Miscellaneous Infections Caused by Fungi and Pneumocystis

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Miscellaneous Infections Caused by Fungi and Pneumocystis

This chapter continues the discussion of infectious diseases involving the lungs and considers miscellaneous infections caused by fungi and Pneumocystis. For some of the organisms discussed, infection is clearly a potential problem for the relatively normal host, the individual with intact immunologic defense mechanisms. Histoplasmosis, coccidioidomycosis, and blastomycosis are the major fungal infections in this category, yet even for these diseases, impairment of normal defense mechanisms may substantially alter the presentation, clinical consequences, and natural history of the illness.

For many other fungi and for Pneumocystis, the normal host is essentially protected from the organism. Disease occurs almost exclusively as a consequence of an underlying illness or a breakdown of normal defense mechanisms. Aspergillus is perhaps the most important fungus of this sort and is the main one considered in this chapter. Pneumocystis, which has a debatable taxonomic status, is considered both in this chapter and in the discussion of AIDS in Chapter 26. The less common fungi (e.g., Mucor and Candida) and protozoa (e.g., Toxoplasma) affecting the immunosuppressed host are not considered in detail here, but further information can be obtained from the references at the end of this chapter.

Fungal Infections

Histoplasmosis

Histoplasmosis is caused by the fungus Histoplasma capsulatum, found primarily in the soil of river valleys in temperate zones of the world. The Mississippi and Ohio River valleys of the central United States are particularly notable as regions where this organism is endemic. In Canada, the St. Lawrence River valley has a high incidence of the disease. Histoplasma is a dimorphic fungus; it exhibits two types of morphology depending upon the conditions for growth. In the soil, the organism takes the form of branching hyphae. In the body at 37°C, the organism appears as a round or oval yeast.

Features of Histoplasma capsulatum are:

Histoplasma organisms flourish best in soil that has been contaminated by bird droppings. When the soil becomes dry or disrupted (e.g., with construction equipment), the infectious spores become airborne, are inhaled by humans, and eventually reach the distal regions of the lung. Contact with chicken houses, bat-infested caves, or starling, blackbird, or pigeon roosts often exposes individuals or groups working in the contaminated area to the fungus. Riverbanks lined with trees are favorite places for blackbird nesting.

After an individual has been exposed and H. capsulatum has entered the lung, the organism (at body temperature) undergoes conversion to the yeast phase. An inflammatory response ensues in the lung parenchyma, with recruitment of phagocytic cells (macrophages). Initially, the yeast may not be killed within the macrophage, so the organism commonly spreads to regional lymph nodes and via the bloodstream to other organs, such as the spleen. Within 3 weeks, lymphocyte-mediated delayed hypersensitivity against Histoplasma generally develops, and the pathologic response becomes granulomatous in nature. Central areas of caseous necrosis often occur within the granulomas, making the pathologic response similar to that of tuberculosis.

When the initial or primary lesions heal, residua are absent or take the form of small fibrotic pulmonary nodules that may contain areas of calcification. Similarly, small foci of calcification within the spleen may provide evidence of prior infection. However, there are alternatives to this benign pathologic course after exposure. In some cases, particularly in the immunosuppressed host or in the infant or young child, dissemination of the organism to other organs is not controlled by host defense mechanisms, and the patient is said to have progressive disseminated histoplasmosis. In other cases, particularly in patients with significant underlying airways disease or emphysema, progressive parenchymal inflammation, destruction, and cavity formation occur in the lung, often called progressive or chronic pulmonary histoplasmosis.

Types of Infection

Three clinical syndromes associated with histoplasmosis correspond to the three types of pathologic response just mentioned. In the normal immunocompetent host, a benign self-limited infection called acute or primary histoplasmosis generally develops, with relatively few if any clinical sequelae. Often the affected person is symptom free during the acute infection, particularly when the level of exposure has been relatively low. Other individuals have a variety of nonspecific symptoms that may include some combination of cough, fever, chills, chest pain, headache, malaise, myalgias, and weight loss. The chest radiograph may reveal one of several types of patterns, most commonly a pulmonary infiltrate with or without hilar adenopathy. The typical clinical syndrome resolves within a few weeks without therapy. The only clues remaining from the acute infection are often one or several pulmonary nodules (which can be calcified) seen on chest radiograph. The nodules represent an encapsulated focus of granulomatous inflammation. Immunologic testing by means of skin tests or serologic studies may indicate prior exposure to the organism. Rarely, and generally following a particularly intense acute exposure, patients may develop a serious or fatal clinical course as a result of acute histoplasmosis.

Clinical syndromes with histoplasmosis are:

The syndrome of progressive disseminated histoplasmosis usually occurs in immunocompromised hosts or in infants or young children. These patients appear to have in common an impairment of cell-mediated immunity that predisposes them to progressive disseminated histoplasmosis. Thus, progressive disseminated histoplasmosis now is seen most commonly in patients treated with corticosteroids or cytotoxic agents or in those who have human immunodeficiency virus (HIV)/AIDS. This potentially life-threatening illness is often associated with widespread pulmonary involvement accompanied by prominent systemic symptoms and infection of other organ systems.

Chronic pulmonary histoplasmosis is generally seen in individuals with preexisting structural abnormalities of the lung, primarily chronic obstructive lung disease with emphysema. The clinical and radiographic patterns often resemble those of tuberculosis. Patients may have cough, sputum production, fever, fatigue, and weight loss. The chest radiograph shows disease localized mainly to the upper lobes, with parenchymal infiltrates, often streaky in appearance, and cavity formation.

Diagnosis of histoplasmosis depends on the type of infection: acute, disseminated, or chronic. The options available to the clinician are culture of the organism, identification in tissue, detection of Histoplasma antigen in the urine, or documentation of an immunologic response by serologic studies. To identify the organism microscopically, special stains such as methenamine silver are required. The specific usefulness and limitations of each of these methods can be found in resources listed in the References section.

Treatment of pulmonary histoplasmosis also depends on the particular type of infection. Acute histoplasmosis generally requires no therapy and is a self-limited illness. Disseminated histoplasmosis requires treatment with a regimen using amphotericin B, typically followed by itraconazole. Chronic pulmonary histoplasmosis is generally treated with itraconazole alone or with amphotericin B followed by itraconazole, depending on disease severity.

Coccidioidomycosis

Like histoplasmosis, coccidioidomycosis also affects normal hosts, but its clinical consequences may be altered in special categories of patients, especially those with impairment of host defense mechanisms. The causative organism, Coccidioides immitis, is a dimorphic fungus. In soil the organisms show mycelia, whereas staining of tissue specimens shows characteristic round, thick-walled structures called spherules, which often contain multiple endospores within them.

Features of Coccidioides immitis are:

Unlike Histoplasma organisms, the organisms of Coccidioides are limited to the western hemisphere, most classically within the San Joaquin Valley region of California. Other areas where the organism is endemic include parts of New Mexico, Nevada, Texas, and Arizona, as well as regions of Mexico, Central America, and South America.

After the host inhales contaminated material, some spores may evade the nonspecific host defenses and reach the alveoli, leading to development of primary disease. Pathologically, the inflammatory response to the organism is also a granulomatous one, once delayed hypersensitivity to Coccidioides has developed. The normal host generally has a relatively self-limited illness resulting from the primary infection. When dissemination occurs, it usually does so in specific groups of predisposed individuals: immunosuppressed patients, pregnant women, and for unclear reasons, certain ethnic groups, particularly Filipinos, African Americans, and Native Americans. Chronic pulmonary coccidioidomycosis is found in some patients as a sequela to primary disease, perhaps related to underlying lung disease or immune impairment.

Primary infection with Coccidioides immitis may be subclinical and unassociated with symptoms, or it may produce respiratory tract symptoms or manifestations of hypersensitivity to the organism. When symptoms occur, they often include fever, cough, headache, and chest pain. Skin manifestations, presumably representing a form of hypersensitivity, are common. One example is erythema nodosum, which consists of tender red nodules on the anterior surface of the lower legs. Some patients develop polyarthritis, another manifestation of hypersensitivity. The chest radiograph taken during the primary infection frequently shows a pulmonary infiltrate, often with associated hilar adenopathy and sometimes with a pleural effusion.

Clinical syndromes with coccidioidomycosis are:

The acute (primary) infection is usually self-limited, resolving within a few weeks without treatment. Residual findings on chest radiograph may be absent or may consist of one or more pulmonary nodules or thin-walled cavities. Calcification of the nodules can occur but is less common than with histoplasmosis, and the nodules may resemble a primary pulmonary malignancy.

Disseminated disease, resulting from hematogenous spread of the organism, is often associated with an ominous prognosis. Certain ethnic groups are at high risk for this complication, as are pregnant women and immunosuppressed patients, especially organ transplant recipients and patients with HIV/AIDS.

Chronic pulmonary involvement by coccidioidomycosis can take several forms, including one or more chronic cavities or upper lobe disease with streaky infiltrates and/or nodules resembling tuberculosis. Patients often have fever, cough (sometimes with hemoptysis), malaise, and weight loss and may appear subacutely or chronically ill.

As with histoplasmosis, the diagnosis of coccidioidomycosis depends on the type of clinical presentation and relies on culture, demonstration in tissue (e.g., with methenamine silver staining), or evidence of an immune response to the organism. The specific uses and interpretation of skin testing and serologic techniques for diagnosis are discussed in the various more detailed references. Because of the dangers posed to hospital personnel when culturing the organism, the microbiology laboratory should be notified if there is a high clinical suspicion for coccidioidomycosis in specimens sent for culture.

Treatment considerations are similar to those for histoplasmosis. Primary infections generally do not require therapy, although patients at high risk for dissemination are commonly treated with an oral azole antifungal agent (e.g., itraconazole, fluconazole.) Chronic pulmonary disease requires therapy, usually with an oral azole, and surgery plays an occasional role in specific clinical settings. Disseminated disease is treated with an azole or amphotericin B. Patients who are undergoing prolonged immunosuppressive therapy commonly receive an oral azole.

Blastomycosis

Blastomycosis is due to the soil-dwelling fungus Blastomyces dermatitidis. It occurs primarily in the midwestern and southeastern United States, often overlapping the areas in which histoplasmosis is seen. Infection is initiated by inhalation of spores that have become airborne. The primary inflammatory response in the lung consists largely of neutrophils; the subsequent response includes macrophages and T lymphocytes. As a result, the findings on histopathology show a combination of granulomas and a pyogenic (neutrophilic) response. If the latter is prominent, the response may mimic a bacterial infection. The organism can disseminate, especially to skin, but the frequency of dissemination is unknown.

Acute infection with Blastomyces may resemble a bacterial pneumonia.

Acute pulmonary infection with Blastomyces often resembles a bacterial pneumonia. Patients frequently have a relatively abrupt onset of symptoms including fever, chills, and cough accompanied by purulent sputum production. However, subacute or chronic cases can be seen. Asymptomatic cases of blastomycosis have been reported, but their relative frequency compared with symptomatic cases is unknown. As with the other fungi, patients with impaired cellular immunity are at increased risk for development of more rapidly progressive or severe disease. Skin lesions are common, usually appearing as a characteristic irregular patch with a crusted surface, but nodules and ulcers also may occur.

The chest radiograph of patients with blastomycosis is variable. It may show unilateral or bilateral pulmonary infiltrates that can resemble bacterial pneumonia, or localized densities that can resemble carcinoma. Diagnosis can often be confirmed by demonstrating the characteristic yeast forms in sputum or tissue, or by culture of sputum. An immunoassay for detecting Blastomyces dermatitidis antigens in urine has been developed, although the sensitivity and specificity of the test are not optimal. Serologic testing is not useful.

Blastomycosis is generally treated with itraconazole, but amphotericin B is employed for life-threatening disease. However, many cases of blastomycosis are self-limited. Whether all cases require treatment, particularly if the diagnosis is made as the disease seems to be resolving clinically, is not clear. However, most authorities agree that a patient with active symptoms when the disease is diagnosed should receive treatment.

Aspergillosis

Of all the fungi, Aspergillus is particularly notable for the variety of clinical presentations seen and the types of individuals predisposed. Unlike Histoplasma, Coccidioides, and Blastomyces, Aspergillus species are widespread throughout nature, not limited to particular geographic areas, and not dimorphic in appearance but always occur as mycelia (i.e., branching hyphal forms). Because virtually everyone is exposed to the organism, it is clear that disease must be associated with certain predisposing factors, which now are well defined.

Features of Aspergillus infection are:

Four major clinical forms of disease caused by Aspergillus and the different settings in which these diseases occur are considered here. The first form, allergic bronchopulmonary aspergillosis, is a hypersensitivity reaction to airway colonization with Aspergillus, seen almost exclusively in patients with underlying asthma or cystic fibrosis. The second form, aspergilloma, is a saprophytic colonization of a preexisting cavity in the lung by a mycetoma (“fungus ball”) composed of a mass of Aspergillus hyphae. The third form, invasive aspergillosis, involves tissue invasion by the organism and is seen in patients with significant impairment of their immune defense mechanisms. The fourth and least well-recognized form, chronic necrotizing pulmonary aspergillosis, involves a subacute to chronic invasion and destruction of the pulmonary parenchyma by Aspergillus, often complicated by cavity formation and secondary development of a mycetoma.

Clinical syndromes with aspergillosis are:

Allergic Bronchopulmonary Aspergillosis

The presence of underlying reactive airways disease—asthma—appears to be the important predisposing factor for development of allergic bronchopulmonary aspergillosis. In this condition, the organism resides in the patient’s airways, where it appears to be important as an antigen rather than as an infectious invasive fungus. Both type I (immediate, immunoglobulin [Ig]E-mediated) and type III (immune complex, IgG-mediated) immune reactions to the organism develop in affected persons.

Clinically, patients with allergic bronchopulmonary aspergillosis have manifestations of moderate to severe asthma (wheezing, dyspnea, and cough) and often low-grade fever and production of characteristic brownish plugs of sputum. Aspergillus species frequently can be cultured from these plugs of sputum. The chest radiograph may show transient pulmonary infiltrates, which can be a consequence of bronchial obstruction by the plugs or a result of eosinophilic infiltration of lung tissue. Bronchiectasis of proximal airways can be present, and these dilated airways may be filled with mucous plugs.

Diagnosis is made in the proper clinical setting of underlying asthma and is based on culturing the organism, demonstrating the host’s immune response to the fungus, or both. For example, skin tests against Aspergillus antigen show a positive immediate reaction (reflecting type I immunity), often accompanied by a delayed reaction (called an Arthus reaction) after several hours (reflecting type III immunity). Precipitins in the blood and specific IgE against the organism frequently can be identified.

Treatment of allergic bronchopulmonary aspergillosis is aimed primarily at the host’s immunologic response to the organism. Therefore, corticosteroids are the mainstay of treatment of this syndrome. Concomitant therapy with a well-tolerated oral azole agent seems to be associated with better outcomes and is now considered standard treatment.

Aspergilloma

The second type of clinical problem resulting from Aspergillus is the aspergilloma, also referred to as a mycetoma or “fungus ball.” The major predisposing feature for this entity is the presence of a preexisting cavity within the pulmonary parenchyma. Tuberculosis, sarcoidosis, or non-Aspergillus fungal infections are a few examples of diseases in which cavities may be seen and therefore in which an aspergilloma may be a complicating problem. In these cases, the organism is essentially a saprophyte or colonizer of the cavity, with little tissue invasion. The fungus ball itself represents a mass of fungal mycelia lying within the cavity proper. Fungi other than Aspergillus can occasionally result in a mycetoma.

Clinically, patients with an aspergilloma present either with hemoptysis or with no symptoms but suggestive findings on chest radiograph. Classically the radiograph demonstrates an apparent mass in the upper lobes surrounded by a lucent rim, representing air in the cavity around the fungus ball (Fig. 25-1). When the patient changes position, the fungus ball often changes position within the cavity, owing to the effects of gravity.

Diagnosis of an aspergilloma is strongly suggested by the characteristic radiographic appearance and is confirmed by culture of the organism or demonstration of the presence of precipitins against Aspergillus species. Treatment is often unnecessary when the patient has no symptoms from the lesion. In some patients, particularly those with significant amounts of hemoptysis, surgery is performed to remove the diseased area containing the fungus ball. For patients with severe lung disease who are unable to tolerate surgery, bronchial artery embolization can be performed. In this procedure, the bleeding vessel is identified angiographically, and a small piece of synthetic material is released into the vessel to block it and stop the bleeding. Systemic administration of antifungal agents is not effective treatment of this syndrome, although direct instillation of amphotericin B into the cavity has been performed in some cases, with limited success.

Invasive Aspergillosis

Invasive aspergillosis is the third clinical presentation of Aspergillus infection in the lung. This is the most life-threatening manifestation, occurring almost exclusively in patients with marked impairment of host immune defense mechanisms. The most important risk factor is neutropenia (insufficient numbers of polymorphonuclear leukocytes), but patients often also have impairment of cellular immunity as a consequence of hematopoietic stem cell transplantation or treatment with chemotherapeutic agents or high-dose corticosteroids.

Pathologically, the organism invades and spreads through lung tissue, but it also tends to invade blood vessels within the lung. As a result of vascular involvement by the fungus, hemoptysis can occur, vessels can become occluded, and areas of pulmonary infarction can develop.

Clinically, patients are extremely ill, with fever, cough, dyspnea, and often pleuritic chest pain. The chest radiograph may show localized or diffuse pulmonary infiltrates, reflecting either tissue invasion and a fungal pneumonia or pulmonary infarction secondary to vascular occlusion.

Diagnosis of invasive aspergillosis generally requires identification of the organism—for example, by methenamine silver staining on a bronchoalveolar lavage or biopsy specimen of lung tissue. A positive assay for the fungal cell wall constituents galactomannan or β-D-glucan supports the diagnosis, although many false positives and negatives occur. Treatment consists of voriconazole or amphotericin B, but the mortality rate is extremely high even with appropriate use of either agent.

Chronic Necrotizing Pulmonary Aspergillosis

The final type of Aspergillus infection involving the lung is chronic necrotizing pulmonary aspergillosis. In this form, patients frequently have underlying lung disease or some relatively mild impairment of either pulmonary or systemic host defense mechanisms, as occurs with diabetes mellitus or treatment with low-dose corticosteroids. The name of this disorder describes the clinical process, which is characterized by an indolent localized invasion of pulmonary parenchyma by Aspergillus organisms. Necrosis of the involved tissue often results in cavity formation, which may become the site for an aspergilloma. Because of tissue invasion, the infection is treated with oral voriconazole or itraconazole, or intravenous micafungin or amphotericin B.

Cryptococcosis

Cryptococcosis is due primarily to infection with Cryptococcus neoformans, an encapsulated yeast that can be recovered worldwide, particularly in soil contaminated with bird droppings. Human disease is initiated by inhalation of infectious particles. Pulmonary defense mechanisms are generally quite effective in clearing this infection, but in some normal individuals, as well as those with HIV/AIDS, malignancy, organ transplantation, or under treatment with corticosteroids, a focal pneumonia can develop that is inconsistently symptomatic with a productive cough and fever. Dissemination of the organism to other organs may then occur, the most common and feared of which is development of meningoencephalitis.

The diagnosis of cryptococcosis is definitively established by demonstrating the presence of Cryptococcus within tissues. Ideally this is achieved by culture, but a positive cryptococcal antigen test or visualization of yeast forms in the proper clinical setting is considered highly suggestive of the diagnosis.

Pulmonary cryptococcosis has a high likelihood of resolution without treatment in an immunocompetent host. However, because of the risk of dissemination and central nervous system infection, treatment with fluconazole is generally recommended. Central nervous system or other severe extrapulmonary disease due to Cryptococcus requires treatment with intravenous amphotericin B, frequently with concomitant flucytosine. To reduce the risk of disease recurrence, immunosuppressed patients generally require prolonged (and sometimes lifetime) courses of oral fluconazole after the acute phase of treatment.

Pneumocystis Infection

Although Pneumocystis jiroveci (formerly called Pneumocystis carinii) has been recognized for several decades as a cause of pneumonia in immunocompromised patients, its clinical importance as a major pathogen in patients with AIDS sparked renewed interest in the organism, its treatment, and prevention of infection in high-risk patients. Use of highly active antiretroviral therapy (ART) regimens to treat HIV and prevent Pneumocystis infection has considerably decreased the number of AIDS-related Pneumocystis cases. Nevertheless, it remains an important pulmonary pathogen, not only in HIV-infected patients but also in a variety of other immunosuppressed patients.

The taxonomy of Pneumocystis has changed a number of times since its discovery in 1909. For many years the organism was considered a protozoan, but techniques involving nucleic acid sequencing of ribosomal RNA and studies of enzyme structure and cell wall composition have shown that the organism is more closely related to fungi than protozoa. Pneumocystis is now classified in a unique category of fungi. The recent nomenclature change of Pneumocystis carinii to Pneumocystis jiroveci recognizes the pathologist Otto Jirovec, who first described the organism in humans.

Features of Pneumocystis jiroveci are:

Pneumocystis appears to be widely distributed in nature. It normally can be found in the lungs of a variety of animals as well as in humans. Yet the organisms do not cause disease in normal hosts, only in individuals with significant impairment in host defenses, specifically cellular immunity. The key cell appears to be the helper T lymphocyte CD4+, whose numbers, function, or both can be diminished by specific diseases or immunosuppressive drugs. Before the recognition of AIDS, P. jiroveci pneumonia was seen most commonly in patients with severe malnutrition, malignancy, organ transplantation, or other diseases requiring treatment with corticosteroids or other immunosuppressive agents. However, after the identification of AIDS and before the introduction of ART, the majority of cases were seen in patients with AIDS and greatly reduced numbers of CD4+ lymphocytes. The problem of Pneumocystis pneumonia as it occurs in AIDS is discussed in more detail in Chapter 26.

Pneumocystis cysts, which are seen in the lung tissue of infected patients, appear on light-microscopic examination as round or cup-shaped structures. They do not stain well with routine hematoxylin and eosin stain; instead they require special stains such as methenamine silver (Fig. 25-2). The tissue response to the organism seen on microscopic examination of lung tissue includes infiltration of mononuclear cells within the pulmonary interstitium and exudation of foamy fluid (containing cysts) into alveolar spaces. An exuberant host inflammatory response to the organism contributes to the pulmonary injury. As a result, many patients with Pneumocystis pneumonia are treated with corticosteroids in addition to antimicrobial therapy against Pneumocystis early in the course of the disease to suppress this response.

Clinically, Pneumocystis pneumonia usually manifests with dyspnea and fever in immunocompromised patients. Interestingly, in patients for whom treatment with corticosteroids was the risk factor for developing Pneumocystis pneumonia, symptoms frequently develop (and the infection is recognized) as the dose of corticosteroids is being tapered. This observation further supports the concept that the host inflammatory reaction to the organism, which is suppressed by corticosteroids and blossoms only as the steroid dose is being tapered, is responsible for much of the clinical presentation. The chest radiograph commonly shows diffuse bilateral infiltrates, which can have the appearance of either an interstitial or an alveolar filling pattern (Fig. 25-3). Alveolar filling and resultant areas of shunting often make hypoxemia a particularly prominent clinical feature in these patients. Although the disease is often insidious in onset in AIDS patients, it commonly manifests in other immunocompromised patients as a relatively acute-onset pneumonia that, if untreated, can rapidly progress to respiratory failure and death within days.

Clinical features of Pneumocystis pneumonia are:

Because the organism is extremely difficult to cultivate in the laboratory setting, diagnosis depends on demonstrating the organism on stains of tissue sections, bronchoalveolar lavage fluid, or sputum that has been induced by having the patient inhale a hypertonic saline aerosol. Use of monoclonal antibodies (and more recently, polymerase chain reaction [PCR] technology) as a means of detecting the organism in sputum or bronchoalveolar lavage fluid has improved the detection rate compared with use of previous staining methods. No serologic or skin testing methods are available for diagnosis, although a positive β-D-glucan assay is observed in many patients.

The treatment of choice for Pneumocystis infection is a combination of trimethoprim and sulfamethoxazole. Pentamidine, atovaquone, or one of several other regimens are alternative options in patients who cannot tolerate trimethoprim-sulfamethoxazole. In high-risk patients, such as transplant recipients or children receiving chemotherapy for leukemia, low doses of the same agents are used prophylactically to prevent the infection.

References

Fungal Infections (General References)

Chong, S, Lee, KS, Yi, CA, et al. Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients. Eur J Radiol. 2006;59:371–383.

Dismukes, WE. Introduction to antifungal drugs. Clin Infect Dis. 2000;30:653–657.

Lewis, RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86:805–817.

Limper, AH, Knox, KS, Sarosi, GA, et al. An official American Thoracic Society Statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2010;183:96–128.

Pagano, L, Caira, M, Fianchi, L. Pulmonary fungal infections with yeasts and Pneumocystis in patients with hematological malignancy. Ann Med. 2005;37:259–269.

Pagano, L, Fianchi, L, Leone, G. Fungal pneumonia due to molds in patients with hematological malignancies. J Chemother. 2006;18:339–352.

Sanchez, A, Larsen, R. Emerging fungal pathogens in pulmonary disease. Curr Opin Pulm Med. 2007;13:199–204.

Saubolle, MA. Fungal pneumonias. Semin Respir Infect. 2000;15:162–177.

Yao, Z, Liao, W. Fungal respiratory disease. Curr Opin Pulm Med. 2006;12:222–227.

Histoplasmosis

Buck, BE, Malinin, TI, Davis, JH. Transmission of histoplasmosis by organ transplantation. N Engl J Med. 2001;344:310.

McLeod, DS, Mortimer, RH, Perry-Keene, DA, et al. Histoplasmosis in Australia: report of 16 cases and literature review. Medicine (Baltimore). 2011;90:61–68.

Wheat, LJ, Freifeld, AG, Kleiman, MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807–825.

Wheat, J, Sarosi, G, McKinsey, D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis. 2000;30:688–695.

Wood, KL, Hage, CA, Knox, KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med. 2003;167:1279–1282.

Coccidioidomycosis

Galgiani, JN. Coccidioidomycosis: a regional disease of national importance. Ann Intern Med. 1999;130:293–300.

Galgiani, JN, Ampel, NM, Blair, JE, et al. Coccidioidomycosis. Clin Infect Dis. 2005;41:1217–1223.

Galgiani, JN, Ampel, NM, Catanzaro, A, et al. Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis. 2000;30:658–661.

Parish, JM, Blair, JE. Coccidioidomycosis. Mayo Clin Proc. 2008;83:343–348.

Ruddy, BE, Mayer, AP, Ko, MG, et al. Coccidioidomycosis in African Americans. Mayo Clin Proc. 2011;86:63–69.

Saubolle, MA, McKellar, PP, Sussland, D. Epidemiologic, clinical and diagnostic aspects of coccidioidomycosis. J Clin Microbiol. 2007;45:26–30.

Spinello, IM, Johnson, RH, Baqu, S. Coccidioidomycosis and pregnancy: A review. Ann NY Acad Sci. 2007;1111:358–364.

Aspergillosis

Agarwal, R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135:805–826.

Almyroudis, NG, Holland, SM, Segal, BH. Invasive aspergillosis in primary immunodeficiencies. Med Mycol. 2005;43(Suppl 1):S247–S259.

Cockrill, BA, Hales, CA. Allergic bronchopulmonary aspergillosis. Annu Rev Med. 1999;50:303–316.

Herbrecht, R, Denning, DW, Patterson, TF, Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–415.

Shibuya, K, Ando, T, Hasegawa, C, et al. Pathophysiology of pulmonary aspergillosis. J Infect Chemother. 2004;10:138–145.

Paterson, DL, Singh, N. Invasive aspergillosis in transplant recipients. Medicine. 1999;78:123–138.

Reichenberger, F, Habicht, JM, Gratwohl, A, et al. Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients. Eur Respir J. 2002;19:743–755.

Segal, BH. Medical progress: aspergillosis. N Engl J Med. 2009;360:1870–1884.

Sharma, OP, Chwogule, R. Many faces of pulmonary aspergillosis. Eur Respir J. 1998;12:705–715.

Soubani, AO, Chandrasekar, PH. The clinical spectrum of pulmonary aspergillosis. Chest. 2002;121:1988–1999.

Stevens, DA, Kan, VL, Judson, MA, et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis. 2000;30:696–709.

Walsh, TJ, Anaissie, EJ, Denning, DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360.

Pneumocystis Infection

Hughes, WT, Rivera, GK, Schell, MJ, et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1987;316:1627–1632.

Kovacs, JA, Gill, VJ, Meshnick, S, et al. New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii/jiroveci pneumonia. JAMA. 2001;286:2450–2460.

Kovacs, JA, Masur, H. Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment. JAMA. 2009;301:2578–2585.

Pop, SM, Kolls, JK, Steele, C. Pneumocystis: immune recognition and evasion. Int J Biochem Cell Biol. 2006;38:17–22.

Russian, DA, Levine, SJ. Pneumocystis carinii pneumonia in patients without HIV infection. Am J Med Sci. 2001;321:56–65.

Thomas, CF, Limper, AH. Current insights into the biology and pathogenesis of Pneumocystis pneumonia. Nat Rev Microbiol. 2007;5:298–308.

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