Case Report: Cryptococcal Pleural Effusion Preceding Cryptococcal Meningitis in AIDS EMILY E. GRUM, MD,
RICHARD SCHWAB, MD,
ABSTRACT: The authors report a case in which a small cryptococcal pleural effusion preceded the development of severe cryptococcal meningitis in an HIV -positive patient. The appearance of an isolated transient pleural effusion is a very unusual presentation for AIDS-related complications. The authors suggest that cryptococcal infection be considered in this setting. KEY INDEXING TERMS: Acquired Immune Deficiency Syndrome; Cryptococcus; Pleural Effusion; Meningitis. [Am J Med Sci 1991; 301(5): 329-330.]
C
ryptococcus neoformans is an important fungal pathogen causing serious infections in patients with AIDS.l The most frequent clinical manifestation of this infection is meningitis, which is typically quite refractory to treatment and often fatal. 1 Theoretically, earlier diagnosis of cryptococcal meningitis might improve therapeutic outcome. A clinical sign that could be detected prior to the development of fulminant meningitis would, therefore, be helpful. The following case suggests that a small antecedent pleural effusion may occasionally provide such a clue. Case Report A 35·year-old black man, known to be HIV -positive since 1984, presented to the Philadelphia VA Medical Center with fever and a 10 pound weight loss over a period of one month. He denied cough, sputum production, hemoptysis, pleuritic chest pain, shortness of breath, or headache. Social history was significant for intravenous use of heroin for 20 years with admitted sharing of needles. He denied homosexual behavior. There was no prior history of opportunistic infection. On presentation, he had a rectal temperature of 38.4 0 C, blood pressure of 90/60 mm Hg, respiratory rate of 24/minute, and a pulse of 96/minute. Lung examination revealed decreased breath sounds at the right base with dullness to percussion. The remainder of his physical examination was unremarkable.
From the Department of Medicine, Medical College of Pennsylvania, VA Medical Center, and the Department of Medicine, Division of Pulmonary Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Correspondence: Mitchell Margolis, MD, Philadelphia VA Medical Center, Pulmonary Division, Philadelphia, PA 19104. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
MITCHELL L. MARGOLIS, MD
Laboratory data included a room air blood gas with a pH of 7.42, pC0 2 32 mm Hg, and p02 99 mm Hg. White blood cell count was 4100/mm 3 with 60% neutrophils, 8% bands, 16% lymphocytes, 8% monocytes, and 8% eosinophils. Liver function tests were notable for an SGOT of80 U/L (normal 5-40) and a gamma glutamyltransferase of 159 U/L (normal 10-75). The hematocrit was 36%. Elec· trolytes and coagulation studies were normal. Routine blood cultures were negative. A chest radiograph revealed a small right pleural effusion (Figure 1) which layered out on a right lateral decubitus film. No parenchymal pulmonary disease was noted. Thoracentesis revealed straw-colored fluid with a white blood count of 222/mm 3 (95% neutrophils and 5% lymphocytes). The pleural/serum protein ratio was 0.76 and the pleural fluid LDH was 220 units/liter. A gram stain of the fluid showed rare mononuclear cells and no organisms. Acidfast and fungal smears were negative. A repeat chest radiograph five days later showed considerable diminution in the size of the right pleural effusion. Closed pleural biopsy was deemed hazardous in view of the small amount of residual fluid. The patient's fevers and night sweats resolved and he was discharged. Eight days later, the patient returned to the emergency room complaining of a severe frontal headache, fever, and generalized fatigue. He denied any pulmonary symptoms. Physical examination was remarkable for a temperature of 40.3 0 C, mild mental obtundation, nuchal rigidity, and clear lung fields. A chest radiograph demonstrated that the right pleural effusion had completely resolved. Again, no parenchymal infiltrates were noted. Lumbar puncture revealed that the CSF white blood cell count was 2/mm 3 (both lymphocytes), red blood cell count 40/mm 3 , protein 46 mg/dl, and glucose 57 mg/dl. The India ink stain was positive and CSF cryptococcal antigen was present at a titer of 1:256. Concomitant serum cryptococcal antigen was present at a titer of 1:128. Culture ofthe CSF grew Cryptococcus neoformans three days later. The next day the pleural fluid culture from the original admission also grew Cryptococcus neoformans. Intravenous amphotericin was begun and the patient gradually improved with complete resolution of meningeal signs. There was no recurrence of the pleural effusion.
Discussion
An isolated pleural effusion is an unusual clinical problem in an HIV -positive individual and our patient initially presented a difficult diagnostic dilemma. The three most common opportunistic pulmonary infections in acquired immune deficiency syndrome (AIDS), Pneumocystis carin ii, cytomegalovirus (CMV), and Mycobacterium avium-intracellulare (MAl), are only rarely associated with significant pleural fluid formation. When an effusion does evolve, there is usually evidence of associated pulmonary parenchymal or disseminated disease. 2- 6 Kaposi's sarcoma and various lymphoreticular neoplasms may also cause pleural effusion in patients with AIDS. However, there is almost
329
Cryptococcal Pleural Effusion
not reveal a similar case. Although a small antecedent effusion does not appear to be a sensitive marker for cryptococcal meningitis, its appearance in an HIVpositive patient, especially in the absence of an obvious alternative etiology, should prompt consideration of cryptococcal disease in the differential diagnosis. In our case, the specific etiology of the pleural effusion was not established until the pleural fluid culture turned positive 18 days after the thoracentesis. This was actually four days after the patient presented with meningitis. This delay is not unusual for Cryptococcus neoformans, which may require up to six weeks for growth if the inoculum is small. l1 In retrospect, had the pleural fluid been sent for cryptococcal antigen determination, an earlier diagnosis might have been established, since it has been suggested that pleural cryptococcal antigen determination may be of value in cryptococcosis when cultures of pleural fluid are negative.s We recommend that HIV-positive patients with unexplained pleural effusions have pleural fluid and serum cryptococcal antigen determinations. These may permit early institution of treatment prior to the development of a positive pleural fluid culture or clinical meningitis. Based on our experience and one similar report, 5 we suggest that when a small undiagnosed pleural effusion is noted in an HIV -positive patient, cryptococcal disease be considered, particularly when there is no evidence of other illnesses that might account for pleural fluid formation, such as disseminated Kaposi's sarcoma, lymphoma, TB, MAl, or CMV infection. Figure 1. Posterior-anterior chest radiograph reveals blunting of the right costophrenic angle.
always evidence of skin or lymphatic dissemination by the time a pleural effusion is seen. 2 Bacterial pneumonias, drug reactions, tuberculosis, pulmonary emboli, and many other agents may also cause pleural effusions in patients with AIDS, but there was no clinical evidence to support any of these in our patient. Pleural effusion is also an unusual manifestation of cryptococcal infection,5,7,s and when it does occur, it is almost always accompanied by pulmonary parenchymal disease, usually in the form of infiltrates or nodules. 5,7,s A subpleural nodule is often found immediately subjacent to the effusion, suggesting that the pathogenesis of such an effusion involves direct spread from the subpleural focus. 9 While it is known that pulmonary cryptococcosis may precede meningitis by two to 20 weeks,lO the pleural-meningeal sequence noted in our patient appears to be quite unusual. Indeed, our retrospective review of 16 cases of AIDS-related cryptococcal meningitis seen at the Hospital of the University of Pennsylvania, Graduate Hospital, and the Philadelphia VA Medical Center between 1982 and 1989 did
330
References 1. Wasser L, Talavera W: Pulmonary cryptococcosis in AIDS. Chest 92:692-695, 1987. 2. Davis SD, Henschke CI, Chamides BK, Westcott JL: Intrathoracic Kaposi's sarcoma in AIDS patients: Radiographic-pathologic correlation. Radiology 163:495-450, 1987. 3. Marinelli DL, Albelda SM, Williams TM, Kern JA, Iozzo RV, Miller WT: Nontuberculous mycobacterial infection in AIDS: Clinical, pathologic, and radiographic features. Radiology 160: 77-82, 1986. 4. Suster B, Akerman M, Orenstein M, Wax MR: Pulmonary manifestations of AIDS: Review of 106 episodes. Radiology 161:8793,1986. 5. Newman TG, Soni A, Acaron S, Huang CT: Pleural cryptococcosis in the acquired immune deficiency syndrome. Chest 91: 459-461, 1987. 6. Jacobson MA, Mills J: Cytomegalovirus Infection. Clin Chest Med 9:443-448,1988. 7. Epstein R, Cole R, Hunt KK: Pleural effusion secondary to pulmonary cryptococcosis. Chest 61:296-298, 1972. 8. Young EJ, Hirsh DD, Fainstein V, Williams TW: Pleural effusions due to cryptococcus neoformans: A review of the literature and report of two cases with cryptococcal antigen determinations. Am Rev Resp Dis 121:743-747, 1980. 9. Salyer WR, Salyer DC: Pleural involvement in cryptococcosis. Chest 66:139-140, 1974. 10. Kerkering TM, Duma RJ, Shadomy S: The evolution of pulmonary cryptococcosis. Ann Intern Med 94:611-616,1981. 11. Davis CE: Cryptococcus, in Braude AI, Davis CE, FiererJ (eds.): Infectious Diseases and Medical Microbiology, Second Edition Philadelphia, WB Saunders, 1986, pp 564-571.
May 1991 Volume 301 Number 5
RICHARD SCHWAB, MD,
ABSTRACT: The authors report a case in which a small cryptococcal pleural effusion preceded the development of severe cryptococcal meningitis in an HIV -positive patient. The appearance of an isolated transient pleural effusion is a very unusual presentation for AIDS-related complications. The authors suggest that cryptococcal infection be considered in this setting. KEY INDEXING TERMS: Acquired Immune Deficiency Syndrome; Cryptococcus; Pleural Effusion; Meningitis. [Am J Med Sci 1991; 301(5): 329-330.]
C
ryptococcus neoformans is an important fungal pathogen causing serious infections in patients with AIDS.l The most frequent clinical manifestation of this infection is meningitis, which is typically quite refractory to treatment and often fatal. 1 Theoretically, earlier diagnosis of cryptococcal meningitis might improve therapeutic outcome. A clinical sign that could be detected prior to the development of fulminant meningitis would, therefore, be helpful. The following case suggests that a small antecedent pleural effusion may occasionally provide such a clue. Case Report A 35·year-old black man, known to be HIV -positive since 1984, presented to the Philadelphia VA Medical Center with fever and a 10 pound weight loss over a period of one month. He denied cough, sputum production, hemoptysis, pleuritic chest pain, shortness of breath, or headache. Social history was significant for intravenous use of heroin for 20 years with admitted sharing of needles. He denied homosexual behavior. There was no prior history of opportunistic infection. On presentation, he had a rectal temperature of 38.4 0 C, blood pressure of 90/60 mm Hg, respiratory rate of 24/minute, and a pulse of 96/minute. Lung examination revealed decreased breath sounds at the right base with dullness to percussion. The remainder of his physical examination was unremarkable.
From the Department of Medicine, Medical College of Pennsylvania, VA Medical Center, and the Department of Medicine, Division of Pulmonary Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Correspondence: Mitchell Margolis, MD, Philadelphia VA Medical Center, Pulmonary Division, Philadelphia, PA 19104. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
MITCHELL L. MARGOLIS, MD
Laboratory data included a room air blood gas with a pH of 7.42, pC0 2 32 mm Hg, and p02 99 mm Hg. White blood cell count was 4100/mm 3 with 60% neutrophils, 8% bands, 16% lymphocytes, 8% monocytes, and 8% eosinophils. Liver function tests were notable for an SGOT of80 U/L (normal 5-40) and a gamma glutamyltransferase of 159 U/L (normal 10-75). The hematocrit was 36%. Elec· trolytes and coagulation studies were normal. Routine blood cultures were negative. A chest radiograph revealed a small right pleural effusion (Figure 1) which layered out on a right lateral decubitus film. No parenchymal pulmonary disease was noted. Thoracentesis revealed straw-colored fluid with a white blood count of 222/mm 3 (95% neutrophils and 5% lymphocytes). The pleural/serum protein ratio was 0.76 and the pleural fluid LDH was 220 units/liter. A gram stain of the fluid showed rare mononuclear cells and no organisms. Acidfast and fungal smears were negative. A repeat chest radiograph five days later showed considerable diminution in the size of the right pleural effusion. Closed pleural biopsy was deemed hazardous in view of the small amount of residual fluid. The patient's fevers and night sweats resolved and he was discharged. Eight days later, the patient returned to the emergency room complaining of a severe frontal headache, fever, and generalized fatigue. He denied any pulmonary symptoms. Physical examination was remarkable for a temperature of 40.3 0 C, mild mental obtundation, nuchal rigidity, and clear lung fields. A chest radiograph demonstrated that the right pleural effusion had completely resolved. Again, no parenchymal infiltrates were noted. Lumbar puncture revealed that the CSF white blood cell count was 2/mm 3 (both lymphocytes), red blood cell count 40/mm 3 , protein 46 mg/dl, and glucose 57 mg/dl. The India ink stain was positive and CSF cryptococcal antigen was present at a titer of 1:256. Concomitant serum cryptococcal antigen was present at a titer of 1:128. Culture ofthe CSF grew Cryptococcus neoformans three days later. The next day the pleural fluid culture from the original admission also grew Cryptococcus neoformans. Intravenous amphotericin was begun and the patient gradually improved with complete resolution of meningeal signs. There was no recurrence of the pleural effusion.
Discussion
An isolated pleural effusion is an unusual clinical problem in an HIV -positive individual and our patient initially presented a difficult diagnostic dilemma. The three most common opportunistic pulmonary infections in acquired immune deficiency syndrome (AIDS), Pneumocystis carin ii, cytomegalovirus (CMV), and Mycobacterium avium-intracellulare (MAl), are only rarely associated with significant pleural fluid formation. When an effusion does evolve, there is usually evidence of associated pulmonary parenchymal or disseminated disease. 2- 6 Kaposi's sarcoma and various lymphoreticular neoplasms may also cause pleural effusion in patients with AIDS. However, there is almost
329
Cryptococcal Pleural Effusion
not reveal a similar case. Although a small antecedent effusion does not appear to be a sensitive marker for cryptococcal meningitis, its appearance in an HIVpositive patient, especially in the absence of an obvious alternative etiology, should prompt consideration of cryptococcal disease in the differential diagnosis. In our case, the specific etiology of the pleural effusion was not established until the pleural fluid culture turned positive 18 days after the thoracentesis. This was actually four days after the patient presented with meningitis. This delay is not unusual for Cryptococcus neoformans, which may require up to six weeks for growth if the inoculum is small. l1 In retrospect, had the pleural fluid been sent for cryptococcal antigen determination, an earlier diagnosis might have been established, since it has been suggested that pleural cryptococcal antigen determination may be of value in cryptococcosis when cultures of pleural fluid are negative.s We recommend that HIV-positive patients with unexplained pleural effusions have pleural fluid and serum cryptococcal antigen determinations. These may permit early institution of treatment prior to the development of a positive pleural fluid culture or clinical meningitis. Based on our experience and one similar report, 5 we suggest that when a small undiagnosed pleural effusion is noted in an HIV -positive patient, cryptococcal disease be considered, particularly when there is no evidence of other illnesses that might account for pleural fluid formation, such as disseminated Kaposi's sarcoma, lymphoma, TB, MAl, or CMV infection. Figure 1. Posterior-anterior chest radiograph reveals blunting of the right costophrenic angle.
always evidence of skin or lymphatic dissemination by the time a pleural effusion is seen. 2 Bacterial pneumonias, drug reactions, tuberculosis, pulmonary emboli, and many other agents may also cause pleural effusions in patients with AIDS, but there was no clinical evidence to support any of these in our patient. Pleural effusion is also an unusual manifestation of cryptococcal infection,5,7,s and when it does occur, it is almost always accompanied by pulmonary parenchymal disease, usually in the form of infiltrates or nodules. 5,7,s A subpleural nodule is often found immediately subjacent to the effusion, suggesting that the pathogenesis of such an effusion involves direct spread from the subpleural focus. 9 While it is known that pulmonary cryptococcosis may precede meningitis by two to 20 weeks,lO the pleural-meningeal sequence noted in our patient appears to be quite unusual. Indeed, our retrospective review of 16 cases of AIDS-related cryptococcal meningitis seen at the Hospital of the University of Pennsylvania, Graduate Hospital, and the Philadelphia VA Medical Center between 1982 and 1989 did
330
References 1. Wasser L, Talavera W: Pulmonary cryptococcosis in AIDS. Chest 92:692-695, 1987. 2. Davis SD, Henschke CI, Chamides BK, Westcott JL: Intrathoracic Kaposi's sarcoma in AIDS patients: Radiographic-pathologic correlation. Radiology 163:495-450, 1987. 3. Marinelli DL, Albelda SM, Williams TM, Kern JA, Iozzo RV, Miller WT: Nontuberculous mycobacterial infection in AIDS: Clinical, pathologic, and radiographic features. Radiology 160: 77-82, 1986. 4. Suster B, Akerman M, Orenstein M, Wax MR: Pulmonary manifestations of AIDS: Review of 106 episodes. Radiology 161:8793,1986. 5. Newman TG, Soni A, Acaron S, Huang CT: Pleural cryptococcosis in the acquired immune deficiency syndrome. Chest 91: 459-461, 1987. 6. Jacobson MA, Mills J: Cytomegalovirus Infection. Clin Chest Med 9:443-448,1988. 7. Epstein R, Cole R, Hunt KK: Pleural effusion secondary to pulmonary cryptococcosis. Chest 61:296-298, 1972. 8. Young EJ, Hirsh DD, Fainstein V, Williams TW: Pleural effusions due to cryptococcus neoformans: A review of the literature and report of two cases with cryptococcal antigen determinations. Am Rev Resp Dis 121:743-747, 1980. 9. Salyer WR, Salyer DC: Pleural involvement in cryptococcosis. Chest 66:139-140, 1974. 10. Kerkering TM, Duma RJ, Shadomy S: The evolution of pulmonary cryptococcosis. Ann Intern Med 94:611-616,1981. 11. Davis CE: Cryptococcus, in Braude AI, Davis CE, FiererJ (eds.): Infectious Diseases and Medical Microbiology, Second Edition Philadelphia, WB Saunders, 1986, pp 564-571.
May 1991 Volume 301 Number 5
![[Cryptococcal meningitis in patients with diabetes and AIDS].](/assets/img/hold.png)
