A Multicenter Study of Pneumocystis Choroidopathy Michel J. Shami, M.D., William Freeman, M.D., Dorothy Friedberg, M.D., Elizabeth Siderides, M.D., Allen Listhaus, M.D., and Everett Ai, M.D.
We studied 21 patients with the acquired immunodeficiency syndrome and presumed Pneumocystis carinii choroidopathy. The lesions were characteristically yellow to pale yellow in color, appeared at the level of the choroid, and were found in the posterior pole. They varied in size from 300 to 3,000 um, initially increasing in number before treatment and eventually resolving after systemic antimicrobial therapy. Of the 21 patients, 18 (86%) had received inhaled pentamidine as prophylaxis against Pneumocystis pneumonia. Visual acuity and visual field testing showed little evidence of retinal destruction. Survival after the diagnosis of the choroidopathy ranged from two to 36 weeks. Pneumacystis choroidopathy offers an easily accessible due to disseminated Pneumocystis infection. When comparing drugs for Pneumacystis prophylaxis, careful ocular examination can provide one indicator of the relative efficacy of protection against extrapulmonary disease. PNEUMOCYSTIS CARINII pneumonia is the most common opportunistic infection in patients with the acquired immunodeficiency syndrome. Pneumocystis pneumonia affects more than 80% of patients with AIDS and is the initial manifestation of AIDS in more than 60% of patients.P This condition is caused by the opportunistic protozoan P. carinii, which is a
Accepted for publication April 23, 1991. From the Departments of Ophthalmology, Pacific Presbyterian Medical Center, San Francisco, California (Drs. Shami and Ai), University of California at San Diego, School of Medicine, La Jolla, California (Drs. Freeman and Listhaus), and New York University Medical Center, New York, New York (Drs. Friedberg and Siderides). This study was supported in part by National Institutes of Health grant EY07366 and the University of California AIDS Task Force (Dr. Freeman). Reprint requests to Michel J. Shami, M.D., Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430.
unicellular parasite. The organism exists exclusively in the extracellular space, and clinical infection is usually limited to the lungs." The diagnosis is usually made by demonstrating the organism in pulmonary specimens. Extrapulmonary Pneumocystis infection has been reported in cases of immunodeficiency, including AIDS.4.21 The extrapulmonary sites of involvement include the lymph nodes, spleen, liver, bone marrow, small intestine, pericardium, myocardium, hard palate, periureteral soft tissues, and the choroid. The choroidal infection was first reported histopathologically in an autopsy series by Rao and associatesf in three patients with AIDS who clinically demonstrated characteristic yellow choroidal infiltrates. This report was followed by the demonstration by Freeman and associates" of P. carinii organisms in a choroidal biopsy specimen from a patient with AIDS who had clinically similar choroidal lesions. Macher and associates" had previously described a patient with AIDS and disseminated Pneumocystis infection in whom organisms were found in the choroid at autopsy, but there was no clinical correlation. The treatment of Pneumocystis pneumonia in patients with AIDS with trimethoprim-sulfamethoxazole or intravenous pentamidine is initially effective in most patients; however, more than 60% of patients have a recurrence within 18 months unless prophylactic treatment is Instituted." Inhaled pentamidine is widely used as prophylaxis and appears to be effective in preventing recurrent Pneumocystis pneumonia in patients with AIDS.26,27 Aerosolized pentamidine may modify the pulmonary infection; however, it does not eliminate the systemic spread of the organism." Recognition of choroidal infiltration by P. carinii is an important and accessible indication of systemic dissemination of the parasite. We reviewed a large series of patients with Pneumocystis choroidopathy to determine the demographic and clinical characteristics of the disease. We evaluated the effect of the lesions
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on visual acuity, their rate of growth and response to therapy, and their fluorescein anglographic characteristics.
Patients and Methods We studied the medical and ophthalmologic records of 21 patients with P. carinii choroidopathy diagnosed at three different medical centers. The dates of AIDS diagnosis and of first Pneumocystis pneumonia episode, medications used as prophylaxis against the pneumonia, associated systemic and ocular infections, and the dates of death were all gathered by chart review. All patients were followed up clinically by indirect ophthalmoscopy and fundus photography. Fluorescein angiography was performed in seven patients when the choroidopathy was initially diagnosed. Visual field studies were performed in four patients. Visual fields were studied in conjunction with color fundus photography. The size of each lesion and its location were determined from fundus photography and converted to degrees using the optic nerve head for measurements (vertical axis 7 degrees and horizontal axis 5 degrees; equivalent to 1.5 x 1.0 mm). Automated perimetry was performed in four patients by using the Humphrey 24-2 program (Allergan Humphrey Inc., San Leandro, California) in one patient (6-degree resolution) and by superimposing the 30-1 and 30-2 programs in three patients (3-degree resolution). Histopathologic confirmation of Pneumocystis choroidopathy was obtained in two patients, one of whom was described previously. 22
Results Of the 21 patients, there were 20 men and one woman, ranging in age from 27 to 47 years. Eight patients were treated with systemic trimethoprim-sulfamethoxazole for their initial Pneumocystis pneumonia; three patients received intravenous pentamidine; one patient was treated with trimethoprim-sulfamethoxazole and then intravenous pentamidine; and one patient received dapsone and pyrimethamine as the initial treatment. One patient never had Pneumocystis pneumonia but re-
July, 1991
ceived inhaled pentamidine for ten months before the diagnosis of the choroidopathy. In seven patients, the regimen used to treat the initial episode of Pneumocystis pneumonia was not known. Of the 21 patients with Pneumocystis choroidopathy, 18 were receiving inhalational pentamidine prophylaxis at the time of diagnosis of ocular involvement. Two patients with choroidal Pneumocystis had not received inhaled pentamidine. In one patient, it was not possible to determine whether inhalational pentamidine had been received (Table). The average length of time between the diagnosis of Pneumocystis choroidopathy and death was four months (range, 0.5 to nine months). Two patients were alive at nine months and five months after the diagnosis of the choroidopathy. The average length of time between the initial Pneumocystis pneumonia episode and the choroidopathy was 15.6 months. In two patients, the choroidopathy was diagnosed at the time of Pneumocystis pneumonia. The average length of time between the start of inhaled pentamidine and the diagnosis of the choroidopathy was 12.4 months. The choroidal lesions were characteristically round with irregular borders (Fig. 1). In two patients they appeared confluent. The lesions were bilateral in 16 patients (76%) and unilateral in five (24%). One patient had lesions in one eye but eventually developed bilateral disease. The lesions appeared yellow initially and became pale yellow in appearance while resolving. The size of the lesions varied from 300 to 3,000 J,Lm. The number of lesions varied from two to 50 per eye. In 15 of 37 affected eyes (40.5%), the lesions were within the temporal vascular arcades, within 1 disk diameter of the optic nerve head, or both, but not anterior to the posterior pole. In 20 affected eyes (54%), the lesions were posterior to the equator, including the posterior pole. In two affected eyes (5.5%), the lesions were only present between the posterior pole and the equator. No lesions were seen anterior to the equator. No vitreous reaction was seen except in patients with associated cytomegalovirus retinitis. By using the disk diameter as a reference and assuming it to be 1.5 x 1.0 mm, we compared serial fundus photographs of corresponding retinal fields in six patients. The borders of the untreated lesions appeared to advance in all directions at a rate of 750 J,Lm per month (range, 132 to 1,500 J,Lm per month)(Fig. 2). Five patients demonstrated an increase in the number of lesions during the first month of observation.
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TABLE SUMMARY OF THE DRUG REGIMEN USED FOR TREATMENT OF PNEUMOCYST/S CAR/Nil PNEUMONIA"
PNEUMOCYSTIS PNEUMONIA
NO. OF RECURRENCES
Trlmethoprim-sulfamethoxazole
2
Intravenous pentamidine. trimethoprlmsulfamethoxazole
Inhaled pentamidine
Trlmethoprim-sulfamethoxazole then pentamidine NA Trimethoprim-sulfamethoxazole
3
Intravenous pentamidine. dapsone NA
Inhaled pentamidine
5 6 7 8 9 10 11t 12 13 14t
NA Trlmethoprim-sulfamethoxazole
1 1 1 3 0 2 0 0 3 NA
15 16
NA
TREATMENT FOR FIRST CASENO.
2 3 4
17 18 19
20 21
1 2
NA Trlmethoprim-sulfamethoxazole Intravenous pentamidine NA Intravenous pentamidine Intravenous pentamidine NA Dapsone. pyrimethamine
Trimethoprlm-sulfamethoxazole
Dapsone. trimethoprimsulfamethoxazole NA NA NA
PROPHYLAXIS
NA Inhaled pentamidine inhaled pentamidine Inhaled pentamidine
Dapsone
Inhaled pentamidine Inhaled pentamidine Inhaled pentamidine
Intravenous pentamidine
Inhaled pentamidine
Intravenous pentamidine
Inhaled pentamidine Inhaled pentamidine
NA Dapsone. trlmethoprimsulfamethoxazole. intravenous pentamidine NA Intravenous pentamidine
5 3 0 0 0
NA Trimethoprlm-sulfamethoxazole Trimethoprim-sulfamethoxazole Never had Pneumocystis pneumonia Trimethoprim-sulfamethoxazole
TREATMENT OF RECURRENCES
Inhaled pentamidine Inhaled pentamidine
Inhaled pentamidine Inhaled pentamidine None Inhaled pentamidine Inhaled pentamidine
o until after Pneumocystis
choroidopathy diagnosis 1
None
None
Trimethoprlm-sulfamethoxazole
Inhaled pentamidine
"NA indicates not available. tprevlously reported by Freldberg and associates.33
In five patients, the lesions disappeared during a period of four months. One of these patients was given intravenous pentamidine one month before the diagnosis of the choroidopathy to treat systemic dissemination of P. carinii. The other three patients were treated with intravenous pentamidine after the diagnosis of the choroidopathy with resolution of the lesions during a period of six weeks to four months (Fig. 3). In one patient, we observed resolution of the lesions, but precise information about intravenous pentamidine treatment could not be obtained. fluorescein angiograms in seven patients disclosed early hypofluorescence corresponding to the lesions with late staining of the lesions, which appeared deep to the retinal circulation (Fig. 4). Four patients were tested with automated perimetry, with attention directed to the
Fig. 1 (Shami and associates). Choroidal infiltrates secondary to P. carinii in a 41-year-old man. The lesions are round with irregular borders.
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Fig. 2 (Shami and associates). Top left, Jan. 23, 1989. Choroidal Pneumocystis lesion superonasal to optic nerve head in left eye. A resolving cotton-wool spot with small intraretinal hemorrhages is seen 1,000 ....m from the optic nerve head superotemporally. Top right, March 8, 1989. Six weeks later, the Pneumocystis lesion has increased in size and the lesion has become denser in appearance. A new lesion has appeared superior to the large lesion. Lower left, April 20, 1989. A total of 12 weeks after the initial photograph, the largest Pneumocystis lesion has increased in size and three new satellite lesions are seen, one at the inferotemporal edge of the largest lesion and two superonasal to it. Lower right, A digital, size- and orientation-corrected montage of these three photographs. The black circles represent the borders of the main Pneumocystis lesion at six-week intervals. The area of the lesion has more than doubled in 12 weeks with the borders advancing at a rate between 200 and 1,000 ....m in each six-week interval (33 to 167 ....m per week).
areas of choroidal involvement. In one patient a depression of 8 to 11 dB over the lesions was found with good reliability indices (Fig. 5). A second patient demonstrated a depression of 6 to 8 dB over some but not alI lesions in both eyes. Automated perimetry in the other two patients did not show any defect over the lesions.
Discussion
The recent recognition of Pneumocystis choroidopathy is important in the treatment of immunosuppressed patients. We studied a large number of patients with Pneumocystis choroidopathy to understand the clinical characteris-
Vol. 112, No. 1
Pneumocystis Choroidopathy
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Fig. 3 (Shami and associates). Left, July 27, 1989. Choroidal Pneumocystis lesion temporal to the macula. Right, Nov. 10, 1989. The lesion has almost completely resolved after intravenous pentamidine treatment.
tics of the disease, the response of the lesions to treatment, and the visual consequences of the infection. Our study shows that Pneumocystis lesions are typically yellow in color and are usually round with irregular borders. In some cases, the lesions progressed and became confluent. The choroidal infiltrates were not associated with any vitreous inflammation unless other infectious retinitis was present. All lesions were located posterior to the equator. In four patients, we observed resolution dur-
ing a period of six weeks to four months after intravenous pentamidine treatment. One of those patients was treated with intravenous pentamidine for systemic pneumocystosis before the diagnosis of the choroidopathy. In this patient, the resolution of the lesions appeared to result from this treatment; the infiltrates were probably present before the date the patient was referred to us. The other three patients were treated with intravenous pentamidine after the diagnosis of the choroidopathy. Extrapulmonary Pneumocystis infection is in-
Fig. 4 (Shami and associates). Left, Early-phase transit of the right eye of a patient with subfoveal Pneumocystis choroidal infiltrates shows hypofluorescence corresponding to the lesion. Right, Late phase of the study shows staining of the choroidal lesions.
20
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t4 5 11 7 10 •
'.
12
•7
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0
11.
171 to
o! 8 0
0
12
0
16 6 14
j. . II -5
t
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10 5 • -II • -8 -7 • 5 5 7 -S • • • 3O'IA • 10
17
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Fig. 5 (Shami and associates). Left, Pneumocystis choroidal infiltrate inferotemporal to the fovea. Right, Automated perimetry superimposing the 30-1 and 30-2 programs shows a depression of 8 to 11 dB corresponding to the choroidal infiltrate shown on the fundus photograph.
creasingly recognized in patients with AIDS receiving inhaled pentamidine prophylaxis, since after aerosolized administration the drug is recovered exclusively from the lungs with little extrapulmonary distribution." Furthermore, aerosol pentamidine does not always distribute equally throughout the lungs, and upper lobe Pneumocystis pneumonia is becoming an increasingly common event." This may allow the extrapulmonary spread of the organism to distant organs, including the choroid.
One of our patients never had Pneumocystis pneumonia but was taking aerosol pentamidine prophylaxis. This suggests that the aerosol pentamidine might have been an effective prophylaxis against the pneumonia, but it allowed extrapulmonary spread of the protozoan as implicated by the choroidopathy. Two of our patients who gave a history of Pneumocystis pneumonia, but who had received no inhaled pentamidine prophylaxis, demonstrated the presence of choroidal infection, which suggest-
Fig. 6 (Shami and associates). Subfoveal choroidal infiltrate secondary to Pneumocystis carinii in a patient who maintained visual acuity of 20/20 in both eyes.
Pneumocystis Choroidopathy
Vol. 112, No. 1
ed that extrapulmonary spread might have occurred at the time of the initial infection despite treatment with trimethoprim-sulfamethoxazole. The recognition of Pneumocystis choroidopathy as a sign of systemic dissemination of the protozoan makes ocular examination imperative before assuming the infection to be confined to the lungs and possibly amenable to treatment with inhaled pentamidine alone." Dugel and associates" reported the resolution of the choroidal lesions during three weeks in two patients, one treated with intravenous trimethoprim-sulfamethoxazole and the other with intravenous pentamidine. Koser, [ampol, and Maclronnell" observed a much slower regression of the lesions in their patients treated with systemic anti-Pneumocystis therapy. Although systemic treatment can be considered when the diagnosis of choroidopathy is made, it is not yet clear whether the resolution of the lesions could be used as an indicator of eradication of all sites of extrapulmonary infection. The true incidence of Pneumocystis choroidopathy cannot be determined from our study, because the infection appears to be asymptomatic and the lesions were incidentally detected in patients who were referred for examination. Angiographically, the lesions demonstrated hypofluorescence at the level of the choroid in the early phases and stained late. This is compatible with the foamy eosinophilic space occupying lesions seen histopathologically. In our series, the choroidal infiltrates were not associated with decrease in visual acuity despite the presence of a subfoveal lesion in one patient who maintained visual acuity of 20/20 (Fig. 6). The visual fields, however, demonstrated a depression over areas corresponding to the choroidal infiltrates in two patients. The depressions appear to be of a mild degree, a finding compatible with the histopathologic changes, which demonstrate infiltration of the choroid and the choriocapillaris with no destruction of the overlying neurosensory retina." References 1. Suffredini, A. F., and Masur, H.: Pneumocystis carinii infection in AIDS. In Wormser, G. P., Stahl, R. E., and Bottone, E. J. (eds.): AIDS, Acquired Immune Deficiency Syndrome, and Other Manifestations of HIV Infection. Park Ridge, NJ, Noyes Publications, 1987, pp. 445-477.
21
2. Glatt, A. E., Chirgwin, K.: Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Arch. Intern. Med. 150:271, 1990. 3. Hughes, W. T.: Pneumocystis carinii pneumonia. N. Engl. J. Med. 297:1381, 1977. 4. Unger, P. D., Rosenblum, M., and Krown, S. E.: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum. Pathol. 19:113, 1988. 5. Awen, C. F., and Baltzan, M. A.: Systemic dissemination of Pneumocystis carinii pneumonia. Can. Med. Assoc. J. 104:809, 1971. 6. Anderson, C. D., and Barrie, H. J.: Fatal Pneumocystis pneumonia in an adult. Report of a case. Am. J. Clin. Pathol. 34:365, 1960. 7. [arnum, S., Rasmussen, E. F., Ohlsen, A. S., and Sorensen, A. W. S.: Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann. Intern. Med. 68:138, 1968. 8. Barnett, R. N., Hull, J. G., Vortel, V., and Schwarz, J.: Pneumocystis carinii in lymph nodes and spleen. Arch. Pathol. 88: 175, 1969. 9. Burke, B. A., and Good, R. A.: Pneumocystis carinii infection. Medicine 52:23, 1973. 10. LeGolvan, D. P., and Heidelberger, K. P.: Disseminated, granulomatous Pneumocystis carinii pneumonia. Arch. Pathol. 95:344, 1973. 11. Rahimi, S. A.: Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch. Pathol. 97:162,1974. 12. Coulman, C. U., Greene, I., and Archibald, R. W.: Cutaneous pneumocystosis. Ann. Intern. Med. 106:396, 1987. 13. Gallant, J. E., Enriquez, R. E., Cohen, K. L., and Hammers, L. W.: Pneumocystis carinii thyroiditis. Am. J. Med. 84:303, 1988. 14. Schinella, R. A., Breda, S. D., and Hammerschlag, P. E.: Otic infection due to Pneumocystis carinii in an apparently healthy man with antibody to the human immunodeficiency virus. Ann. Intern. Med. 106:399,1987. 15. Gherman, C. R., Ward, R. R., and Bassis, M. L.: Pneumocystis carinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiency syndrome. Am. J. Med. 85:250, 1988. 16. Carter, T. R., Cooper, P. H., Petri, W. A., Ir., Kim, C. K., Walzer, P. D., and Guerrant, R. L.: Pneumocystis carinii infection of the small intestine in a patient with acquired immunodeficiency syndrome. Am. J. Clin. Pathol. 89:679, 1988. 17. Grimes, M. M., LaPook, J. D., Bar, M. H., Wasserman, H. S., and Dwork, A.: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum. Pathol. 18:307,1987. 18. Poblete, R. B., Rodriguez, K., Foust, R. T., Reddy, K. R., and Saldana, M. J.: Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome (AIDS). Ann. Intern. Med. 110:737, 1989. 19. Pilon, V. A., Echols, R. M., Celo, J. S., and
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Elmendorf, S. L.: Disseminated Pneumocystis carinii infection in AIDS. N. Eng!. J. Med. 316:1410, 1987. 20. Raviglione, M. c., Garner, G. R., and Mullen, M. P.: Pneumocystis carinii in bone marrow. Ann. Intern. Med. 109:253, 1988. 21. Armstrong, D., and Bernard, E.: Aerosol pentamidine. Ann. Intern. Med. 109:852, 1988. 22. Rao, N. A., Zimmerman, P. L., Boyer, D., Biswas, J., Causey, D., Beniz, J., and Nichols, P. W.: A clinical, histopathologic, and electron microscopic study of Pneumocystis carinii choroiditis. Am.]. Ophthalmo!. 107:218, 1989. 23. Freeman, W. R., Gross, J. G., Labelle, ]., Oteken, K., Katz, B., and Wiley, C. A.: Pneumocystis carinii choroidopathy. A new clinical entity. Arch. Ophthalmo!. 107:863, 1989. 24. Macher, A. M., Bardenstein, D. S., Zimmerman, L. E., Steigman, C. K., Pastore, L., Peretz, D. M., and Eron, L. J.: Pneumocystis carinii choroiditis in a male homosexual with AIDS and disseminated pulmonary and extrapulmonary P. carinii infection. N. Eng!. J, Med. 316:1092,1987. 25. Glatt, A. E., Chingwin, K., and Landesman, S. H.: Treatment of infections associated with human immunodeficiency virus. N. Eng!. J. Med. 318:1439, 1988. 26. Bernard, E. M., Pagel, L., Schmitt, H. J., Donnelly, H., and Armstrong, D.: Clinical trials with aerosol pentamidine for prevention of Pneumocystis carinii pneumonia. Clin. Res. 35:468A, 1987.
July, 1991
27. Salamone, F. R., and Cunha, B. A.: Update on pentamidine for the treatment of Pneumocystis carinii pneumonia. Clin. Pharm. 7:501, 1988. 28. Center for Disease Control Update: Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 38:1,1989. 29. Abd, A. G., Nierman, D. M., Ilowite, ]. S., Pierson, R. N., Jr., and Bell, A. L., Jr.: Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis. Chest 94:329,1988. 30. Montgomery, A. B., Debs, R. J., Luce, ]. M., Corkery, K. J., Turner, J., Brunette, E. N., Lin, E. T., and Hopewell, P. c.: Aerosolised pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet 2:480, 1987. 31. Dugel, P. U., Rao, N. A., Forster, D. J., Chong, L. P., Frangieh, G. T., and Sattler, F.: Pneumocystis carinii choroiditis after long-term aerosolized pentamidine therapy. Am. J. Ophthalmo!. 110:113, 1990. 32. Koser, M. W., ]ampol, L. M., and MacDonell, K.: Treatment of Pneumocystis carinii choroidopathy. Arch. Ophthalmo!. 108:1214, 1990. 33. Friedberg, D. N., Greene, J. B., and Brook, D. L.: Asymptomatic disseminated Pneumocystis carinii infection detected by ophthalmoscopy. Lancet 336, 1256, 1990.
We studied 21 patients with the acquired immunodeficiency syndrome and presumed Pneumocystis carinii choroidopathy. The lesions were characteristically yellow to pale yellow in color, appeared at the level of the choroid, and were found in the posterior pole. They varied in size from 300 to 3,000 um, initially increasing in number before treatment and eventually resolving after systemic antimicrobial therapy. Of the 21 patients, 18 (86%) had received inhaled pentamidine as prophylaxis against Pneumocystis pneumonia. Visual acuity and visual field testing showed little evidence of retinal destruction. Survival after the diagnosis of the choroidopathy ranged from two to 36 weeks. Pneumacystis choroidopathy offers an easily accessible due to disseminated Pneumocystis infection. When comparing drugs for Pneumacystis prophylaxis, careful ocular examination can provide one indicator of the relative efficacy of protection against extrapulmonary disease. PNEUMOCYSTIS CARINII pneumonia is the most common opportunistic infection in patients with the acquired immunodeficiency syndrome. Pneumocystis pneumonia affects more than 80% of patients with AIDS and is the initial manifestation of AIDS in more than 60% of patients.P This condition is caused by the opportunistic protozoan P. carinii, which is a
Accepted for publication April 23, 1991. From the Departments of Ophthalmology, Pacific Presbyterian Medical Center, San Francisco, California (Drs. Shami and Ai), University of California at San Diego, School of Medicine, La Jolla, California (Drs. Freeman and Listhaus), and New York University Medical Center, New York, New York (Drs. Friedberg and Siderides). This study was supported in part by National Institutes of Health grant EY07366 and the University of California AIDS Task Force (Dr. Freeman). Reprint requests to Michel J. Shami, M.D., Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430.
unicellular parasite. The organism exists exclusively in the extracellular space, and clinical infection is usually limited to the lungs." The diagnosis is usually made by demonstrating the organism in pulmonary specimens. Extrapulmonary Pneumocystis infection has been reported in cases of immunodeficiency, including AIDS.4.21 The extrapulmonary sites of involvement include the lymph nodes, spleen, liver, bone marrow, small intestine, pericardium, myocardium, hard palate, periureteral soft tissues, and the choroid. The choroidal infection was first reported histopathologically in an autopsy series by Rao and associatesf in three patients with AIDS who clinically demonstrated characteristic yellow choroidal infiltrates. This report was followed by the demonstration by Freeman and associates" of P. carinii organisms in a choroidal biopsy specimen from a patient with AIDS who had clinically similar choroidal lesions. Macher and associates" had previously described a patient with AIDS and disseminated Pneumocystis infection in whom organisms were found in the choroid at autopsy, but there was no clinical correlation. The treatment of Pneumocystis pneumonia in patients with AIDS with trimethoprim-sulfamethoxazole or intravenous pentamidine is initially effective in most patients; however, more than 60% of patients have a recurrence within 18 months unless prophylactic treatment is Instituted." Inhaled pentamidine is widely used as prophylaxis and appears to be effective in preventing recurrent Pneumocystis pneumonia in patients with AIDS.26,27 Aerosolized pentamidine may modify the pulmonary infection; however, it does not eliminate the systemic spread of the organism." Recognition of choroidal infiltration by P. carinii is an important and accessible indication of systemic dissemination of the parasite. We reviewed a large series of patients with Pneumocystis choroidopathy to determine the demographic and clinical characteristics of the disease. We evaluated the effect of the lesions
©AMmuCAN JOURNAL OF OPHTIiALMOLOGY 112:15-22, JULY, 1991
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on visual acuity, their rate of growth and response to therapy, and their fluorescein anglographic characteristics.
Patients and Methods We studied the medical and ophthalmologic records of 21 patients with P. carinii choroidopathy diagnosed at three different medical centers. The dates of AIDS diagnosis and of first Pneumocystis pneumonia episode, medications used as prophylaxis against the pneumonia, associated systemic and ocular infections, and the dates of death were all gathered by chart review. All patients were followed up clinically by indirect ophthalmoscopy and fundus photography. Fluorescein angiography was performed in seven patients when the choroidopathy was initially diagnosed. Visual field studies were performed in four patients. Visual fields were studied in conjunction with color fundus photography. The size of each lesion and its location were determined from fundus photography and converted to degrees using the optic nerve head for measurements (vertical axis 7 degrees and horizontal axis 5 degrees; equivalent to 1.5 x 1.0 mm). Automated perimetry was performed in four patients by using the Humphrey 24-2 program (Allergan Humphrey Inc., San Leandro, California) in one patient (6-degree resolution) and by superimposing the 30-1 and 30-2 programs in three patients (3-degree resolution). Histopathologic confirmation of Pneumocystis choroidopathy was obtained in two patients, one of whom was described previously. 22
Results Of the 21 patients, there were 20 men and one woman, ranging in age from 27 to 47 years. Eight patients were treated with systemic trimethoprim-sulfamethoxazole for their initial Pneumocystis pneumonia; three patients received intravenous pentamidine; one patient was treated with trimethoprim-sulfamethoxazole and then intravenous pentamidine; and one patient received dapsone and pyrimethamine as the initial treatment. One patient never had Pneumocystis pneumonia but re-
July, 1991
ceived inhaled pentamidine for ten months before the diagnosis of the choroidopathy. In seven patients, the regimen used to treat the initial episode of Pneumocystis pneumonia was not known. Of the 21 patients with Pneumocystis choroidopathy, 18 were receiving inhalational pentamidine prophylaxis at the time of diagnosis of ocular involvement. Two patients with choroidal Pneumocystis had not received inhaled pentamidine. In one patient, it was not possible to determine whether inhalational pentamidine had been received (Table). The average length of time between the diagnosis of Pneumocystis choroidopathy and death was four months (range, 0.5 to nine months). Two patients were alive at nine months and five months after the diagnosis of the choroidopathy. The average length of time between the initial Pneumocystis pneumonia episode and the choroidopathy was 15.6 months. In two patients, the choroidopathy was diagnosed at the time of Pneumocystis pneumonia. The average length of time between the start of inhaled pentamidine and the diagnosis of the choroidopathy was 12.4 months. The choroidal lesions were characteristically round with irregular borders (Fig. 1). In two patients they appeared confluent. The lesions were bilateral in 16 patients (76%) and unilateral in five (24%). One patient had lesions in one eye but eventually developed bilateral disease. The lesions appeared yellow initially and became pale yellow in appearance while resolving. The size of the lesions varied from 300 to 3,000 J,Lm. The number of lesions varied from two to 50 per eye. In 15 of 37 affected eyes (40.5%), the lesions were within the temporal vascular arcades, within 1 disk diameter of the optic nerve head, or both, but not anterior to the posterior pole. In 20 affected eyes (54%), the lesions were posterior to the equator, including the posterior pole. In two affected eyes (5.5%), the lesions were only present between the posterior pole and the equator. No lesions were seen anterior to the equator. No vitreous reaction was seen except in patients with associated cytomegalovirus retinitis. By using the disk diameter as a reference and assuming it to be 1.5 x 1.0 mm, we compared serial fundus photographs of corresponding retinal fields in six patients. The borders of the untreated lesions appeared to advance in all directions at a rate of 750 J,Lm per month (range, 132 to 1,500 J,Lm per month)(Fig. 2). Five patients demonstrated an increase in the number of lesions during the first month of observation.
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TABLE SUMMARY OF THE DRUG REGIMEN USED FOR TREATMENT OF PNEUMOCYST/S CAR/Nil PNEUMONIA"
PNEUMOCYSTIS PNEUMONIA
NO. OF RECURRENCES
Trlmethoprim-sulfamethoxazole
2
Intravenous pentamidine. trimethoprlmsulfamethoxazole
Inhaled pentamidine
Trlmethoprim-sulfamethoxazole then pentamidine NA Trimethoprim-sulfamethoxazole
3
Intravenous pentamidine. dapsone NA
Inhaled pentamidine
5 6 7 8 9 10 11t 12 13 14t
NA Trlmethoprim-sulfamethoxazole
1 1 1 3 0 2 0 0 3 NA
15 16
NA
TREATMENT FOR FIRST CASENO.
2 3 4
17 18 19
20 21
1 2
NA Trlmethoprim-sulfamethoxazole Intravenous pentamidine NA Intravenous pentamidine Intravenous pentamidine NA Dapsone. pyrimethamine
Trimethoprlm-sulfamethoxazole
Dapsone. trimethoprimsulfamethoxazole NA NA NA
PROPHYLAXIS
NA Inhaled pentamidine inhaled pentamidine Inhaled pentamidine
Dapsone
Inhaled pentamidine Inhaled pentamidine Inhaled pentamidine
Intravenous pentamidine
Inhaled pentamidine
Intravenous pentamidine
Inhaled pentamidine Inhaled pentamidine
NA Dapsone. trlmethoprimsulfamethoxazole. intravenous pentamidine NA Intravenous pentamidine
5 3 0 0 0
NA Trimethoprlm-sulfamethoxazole Trimethoprim-sulfamethoxazole Never had Pneumocystis pneumonia Trimethoprim-sulfamethoxazole
TREATMENT OF RECURRENCES
Inhaled pentamidine Inhaled pentamidine
Inhaled pentamidine Inhaled pentamidine None Inhaled pentamidine Inhaled pentamidine
o until after Pneumocystis
choroidopathy diagnosis 1
None
None
Trimethoprlm-sulfamethoxazole
Inhaled pentamidine
"NA indicates not available. tprevlously reported by Freldberg and associates.33
In five patients, the lesions disappeared during a period of four months. One of these patients was given intravenous pentamidine one month before the diagnosis of the choroidopathy to treat systemic dissemination of P. carinii. The other three patients were treated with intravenous pentamidine after the diagnosis of the choroidopathy with resolution of the lesions during a period of six weeks to four months (Fig. 3). In one patient, we observed resolution of the lesions, but precise information about intravenous pentamidine treatment could not be obtained. fluorescein angiograms in seven patients disclosed early hypofluorescence corresponding to the lesions with late staining of the lesions, which appeared deep to the retinal circulation (Fig. 4). Four patients were tested with automated perimetry, with attention directed to the
Fig. 1 (Shami and associates). Choroidal infiltrates secondary to P. carinii in a 41-year-old man. The lesions are round with irregular borders.
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AMERICAN JOURNAL OF OPHTIiALMOLOGY
Fig. 2 (Shami and associates). Top left, Jan. 23, 1989. Choroidal Pneumocystis lesion superonasal to optic nerve head in left eye. A resolving cotton-wool spot with small intraretinal hemorrhages is seen 1,000 ....m from the optic nerve head superotemporally. Top right, March 8, 1989. Six weeks later, the Pneumocystis lesion has increased in size and the lesion has become denser in appearance. A new lesion has appeared superior to the large lesion. Lower left, April 20, 1989. A total of 12 weeks after the initial photograph, the largest Pneumocystis lesion has increased in size and three new satellite lesions are seen, one at the inferotemporal edge of the largest lesion and two superonasal to it. Lower right, A digital, size- and orientation-corrected montage of these three photographs. The black circles represent the borders of the main Pneumocystis lesion at six-week intervals. The area of the lesion has more than doubled in 12 weeks with the borders advancing at a rate between 200 and 1,000 ....m in each six-week interval (33 to 167 ....m per week).
areas of choroidal involvement. In one patient a depression of 8 to 11 dB over the lesions was found with good reliability indices (Fig. 5). A second patient demonstrated a depression of 6 to 8 dB over some but not alI lesions in both eyes. Automated perimetry in the other two patients did not show any defect over the lesions.
Discussion
The recent recognition of Pneumocystis choroidopathy is important in the treatment of immunosuppressed patients. We studied a large number of patients with Pneumocystis choroidopathy to understand the clinical characteris-
Vol. 112, No. 1
Pneumocystis Choroidopathy
19
Fig. 3 (Shami and associates). Left, July 27, 1989. Choroidal Pneumocystis lesion temporal to the macula. Right, Nov. 10, 1989. The lesion has almost completely resolved after intravenous pentamidine treatment.
tics of the disease, the response of the lesions to treatment, and the visual consequences of the infection. Our study shows that Pneumocystis lesions are typically yellow in color and are usually round with irregular borders. In some cases, the lesions progressed and became confluent. The choroidal infiltrates were not associated with any vitreous inflammation unless other infectious retinitis was present. All lesions were located posterior to the equator. In four patients, we observed resolution dur-
ing a period of six weeks to four months after intravenous pentamidine treatment. One of those patients was treated with intravenous pentamidine for systemic pneumocystosis before the diagnosis of the choroidopathy. In this patient, the resolution of the lesions appeared to result from this treatment; the infiltrates were probably present before the date the patient was referred to us. The other three patients were treated with intravenous pentamidine after the diagnosis of the choroidopathy. Extrapulmonary Pneumocystis infection is in-
Fig. 4 (Shami and associates). Left, Early-phase transit of the right eye of a patient with subfoveal Pneumocystis choroidal infiltrates shows hypofluorescence corresponding to the lesion. Right, Late phase of the study shows staining of the choroidal lesions.
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July, 1991
AMERICAN JOURNAL OF OPHTHALMOLOGY
t4 5 11 7 10 •
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12
•7
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0
11.
171 to
o! 8 0
0
12
0
16 6 14
j. . II -5
t
0
10 5 • -II • -8 -7 • 5 5 7 -S • • • 3O'IA • 10
17
15
.'
•
•
0
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~ .--.:...~+.~~~L.!-.3O' Z5~ 9
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8
17
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Fig. 5 (Shami and associates). Left, Pneumocystis choroidal infiltrate inferotemporal to the fovea. Right, Automated perimetry superimposing the 30-1 and 30-2 programs shows a depression of 8 to 11 dB corresponding to the choroidal infiltrate shown on the fundus photograph.
creasingly recognized in patients with AIDS receiving inhaled pentamidine prophylaxis, since after aerosolized administration the drug is recovered exclusively from the lungs with little extrapulmonary distribution." Furthermore, aerosol pentamidine does not always distribute equally throughout the lungs, and upper lobe Pneumocystis pneumonia is becoming an increasingly common event." This may allow the extrapulmonary spread of the organism to distant organs, including the choroid.
One of our patients never had Pneumocystis pneumonia but was taking aerosol pentamidine prophylaxis. This suggests that the aerosol pentamidine might have been an effective prophylaxis against the pneumonia, but it allowed extrapulmonary spread of the protozoan as implicated by the choroidopathy. Two of our patients who gave a history of Pneumocystis pneumonia, but who had received no inhaled pentamidine prophylaxis, demonstrated the presence of choroidal infection, which suggest-
Fig. 6 (Shami and associates). Subfoveal choroidal infiltrate secondary to Pneumocystis carinii in a patient who maintained visual acuity of 20/20 in both eyes.
Pneumocystis Choroidopathy
Vol. 112, No. 1
ed that extrapulmonary spread might have occurred at the time of the initial infection despite treatment with trimethoprim-sulfamethoxazole. The recognition of Pneumocystis choroidopathy as a sign of systemic dissemination of the protozoan makes ocular examination imperative before assuming the infection to be confined to the lungs and possibly amenable to treatment with inhaled pentamidine alone." Dugel and associates" reported the resolution of the choroidal lesions during three weeks in two patients, one treated with intravenous trimethoprim-sulfamethoxazole and the other with intravenous pentamidine. Koser, [ampol, and Maclronnell" observed a much slower regression of the lesions in their patients treated with systemic anti-Pneumocystis therapy. Although systemic treatment can be considered when the diagnosis of choroidopathy is made, it is not yet clear whether the resolution of the lesions could be used as an indicator of eradication of all sites of extrapulmonary infection. The true incidence of Pneumocystis choroidopathy cannot be determined from our study, because the infection appears to be asymptomatic and the lesions were incidentally detected in patients who were referred for examination. Angiographically, the lesions demonstrated hypofluorescence at the level of the choroid in the early phases and stained late. This is compatible with the foamy eosinophilic space occupying lesions seen histopathologically. In our series, the choroidal infiltrates were not associated with decrease in visual acuity despite the presence of a subfoveal lesion in one patient who maintained visual acuity of 20/20 (Fig. 6). The visual fields, however, demonstrated a depression over areas corresponding to the choroidal infiltrates in two patients. The depressions appear to be of a mild degree, a finding compatible with the histopathologic changes, which demonstrate infiltration of the choroid and the choriocapillaris with no destruction of the overlying neurosensory retina." References 1. Suffredini, A. F., and Masur, H.: Pneumocystis carinii infection in AIDS. In Wormser, G. P., Stahl, R. E., and Bottone, E. J. (eds.): AIDS, Acquired Immune Deficiency Syndrome, and Other Manifestations of HIV Infection. Park Ridge, NJ, Noyes Publications, 1987, pp. 445-477.
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2. Glatt, A. E., Chirgwin, K.: Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Arch. Intern. Med. 150:271, 1990. 3. Hughes, W. T.: Pneumocystis carinii pneumonia. N. Engl. J. Med. 297:1381, 1977. 4. Unger, P. D., Rosenblum, M., and Krown, S. E.: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum. Pathol. 19:113, 1988. 5. Awen, C. F., and Baltzan, M. A.: Systemic dissemination of Pneumocystis carinii pneumonia. Can. Med. Assoc. J. 104:809, 1971. 6. Anderson, C. D., and Barrie, H. J.: Fatal Pneumocystis pneumonia in an adult. Report of a case. Am. J. Clin. Pathol. 34:365, 1960. 7. [arnum, S., Rasmussen, E. F., Ohlsen, A. S., and Sorensen, A. W. S.: Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann. Intern. Med. 68:138, 1968. 8. Barnett, R. N., Hull, J. G., Vortel, V., and Schwarz, J.: Pneumocystis carinii in lymph nodes and spleen. Arch. Pathol. 88: 175, 1969. 9. Burke, B. A., and Good, R. A.: Pneumocystis carinii infection. Medicine 52:23, 1973. 10. LeGolvan, D. P., and Heidelberger, K. P.: Disseminated, granulomatous Pneumocystis carinii pneumonia. Arch. Pathol. 95:344, 1973. 11. Rahimi, S. A.: Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch. Pathol. 97:162,1974. 12. Coulman, C. U., Greene, I., and Archibald, R. W.: Cutaneous pneumocystosis. Ann. Intern. Med. 106:396, 1987. 13. Gallant, J. E., Enriquez, R. E., Cohen, K. L., and Hammers, L. W.: Pneumocystis carinii thyroiditis. Am. J. Med. 84:303, 1988. 14. Schinella, R. A., Breda, S. D., and Hammerschlag, P. E.: Otic infection due to Pneumocystis carinii in an apparently healthy man with antibody to the human immunodeficiency virus. Ann. Intern. Med. 106:399,1987. 15. Gherman, C. R., Ward, R. R., and Bassis, M. L.: Pneumocystis carinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiency syndrome. Am. J. Med. 85:250, 1988. 16. Carter, T. R., Cooper, P. H., Petri, W. A., Ir., Kim, C. K., Walzer, P. D., and Guerrant, R. L.: Pneumocystis carinii infection of the small intestine in a patient with acquired immunodeficiency syndrome. Am. J. Clin. Pathol. 89:679, 1988. 17. Grimes, M. M., LaPook, J. D., Bar, M. H., Wasserman, H. S., and Dwork, A.: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum. Pathol. 18:307,1987. 18. Poblete, R. B., Rodriguez, K., Foust, R. T., Reddy, K. R., and Saldana, M. J.: Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome (AIDS). Ann. Intern. Med. 110:737, 1989. 19. Pilon, V. A., Echols, R. M., Celo, J. S., and
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AMEIuCAN JOURNAL OF OPHTHALMOLOGY
Elmendorf, S. L.: Disseminated Pneumocystis carinii infection in AIDS. N. Eng!. J. Med. 316:1410, 1987. 20. Raviglione, M. c., Garner, G. R., and Mullen, M. P.: Pneumocystis carinii in bone marrow. Ann. Intern. Med. 109:253, 1988. 21. Armstrong, D., and Bernard, E.: Aerosol pentamidine. Ann. Intern. Med. 109:852, 1988. 22. Rao, N. A., Zimmerman, P. L., Boyer, D., Biswas, J., Causey, D., Beniz, J., and Nichols, P. W.: A clinical, histopathologic, and electron microscopic study of Pneumocystis carinii choroiditis. Am.]. Ophthalmo!. 107:218, 1989. 23. Freeman, W. R., Gross, J. G., Labelle, ]., Oteken, K., Katz, B., and Wiley, C. A.: Pneumocystis carinii choroidopathy. A new clinical entity. Arch. Ophthalmo!. 107:863, 1989. 24. Macher, A. M., Bardenstein, D. S., Zimmerman, L. E., Steigman, C. K., Pastore, L., Peretz, D. M., and Eron, L. J.: Pneumocystis carinii choroiditis in a male homosexual with AIDS and disseminated pulmonary and extrapulmonary P. carinii infection. N. Eng!. J, Med. 316:1092,1987. 25. Glatt, A. E., Chingwin, K., and Landesman, S. H.: Treatment of infections associated with human immunodeficiency virus. N. Eng!. J. Med. 318:1439, 1988. 26. Bernard, E. M., Pagel, L., Schmitt, H. J., Donnelly, H., and Armstrong, D.: Clinical trials with aerosol pentamidine for prevention of Pneumocystis carinii pneumonia. Clin. Res. 35:468A, 1987.
July, 1991
27. Salamone, F. R., and Cunha, B. A.: Update on pentamidine for the treatment of Pneumocystis carinii pneumonia. Clin. Pharm. 7:501, 1988. 28. Center for Disease Control Update: Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 38:1,1989. 29. Abd, A. G., Nierman, D. M., Ilowite, ]. S., Pierson, R. N., Jr., and Bell, A. L., Jr.: Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis. Chest 94:329,1988. 30. Montgomery, A. B., Debs, R. J., Luce, ]. M., Corkery, K. J., Turner, J., Brunette, E. N., Lin, E. T., and Hopewell, P. c.: Aerosolised pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet 2:480, 1987. 31. Dugel, P. U., Rao, N. A., Forster, D. J., Chong, L. P., Frangieh, G. T., and Sattler, F.: Pneumocystis carinii choroiditis after long-term aerosolized pentamidine therapy. Am. J. Ophthalmo!. 110:113, 1990. 32. Koser, M. W., ]ampol, L. M., and MacDonell, K.: Treatment of Pneumocystis carinii choroidopathy. Arch. Ophthalmo!. 108:1214, 1990. 33. Friedberg, D. N., Greene, J. B., and Brook, D. L.: Asymptomatic disseminated Pneumocystis carinii infection detected by ophthalmoscopy. Lancet 336, 1256, 1990.
