The patient is a 35-year-old man with AIDS (CD4 count 100 cells/µl) and a non-productive cough. He is taking no medications.
Figure 1. Chest Radiographic Findings
The frontal chest radiograph shows diffuse, bilateral, ill-defined opacity through which bronchovascular structures can be seen. There is no evidence of pleural effusion or lymphadenopathy.
Figure 2. HRCT Findings
HRCT shows extensive, bilateral, ground-glass opacity.
What is the differential diagnosis? Answer
Figure 3. Acute Disease in a Child
Pale, ill-defined, sometimes confluent nodules are present in all lobes. Note also the absence of accentuation of interlobular septa.
Figure 4. Typical Histologic Appearance
This section shows alveoli filled with a foamy pink exudate. Alveolar walls have hypertrophied type II cells and are slightly congested, but show little inflammation.
What is the differential diagnosis?
What is the diagnosis? What special stain would confirm the diagnosis?
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Pneumocystis jiroveci Pneumonia
In the US, pneumocystis pneumonia (PCP), still the most frequent opportunistic infection in AIDS patients, has decreased in frequency over the past decade . In immunocompromised patients without AIDS, it occurs sporadically, especially in those with hematologic malignancies, rheumatologic diseases, and transplants, as well as in those with congenital immunodeficiencies, malnutrition, and old age . The name of the causative agent, which is now classified as a fungus, has been changed to P. jiroveci in honor of the person who first linked the organism to human pneumonia. Whereas different pneumocystis species infect many mammals, P. jiroveci specifically infects only humans. The environmental reservoir and method of transmission of disease are still unclear, although molecular methods now implicate reinfection and person-to-person transmission .
Clinical aspects: AIDS patients with CD4 counts <200 cells/µl and other immunocompromised patients who have recently received corticosteroids are at risk. Patients complain of fever, cough, and dyspnea. Laboratory abnormalities include an increased LDH, decreased DLco, and a chest radiograph with bilateral hazy opacities . In AIDS patients with suspicious clinical findings and chest radiographs, demonstration of the organism is optimized by performing sputum induction followed, if negative, by bronchoalveolar lavage (4). For such patients with normal chest radiographs, a decreased DLco is followed by sputum induction, whereas a normal DLco is followed by HRCT (5). Patients with negative results are then observed. This algorithm minimizes those with false negative results. Diagnosis is usually made on cytologic specimens from induced sputum or BAL . Treatment with HAART has been associated with decreased mortality from PCP in AIDS patients requiring therapy in the ICU .
The classic radiographic appearance of PCP is bilateral, predominantly perihilar, hazy opacity that does not obscure the bronchovascular bundles. When lung opacity is present but does not obscure the bronchovascular bundles, the term ground-glass opacity may be used. While this term is used most extensively in reference to high-resolution computed tomographic (HRCT) findings, it may be used as a descriptor for chest radiographic findings in the appropriate circumstances. Occasionally, PCP will present as a primarily interstitial-appearing abnormality, with lines and reticulation being the dominant features. If the disease remains untreated, the ground-glass opacity may progress to air-space consolidation .
Cystic lung disease is a common manifestation of PCP. These cysts usually represent pneumatoceles, and tend to predominate in the upper lobes. Pneumatoceles due to PCP are usually thin-walled (wall thickness <1 mm) and often clustered, ranging in size from <1 cm to 5 cm. Pneumatoceles often develop within areas of ground-glass opacity, and they can become quite extensive. In patients undergoing treatment, these cysts usually resolve within 6 months. Cysts are often associated with spontaneous pneumothorax, which may be a presenting feature of PCP in 5-10% of patients [7,8,9].
Radiographic findings are usually bilateral, symmetric, and unaccompanied by pleural effusion or lymphadenopathy.
Atypical presentations are occasionally encountered, and include lobar consolidation, solitary or multiple nodules, pleural effusions, and lymphadenopathy. Less common disease distributions, such as unilateral disease or upper lobe predominance, may occasionally be encountered. Cavitation (as opposed to pneumatocele formation) of a solitary nodule due to PCP is unusual, but has been described.
The chest radiograph may be normal in around 18% of patients with proven PCP infection. With awareness of subtle disease manifestations, the frequency of a normal chest radiograph is probably substantially less than that value .
If the patient is treated promptly and survives the infection, PCP usually resolves without sequelae. However, in a small number of patients, pulmonary fibrosis may occur, presenting as architectural distortion, honeycombing, and traction bronchiectasis.
The major manifestation of PCP on HRCT is diffuse, bilateral, ground-glass opacity. In the early phase of infection, minimal reticulation may be present. As the disease progresses, linear opacity and reticulation, due to interlobular septal thickening, become increasingly prominent. In patients with severe disease, diffuse air-space consolidation is often encountered. Pneumatoceles are often encountered on HRCT studies in patients with PCP .
HRCT is more sensitive and specific than chest radiography for the detection of PCP. In the proper clinical setting (a patient with advanced HIV infection not on adequate prophylaxis, who presents with dry cough and a characteristic chest radiograph), HRCT is not required: sputum induction will usually provide the correct diagnosis. However, if the patient's presentation is atypical, or sputum induction is negative in an otherwise presumed typical case, HRCT may provide valuable additional information. For example, in patients with atypical clinical presentations, HRCT may show a different disease pattern, such as symmetric bronchopneumonia or neoplasm, that accounts for the patient's symptoms.
Classically, alveolar spaces are filled with foamy pink exudate accompanied by type II cell hyperplasia and scattered interstitial lymphocytes and plasma cells. The GMS stain shows the spore cases and a Giemsa stain shows the trophic forms within the foamy material.
Another change during acute disease is cyst formation (radiographically, pneumatocele formation). Rather than being confined to the alveolar spaces, organisms sometimes invade alveolar and vascular walls focally to cause parenchymal necrosis. As debris clears, cysts remain. Air trapping by these cysts or by organisms filling bronchioles may cause interstitial emphysema, another manifestation of cystic disease [10,11].
Atypical appearances: The following atypical changes tend to predominate in the upper lobes. These changes result from alveolar injury, tissue necrosis, or varying degrees of fibrosis. Acute alveolar damage with hyaline membranes may be the major or sole histologic finding in PCP. Why it develops is unknown . Organization, rather than resolution, can produce interstitial fibrosis, as well as honeycombing, related to alveolar collapse and dilation of alveolar ducts and respiratory bronchioles. Organization can also lead to air space fibrosis resembling bronchiolitis obliterans organizing pneumonia .
Some pneumonic foci become fibrotic over time. Necrosis and cavitation may also occur in these nodules. Focal calcifications are a characteristic of these lesions, and a GMS stain shows the outlines of spore cases within the calcifications.
Sometimes, single or multiple nodules of varying size have a granulomatous appearance with central pink material surrounded by a chronically inflamed fibrotic wall. Multinucleated giant cells may be seen. Sometimes the granulomas are diffuse and miliary and resemble those of tuberculosis or fungal infection. Organisms are found in the central pink areas .
Finally, extrapulmonary disease, usually with typical foamy exudate, little inflammation, and focal calcifications is an occasional occurrence, with or without overt pulmonary disease .
Typical acute disease is easier to diagnose than atypical acute, subacute, or chronic forms both in AIDS and non-AIDS patients. Because organisms may become localized, open biopsies may occasionally be necessary for diagnosis. Some of the atypical changes may be related to infection with other opportunistic agents, especially CMV, or to high-dose oxygen.
Summary of Radiographic Features of Pneumocystis Pneumonia
Summary of Pathologic Features of Pneumocystis Pneumonia
Diagnosis: Typical pneumocystis pneumonia
References: To return to reference section after viewing abstract, click here before clicking on "abstract".
1. Afessa B, Green W, Chiao J, Frederick W. Pulmonary complications of HIV infection: autopsy findings. Chest 1998; 113:1225-1229. Abstract
2. Thomas Jr C, Limper A. Pneumocystis pneumonia: clinical presentation and diagnosis in patients with and without acquired immune deficiency syndrome. Sem Respir Infect 1998; 13:289-295. Abstract
3. Stringer J. Pneumocystis. Int J Med Microbiol 2002; 292:391-404. Abstract
4. Huang L, Stansell J, Osmond D, Turner J, Shafer K, Fulkerson W, Kvale P, et al. Performance of an algorithm to detect Pneumocystis carinii pneumonia in symptomatic HIV-infected persons. Chest 1999; 115:1025-1032. Abstract
5. Gruden J, Huang L,Turner J, Webb W, Merrifield C, Stansell J, Gamsu G, Hopewell P. High-resolution CT in the evaluation of clinically suspected Pneumocystis carinii pneumonia in AIDS patients with normal, equivocal, or nonspecific radiographic findings. AJR 1997; 169: 967-975. Abstract
6. Morris A, Wachter R, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003 Jan 3;17(1):73-80. Abstract
7. Boiselle P, Crans Jr C, Kaplan M. The changing face of Pneumocystis carinii pneumonia in AIDS patients. AJR 1999; 172:1301-1309. Abstract
8. Chow C, Templeton P, White C. Lung cysts associated with Pneumocystis carinii pneumonia: Radiographic characteristics, natural history, and complications. AJR 1993: 161:527-531. Abstract
9. Feuerstein I, Archer A, Pluda J, Francis P, Falloon J, Masur H, Pass H, Travis W. Thin-walled cavities, cysts, and pneumothorax in Pneumocystis carinii pneumonia: further observations with histopathologic correlation. Radiology 1990:174:697-702. Abstract
10. Watts J, Chandler F. Evolving concepts of infection by Pneumocystis carinii. Pathol Annu Part 1, 1991; 26:93-138.
11. Murry C, Schmidt R. Tissue invasion by Pneumocystis carinii: a possible cause of cavitary pneumonia and pneumothorax. Hum Pathol 1992; 23:1380-1387. Abstract
12. Travis W, Pittaluga S, Lipschik G, Ognibene F, Suffredini A, Masur H, Feuerstein I, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome. Review of 123 lung biopsies from 76 patients with emphasis on cysts, vascular invasion, vasculitis, and granulomas. Am J Surg Pathol 1990;14:615-625. Abstract
13. Ng V, Yajko D, Hadley W. Extrapulmonary pneumocystosis. Clin Microbiol Rev 1997:10;401-418. Abstract
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Differential diagnosis: The differential diagnosis should include those entities known to cause diffuse, bilateral, ground-glass opacity, including hypersensitivity pneumonitis; diffuse pulmonary hemorrhage; idiopathic interstitial pneumonias (especially respiratory bronchiolitis-interstitial lung disease and desquamative interstitial pneumonia); certain infections, including viral and pneumocystis pneumonia; and causes of acute lung injury, particularly toxic exposures.
Answers: The gross picture suggests a diffuse, infectious pneumonic process. The histologic differential diagnosis includes pneumocystis pneumonia, pulmonary edema, pulmonary alveolar proteinosis, and (in an adult) intraalveolar mucin from a bronchioloalveolar carcinoma. Only pneumocystis pneumonia is characterized by the foamy alveolar exudate shown.
A special stain for fungi (Gomori methenamine silver, GMS) showed organisms. These ovoid, to cup-shaped organisms with focal thickening of the cell wall are spore cases (cysts) of Pneumocystis jiroveci (formerly carinii).
Stains for bacteria were negative and no viral inclusions were found.