Pneumocystis Hepatitis and Choroiditis Despite Successful Aerosolized Pentamidine Pulmonary Prophylaxis

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FIGURE 2. Typical Reed-Sternberg cells diagnostic of Hodgkin's disease. A (left), Lobulated large nucleus with macronucleoli and perinucleolar halo . B (middle), Multinucleate cells with macronucleoli. C (right), Multinucleate cell with marked lobulation of nucleus, with macronucleolus and perinucleolar halo (Papanicolaou's stain, original magnification x 4(0). cin , bleomycin, vincristine, dacabazine) was started. A residual mass still remained after five ABVD cycles. The treatment was changed to MOPP (mustargen, oncovine, procarbazine, prednisone) alternating with ABVD. The patient received six cycles of MOPP/ ABVD, but the chest x-ray film and cr showed a residual shadowing, which was most probably due to fibrotic tissue, and the patient has been asymptomatic with no evidence of active disease since. DISCUSSION

Pulmonary involvement is common in Hodgkin's disease.' In patients with treatment for Hodgkin's disease, the differential diagnosis of pulmonary abnormalities may be due to lymphomatous involvement of the pulmonary parenchyma, chemotherapy, radiotherapy, or opportunistic infection, or to any combination of these.' Pulmonary abnormalities in treated patients therefore constitute a diagnostic problem. Whether there is a pulmonary infiltrate or a rare endobronchial involvement, fiberoptic bronchoscopy is the first diagnostic procedure of choice." The reliability of cytologic diagnosis for Hodgkin's disease was demonstrated by all of the common cytologic methods. Reale et ale reported six cases of pulmonary involvement in patients with histologically proved Hodgkin's disease via cytodiagnosis of sputum specimens, but did not specify whether a pulmonary infiltrate was radiologically evident. Staging of known, histologically proved cases of Hodgkin's disease was established cytologically, based on fine needle aspiration of lymph nodes and extranodular lesions," Gribetz et al3 reported 64 fiberoptic bronchoscopic examinations of 58 patients with Hodgkin's and non-Hodgkins lymphoma with radiographic evidence of pulmonary abnormality. In only three cases, bronchial washing and brushing revealed malignant cells that could not be further characterized as either lymphoma or carcinoma. Recently, a case was reported in which diagnoWc Reed-Sternberg cells were obtained on bronchoalveolar lavage but were absent on brushing. s In the case presented herein, a recurring Hodgkin's disease was diagnosed in a patient who had had known Hodgkin's disease and exhibited a new pulmonary infiltrate. The cytologic material, vthich was obtained by brushing, was representative and well preserved, permitting a positive definitive diagnosis of Hodgkin's disease when biopsy failed to diagnose the lesion. The case demonstrates and empha-

sizes the usefulness of applying brushing for cytologic examination during fiberoptic bronchoscopy. REFERENCES 1 Pennington JE, Feldman NT. Pulmonary infiltrates and fever in patients with hematologic malignancy: assessment of transbronchial biopsy. Am J Med 1977; 62:581-87 2 Singer C , Armstrong D , Rosen Pp, Walzer PD, Yu B. Diffuse pulmonary infiltrates in immunosuppressed host: prospective study ofBO cases. Am J Med 1979; 66:110-20 3 Gribetz AR, Chuang MT, Teirstein AS. Fiberoptic bronchoscopy in patient with Hodgkin's and non-Hodgkins lymphomas. Cancer 1980; 46:1476-78 4 MacDonald JB . Lung involvement in Hodgkin's disease . Thorax 1977; 32:664-67 5 Rosenow EC III , Wilson WR, Cockerill FR III . Pulmonary disease in the immunocompromised host. Mayo Clin Proc 1985; 60:473-83 6 Reale FR, Varikojis D, Compton JC, Bibbo M. Cytodiagnosis of Hodgkin's disease in sputum specimens. Acta Cytoll983; 27:25861 7 Friedman M, Kim U , Shimaoka K, Panahon A, Han T, Stutzman L . Appraisal of aspiration cytology in management of Hodgkin's disease. Cancer 1980; 45:1653-63 8 Morales FM, Matthews JI. Diagnosis of parenchymal Hodgkin's disease using bronchoalveolar lavage. Chest 1987; 91:785-87

Pneumocystls Hepatitis and Choroiditis Despite Successful Aerosolized Pentamidine Pulmonary Prophylaxis· Wlllimn A Hagopian, M.D ., Ph.D.; andjon S. Huseby, M.D . A patient who developed PneumocyatW carini hepatitis and choroiditis despite receiving prophylactic pentamidine therapy by aerosol is described. Liver biopsy showed histology typical of Pneumocystis hepatitis, but his respiratory status was stable and his lungs were free of P carini organisms *From the Department of Medicine, University of Washington, the Swedish Hospital Medical Center, and Providence Medical Center, Seattle. Reprint requests: Dr. Huseby, 1200 Harvard &enue, Seattle 98122 CHEST I 96 I 4 I OCTOBER, 1989

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on BAL. Thus, inhaled pentamidine prophylaxis did not prevent extrapulmonary pneumocystosis. Patients receiving pentamidine prophylaxis with unexplained symptoms should undergo investigation for possible extrapulmonary P CGf'inii infection. (Chat 1989; 96:949-51)

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=PneumDCfl8tU carl,," pneumonia

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neumocystis carinii pneumonia (PCP) is a frequent cause of morbidity and mortality in patients with AIDS. Since the frequency of recurrent PCP in AIDS patients has been reported to be 35 percent at six months and 60 percent at one year,I prophylactic treatment seems prudent. The toxicity associated with systemic trimethoprim-sulfamethoxazole and IV pentamidine has prompted the search for

For editorial comment see page 713 alternative prophylactic regimens. Inhaled pentamidine is a frequently prescribed prophylactic treatment in these patients .! It has the advantage of low systemic toxicity while achieving high drug levels in the lung, which is the organ primarily infected with the organisms," Recently there have been increasing reports of disseminated or extrapulmonary pneumocystosis in AIDS patients. Only rarely, however, have the lungs been thought to be free of disease..... We describe a patient who developed P carinii hepatitis and choroiditis while receiving prophylactic pentamidine by aerosol. In our patient, the lungs were protected by the administration of pentamidine by aerosol; however, because of his severely immunosuppressed state, extrapulmonary foci of infection progressed . CASE REpORT

A 29-yeaM>ld man with AIDS was hospitalized for evaluation of fever, ascites, abdominal pain, and decreased visual acuity in the

FIGURE 1. Chest x-ray 61m 2 weeks prior to admission showing a right apical bleb, scarring at the left apex, and no new infiltrates.

FIGURE 2. Liver biopsy specimen revealing acellular nodules of periportal necrosis. Note foamy eosinophilic appearance; some nodules show a mild inflammatory in6ltrate (hematoxylin and eosin stain, original magnification x 120). left eye. pcp had been diagnosed 25 months previously, and subsequent treatment included zidovudine, 200 mg every 4 h, and prophylactic inhaled pentamidine, 150 mg bimonthly. Twelve months prior to the present admission, he developed apical in61trates and apical bullae, and BAL revealed numerous P carinii cysts. He was treated with IV pentamidine therapy and had a prolonged hospitalization with recurrent bilateral pneumothoraces requiring tube thoracostomy. After discharge he again received zidovudine and inhaled pentamidine 300 mg bimonthly. Six months prior to admission, BAL was negative for PCP. Two weeks prior to admission he complained of fever, mild dyspnea, abdominal distention, and decreased visual acuity in his left eye. Arterial blood gas analysis was unchanged from baseline . A chest x-ray 61mshowed a right apical bulla and left apical scarring but no new in6ltrates (Fig 1). A BAL was again negative for PCP. His abdominal distention worsened, and he was admitted to the hospital . Physical examination revealed a mildly ill-appearing man with a distended abdomen. His temperature was 39"C; blood pressure, 110160 mm Hg; respiratory rate, 28/min; and pulse rate, 120 bpm . Neck veins were normal, chest was clear, and results of cardiac examination were normal except for tachycardia. Abdominal examination revealed marked ascites and moderate splenomegaly. There was trace peripheral edema. Laboratory studies revealed the follOwing values: hematocrit, 34 percent; WBCs, of 7,100/mm 3 , with total lymphocytes,

FIGURE 3. Comori methenamine silver stain of the necrotic area shown in Figure 2. Note numerous cup-shaped cysts characteristic of Pneumocyrtls carinii (original magnification x 4(0). Pneumocyslis Hepatitis and Coroldltis (Hagopian, Huseby)

142/cu mm, (normal, 1,()()() to 4,500), and helper-inducer (CD-4) lymphocytes, 91cu mm (normal, 400 to 1 ,BOO). Liver function test results were remarkable for an AST, 216 lUlL (normal, 0 to 41); ALT, 92 lUlL (normal, 0 to 50); alkaline phosphatase, 579 lUlL (normal, 30 to 115); bilirubin, 0.1 mg/dl, albumin, 0.3 Wdl; total protein, 2.7 Wdl; and LDR, 1,142 lUlL (normal, 60 to 220). Paracentesis revealed an opaque fluid that was negative for malignant cells or pathogens. Abdominal cr showed splenomegaly and ascites but a normal-appearing liver and no adenopath~ Ophthalmoscopy revealed multiple yellow-white choroidal lesions 1 to 2 mm in size, deep to the retina. They were confluent in the midperiphery and were thought to represent choroiditis due to Pneumocystis infection. A liver biopsy specimen showed acellular nodules in a periportal distribution (Fig 2). Methenamine silver stain revealed numerous cysts of P carin;; within the acellular nodules (Fig 3). Repeated paracenteses were required for the patient's comfort. Therapy with pentamidine, 4 mglkglday ~ was begun; however, the patient developed progressive hepatic and renal failure and died 18 days after admission.

COMMENTS As the AIDS epidemic has evolved, there have been several changes in the nature of P carinii infection. Lowry and co-workers'? found that in 15 of 24 AIDS patients who had relapses of PCP while taking prophylactic inhaled pentamidine, the upper lobes were involved. This pattern may be associated with bleb formation, as seen in our patient. Relapse localized to the upper lobes could be due to the greater distribution of ventilation to the lower lobes, causing the upper lobes to receive less of the drug. Disseminated and extrapulmonary P carinii infection has also been reported recently Most of these patients were severely immunosuppressed.":" however, in some it was the initial manifestation of AIDS.5.e.8.9 Poblete et al lS reported a very similar case in which Pneumocystis hepatitis developed while the patient was receiving aerosolized pentamidine prophylaxis. Their patient likely had active P carinii pulmonary infection when the hepatitis developed. In contrast, our patient had a normal BAL and a stable chest roentgenogram. This strongly suggests that while the pentamidine prophylaxis effectively prevented pulmonary Pneumocystis, it did not prevent the development of extrapulmonary sites of infection in the eye and liver. Although our patient did not appear marasmic, severe immunodeficiency (indicated by his CD4 count of 9/cu mm) allowed extrapulmonary Pneumocystis to progress. He also had severe hypoproteinemia, common in other cases of hepatic pneumocystosis.15-17 Hepatitis caused by P carini; is rare and has been reported in association with disseminated pneumocystosis in five other cases, all with concurrent lung involvement. 11.IJ.I~18 The histology is similar to that of a Pneumocystis pulmonary infection, revealing periportal structureless acellular nodules of foamy pink material with numerous Pneumocystis organisms demonstrable on silver staining. This case emphasizes that extrapulmonary Pneumocystis infection may develop while a patient is receiving inhaled pentamidine prophylaxis and can progress without active pulmonary pneumocystosis. Since autopsies are rarely done

on patients with AIDS, it is possible that the incidence of extrapulmonary Pneumocystis infection is greater than previously recognized. Even in patients whose lungs are free of Pneumocystis, an aggressive diagnostic work-up should be performed in symptomatic patients to rule out extrapulmonary infection caused by this organism. REFERENCES 1 Abramowicz M, ed. Prevention of Pneumocystis carinii pneumonia Med Lett 1988; 30:93-95 2 Armstrong D, Bernard E. Aerosol pentamidine. Ann Intern Med 1988; 109:852-54 3 Corkery KJ, Luce JM, Montgomery AB. Aerosolized pentamidine for treatment and prophylaxis of Pneumocystis carinii pneumonia: an update. Respir Care 1988; 33:676-84 4 Gallant JE, Enriquez RE, Cohen KL, Hammers LW Pneumacystis carinii thyroiditis. Am J Med 1988; 84:303-06 5 Gherman CR, Ward RR, Bassis ML. Pneumocystis carinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiency syndrome. Am J Med 1988; 85:250-52 6 Schinella RA, Breda SD, Hammerschlag PEe Otic infection due to Pneumocystis carinii in an apparently healthy man with antibody to the human immunodeficiency virus. Ann Intern Med 1987; 106:399-400 7 Coulman CU, Greene I, Archibald RWR. Cutaneous pneumocystis. Ann Intern Med 1987; 106:396-98 8 Breda SD, Hammerschlag PE, Gigliotti F, Schinella R. Pneumocystis carinii in the temporal bone as a primary manifestation of AIDS. Ann Otol Rhinol Laryngoll988; 97:427-31 9 Carter TR, Cooper PH, Petri WA, Kim CK, Walzer PD, Guerrant RL. Pneumocystis carinii of the small intestine in a patient with the acquired immunodeficiency syndrome. Am J Clio Patholl988; 89:679-83 10 Lowery S, Fallat R, Feigal D~ Montgomery AB. Changing patterns of l! carinii pneumonia (PCP) on pentamidine aerosol prophylaxis, abstract 7167. In: Program and Abstracts. Stockholm: Fourth International Conference of AIDS, 1988:419 11 Awen C, Baltzan M. Systemic dissemination of Pneumocystis carinii pneumonia. Can Med Assoc J 1971; 104:809-12 12 Pilon VA, Echols RM, Celo JS, Elmendorf SL. Disseminated Pneumocystis carinii infection in AIDS. N Engl J Med 1987; 316:1410-11 13 Grimes MM, LaPook JD, Bar MH, Wasserman HS, Dwork A. Disseminated Pneumocystis carinii infection in a patient with acquired Immunodeficiency syndrome. Human Pathol 1987; 18:307-08 14 Macher AM, Bardenstein DS, Zimmerman LE, Steigman CK, Pastore L, Portez DM, et ale Pneumocystis carinii choroiditis in a male homosexual with AIDS and disseminated pulmonary and extrapulmonary e carinii infection [Letter]. N Eng) J Med 1987; 316:1092 15 Poblete RB, Rodriguez K, Foust RT, Reddy KR, Saldana MJ. Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome. Ann Intern Med 1989; 110:737-38 16 Jarnum S, Rasmussen EF, Ohlsen AS, Sorensen AW. Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann Intern Med 1968; 68:138-45 17 Rahimi SA. Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Patho11974; 97:162-65 18 Steigman CK, Pastore L, Park CH, Fox CH, DeVinates ML, Connor DH, et ale AIDS case for diagnosis series. Milit Med 1987; 152:MI-M8

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