Diagnosis: Pneumocystis pneumonia with necrosis and cavitation. Chronic lymphocytic leukemia with no evidence of disease in lung (autopsy confined to lung).

Comment: In this case, examination of the BAL fluid for pneumocystis was not requested, the diagnosis was not suspected, and no therapy was given. No other pathogen other than a rare CMV-infected cell was found in the lungs, which showed foamy exudate in sections from all lobes. The total course was brief, as described in non-AIDS patients. Before his symptoms began, he had received prednisone (50-70 mg/da) for over a month, which put him at risk for pneumocystis pneumonia. His disease and the prednisone put him in a category where pneumocystis prophylaxis has been advocated by some for prevention.

Pneumocystis Pneumonia

Introduction: Pneumocystis pneumonia is caused by P. carinii, a fungus formerly considered to be a protozoan [1, 2]. Its fungal classification is based in part on 16S ribosomal RNA similarities to fungi, particularly ascomycetes, with spore cases. Its staining with the Gomori methenamine silver stain for fungi also supports its new classification [3, 4]. Most people have serum antibodies to the organism by age 3 [4], and pneumonia has been assumed to be caused by reactivation of a latent infection. Recent genetic analyses of pneumocystis organisms, however, have shown that separate episodes of pneumonia in one person may sometimes be associated with different strains, indicating that reinfection may occur [5]. On the basis of other genetic studies, person to person transmission has been postulated to account for a few, but not most, clustered cases [6]. Not a disease entirely of severely immunocompromised patients, pneumocystis pneumonia has been described in a cluster of older adults (aged 66 to 78) with only minor evidence of cellular immune deficiency [7]. In AIDS, the incidence of the disease has declined following the widespread use of prophylaxis [3]. As a result of identifying corticosteroids as a risk factor for pneumocystis pneumonia in other immunocompromised groups, prophylaxis may result in a decline in those groups also [8].

Characteristics of organisms: An effort is being made to change the current terminology that assumes a protozoan classification to one that indicates a fungus. Spore cases (formerly cysts) and trophic forms (formerly trophozoites) are the chief forms. The thick-walled spore cases contain up to 8 intracystic bodies (formerly sporozoites) that become trophic forms when they leave the spore case, perhaps via an opening related to the thickenings in the spore case. The trophic form, a 2-8 µm, thin-walled form, then matures into a spore case [2]. The organisms have not been grown in long-term culture, and the life cycle is still not understood [3].

Clinical features: General and more specific factors that predispose to pneumocystis pneumonia are listed in Tables 1 & 2. One study described differences in the clinical features in AIDS patients (N = 39) and those in patients with other immunodeficiencies (N = 49). AIDS patients had a longer prodrome before presentation (28 da vs 5 da), a lower mean respiratory rate (23 vs 30), and a higher median room air oxygen tension (69 mm Hg vs 52 mm Hg) than others. Also, more adverse reactions to trimethoprim-sulfamethoxazole occurred in AIDS patients (65% vs 12%). Symptoms--fever, dyspnea, cough, and sputum production--were similar in both groups [9]. In another study of 116 non-AIDS patients with pneumocystis pneumonia, respiratory failure occurred in 43%, another indication of more severe disease in these patients [10]. Extrapulmonary manifestations may be present in a small percentage of both groups (see below) [3]. On physical examination, lungs may be normal, or rales may be present. LDH is often elevated. Typically, blood gases show hypoxemia and hypocarbia, and an increased A-a oxygen difference at rest. Pneumothorax may occur. PFTs may show a decreased DLCO (<80%) [3].

Table 1. Factors that Predispose to Pneumocystis Pneumonia [11]

Table 2. Specific Risk Factors for Pneumocystis Pneumonia

AIDS [12]

Non-AIDS [10]

CD4 level <200/µl

Corticosteroids within 1 mo of diagnosis (>16 mg/da for >8 wks)

Lack of prophylactic therapy

Underlying immunosuppression [8]

Male sex

Declining DLCO

CD4 level >200/µl

Recurrent unexplained fever, night sweats, thrush, weight loss

Radiographic changes: Typically, bilateral, interstitial and alveolar opacities preferentially involve the perihilar regions and bases. Air bronchograms are common in advanced disease. About 5% of radiographs are normal. Nodules, thick and thin-walled cavities, miliary nodules, and pneumothorax are occasional occurrences, putting pneumocystis pneumonia in the differential diagnosis of many different radiographic patterns [13]. Effusions and hilar adenopathy are rare [14].

CT and HRCT findings: Patchy ground-glass opacity ± reticulation is typical of pneumocystis pneumonia. In a patient with clinically suspected pneumocystis pneumonia but with equivocal radiographs, lack of ground-glass opacities on HRCT makes the diagnosis of PCP very unlikely, and seems to obviate the need for induced sputum, BAL, or empirical therapy [15]. In cases of extrapulmonary pneumocystis infection, CT may show punctate calcifications in involved organs [16].

Diagnosis: Although some physicians treat pneumocystis pneumonia empirically based on a high clinical suspicion [3], specific diagnosis depends on finding the organism in lung secretions, as it cannot be grown in culture. In AIDS patients, when clinical features and a radiograph are suspicious for PCP, the frequent identification of organisms in induced sputum eliminates the need for bronchoscopy. In other risk groups, identification of organisms in lavage fluid stained with a Giemsa or immunoperoxidase stain is important for diagnosis because induced sputum samples are frequently not diagnostic [17]. Part of the explanation of this discrepancy in test results may be the finding that lavage fluid spore case burden of AIDS patients is significantly greater than that in non-AIDS patients [18].

Commonly used diagnostic procedures are summarized in Table 3. In AIDS patients, induced sputum or BAL is usually sufficient for diagnosis. Invasive methods may be needed for non-AIDS patients and AIDS patients with atypical disease [19].

Table 3. Diagnostic Tests for Pneumocystis Pneumonia

Pathology--Usual features: The basic pattern is a filling of the alveolar space with foamy pink exudate composed of spore cases, trophic forms, protein, cell debris, and membranous surfactant material [22]. The foamy appearance is a manifestation of closely packed trophic forms [23]. The exudate is PAS-D positive, and the inflammatory response varies from none to moderate. Type II cell hyperplasia is common [24]. Ultrastructural studies show that trophic forms adhere to, and damage, type I cells but do not usually penetrate the alveolar wall [25].

Atypical histologic features: Even in the pre-AIDS era, atypical features were noted in around 50% of cases [24]. These patterns include absence of foamy exudate or presence of hyaline membranes, organizing alveolar damage, interstitial inflammation and fibrosis, nodules, thick- or thin-walled cavities, epithelioid granulomas, vascular permeation or vasculitis [26], infarcts, desquamative interstitial pneumonia-like or lymphocytic interstitial pneumonia-like reactions, or calcification of exudate [24, 26-28]. Reliance on the GMS stain thus becomes important for histologic diagnosis [27]. These atypical pulmonary forms of disease are often accompanied by extrapulmonary pneumocystis infection [26]. Other associations of atypical pulmonary pneumocystis include very low CD4+ lymphocyte counts, spontaneous pneumothorax, prior episodes of PCP or other pulmonary complications, and a high prevalence of CMV infection at autopsy. In one autopsy study, 9 of 14 with atypical patterns had received aerosolized pentamidine for a mean of 16 mo before death. Only 1/2 of cases were diagnosed during life. The authors concluded that although there has been a drop in overall frequency of pneumocystis pneumonia, atypical disease has increased in frequency [29].

Extrapulmonary pneumocystis infection: Dissemination, either hematogenous or lymphogenous, is rare. In non-AIDS patients, only 16 cases were reported up to 1996, whereas in AIDS patients, at least 90 cases were reported, but the incidence rate is unknown [4]. Although many AIDS patients were receiving aerosolized pentamidine, some were not [4, 29]. In non-AIDS patients, disease was not clinically evident or diagnosed in most [4]. In contrast, in AIDS patients extrapulmonary disease is often clinically evident. Other features are listed in Table 4. Although calcification in the lesions can be recognized by CT and suggest the disease, diagnosis is by biopsy.

Table 4: Extrapulmonary Pneumocystis Infection in AIDS Patients [4]

Pathologic features of extrapulmonary pneumocystis infection: At extrapulmonary sites, yellow to tan nodules may be seen grossly. Histologically, the foamy exudate containing spore cases and trophic forms is identical to that in the lung. Lesions may have no inflammatory reaction, or there may be a granulomatous reaction with foamy macrophages, giant cells, and chronic inflammatory cells. Dystrophic calcification, which can sometimes be seen on noncontrast CT scans as punctate or ring calcifications, may occur [16, 30, 31]. In a few cases, extrapulmonic organ failure develops even in cases with little or no pulmonary infection [32-34] .

Pathogenesis of pulmonary disease: Pneumocystis is an extracellular pathogen. Infection begins by attachment of the trophic forms to alveolar epithelial cells with the help of fibronectin and vitronectin [35]. Epithelial permeability increases and cells are damaged. Alveolar exudate and organisms impair the diffusion capacity [3]. Defects in cell-mediated immunity are a common feature in persons at risk for pneumocystis pneumonia. Animal experiments have examined separate components of the immune response and found that CD4+ T cells are most important in host defense, but that CD8+ T cells and B cells also make contributions [36]. Further, at the cytokine level in the mouse, two cytokines together, TNF and IFN-gamma, have been shown to be important in defense against pneumocystis infection. When genes for the TNF receptors and for IFN-gamma are inactive, the animals develop a marked lymphoid inflammatory response to the organisms, but do not clear them. In contrast, in wild type animals and those deprived of only one of the two genes, organisms are cleared promptly [37].

Treatment and outcome--AIDS:Trimethoprim-sulfamethoxazole is the major drug for treatment and prophylaxis; alternative therapies are also available. Guidelines for prophylaxis, for treatment of infection, and for use of adjunctive corticosteroids in AIDS have been recently reviewed [3, 38]. A recent report indicates that prophylaxis can be stopped safely in some AIDS patients who receive retroviral therapy and maintain CD4+ T lymphocyte counts at a level >200/µl and >14% of total lymphocytes [39].

Non-AIDS:The pros and cons of prophylaxis for PCP in non-AIDS patients is receiving more attention. Because of adverse reactions to trimethoprim-sulfamethoxazole and interference with detecting other bacterial infections, prophylaxis is advocated only for immunosuppressed, but not non-immunosuppressed patients receiving an equivalent of 20 mg or more of prednisone for more than one month [8]. The in-hospital mortality in non-AIDS patients (34%) [10] is greater than that in AIDS patients before adjunctive corticosteroid therapy (9-25%) [3].


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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 5/6/99

Copyright 1999 by Martha L. Warnock. All rights reserved.