessels. Blood cultures are often positive in disseminated disease. In culture, banana-shaped conidia are seen. Liposomal amphotericin B is the drug of choice. Indwelling catheters should be removed or replaced. In 2006, an outbreak of Fusarium keratitis (infection of the cornea) occurred in people who used a certain contact lens solution.

SELF-ASSESSMENT QUESTIONS

1. Regarding C. albicans, which one of the following is most accurate?

(A) The diagnosis of disseminated candidiasis is typically made by detecting IgM antibodies.

(B) It exists as a yeast on mucosal surfaces but forms pseudohyphae when it invades tissue.

(C) Antibody-mediated immunity is a more important host defense than cell-mediated immunity.

(D) A positive skin test can be used to confirm the diagnosis of skin infection caused by C. albicans.

(E) In the clinical laboratory, it is diagnosed by isolating a mold with nonseptate hyphae when cultures are grown at room temperature.

2. Regarding Cryptococcus neoformans, which one of the following is most accurate?

(A) It is a dimorphic fungus, growing as a mold in the soil and a yeast in the body.

(B) It is acquired primarily by ingestion of food contaminated with pigeon guano.

(C) Dark field microscopy is typically used to visualize the organism in spinal fluid.

(D) Pathogenesis involves an exotoxin that acts as a superantigen recruiting lymphocytes into the spinal fluid.

(E) Laboratory diagnosis of cryptococcal meningitis can be achieved by detecting the capsular polysaccharide of the organism in the spinal fluid.

3. Regarding Aspergillus fumigatus and aspergillosis, which one of the following is most accurate?

(A) The natural habitat of A. fumigatus is the hair follicles of the human skin.

(B) In the clinical laboratory, cultures of A. fumigatus incubated at 37°C form yeast colonies.

(C) The India ink stain is typically used to visualize A. fumigatus in the clinical laboratory.

(D) A. fumigatus causes “fungus balls” in patients with lung cavities caused by tuberculosis.

(E) The main predisposing factor to allergic bronchopulmonary aspergillosis is neutropenia.

4. Regarding Mucor species, which one of the following is most accurate?

(A) Infection is acquired by the ingestion of food contaminated by spores of the organism.

(B) Diabetic ketoacidosis is a major predisposing factor for invasive mucormycosis.

(C) Mucor species have septate hyphae in contrast to Aspergillus species, which have nonseptate hyphae.

(D) In biopsy specimens obtained from patients with invasive disease, Mucor species appear as pseudohyphae.

(E) Skin tests using mucoroidin as the immunogen are used to determine whether the patient has been infected with Mucor species.

5. Your patient is a 20-year-old woman who is human immunodeficiency virus (HIV) antibody positive with a CD4 count of 50. She has recovered from cryptococcal meningitis. Which one of the following is the best choice of drug to use as long-term prophylaxis to prevent another episode of cryptococcal meningitis?

(A) Amphotericin B

(B) Caspofungin

(C) Fluconazole

(D) Flucytosine

(E) Terbinafine

6. Your patient is a 1-month-old infant with whitish lesions in the mouth that are diagnosed as oropharyngeal candidiasis (thrush). Which one of the following is the best choice of drug to treat this infection?

(A) Amphotericin B

(B) Caspofungin

(C) Fluconazole

(D) Flucytosine

(E) Terbinafine

7. Your patient is a 50-year-old woman with leukemia who is neutropenic from her cancer chemotherapy. She now has disseminated aspergillosis that does not respond to amphotericin B. Which one of the following is the best choice of drug to treat this infection?

(A) Amphotericin B

(B) Caspofungin

(C) Fluconazole

(D) Flucytosine

(E) Terbinafine

ANSWERS

1. (B)

2. (E)

3. (D)

4. (B)

5. (C)

6. (C)

7. (B)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 658. Please consult these summaries for a rapid review of the essential material.

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Mycology section of PART XIII: USMLE (National Board) Practice Questions starting on page 708. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.