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.

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