Pneumocystosis

Extrapulmonary pneumocystosis recently has been reported in a number of tissues. Most cases occurred in patients receiving aerosolized pentamidine prophylaxis. We report a case of disseminated pneumocystosis presenting as a large pleural effusion without apparent lung involvement where Pneumocystis carinii was the only pathogen identified. The absence of parenchymal lesions on chest x-ray film, the lack of hypoxemia and the minimal uptake of gallium all argue against significant lung involvement. The patient was successfully treated with chest tube drainage, intravenous and inhaled pentamidine and orally administered dapsone and trimethoprim. The addition of inhaled pentamidine to intravenously administered pentamidine may have increased pleural fluid levels substantially and its use coincided with the patient's improvement.

Pneumocystis carinii pneumonia is a common opportunistic infection in AIDS, but pleural effusions occur rarely and typically are small.[1,2] Extrapulmonary pneumocystosis has been reported in a number of tissues including kidney, bone marrow, spleen, lymph node, and liver.[3,4] Most cases occur in patients receiving aerosolized pentamidine prophylaxis[3,4] and probably result from the poor systemic absorption. We report a case of disseminated pneumocystosis in such a patient who presented with a large pleural effusion without apparent lung involvement. We discuss the roles of intravenously administered and inhaled pentamidine in his successful treatment.

CASE REPORT

A 27-year-old man was successfully treated 18 months earlier for P carinii pneumonia with dapsone and trimethoprim, since he was intolerant of trimethoprim-sulfamethoxizole. He began receiving zidovudine and inhaled pentamidine (300 mg/month). Eight weeks prior to admission, he developed cryptococcal meningitis which responded rapidly to the experimental agent Schering 39304. A chest x-ray film showed a small free-flowing right pleural effusion and slight enlargement of the left hilum. He was briefly hospitalized two weeks later with fever and pharyngitis. The CSF cryptococcal antigen titer had fallen, but the chest x-ray film showed a small free-flowing right hydropneumothorax. Thoracentesis revealed a hazy, yellow fluid with a pH value of 7.41; protein value, 2.7 g/dl; LDH level, 406 U?L; glucose level, 124 mg/100 ml; 512 RBCs/cu mm; and no WBCs. No organisms were seen on a Gram stain; no other stains were done. Cultures for bacteria, fungi, and mycobacteria were negative. His symptoms resolved without treatment. The hydropneumothorax was treated conservatively.

One week prior to admission he complained of discomfort on the right chest wall. He was afebrile. A chest x-ray film showed a large free-flowing right pleural effusion with no apparent pulmonary parenchymal disease (Fig 1). Thoracentesis yielded 200 ml of bloody fluid with a pH value of 7.42; LDH 725 U/L; glucose level, 99 mg/dl; protein value, 1.9 g/dl; 370,000 RBCs/cu mm; and 136 WBC/cu mm (S 12, L 4, M 76). Diff-Quick (Dade Diagnostics) and Papanicolaou stains showed erythrocytes, lymphocytes, foamy histiocytes and rare mesothelial cells. In addition, Diff-Quick-stained smears revealed innumerable P carinii trophozoites (Fig 2). A Gomori methenamine silver stain revealed cyst forms of P carinii. The trophozoites did not stain. Cultures for bacteria, fungi and mycobacteria were negative. Therapy with dapsone (100 mg/day) and trimethoprim (20 mg/kg/day) was started.

Four days later, the effusion was substantially larger as evidenced on a chest x-ray film and he was hospitalized. Room air oxygen saturation (pulse oximetry) was 99 percent. On hospital day 1, a chest tube was inserted, 3,000 ml of bloody fluid was removed from the right side of the chest, and intravenously administered pentamidine (4 mg/kg/day) was started. A gallium scan showed minimal uptake of tracer in the lungs. Chest and abdominal CT scans showed hilar lymphadenopathy and hypodense splenic lesions. Pleurodesis with tetracycline was unsuccessfully attempted on day 2. The chest tube continued to drain 400 ml/day with a persistent air leak. Pneumocystis carinii organisms were seen in the pleural fluid as late as ten days after starting intravenously administered pentamidine. We considered intrapleural instillation of pentamidine, but there has been no experience with this approach and we feared that this would induce serious arrhythmias.[5] After 14 days of intravenous therapy, pentamidine levels later measured by high pressure liquid chromatography (HPLC) (E. M. Bernard, Memorial Sloan-Kettering Cancer Center) were 64 ng/ml in the serum (trough) and 24 ng/ml (38 percent of serum level) in a simultaneous sample of pleural fluid. Dapsone (100 mg/day) was added to the regimen on day 14 and inhaled pentamidine (600 mg/day) on day 15. The patient's serum albumin level fell to 1.2 mg/100 ml and peripheral hyperalimentation with albumin supplementation was begun. After the addition of inhaled pentamidine, random pleural fluid pentamidine levels were as high as 83 ng/ml. No further serum levels were obtained. On day 20, no P carinii organisms were seen in the pleural fluid. Therapy with intravenous and inhaled pentamidine was discontinued after 23 days of intravenous and 10 days of inhaled therapy once the chest tube output ceased. He was discharged on a regimen of dapsone and trimethoprim. An abdominal CT scan three months later showed persistence of the splenic lesions. A chest x-ray film six months later showed only a persistently blunted right costophrenic angle. The patient survived for another year on a regimen of dapsone therapy without evidence of recurrent P carinii pneumonia.

DISCUSSION

This patient developed a massive pleural effusion in which P carinii was the only pathogen identified, with no apparent lung involvement. His hilar lymphadenopathy and splenic lesions were consistent with disseminated pneumocystosis.[3,4] Pleural effusions are uncommon in pulmonary pneumocystosis and are generally small.[1,2,6] Nodular pleural lesions have been reported at lung biopsy and autopsy and may be associated with pulmonary vasculitis or disseminated pneumocystosis,[3,4] but extensive involvement of the pleura without apparent lung infection has not been described. Pulmonary pneumocystosis in this patient cannot be completely excluded, since neither bronchoalveolar lavage nor lung biopsy was done. Indeed, subclinical Pneumocystis pneumonia has been reported at lung biopsy[7] and autopsy,[8,9] and gallium scanning may be less sensitive in patients receiving inhaled pentamidine.[10] However, the absence of parenchymal lesions on a chest x-ray film and the CT and gallium scans, and the lack of hypoxemia all argue against significant lung involvement.

This patient's improvement followed the resumption of dapsone therapy and the addition of inhaled pentamidine. Although dapsone therapy failed initially, its combination with intravenous and inhaled pentamidine therapy may have been helpful. However, it is more likely that the addition of inhaled pentamidine produced effective pentamidine levels in the pleural fluid. Comparison of the pleural fluid levels before and after the addition of inhaled pentamidine support this view. After ten days of intravenously administered pentamidine, the trough serum level--which should have reached a steady state--was typical of levels reported after an intravenous 4 mg/kg dose,[11] but the simultaneous pleural fluid level was only 40 percent of this serum level. Higher pleural fluid levels were measured after the addition of inhaled pentamidine. Inhaled pentamidine (300 mg) only slightly increases serum levels (about 14 ng/ml),[12] but it produces levels as high as 700 ng/ml in bronchoalveolar lavage fluid.[13] Inhaled pentamidine may have increased the pleural fluid level by transfer across the inflamed pleural membrane or through the air leak of the hydropneumothorax. Daily inhaled pentamidine may be useful for other patients with resistant pleural disease.

REFERENCES

[1] Suster B, Akerman M, Orenstein M, Wax MR. Pulmonary manifestations of AIDS: review of 106 episodes. Radiology 1986; 161:87-93

[2] Chaffey MH, Klein JS, Gamsu G, Blanc P, Golden JA. Radiographic distribution of Pneumocystis carinii pneumonia in patients with AIDS treated with prophylactic inhaled pentamidine. Radiology 1990; 175:715-19

[3] Telzak EE, Cote RJ, Gold JW, Campbell SW, Armstrong D. Extrapulmonary Pneumocystis carinii infections. Rev Infect Dis 1990; 12:380-86

[4] Northfelt DW, Clement MJ, Safrin S. Extrapulmonary pneumocystosis:clinical features in human immundodeficiency virus infection. Medicine 1990; 69:392-98

[5] Wharton JM, Demopulos PA, Goldschlager N. Torsades de pointes during administration of pentamidine isothionate. Am J Med 1987; 83:571-76

[6] Balachandran I, Jones DB, Humphrey DM. A case of pneumocystis carinii in pleural fluid with cytologic, histologic, and ultrastructural documentation. Acta Cytologica 1990; 34:486-90.

[7] Dyner TS, Lang W, Busch DF, Gordon PR. Intravascular and pleural involvement by Pneumocystis carinii in a patient with acquired immunodeficiency syndrome. Ann Intern Med 1989; 111:94-95

[8] Davey RT, Margolis D, Kleiner D, Deyton L, Travis W, et al. Digital necrosis and disseminated Pneumocystis carinii infection after aerosolized pentamidine prophylaxis. Ann Intern Med 1989; 111:681-82

[9] Rao NA, Zimmerman PL, Boyer D, Biswas J, Causey D, Beniz J, et al. A clinical, histopathologic, and electron microscopic study of Pneumocystis carinii choroiditis. Am J Ophthalmol 1989; 107:218-28

[10] Jules-Elysee KM, Stover DE, Zaman MB, Bernard EM, White DA. Aerosolized pentamidine: effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann Intern Med 1990; 112:750-57

[11] Conte JE, Chernoff D, Feigal DW, Joseph P, McDonald C, Golden JA. Intravenous or inhaled pentamidine for treating Penumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med 1990; 113:203-09

[12] Conte JE, Golden JA. Concentrations of aerosolized pentamidine in bronchoalveolar lavage, systemic absorption, and excretion. Antimic Agents Chemother 1988; 32:1490-93

[13] Montgomery AB, Debs RJ, Luce JM, Corkery KJ, Turner J, Brunette EN, et al. Selective delivery of pentamidine to the lung by aerosol. Am Rev Respir Dis 1988; 137:477-78

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