26: Miscellaneous infections caused by fungi, including Pneumocystis
OUTLINE
Fungal Infections, 308
Histoplasmosis, 308
Coccidioidomycosis, 310
Blastomycosis, 311
Aspergillosis, 311
Cryptococcosis, 314
Other Fungi, 314
Pneumocystis Infection, 314
This chapter continues the discussion of infectious diseases involving the lungs and considers miscellaneous infections caused by fungi, including Pneumocystis. For some of the organisms discussed, infection is a common potential problem for 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. As an example, after the introduction of tumor necrosis factor-α inhibitor agents for the treatment of autoimmune diseases, it was recognized that they impart a substantial risk for developing pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis. For many other fungi, including 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 is considered both in this chapter and in the discussion of acquired human immunodeficiency syndrome (AIDS) in Chapter 27.
Fungal infections
Histoplasmosis
Histoplasmosis is caused by the fungus Histoplasma capsulatum, which is found primarily in the soil of river valleys in temperate zones throughout the world. In North America, the Mississippi and Ohio River valleys of the central United States and the St. Lawrence River valley in Canada have a particularly high incidence of the disease. However, the organism is present in many regions of the world; as examples, case series from Brazil, Argentina, Australia, India, South Africa, China, and other countries have been reported. Histoplasma is a dimorphic fungus; it exhibits one of two types of morphology depending on 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:
1.Common in river valleys of central North America and other regions
2.Found in soil contaminated by bird droppings
3.Present in yeast form in tissue
4.Elicits granulomatous response in tissue
Histoplasma organisms flourish best in soil that has been contaminated by nitrogen-rich bird droppings, which promote sporulation of the fungus. When the soil becomes dry or disrupted (e.g., with construction equipment), the infectious spores become airborne and are inhaled by humans, potentially reaching 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 frequent places for blackbird nesting.
Once 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 macrophages. Commonly, the yeast is not killed within the macrophage, and the organism 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 typically develops, and the pathologic response becomes granulomatous. Central areas of caseous necrosis can occur within the granulomas, making the pathologic appearance 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 (seen on computed tomography [CT] scan) may suggest prior infection. However, in some cases, particularly in the immunosuppressed host or in the infant or young child, the host defense mechanisms do not control the initial infection, the organism disseminates more widely, and the patient is said to have progressive disseminated histoplasmosis. In other cases, particularly in patients with significant underlying airway 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 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 with primary histoplasmosis have nonspecific symptoms that may include some combination of cough, fever, chills, chest pain, headache, malaise, myalgias, and weight loss. The chest radiograph most commonly reveals a pulmonary infiltrate with or without hilar
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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 typically indicates 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:
1.Acute (primary) histoplasmosis
2.Progressive disseminated histoplasmosis
3.Chronic pulmonary histoplasmosis
The syndrome of progressive disseminated histoplasmosis usually occurs in immunocompromised hosts or in infants or young children. These patients appear to have in common some impairment of cellmediated immunity that predisposes them to progressive disseminated histoplasmosis. Thus, progressive disseminated histoplasmosis is now seen most commonly in patients treated with corticosteroids or cytotoxic agents, or in those who have human immunodeficiency virus (HIV)/AIDS. This potentially lifethreatening 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.
A rare but devastating complication of histoplasmosis is fibrosing mediastinitis, a condition characterized by progressive dense fibrosis of the mediastinum that can produce compression of the great vessels, bronchi, or the esophagus with severe clinical sequelae. The pathogenesis of this condition is not well understood, but the fact that the condition is progressive in the absence of viable Histoplasma organisms has led to the hypothesis that it results from ongoing immune stimulation by nondigestible fungal antigens that are present in mediastinal lymph nodes. Unfortunately, because the presence of living fungi is not required for the disease to worsen, antifungal therapy has little impact on the progression of the disease.
The 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, bronchoalveolar lavage (BAL) fluid, or blood; 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.
Treatment of pulmonary histoplasmosis also depends on the specific clinical syndrome. Acute histoplasmosis generally requires no therapy and is a self-limited illness. Disseminated histoplasmosis generally 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 the risk for severe disease is much higher in patients with impaired immunity. 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 often containing multiple endospores.
Features of Coccidioides immitis:
1.Present in yeast form in tissue
2.Endemic in western and southwestern United States, Mexico, Central and South America
3.Elicits granulomatous response in tissue
Unlike Histoplasma organisms, the organisms of Coccidioides are limited to the western hemisphere. In the United States, the highest incidence is in California, especially within the San Joaquin Valley region of California (where disease caused by Coccidioides is referred to as “Valley Fever”). 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 nonspecific host defenses and reach the alveoli, leading to the development of primary disease. Pathologically, once delayed hypersensitivity to Coccidioides has developed, the inflammatory response to the organism is also a granulomatous one.
The normal host generally has a self-limited illness resulting from the primary infection with C. immitis or may be asymptomatic, with the disease going undetected. When symptoms do 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 typically shows a pulmonary infiltrate, often with associated hilar adenopathy and sometimes with a pleural effusion.
Clinical syndromes with coccidioidomycosis:
1.Acute (primary) coccidioidomycosis
2.Disseminated coccidioidomycosis
3.Chronic pulmonary coccidioidomycosis
The acute (primary) infection usually resolves 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 and be mistaken for a primary pulmonary malignancy.
Disseminated disease, resulting from hematogenous spread of the organism outside of the lungs, occurs in less than 5% of recognized cases and probably less than 1% of all cases because many go unrecognized. Disseminated coccidiomycosis is often associated with an ominous prognosis. Certain ethnic groups (patients of Filipino or African ancestry) are at higher risk for developing disseminated disease, 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
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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. Diagnosis is commonly based on serology, used in combination with the clinical presentation. 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. Blastomycosis has been reported much less frequently outside of North America, most commonly in Africa, with a few cases identified in Mexico, Central and South America, India, and the Middle East. Infection is initiated by inhalation of spores that have become airborne. The primary inflammatory response in the lung consists largely of phagocytosis by neutrophils, monocytes, and alveolar macrophages. Once in the tissue, the spores convert to a yeast phase, which is much more resistant to phagocytosis. The acquired host response is primarily cellular and mediated by antigen-specific T cells and activated macrophages. 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 in an estimated 20% of patients, especially to the skin, usually in conjunction with an active pulmonary infection.
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. Studies during outbreaks indicate that up to 50% of blastomycosis cases are asymptomatic. As with the other fungi, patients with impaired cellular immunity are at increased risk for the development of more rapidly progressive or severe disease. Skin lesions are common, usually appearing as a characteristic irregular patch with a crusted or verrucous 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. Antigen testing can be performed on urine, serum, bronchoalveolar lavage, and cerebrospinal fluid. Of note, the Blastomyces urine antigen test has significant cross-reactivity with Histoplasma antigens, but treatment is similar for both infections. Serologic testing is not useful because of low sensitivity and specificity.
Mild to moderate blastomycosis is generally treated with itraconazole. Patients with severe or disseminated disease are treated with amphotericin B. However, many cases of blastomycosis are selflimited. Whether all cases require treatment, particularly if the diagnosis is made as the disease seems to be resolving clinically, is not clear. 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). Aspergillus is ubiquitous, and virtually everyone is exposed at some point. However, the disease only develops in patients with certain predisposing factors, as discussed later.
Features of Aspergillus infection:
1.Widespread distribution
2.Present as branching hyphae in tissue
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 (ABPA), 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, which is often complicated by cavity formation and secondary development of a mycetoma.
Clinical syndromes with aspergillosis:
1.Allergic bronchopulmonary aspergillosis
2.Mycetoma (aspergilloma)
3.Invasive aspergillosis
4.Chronic necrotizing pulmonary aspergillosis
Allergic bronchopulmonary aspergillosis
The presence of underlying reactive airway disease—asthma—appears to be the important predisposing factor for development of ABPA. This condition does not represent a true infection, in that the organism does not invade the tissues; rather, the organism colonizes the patient’s airways, where it provides intense antigenic stimulation. 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 ABPA have manifestations of difficult to control asthma (wheezing, dyspnea,
and cough) and often low-grade fever and production of characteristic brownish plugs of sputum.
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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 with mucoid impaction is a frequent manifestation.
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 ABPA is aimed primarily at controlling 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 is recommended for patients who develop an acute exacerbation or are unable to taper corticosteroids, with some authorities recommending azoles in all patients with ABPA at presentation. Patients with mild disease or those who are unable to tolerate corticosteroids may be treated with an azole alone. For patients with severe or refractory disease, advanced biologic agents such as omalizumab (anti-IgE) or mepolizumab (anti-IL-5) may be considered, although clear data on the benefits are not yet available.
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. The fungus ball itself represents a mass of fungal mycelia lying within the cavity proper. Tuberculosis, sarcoidosis, and non-Aspergillus fungal infections are a few examples of diseases in which cavities may be seen and, therefore, in which an aspergilloma may become a complicating problem. In these cases, the organism is essentially a saprophyte or colonizer of the cavity, with little tissue invasion. Fungi other than Aspergillus can occasionally result in a mycetoma.
Clinically, patients with an aspergilloma present either with hemoptysis or with no symptoms, but with 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. 26.1).
When the patient changes position, the fungus ball often changes position within the cavity, owing to the effects of gravity.
FIGURE 26.1 Posteroanterior radiograph (A) and axial chest CT section (B) show
bilateral upper lobe aspergillomas. Each fungus ball appears as a mass sitting
within a radiolucent thin-walled cavity. Source: (Courtesy of Dr. Laura Avery.)
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 may be unnecessary when the patient has no symptoms from the lesion, but continued follow-up is required to confirm stability. 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 vessels are identified angiographically, and small pieces of synthetic material are released into one or more vessels to occlude them and stop the bleeding. Administration of an oral azole may provide some benefit in reducing symptoms of cough, but is rarely a cure and requires months of therapy.
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, 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 invasion by the fungus, hemoptysis is common, 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 and septic shock. The chest radiograph may show localized or diffuse pulmonary infiltrates, reflecting either parenchymal invasion or pulmonary infarction secondary to vascular occlusion. Once vascular invasion occurs, embolic infectious foci may develop, including brain abscesses and endophthalmitis.
A definitive diagnosis is made by using special stains—for example, by methenamine silver to demonstrate tissue invasion by the organism on lung biopsy. However, biopsy may not be practical due to the risks of complications, especially hemorrhage, in these very ill patients. Thus, less invasive diagnostic testing is usually utilized first. Stain and culture of sputum or bronchoalveolar lavage fluid is
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typically done. Positive assays of serum or bronchoalveolar lavage fluid for the fungal cell wall constituents galactomannan or β-D-glucan support the diagnosis, as does a positive polymerase chain reaction (PCR) detecting fungal nucleic acid. In the setting of clinical and radiographic findings which are suggestive of invasive aspergillosis, detection of the organism in sputum or BAL combined with positive biomarkers is generally sufficient for a presumptive diagnosis. Treatment consists of voriconazole, posaconazole, isavuconazole, an echinocandin, or amphotericin B, but the mortality rate is extremely high even with appropriate use of one of these agents.
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 lowdose corticosteroids. The clinical process 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 primarily due to infection with Cryptococcus neoformans or Cryptococcus gattii, which are encapsulated yeasts 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. However, in some normal individuals as well as in those with impaired cell-mediated immunity as a result of HIV/AIDS, malignancy, organ transplantation, or treatment with corticosteroids, a focal pneumonia can develop, which 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 if infection is documented. Central nervous system, severe pulmonary, or 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.
Other fungi
Other fungi are less frequent causes of respiratory infection. Candida albicans is an extraordinarily common contaminant of sputum (particularly in patients treated with antibiotics), but it is an uncommon cause of pneumonia, even in immunosuppressed patients. In contrast, Mucor and other zygomycetes are opportunistic fungi that may cause life-threatening pulmonary infection in the immunocompromised host, including patients with underlying diabetes mellitus.