(CHEST 2002; 122:1840-1843)
A 38-year-old man with AIDS and a prior episode A of Pneumocystis carinii pneumonia (PCP) presented with a 2-month history of progressive dyspnea, nonproductive cough, night sweats, and weight loss. Medications included nelfinavir, 750 mg three times daily; stavudine, 40 mg twice daily; didanosine, 200 mg twice daily; and trimethoprim/ sulfamethoxazole (TMP/SMX) prophylaxis once daily. However, according to the pharmacy records, the patient had not been compliant with the TMP/SMX therapy. He denied tuberculosis exposure or recent travel.
On physical examination, the patient was afebrile and had faint crackles at the lung bases. The results of laboratory studies were notable for the following: WBC count, 12,700 cells/[micro]L; normal differential analysis; and lactate dehydrogenase level, 313 U/L (normal range, 100 to 210 U/L). Arterial blood gas measurements while breathing room air revealed the following: pH, 7.47; PaC[O.sub.2], 33 mm Hg; and a Pa[O.sub.2], 77 mm Hg. Several weeks prior to admission, the CD4 cell count was 90 cells/[micro]L, and the HIV RNA level was undetectable (ie < 25 copies per mL). A radiograph (Fig 1) and a CT scan (Fig 2) of the chest revealed multiple large nodules measuring 1 to 3 cm in diameter, distributed throughout both lung fields. The result of the direct fluorescence antibody test for P carinii that was performed on the patient's BAL fluid was negative. The findings of transbronchial biopsies showed only nonspecific inflammation. A video-assisted thoracoscopy (VATS) biopsy of the left lower lobe revealed well-formed granulomas with caseating necrosis.
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What is the differential diagnosis of the pulmonary nodular masses in AIDS patients, and what disorder was ultimately diagnosed using the VATS lung biopsy specimen in the context of the medical history?
Diagnosis: Nodular pneumocystosis with caseating granulomas
Prior to the widespread availability of antiretroviral therapy and TMP/SMX prophylaxis, PCP was one of the most common opportunistic infection in AIDS patients. Even today, PCP remains a frequent opportunistic infection associated with HIV. (1) The typical radiographic appearance of PCP is bilateral perihilar alveolar infiltrates, which may become diffuse. (2) Other radiographic findings for PCP include normal, interstitial infiltrates, segmental or lobar consolidation, cavities, and nodules. (3-5) The incidences of PCP-associated upper lobe disease, cysts, and spontaneous pneumothoraces were increased in AIDS patients who were receiving aerosolized pentamidine prophylaxis. (2) Nodules of various sizes also have been associated with both HIV-related and sporadic PCP, and some have been known to cavitate. (2) Interestingly, the presence of granulomas may correlate with the presence of nodule formation. (4,6,7) Other causes of pulmonary nodules or masses in HIV-positive individuals include lymphoma, primary lung cancer, septic emboli, Kaposi sarcoma, and mycobacterial and fungal infections.
The histopathology of PCP typically consists of a foamy, acellular, and eosinophilic intra-alveolar exudate. On the other hand, the lung biopsy of our patient revealed caseating granulomas (Fig 3) with central areas of necrosis. Staining of the lung tissue with Gomori methenamine-silver stain showed clusters of P carinii cysts located principally within the necrotic areas. The results of staining with special stains for fungi and mycobacteria were negative, and there were no viral inclusions identified. The findings of bacterial, fungal, and mycobacterial cultures of sputum, blood, BAL fluid, and lung biopsy specimens were all negative. There was no evidence of capillaritis to suggest a diagnosis of Wegener granulomatosis or microscopic polyangiitis.
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A granulomatous response to P carinii is unusual. (3,4,6) About 25 years ago, Cruickshanks reported the first case of caseating granulomatous PCP in a renal transplant patient. The prevalence of granulomas in a patient with HIV-related PCP has been estimated to be approximately 5%. (3-6) Wakabayashi and coworkers (9) described the only previously reported case of PCP-associated granulomas with caseation in an AIDS patient receiving indinavir therapy. (10)
It is interesting to posit that due to the highly active antiretroviral therapy (HAART), our patient may have had relatively less immune impairment, allowing for the development of well-formed caseating granulomas in response to the PCP. Naccache and coworkers (11) reported two cases of pulmonary granulomatous disorders after the initiation of HAART in which no infectious agent could be identified. It was hypothesized that the sarcoid-like reaction was triggered by the immune reconstitution as a result of HAART because infectious and environmental causes were excluded. (11) In our patient, it is less likely that the granulomatous nodules were due solely to HAART because of the presence of caseation, which typically signifies an infectious cause. Moreover, P carinii organisms were found to be closely associated with the granulomas. Flanery and colleagues (3) noted that antiretroviral agents may modify the radiographic and histopathologic manifestations of PCP resulting in a granulomatous response. In 1998, five patients with advanced AIDS developed a granulomatous, focal lymphadenitis due to Mycobacterium avium after the initiation of indinavir therapy. (12) Other reports of unusual inflammatory reactions occurring in AIDS patients following the initiation of HAART included vitritis in the setting of cytomegalovirus retinitis, (13) paradoxical reactions associated with HIV-related tuberculosis, (14) and hepatic necrosis due to the reactivation of chronic hepatitis C. (15) These cases support the notion that an improvement of the immune response may alter the clinical, radiographic, or histopathologic appearance of an opportunistic infection in an otherwise immunodeficient host.
Two other issues in this case warrant emphasis. First, it is imperative that even with HAART administration, PCP prophylaxis be continued until the CD4 cell count rises above 200 cells/[micro]L for more than 3 consecutive months. (16) Our patient was still severely immunocompromised, as evinced by the low CD4 cell count a few weeks prior to presentation. Thus, he required continuation of PCP prophylaxis. Second, although BAL and transbronchial biopsy are highly sensitive tests for diagnosing PCP in AIDS patients, the results of both of these tests were negative due, perhaps, to the confinement of the organisms within the granulomas. In summary, we hypothesize that in our patient, a partial restoration of immune function from HAART administration, but inadequate PCP prophylaxis, led to the unusual tissue response of caseating granulomas. He was treated with TMP/SMX, and improved clinically and radiographically over the ensuing few weeks.
* From the Division of Pulmonary Sciences and Critical Care Medicine (Drs. Winn, Schwarz, and Chan), the Division of Infectious Diseases (Dr. Stoeckli), and the Department of Pathology (Dr. Wilson), University of Colorado Health Sciences Center, Denver, CO; and the Denver Community Programs for Clinical Research on AIDS (Dr. Burmah), Denver Health Medical Center, Denver, CO.
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(15) Karras A, Rabian C, Zylberberg H, et al. Severe anoxic hepatic necrosis in an HIV-l-hepatitis C virus-co-infected patient starting antiretroviral triple combination therapy. AIDS 1998; 12:827-839
(16) Ledergerber B, Mocroft A, Reiss P, et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. N Engl J Med 2001; 344:168-174
Manuscript received June 29, 2001; revision accepted August 15, 2001.
Correspondence to: Robert A. Winn, MD, Campus Box C272, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262; e-mail: firstname.lastname@example.org
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