Ocular opportunistic infection incidences among patients who are HIV positive compared to patients who are HIV negative12

Ocular Opportunistic Infection Incidences among Patients Who Are HIV Positive Compared to Patients Who Are HIV Negative William

G. Hodge, MD, MPH,‘t2

Stuart R. Seiff, MD,

FACS,3 Todd P. Margolis,

MD,

PhD’

Objective: The purpose of the study was to examine the incidence of ocular opportunistic infections among patients who are human immunodeficiency virus (HIV) positive compared to patients who are HIV negative. Design: The study design was a retrospective cohort study. Participants: All patients were recruited from 1984 until 1995 at the San Francisco General Hospital. Intervention: lncidences for numerous diagnoses were compared among the exposure group (HIV positive) and nonexposed control group (HIV negative). Main Outcome Measures: The diagnoses studied were cytomegalovirus (CMV) retinitis, herpes zoster ophthalmicus, Pneumocystis carinii choroidopathy, herpes simplex keratitis, Toxoplasma retinitis, fungal retinitis, ocular syphilis, and ocular lymphoma. Results: Among the HIV-positive pool, there were 1800 patient visits with a total of 5200 person-years of followup. Among the HIV-negative control pool, there were 48,200 patient visits with a total of 30,100 person-years of follow-up. Incidence rates were calculated using the product-limit method, and risk ratios were calculated using the Cox proportional hazards model. Incidence rate differences were calculated using the incidence density method. Among the outcomes studied, only CMV retinitis, herpes zoster ophthalmicus, and, to a lesser extent, Toxoplasma retinitis showed both an elevated risk ratio and rate difference among patients who were HIV positive compared to patients who were HIV negative. Of the other outcomes studied, either the risk ratio, rate difference, or both were similar among patients who were HIV positive compared to patients who were HIV negative. Conclusions: Not all ocular infections seen in patients who are HIV positive should be considered opportunistic, because many occur with similar incidence among patients who are HIV negative. The biologic reasons for this will require further study. Ophthalmology 1998; 105:895-900

In 1982, Holland and associates’ first reported ocular abnormalities in patients with the acquired immune deficiency syndrome (AIDS). Since then, many case series have reported that a majority of patients who are HIV positive develop an abnormal ocular examination result Originally Revision

received: April 14, 1997. accepted: November 20, 1997.

’ Francis I. Proctor Foundation and Department UCSF Medical Center, San Francisco, California. ’ University of Ottawa Eye Institute, Ottawa, Ontario, Canada.

Ottawa

of Ophthalmology,

Health

Sciences

Centre,

3 Department of Ophthalmology, San Francisco General Hospital, UCSF Medical Center, San Francisco, California. Performed at the San Francisco General Hospital of the University of Cahfornia, San Francisco, California. Presented in part at the Ocular Microbiology and Immunology meeting of the American Academy of Ophthahnology Annual San Francisco, October 28, 1995. Supported in part by The McLaughlin and a Research to Prevent Blindness The authors have service mentioned

Foundation Merit Award

no financial or proprietary in this article.

of Canada (TPM).

interest

satellite Meeting, (WGH)

in any good or

Reprint requests to William G. Hodge, MD, MPH, University of Ottawa Eye Institute, Ottawa Health Sciences Centre, 501 Smyth Rd, Ottawa, Ontario, Canada KIH 5P6.

at some point in their lifetime.lm5 The lifetime cumulative incidence of at least one ocular abnormality developing ranges from 52% to 100% depending on the series. The ocular abnormalities that occur among patients who are HIV positive have been divided into four categories: (1) a noninfectious microangiopathy seen most often in the retina; (2) ocular opportunistic infections; (3) ocular adnexal neoplasms; and (4) neuro-ophthalmic manifestations. This article will focus mainly on what are considered to be opportunistic infections. Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection among patients who are HIV positive.6-’ ’ Other ocular infections that have been reported in this group include toxoplasmosis,“-‘” herpes zoster ophthalmicus,“-‘” fungal retinitis,5 Pneumocystis 20-23herpes simplex,24~2s and ocular syphich;;$lopathy, lis. There is no question that CMV retinitis is an ocular opportunistic infection among patients who are HIV positive, occurring with an estimated lifetime cumulative incidence of between 25% and 40%.‘*3Z35,36However, it is less clear whether other ocular infections are any more frequent among patients who are HIV positive compared to patients who are HIV negative. The purpose of this study was to determine the incidence of various ocular

895

Ophthalmology

Volume 10.5, Number 5, May I998

sisof Pneumocystischoroidopathyincludedthe clinical criteria first describedby Rao andassociate? aswell assystemicevidenceof Pneumocystisculture from at least one other organ system.A diagnosisof herpessimplexkeratitiswasmadewhen any of the following criteria wereevident: for epithelialdisease, a characteristicdendrite or geographiclesion and decreased Materials and Methods cornea1sensation;for stromal disease,disciform keratitis or necrotizing stromal keratitis and decreasedcornea1sensation. Criteria for diagnosisof Toxoplasmosisincludedclinical eviStudy Design denceof retinochoroiditisand positive serumimmunoglobulin A retrospective cohort study was designed with patients first G levelsto Toxoplasma gondii. Clinical andserologicguidelines entering the cohort at the beginning of 1984. Time = 0 was for diagnosisof this entity have beenoutlined by Holland and defined as the first visit to the ophthalmology department for associates.“’ Criteria for fungal retinitis includedvitritis or retiboth exposed (HIV-positive) and nonexposed (HIV-negative) nitis consistentwith an ocular fungal infection and a positive groups. Patients were observed until February 1995, until death, vitreous or blood culture. A diagnosisof ocular syphilis deor until development of one of the disease outcomes of this pendedon a clinical picture incompatiblewith other classic study. February 1994 was the last time a patient was allowed ocular infectiousor inflammatoryetiologiesand serologicevito enter the cohort.Whenpatientsdevelopedoneof the diseases, denceof a positive fluorescenttreponemalantibody absorbed they wereremovedfrom the cohort for that outcomebut allowed testalongwith response to antitreponemaltherapyat neurosyphto continuein the cohort for the purposeof calculatingthe risk ilis doses.30-34 A positive biopsyresultwasrequiredto diagnose denominatorfor other diseases. New patientswho enteredthe ocular lymphoma.Table 1 summarizes thesediagnosticcriteria. cohort after 1984alsowere includedin the study and observed to the sameendpointsas above.Many patientswho were HIV Inclusion and Exclusion Criteria positive did not have AIDS whenthey first enteredthe cohort, but the majority developed AIDS at somepoint during the For inclusioncriteria, the medicalrecordsof all patientswere follow-up period. reviewed to confirm that the inclusioncriteria for the specific diagnosiswere met. Patientsincluded in the exposuregroup met the following criteria: the patientswere HIV positive as Sampling and Patient Visits shownby serologyandconfirmedby Westernblot analysis.All Consecutivesamplingwas used.All patientswere seenat the patientswereolder than 18yearsof age.Patientswereexcluded SanFranciscoGeneralHospitalof the University of California. if they did not meet the previously stated age criteria or if This county hospitalprovidescomprehensivecare for a large insufficient recordsnegatedour ability to characterizethe panumberof patientswho are HIV positive in the California bay tient’s diagnosticstatus. area. All patients seenthroughout the study had their bestcorrectedvisual acuity, pupillary examination,slit-lampexamiIncidence Calculations and Statistical Analysis nation, anddilated retina examinationperformedat every visit. Follow-up intervals varied dependingon how high a risk a Incidence calculations were performed in one of two ways. patient was for developing one of the ocular diagnosesbut For the purpose of calculating the incidence risk ratio of typically were every 4 to 8 months.Among the HIV-positive various outcomesbetween patients who are HIV positive pool, 1800patient visits with a total of 5200 person-yearsof versus those who are HIV negative, the product-limit follow-up were usedto obtain the diagnosesfor the index dismethod was used to calculate the lo-year cumulative incieases(DiseaseX positive, HIV positive). Among the HIVnegative pool, 48,200 patient visits with 30,100 person-years dence of the outcomes studied. Then incidence risk ratios were calculated as the instantaneoushazard of developing of follow-up were usedto obtain the diagnosesfor the index outcome X using the Cox proportional hazards model with disease(DiseaseX positive, HIV negative). Becausethis is an age, gender, and race as covariates in the model. The asincidencestudy (numberof new cases/time),any patient with sumption of proportionality was verified through analysis only one visit or any patient diagnosedat first visit to the clinic of parallel curves by graphing log(-log(S(t))) versust where was not eligible to be in the cohort. Informed consentfrom S(t) is the disease-freeinterval for eachdiseaseasa function individuals was not required from the involved institutional of time. Medication use and other systemic illnesseswere review board for this study. not controlled for purposely becausethey are surrogatesfor being HIV positive and therefore do not meet the definition for confounding. The relative incidence risk ratios are proDisease Outcomes Studied vided as point estimatesalong with 95% confidence interThe diseaseoutcomesstudiedwereCMV retinitis, herpeszoster vals (CIs). Although the incidence risk ratio as represented affecting the ophthalmicbranchof the trigeminalnerve, Pneuby the instantaneoushazard provides the relative chance of mocystis carinii choroidopathy,herpessimplex keratitis, Toxdeveloping diseaseX in patients who are HIV positive veroplasmaretinitis, fungalretinitis, ocularsyphilis,andonenoninsusthose who are HIV negative, it is a poor indicator of fectiousentity-ocular lymphoma.The definitionsof the spe- the public health impact of a diseaseas artificially high cific outcomeswere as follows: CMV retinitis was diagnosed incidence risk ratios will be obtained when the nonexposed basedon patientshaving the typical clinical appearance of necgroup developsthe outcome very rarely or not at all. Thererotizing retinitis; specific guidelinesoutlining this diagnosis fore, to determinethe public health impact of eachdisease, havebeenpublishedby Hollandandassociates.36 Herpeszoster the incidence rate difference or attributable rate difference infection was diagnosedwhen at least one of the following also was calculated. All incidence rate difference calculatwo clinical criteria occurred:Vl dermatomalskin eruptionor tions were performed with the incidence density method progressiveouterretinal necrosissyndrome.Criteria for diagno(numberof caseevents in numerator/person-yearsof followinfections among a cohort of patients who are HIV positive and compare the incidence of the same infections in a cohort who are HIV negative.

896

Hodge et al * Ocular

Infections

in HIV-positive

and HIV-negative

Patients

Table 1. Diagnostic Criteria for Diseases Studied Disease

Ocular

Criteria

Systemic

CMV retmltlb Herpes eoster ophthalmicus Pneumocystis choroldopathy Herpes simplex keratms Toxoplasma retmiua Fungal retinitis

Typical retmw Vl dermatomal distribution PORN Typical choroidopathy

Ocular

syphilis

Ocular

lymphoma

CMV

= cytomegalovirus;

Laboratory

Not needed Not needed

Not needed Not needed Culture

Lesions not typical

Needed from at least one other organ Not needed Not needed Not necessarily needed Not needed

Lesions not typical

Not needed

or

Epithelial or stromal Typical or atypvzal retuutls Vitrltis/retimtis

PORN

Criteria

= progressive

outer retinal

necrosis syndrome;

up m denominator), and the lo-year incidence rate difference was calculated. All calculations were performed with the aid of the computer software STATA (Stata Corporation, College Station, TX).

Results For CMV retinitis, a total of 790 patients were diagnosed among the HIV-positive pool, whereas 0 patient was diagnosed among the HIV-negative pool. Among patients with Pneumocystis choroidopathy, only four patients were identified, all from the HIVpositive pool. For patients with ocular syphilis, only two patients were identified, both from the HIV-positive pool. Hence, the relative risk ratios for developing these three entities among HIV-positive patients compared to HIV-negative patients are infinite, but the attributable risk was negligible for Pneumocystis choroidopathy and ocular syphilis. For herpes zoster, 55 cases were identified among the HIVpositive pool compared to 40 among the HIV-negative pool. Using the Cox proportional hazards model, this is a relative incident risk ratio of 6.6/l for HIV-positive patients compared to HIV-negative control subjects (95% CI, 5.1-7.6). For toxoplasmosis retinitis, four cases were identified among the HIVpositive pool compared to nine cases among the HIV-negative pool for a relative incident risk ratio of 2.1/l (95% CI, l.l3.1). For herpes simplex infections, 7 cases occurred among the HIV-positive pool and 27 among the HIV-negative control subjects. The relative incident risk ratio was 1.2/l (95% CI, 0.72.4). For fungal retinitis, only one case was found in both the HIV-positive and HIV-negative pools for a relative incident risk ratio of 4.9 (but the 95% CI clearly crosses unity at 0.5-6.9). Finally, no cases of lymphoma were found in either pool of patients. Table 2 summarizes the lo-year cumulative incidences, IO-year incidence density, risk ratios, and IO-year incident density rate differences among the diseases studied.

Discussion Despite 16 years of documentation of HIV-related ocular infections, the true incidence of these infections and, more important, the relative incidence of these infections compared to patients who are HIV negative remain surpris-

FTA-ABS

= fl uorescent

Criteria

needed from other organ

Not needed IgG toxoplasmosis (serum) Vltrcous or blood culture FTA-ABS positive Positive treatment Biopsy proven treponemal

antibody

absorption

response

test.

ingly unknown. The objective of this study was to answer these questions by studying the commonly believed “opportunistic infections” among patients who are HIV positive and comparing their incidence with patients who are HIV negative. As would be expected, CMV retinitis is the most important ocular opportunistic infection among patients who are HIV positive. The relative risk ratio was infinite compared to HIV-negative control subjects. Furthermore, the rate difference (or risk attributable to HIV infection) was the highest among all infections at 1.5 cases per persondecade higher in those who were HIV positive. In contrast, although the relative risk ratio for Pneumocystis choroidopathy infection and ocular syphilis also was infinite among patients who are HIV positive compared to patients who are HIV negative, the attributable risks were extremely low, a reflection of the overall low incidences of these disease entities among patients who are HIV positive. Herpes zoster ophthalmicus was found to be an important ocular opportunistic infection among patients who are HIV positive with a relative incidence risk ratio of 6.6/l compared to patients who are HIV negative and the second highest attributable rate difference among any of the infections studied. Toxoplasmosis retinitis also proved to occur more frequently among patients who were HIV positive but with a much smaller relative incidence risk ratio than herpes zoster. Herpes simplex keratitis and fungal retinitis were not found to have a statistically significant higher incidence among patients who are HIV positive, and ocular lymphoma was not diagnosed over the tenure of our study between either group. In any analytic clinical research study, possible explanations for the results include chance, bias, and confounding. In this study, with more than 35,000 personyears of follow-up, it is extremely unlikely that chance could be an important factor. Several diseases had fewto-no cases identified. A small number of cases do decrease the power to detect a difference between groups. However, the accruitment of so few cases among patients who are HIV positive at such a large center and

a97

Ophthalmology Table

2. Ocular

Disease

Infection HIV

Pos,

HIV

Neg

(no.

CMV retinitis Pneumocystis choroidopathy Ocular syphihs Herpes zoster Toxoplasmosis retmms Herpes simplex Fungal retinms Owlar lymphoma

Incidences

of cases)

790, 0 4, 0 2, 0 55, 40 4, 9 7, 27 1, 1 0, 0

Volume 105, Number 5, May 1998 Summarized

among

density

rate difference

Patients

Relative Pas,

CI HIV

Neg,

ID

Pos

ID

Nq

HIV

77.7, 1.5 0.8, 0.008 0.38, 0.004 10.4, 0.11 0.77, 0.0077 1.29, 0.013 0.20, 0.002 0, 0

HIV

0, 0 a 0 0, 0 1.29, 0.30, 0.90, 0.033, 0, 0

0.013 0.003 0.009 0.00033

mcldencc calculated (uniwdecades-‘).

Point (with

6.6/l 2.1/ 1.2/l 4.9/l

Risk

Estimate 95% CI)

InfinIte Intinite Infinite (5.1-7.6) (1.1-3.2) (0.7-2.4) (0.5-6.9)

m lmlts of %/lo

Incidence Difference*

Rate

1.5 0.008 0.004 0.097 0.0047 0.0040 0.0017

yr, calculated

by the product-

in units of decades-’

over such a long period of follow-up actually supports the clinical reality that these entities are not significant ocular public health problems in this patient population. The main bias introduced in this retrospective cohort design is misclassification bias. Were some patients in the HIV-negative pool really HIV positive but their HIV status not tested? Let us calculate the potential direction and magnitude of this bias. To calculate the potential magnitude of misclassification of HIV status, we can use seroprevalence data already in the literature to determine whether our results would be affected to any significant degree. The HIV seroprevalence studies among males vary from very low rates of 0.54% in the entire Kansas City metropolitan area3’ to as high as 3% in an American urban inner city catchment area.“’ For our study, let us assume the misclassification bias to be 5%. This would allow for the extreme seroprevalence data just cited as well as new incident cases of HIV seroconversion over the time period of the study. With a misclassification bias of 5%, none of the incidence risk ratios or rate differences studied between groups would have changed significantly. Many different ophthalmologists and ophthalmologists-in-training have been involved with producing diagnostic information for this study. There is no doubt that over a loyear period, some diagnoses may have been omitted or misclassified. Nevertheless, in our opinion, the potential usefulness of such a large amount of information available for this study far outweighs its disadvantages. A second potential bias inherent to all cohort studies is the possibility that differential follow-up between patients who are HIV positive and patients who are HIV negative may have biased our measures of association. For example, a typical individual in the HIV-positive pool, especially one whose CD4 count was less than 50, would tend to be observed more regularly and have a dilated peripheral retina examination performed more often than would a typical individual in the HIVnegative pool. However, most of the diseases that could occur in patients from the HIV-negative pool are symptomatic, thus decreasing the impact of this bias. Furthermore, any bias that would remain would tend to

898

and HIV-negative

CI HIV

CMV = cytomegalovtrus; Pas = powwe; Neg = negative; Cl = lo-year cumulatwc limit method; ID = incidence density in mms of cases/person decade of follow-up * Incidence

HIV-positive

underestimate the incidence of diseases in the HIVnegative group and therefore artificially increase the HIV+ to HIV- risk ratios or rate differences. Because the main conclusion from this study is that many ocular infections often considered to occur at higher rates among patients who are HIV positive are no more frequent than among patients who are HIV negative, this bias would only further strengthen our conclusion if it could be eliminated. Confounding is not an issue of concern in this incidence study. We are trying to compare infection incidences among patients who are HIV positive and those who are HIV negative. Other variables do differ between these groups such as medication use and background illnesses (e.g., Pneumocystis carinii pneumonia, Kaposi’s sarcoma). However, the comparison of realistic clinical importance is the incidence of disease X in patients who are HIV positive (with all their background illnesses and medications) compared to the incidence in patients who are HIV negative. To control for these variables in our Cox regression model would have been controlling for HIV status itself, and a very unrealistic, clinically irrelevant comparison would have been made (HIV-positive patients without medications and without background illnesses compared to HIV-negative patients). The results of this study have importance and application to both the clinician in practice and the public health officials involved in eye care. For the clinician in practice, the results of this study may be able to serve as a guide, for example, in the differential diagnosis of an atypical peripheral retinal lesion. If the main diseases on the differential diagnosis of a patient who is HIV positive with a small retinal infiltrate with adjacent hemorrhage are CMV retinitis versus fungal retinitis, then the chances are overwhelming that the lesion is an atypical CMV lesion. Similarly, a dendritic or pseudodendritic keratitis in a patient who is HIV negative probably would represent herpes simplex keratitis on a statistical basis. However, in a patient who is HIV positive, herpes zoster would assume a greater likeli-

Hodge et al * Ocular

Infections

in HIV-positive

hood, especially if accompanied by a history of dermatomal zoster. From the public health point of view, these data support concentrating research efforts on the diseases with the highest risk ratios and attributable risks. The CMV retinitis is an obvious disease that falls into this category. The other main disease that would be considered a priority from an ocular public health point of view would be herpes zoster. In summary, this is the first study that has attempted to calculate the relative incidences of specific ocular infections among patients who are HlV positive compared to patients who are HIV negative. The CMV retinitis, as expected, was the most important opportunistic ocular infection, Herpes zoster ophthalmicus and, to a lesser extent, Toxoplasmosis retinitis also were found to occur more frequently among HIVpositive patients. Pneumocystis choroidopathy and ocular syphilis also were found to occur more frequently among HIV-positive patients, but the absolute number of cases found of these two entities in the HIV-positive group was extremely low. None of the other conditions studied were found to occur at a greater risk among HIV-positive patients compared to HIV-negative control subjects.

References 1. Holland GN, Pepose JS, Pettit TH, et al. Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology 1983;90:859-73. 2. Freeman WR, Chen A, Henderly DE, et al. Prevalence and significance of acquired immunodeficiency syndromerelated retinal micro-vasculopathy. Am J Ophthalmol 1989; 107:229-35. 3. Freeman WR, Lerner CW, Mines JA, et al. A prospective study of the ophthalmologic findings in the acquired immune deficiency syndrome. Am J Ophthalmol 1984; 97:133-42. 4. Humphrey RC, Parkin JM, Marsh RJ. The ophthalmological features of AIDS and AIDS related disorders. Trans Am Ophthalmol Sot 1986; 105:505-9. 5. Jabs DA, Green WR, Fox R. et al. Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989;96:1092-9. 6. Holland GN, Gottlieb MS, Yee RD, et al. Ocular disorders associated with a new severe acquired cellular immunodeficiency syndrome.Am J Ophthalmol 1982;93:393-402. 7. Kestelyn P, Lepage P, Van de Perre P. Perivasculitis of the retinal vessels as an important sign in children with AIDSrelated complex. Am J Ophthalmol 1985; 100:614-5. 8. Kestelyn P, Van de Perre P, Rouvroy D, et al. A prospective study of the ophthalmologic findings in the acquired immune deficiency syndrome in Africa. Am J Ophthalmol 1985; 100:230-g. 9. Newman NM, Mandel MR, Gullett J, et al. Clinical and histologic findings in opportunistic infections. Arch Ophthalmol 1983; 101:396-401. 10. Newsome DA, Green WR, Miller ED, et al. Microvascular aspects of acquired immune deficiency syndrome retinopathy. Am J Ophthalmol 1984;98:590-601. 11. Dunn JP, Jabs DA. Cytomegalovirus retinitis in AIDS: natural history, diagnosis, and treatment. AIDS Clin Review 1995-1996;99-129.

and HIV-negative

Patients

12. Berger BB, Egwuagu CE, Freeman WR, et al. Miliary toxoplasmic retinitis in acquired immunodeficiency syndrome. Arch Ophthalmol 1993; 111:373-6. 13. Cochereau-Massin I, LeHoang P, Lautier-Frau M. Ocular toxoplasmosis in human immunodeficiency virus-infected patients. Am J Ophthalmol 1992; 114:130-5. 14. Holland GN, Engstrom RE, Glastow BJ, et al. Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1988; 106:653-67. 15. Parke DW, Font RL. Diffuse toxoplasmic retinochoroiditis in a patient with AIDS. Arch Ophthahnol 1986; 104571-5. 16. Wiess A, Margo CE, Ledford DK, et al. Toxoplasmic retinochoroiditis as an initial manifestation of the acquired

immune deficiency syndrome. Am J Ophthalmol 1987; 103:248-9. 17. Forster DJ, Dugel PU, Frangieh GT, Liggett PE, Rao NA. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol 1990; 1 lo:341 -8. 18. Margolis TP, Lowder CY, Holland GN, et al. Varicellazoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 199 1; 112: 119-3 1. 19. Sellitti TP, Huang AJ, Schiffman J, et al. Association of herpes zoster ophthalmicus with acquired immunodeliciency syndrome and acute retinal necrosis. Am J Ophthalmol 1993; 116:297-301. 20. Rao NA, Zimmerman PL, Boyer D, et al. A clinical histopathologic and electron microscopic study of Pneumocystis carinii choroiditis. Am J Ophthalmol 1989; 107:218-28. 21. Foster RE, Lowder CY, Meisler DM, et al. Presumed Pneumocystis carinii choroiditis: unifocal presentation, regression with intravenous pentamidine, and choroiditis recurrence. Ophthalmology 1991;98: 1360-3. 22. Holland GN, McArthur LJ, Roos RY. Choroidal pneumocystosis. Arch Ophthalmol 1991; 109:1454-7. 23. Koser MW, Jampol LM, MacDonell K. Treatment of Pneumocystis carinii choroidopathy. Arch Ophthalmol 1990; 108:1214-7. 24. Rosenwasser GOD, Greene WH. Simultaneous herpes simplex type I and 2 keratitis in acquired immunodeficiency syndrome. Am J Ophthalmol 1992; 113: 102-3. 25. Shuler JD, Engstrom RE Jr, Holland GN. External ocular disease and anterior segment disorders associated with AIDS. Int Ophthalmol Clin 1989;29:98-104. 26. Centers for Disease Control: primary and secondary syphilis: United States. MMWR 1991;40:314-5, 321-3. 27. Beauvais DA, Michelson JB, Seybold ME, et al. Retroviruses and their play-pals. Surv Ophthalmol 1989;34:5964. 28. Becerra LI, Ksiazek SM, Savino PJ, et al. Syphilitic uveitis. Am J Ophthalmol 1989;96: 1727-30. 29. Bouisse V, Cochereau-Massin I, Jobin D, et al. Uveite syphilitique et infection par le virus de l’immunodeficience humaine. J Fr Ophtalmol 1991; 14:605-9. 30. Gordon S, Eaton M, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with HIV infection. N Engl J Med 1994; 331:1469-73. 31. Passo M, Rosenbaum J. Ocular syphilis in patients with HIV infection. Am J Ophthalmol 1988; 106: l-6. 32. Gass JDM, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990;97: 1288-97. 33. Tamesis RR, Foster S. Ocular syphilis. Ophthalmology 1990;97:1281-7. 34. Hoover DR, Saah AJ, Bacellar H, et al. Clinical mamfesta-

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tions of AIDS in the era of Pneumocystis prophylaxis. N Engl J Med 1993;329:1922-6. 35. Jabs DA, Enger C, Bartlett JG. Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Arch Ophthalmol 1989; 107:75-80. 36. Holland GN, Buhles WC, Mastre B, et al. A controlled retrospective study on ganciclovir treatment for cytomegalovirus retinopathy: use of a standardized system for the assessment of disease outcome. Arch Ophthalmol 1989;107:1759-66.

Historical

37. Holland GN, Engstrom RE Jr, Glasgow BJ, et al. Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1988; 106:653-67. 38. Spare KW, Craig J, Moore-Nichols J, et al. Human immunodeficiency virus (HIV) seroprevalence surveys. Missouri Med 1992; 89:843-T 39. Zuckerman CG, Masters CF. Prevalence of human immunodeficiency virus-l infection in a Baltimore acute care hospital. Maryland Med J 1993;42:765-9.

Image

Early paper insert (large eye) used in trade signs, early 20th century.*

* Courtesy California.

900

of the Museum

of Ophthalmology,

Foundation

of the American

Academy

of Ophthalmology,

San Francisco.