An Unusually High Prevalence of Ocular Toxoplasmosis in Southern Brazil Peter D . Glasner, M.D., Claudio Silveira, M . D . , D e a n n a Kruszon-Moran, M.S., Maria C. Martins, M.D., M i g u e l Burnier, Jr., M . D . , S i l v i a Silveira, D.V.M., Mario E. Camargo, M.D., Robert B. N u s s e n b l a t t , M . D . , Richard A. Kaslow, M . D . , and Rubens Belfort, Jr., M . D . Because of the frequency of ocular toxoplasmosis and its occurrence in multiple siblings in southern Brazil, a population-based household survey was performed to better understand the epidemiologie characteristics of the disease in this region. Of 1,042 individuals examined, 184 (17.7%) were deemed to have ocular toxoplasmosis on the basis of conservative assessment of ophthalmic findings. Of those with ocular toxoplasmosis, 183 (99.5%) had specific IgG antibodies, compared with only 140 of 181 age-matched control subjects (77.4%; P < .001). The prevalence of ocular toxoplasmosis was 0.9% in 1- to 8-year-olds, 4.3% in 9- to 12-year-olds, 14.3% in 13- to 16-year-olds, and 21.3% (95% confidence interval, 18.6% to 24.2%) in all individuals 13 years or older. The prevalence of ocular toxoplasmosis in this population was more than 30 times higher than previous estimates for the same condition elsewhere. The low prevalence in the young children we studied supplements previous data suggesting that, in this population, ocular toxoplasmosis is a se-
Accepted for publication May 5, 1992. From the Epidemiology and Biometry Branch, Divi sion of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (Drs. Glasner and Kaslow, and Ms. KruszonMoran); Clinica Silveira, Erechim, Rio Grande do Sul, Brazil (Drs. Silveira and Silveira); Departamento de Oftalmologia, Escola Paulista de Medicina, Sào Paulo, Brazil (Drs. Martins, Burnier, and Belfort); Departa mento de Immunologia, Laboratorio Fleury, Sào Paulo, Brazil (Dr. Camargo); and Laboratory of Immunology, National Eye Institute, Bethesda, Maryland (Dr. Nussen blatt). This study was supported by funds made avail able through the U.S.-Brazil Presidential Initiative for Science and Technology. Reprint requests to Peter D. Glasner, M.D., Epidemiol ogy and Biometry Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Solar Bldg., Rm. 3A24, Bethesda, MD 20892.
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quela of postnatal rather than congenital infection. O C U L A R TOXOPLASMOSIS has long been consid ered a sequela of congenital infection with Toxoplasma gondii1 and only infrequently has it been reported to follow infection acquired postnatally in an immunocompetent host. 13 Except for two cases described in offspring of immuno competent mothers attributed to prepregnancy infection 4,5 and two cases of infection in newboms attributed to perinatal infection, 6 large studies have shown that pregnant women with intact immune systems transmit to their chil dren only during the pregnancy in which infec tion first developed. 7,8 Accordingly, few cases of ocular toxoplasmosis have been described in siblings, presumably because of the infrequent development of ocular disease secondary to acquired infection. 910 These tenets have been challenged by the following: (1) the identification of over 150 families in southern Brazil in which multiple siblings had ocular toxoplasmosis, 11 and (2) the diagnosis of ocular toxoplasmosis in over 8,000 patients from this same region during the past 30 years (C.S., unpublished data, 1990). To determine the prevalence of this disease in the region, to estimate the relative proportion caused by congenital and acquired infection, and to identify potential risk factors for ocular disease, we initiated a population-based study in the rural area surrounding the city of Erechim in southern Brazil in 1990.
Subjects and Methods Selection of the study population—Erechim (population, 71,000) is in northern Rio Grande do Sul (population, 8,500,000), the most south-
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em state of Brazil that borders on Uruguay and Argentina. Southern Brazil is hilly with a tem perate climate and has been settled in large part by Italian, German, and Polish immigrants dur ing the early part of this century. In much of the rural area, the predominant lifestyle is based on subsistence family farming. The study was based at Clinica Silveira, a private ophthalmology clinic in Erechim. The two ophthalmologists at the clinic are among six ophthalmologists who serve a population of approximately 200,000 from the city of Erechim and the surrounding rural region. A greater proportion of patients with posterior uveitis than would be expected are seen at Clinica Silveira because it specializes in this type of ocular disease in southern Brazil. The study was confined to the rural region within an approximately 20-km radius sur rounding Erechim. This region was selected because of its proximity to personnel and facili ties in Erechim and because of the anecdotal suggestion of a higher prevalence of disease in the surrounding countryside than in the city. Using topographic maps, sections of the area along accessible rural roads were grouped into 40 segments, with an estimated 20 to 25 houses alongside the roads of each segment. To main tain the rural characteristics of the sample, roads close to the city of Erechim and to nearby villages with dense populations indicated on topographic maps were excluded from the seg ments. Less accessible roads, not reliably marked on the maps, were also excluded be cause the absence of road signs in the region would have made it extremely difficult to relo cate houses on these roads once they were selected. A random sample of 12 segments was selected from the previously mentioned 40 for inclusion in the study. Epidemiologie data—The study was per formed from July through September 1990. All households within the defined segments were invited to participate. Local residents accompa nied the interviewers to act as liaisons and to translate to Polish or Italian when requested. The number and ages of household members and whether anyone in the household had a history of eye problems or a history of having been seen by an ophthalmologist were recorded for all households, including those not agree ing to participate. An adult representative of each participating household was asked to enu merate individual household members and to provide general household information on de mographic and socioeconomic status, food
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preparation, sanitation, and farming practices. After obtaining informed consent, household members were scheduled for a visit to one of two local clinics for ophthalmic examination and blood testing. Ophthalmic examinations—After dilation, in dividuals were screened with indirect ophthalmoscopy for the presence of posterior uveitis by the identification of active inflammatory retinal lesions, or pigmented retinal or retinochoroidal lesions consistent with healed retinochoroiditis. Screening eye examinations were per formed by a team of five visiting ophthalmolo gists from the Escola Paulista de Medicina, Sâo Paulo. Individuals suspected of having posterior uveitis on the screening examination were re ferred for a detailed, definitive eye examination performed by one of us (C.S.). After dilation, using slit-lamp and indirect ophthalmoscopy, the size, number, and location of lesions, and inflammatory and vascular ocular disease were documented according to a standardized proto col. Individuals were classified as having possi ble ocular toxoplasmosis if they had the follow ing: (1) one or more healed, focal, pigmented retinal or retinochoroidal lesions with welldelineated margins, or (2) one or more active focal retinal lesions. Individuals considered to have possible ocular toxoplasmosis were fur ther graded by using a subjective scale of the probability of ocular toxoplasmosis ranging from 1 to 5 (1, definite ocular toxoplasmosis; 2, high probability; 3, moderate probability; 4, low probability; and 5, probably not ocular toxoplasmosis). Because no preestablished cri teria were available, these lesions were graded on the basis of the observer's judgment of the probability of ocular toxoplasmosis. The judg ment incorporated the location of the lesions (macular, bilateral, or satellite lesions, for ex ample), the degree and location of pigmenta tion, the size of the lesions, the number of lesions, and the degree of atrophy of the choroid and retina. All grading was done indepen dently of serologie results. The three most frequent reasons for exclusion at the screening eye examination were inability of the patient to cooperate with the examina tion, inability of the examiner to visualize the fundus completely (both occurring mostly in young children), and the patient's need to leave the clinic before being examined because of transportation requirements. Individuals who were not permanent residents of the selected households and those referred from the screen-
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ing examination because of posterior uveitis and who failed to complete the definitive eye examination were also excluded. Participants were defined as all those who completed the screening eye examination, and if indicated, the definitive eye examination. Fundus photography—Fundus photography was performed by using a Zeiss Yena retinal camera and Ektachrome 25 61m (Kodak, Roch ester, New York). Photographs of seven stan dard fields were attempted in all individuals who had a grade of 1 to 4 identified in the definitive eye examination. Photographs were limited to fields with typical lesions or were not completed when the following occurred: (1) there was difficulty in visualizing the posterior pole, (2) there were technical problems with equipment, or (3) an individual was unable to cooperate. All available fundus photographs were read by two of us (R.B.N. and C.S.), who were masked to each other's readings. The results of photographic readings were not used to con firm or alter the diagnosis made in the definitive eye examination. Selection of control subjects without posterior uveitis—For subsequent case-control analyses, a control group with an age distribution compa rable to the patients with posterior uveitis was identified at the stage of the screening examina tion. Selection of one age-matched control sub ject from the pool of participants for each individual who screened positive for posterior uveitis was attempted. Control subjects were required to be free of posterior uveitis and were matched within 5 years of age to each partici pant with posterior uveitis identified in the screening eye examination. Laboratory testing and quality control—Ve nous blood was drawn on all consenting indi viduals who were older than 4 years and able to cooperate. Initial determination of IgG antibodies to T. gondii was performed on all individuals with posterior uveitis and on agematched control subjects, using a standard immunofluorescence test.12 A titer of 1:16 or greater was considered positive. Testing was repeated on 28 samples randomly selected from those that originally tested positive and ten samples randomly selected from those that originally tested negative. One of the 28 sam ples (3.6%) that originally tested positive tested negative on the repeat test. There was complete concordance between the original and repeat measurements for all samples that originally tested negative. Eighteen of the 28 retested
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positive samples (64%) had the same titer; three (11%) had titer differences of one dilu tion; and six (21%) had titer differences of two or more dilutions. Study participants were not tested for syphi lis and tuberculosis because previous experi ence with testing of patients with posterior uveitis indicated the prevalence of syphilis and tuberculosis would be low. To verify these low rates, records of patients with posterior uveitis seen at Clinica Silveira were systematically re viewed. Diagnostic criteria—We restricted the diagno sis of ocular toxoplasmosis to those persons with a grade of 1 to 3 in the definitive eye examination. Although some individuals with grade 4 lesions possibly had ocular toxoplas mosis, we used a more conservative cutoff to avoid overestimating the true population prev alence. Using these criteria, all patients but one were seropositive. Analyses of risk factors for ocular toxoplasmosis were therefore based on cases with a moderate probability of ophthalmoscopically defined disease (grades 1 to 3) and control subjects with no evidence of pos terior uveitis. For determining interobserver variability, grades 1 to 5 were used. Review of patient records—The patient re cords at Clinica Silveira were searched to deter mine the frequency with which participants and nonparticipants had been seen at the clinic and had had posterior uveitis previously diag nosed. Statistical analysis—Analyses were perform ed using Statistical Analysis Software, version 5.18 (SAS Institute, Inc., Cary, North Carolina). To determine the representativeness of the sam ple, differences between participants and nonparticipants in the distributions of their epide miologie characteristics were analyzed using the chi-square or Fisher's exact test. Tests of association between IgG titer and posterior uveitis also using the chi-square or Fisher's exact test were performed to strengthen the clinical diagnosis. Confounding effects of age, gender, socioeconomic status, and segment on potential associations were evaluated by using stratified analyses and the Mantel-Haenszel chi-square test, when the potential confounder was known to be associated with both the exposure variable and the outcome variable of interest. The Mantel-Haenszel summary odds ratio was used in situations in which confound ing existed. Tests for a trend in the relationship between age and diagnosis of ocular toxoplas mosis were performed by using the extended
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Mantel-Haenszel chi-square test. A P value of less than .01 was considered significant; how ever, all P values greater than or equal to .001 were recorded.
Results Characteristics and representativeness of the study sample—Of 380 households (1,662 indi viduals) selected for study, 1,616 members from 366 of the households agreed to partici pate. Initial visits for the screening eye exami nation were made by 1,126 individuals from 327 households. Of these, we excluded 84, including two individuals with posterior uveitis identified on the screening eye examination who did not complete the definitive eye exami nation. Six (7.1%) of these individuals were specifically excluded because of the inability to visualize the fundus completely; five were younger than 6 years. The median age of those excluded was 4 years. The remaining 1,042 individuals constituted the study sample, with an overall participation rate of 63%. The participants were older and more fre quently women than the nonparticipants (P < .001). Among the participants, there was a relative underrepresentation of males younger than 30 years (24% of participants vs 38% of nonparticipants, P < .001) and a relative overrepresentation of women older than 30 years (26% of participants vs 16% of nonpartici pants, P < .001). A history of someone in the household having had eye problems and having been seen by an ophthalmologist was slightly more common among participants than nonparticipants (64% vs 58%). However, there was no significant difference between the propor tion of individuals who had previously been seen or in whom posterior uveitis or ocular toxoplasmosis had been diagnosed at Clinica Silveira. Socioeconomic measures, such as hav ing electricity, a telephone, and a car, were more prevalent in participants than in nonpar ticipants (P < .001). Frequency of ocular toxoplasmosis—Of the 1,042 participants, 215 (20.6%) had possible ocular toxoplasmosis. One hundred twentyeight participants (12.3%) had a grade of 1; 33 participants (3.2%) had a grade of 2; 23 partici pants (2.2%) had a grade of 3; 20 participants (1.9%) had a grade of 4; and 11 participants (1.1%) had a grade of 5. Six individuals (0.6%), all of whom had a grade of 1, had active lesions.
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Only five of ten individuals with a grade of 5 had anti-toxoplasma antibodies, as compared with 201 of 203 (99%) of those individuals with sera available and grades 1 to 4. The overall distribution of cases by age was determined by using the previously described definition (Fig. 1). The prevalence of ocular toxoplasmosis for the total sample was 17.7% (95% confidence interval, 15.4% to 20.1%). The prevalence of ocular toxoplasmosis increased with age. The prevalence was 0.9% (one pa tient) in 1- to 8-year-olds, 4.3% in 9- to 12year-olds, 14.3% in 13- to 16-year-olds, and 24.6% in 17- to 20-year-olds. The prevalence in 13- to 16-year-olds was significantly higher than in either of the two lowest age groups (P = .018). The prevalence of ocular toxoplasmosis appeared to increase from the 13- to 16-yearold age group to the 17- to 20-year-old age group; however, this was not statistically sig nificant by using trend analysis, by comparing to all older persons, or by comparing consecu tive five-year age groups. The overall preva lence of ocular toxoplasmosis in individuals 13 years or older was 21.3% (95% confidence in terval, 18.6% to 24.2%). There was no significant difference in preva lence between males (16.0%; 95% confidence interval, 12.9% to 19.6%) and females (19.1%; 95% confidence interval, 15.9% to 22.7%). However, analysis by age strata showed higher rates for females in the 13- to 16-year-old age group (22.9%) than males in this same age group (4.7%, P = .013). Photographic readings and interobserver variability—Photographs were available on 142 in-
0
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Fig. 1 (Glasner and associates). Prevalence of ocu lar toxoplasmosis (grades 1 through 3) by age group with 95% confidence intervals. Age groups are desig nated by the midpoint of the age interval.
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" -*&r Fig. 2 (Glasner and associates). Examples of fundus photographs of study participants that were graded concordantly on a scale of 1 to 4. Top left. Grade 1; top right, grade 2; bottom left, grade 3; and bottom right, grade 4. dividuals (103 individuals with a grade of 1 [80%], 22 individuals with a grade of 2 [67%], 11 individuals with a grade of 3 [48%], and six individuals with a grade of 4 [30%]). A compar ison of photographic readings by two of us (C.S. and R.B.N.) showed differences of one grade in 65 individuals (45.8%) and two grades in five individuals (3.5%). There was no consis tent trend toward upgrading or downgrading of lesions across grades, by using readings by one of us (C.S.) as a standard. Examples of fundus
photographs of study participants that were graded concordantly on a scale of 1 to 4 are shown in Figure 2. Case-control analyses (socioeconomic status and IgG)—There was a strong association be tween the presence of ocular toxoplasmosis and specific IgG antibodies to T. gondii. Of 184 cases, 183 cases (99.5%) had IgG antibodies to toxoplasmosis, compared with only 140 of the 181 age-matched control subjects (77.4%) (ageadjusted odds ratio, 13; P < .001). There was no
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confounding of this relationship by segment. No association was detected between ocular toxoplasmosis and the socioeconomic status measures (P > .05). Clinic survey of patients with posterior uveitis—Records of 200 patients with posterior uveitis at Clinica Silveira were surveyed; 50 had been tested for syphilis or tuberculosis. Testing consisted of VDRL and standard tuberculin skin tests performed at the local health department, and fluorescent treponemal antibody absorp tion tests performed by Laboratorio Fleury in Säo Paulo. (Twenty-seven patients were tested for both syphilis and tuberculosis, nine for syphilis alone, and 14 for tuberculosis alone.) None of the 24 tested for syphilis using VDRL tests or the 12 using fluorescent treponemal antibody absorption tests were positive. Four of the 41 patients with posterior uveitis (9.8%) tested for tuberculosis had areas of induration greater than 10 mm.
Discussion Population-based data on the prevalence of ocular toxoplasmosis in the world are sparse. The prevalence of ocular toxoplasmosis in the United States has been estimated to be 0.6% both in a community-based survey in Maryland and in a survey of cases by ophthalmologists in Louisiana. 1314 Estimates of the proportion of children with congenital infection who will develop retinochoroiditis vary from 80% by 20 years of age15 to 96% by 10 years of age.16 If one assumes that ocular toxoplasmosis secondary to ac quired infection is uncommon, incidence rates of congenital infection for a one-year birth cohort can be used to estimate the maximal eventual prevalence of retinochoroiditis scars in the same adult population. Estimates of the incidence of congenital infection range from 0.1% in Oslo17 and the United States 18 to 0.3% in France.19 Using these incidence estimates, the prevalence of ocular toxoplasmosis should be no higher than 0.1% to 0.3% for these regions. In our population-based study of this region of southern Brazil, 21.3% of examined individ uals 13 years or older had posterior uveitis attributed to toxoplasmosis on the basis of clinical appearance. This prevalence is over 30 times higher than previous estimates for ocular toxoplasmosis in other parts of the world. Be cause the grade 4 lesions were not included, the
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prevalence in the population is likely to be even greater. The study was designed to achieve a popula tion-based representative sample. Because of the poor quality of the unpaved rural roads and the difficulties in coordinating transportation to the clinics, the 63% participation rate was encouraging. The relative underrepresentation of boys and young adult men and overrepresentation of older women was expected because of the inability of farm laborers to leave farms unattended. As we were unable to detect a difference between the prevalence for men and women in our sample, the resultant gender differences between participants and nonparticipants were unlikely to have biased the over all estimate of the prevalence of ocular disease for the population. The older average age of the participants may have led to a slight overesti mate of the prevalence. Because of a lack of a demonstrated associa tion between ocular toxoplasmosis and socioeconomic status, no bias caused by the partici pants' higher socioeconomic status in our prevalence estimates was expected. Partici pants more frequently reported that someone in the household had had previous eye prob lems, and had been examined by an ophthal mologist. This potential bias may have resulted in a higher estimated prevalence of ocular dis ease. However, there were no differences be tween the proportions of participants and nonparticipants who had been seen at Clinica Silveira, or between the proportions with a previous diagnosis of ocular toxoplasmosis or other posterior uveitis. The higher socioeco nomic status of the participants may help ex plain this difference, because individuals from these households may have been better able to afford to visit an ophthalmologist. We were unable to estimate differences in visits to other ophthalmologists in the community. On the basis of this analysis, there was no evidence of a strong bias in the selection of our sample. Moreover, if all of the nonparticipants were actually free of posterior uveitis, the true preva lence for the sample would still be over 1 1 % — far in excess of any previous estimate. The correlation between physician diagnoses based on analysis of photographic readings was high (that is, differences of more than one grade were infrequent). This analysis served as a surrogate in confirming the diagnostic criteria used by one of us (C.S.) in the definitive eye examination. Even if differences of one grade were important, at most 23 of the 184 cases
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could be reclassified and the resulting estimat ed prevalence would still be over 15%. The results of photographic readings were not used to confirm or alter the diagnosis made by this observer (C.S.) in the definitive eye examination for several reasons. Photographs were not available for many individuals, and when they were available, there was a lack of direct comparability between the photographs and the ophthalmoscopic examination. Rea sons for this lack of comparability included the following: (1) both eyes were often affected but fundus photographs were available for only one eye, (2) sometimes lesions were seen in both the posterior pole and periphery, but only posterior pole lesions were photographed, and (3) photo graphs are not always able to detect subtle ophthalmoscopic findings that might influence grading. Several lines of evidence support the belief that T. gondii is the cause of the posterior uveitis occurring in this unusual epidemiologie pat tern. Toxoplasma organisms have been isolated from eyes that have characteristic lesions. 20 Histopathologic studies of 14 eviscerated or enu cleated eyes of 14 patients from this region of Brazil demonstrated viable and nonviable cysts associated with the characteristic eye lesions 11 (M.B., unpublished data, 1991). In some cases in which only nonviable cysts were observed, Toxoplasma organisms were demonstrated by the polymerase chain reaction. 21 No cysts have been found in contiguous normal-appearing retinal tissue in these same eyes (M.B., unpub lished data, 1991). The clinical appearance of lesions of ocular toxoplasmosis has long been considered to be specific.22 We initially relied solely on ophthal moscopic findings to diagnose disease for the following reasons: (1) we wished to determine the association of the ocular lesions seen with the presence of IgG antibodies to T. gondii, especially for less than characteristic lesions; (2) ocular toxoplasmosis and simultaneous low or undetectable levels of specific IgG antibodies have been described 22 ; and (3) so many individ uals were seropositive in this region of Brazil. For our study sample, serologie testing would not have assisted in making the diagnosis of ocular toxoplasmosis. Using our somewhat conservative clinical criteria, the probability of ocular toxoplasmosis for individuals with pos terior uveitis in this sample was 85.6%. A positive antibody test in someone with posteri or uveitis increased the probability of ocular toxoplasmosis only to 88.8%. That is, serologie
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testing contributed only marginally to the posi tive predictive value of ophthalmoscopic exam ination alone. Whether the single seronegative case was caused by misclassifkation or by un detectable levels of specific IgG antibodies has not yet been determined. Although clinically useful in making the di agnosis in Erechim, the extremely strong asso ciation of IgG antibodies with both posterior uveitis and clinically diagnosed ocular toxo plasmosis provides strong evidence that T. gondii is causally involved in inducing this posterior uveitis. The lesions seen in our study were generally considered to be typical of ocular toxoplasmo sis and had no characteristics suggesting other causes for the posterior uveitis. The essential absence of syphilis and low frequency of Mycobacterium tuberculosis infection in the surveyed patients with posterior uveitis virtually exclud ed these diseases as important causes of poster ior uveitis in this region. Moreover, the patients with posterior uveitis tested for these infections had atypical clinical signs and symptoms that raised a higher suspicion of tuberculous or syphilitic posterior uveitis. Although specific immunologie testing has not yet been per formed on the patients in our sample, no clini cal evidence exists that the population as a whole is immunosuppressed, or that other in fections suggestive of immunocompromise (cytomegalovirus, for example) are occurring at a higher than normal frequency. Congenital infection is an improbable expla nation for the high prevalence of ocular lesions in this region for several reasons. First, com pared with a prevalence of ocular disease in adults of over 20%, congenital infection with T. gondii appears to be relatively uncommon in this population. As mentioned before, clinical ly recognizable congenital toxoplasmosis has infrequently been observed by Erechim physi cians who were well aware of it (C.S., unpub lished data, 1991). Additionally, less than 1% of cord blood specimens collected from hospi tals in Erechim during 1990 tested positive for IgM antibodies to T. gondii (M.E.C., unpub lished data, 1991). Second, the epidemiologie pattern seen in this population was not consistent with the pattern expected of congenital infection. In the household survey, the prevalence of ocular tox oplasmosis was first noticed in the 9- to 12year-old age group. Most of the increase in prevalence occurred by the age of 17 to 20 years. The upper age limit of the infection
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pattern was consistent with previously de scribed patterns for retinochoroiditis in con genital toxoplasmosis 15 · 16 ; however, the paucity of scars in children younger than 9 years was not. Although the frequency has not yet been determined for our study sample, the occur rence of ocular lesions in multiple siblings from so many families in the region 11 could not be the sequela of congenital infection, under current assumptions that intrapartum infection confers lasting immunity. Although we did not find a statistically signif icant increase in the prevalence of ocular toxo plasmosis in patients older than 16 years, there appeared to be an increase in the prevalence in the 17- to 20-year-old age group. A larger sample size or mathematical modeling tech niques may be required to demonstrate this. The early age at which the prevalence of eye disease seems to stabilize suggests that the risk of developing ocular toxoplasmosis decreases for individuals infected at older ages. The in crease in prevalence at a younger age for fe males suggests a role of puberty in acquisition or pathogenesis of ocular lesions. This could be caused by hormonal effects or by a distinctive pattern of exposure to the infectious agent. The following hypotheses have been generat ed to explain the reasons for the unusually high prevalence of ocular toxoplasmosis in southern Brazil: (1) an early age of infection might be associated with a different host immune re sponse, (2) long-term and intense exposure to the organism may increase the chance that an individual with acquired infection will develop ocular complications, (3) strain differences may account for different manifestations of the dis ease (ocular tropism), (4) genetic or other host differences may predispose to the development of posterior uveitis, and (5) other agents or cofactors may interact with T. gondii infection to alter the natural course of the disease. Stud ies to address some of these hypothetical expla nations are in progress. ACKNOWLEDGMENT
George Reed, Ph.D., and Earl Bryant, Ph.D., assisted in statistical sampling design and analysis.
References 1. Perkins, E. S.: Ocular toxoplasmosis. Br. J. Ophthalmol. 57:1, 1973.
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2. Saari, M., Vuorre, I., Neiminen, H., and Räisänen, S.: Acquired toxoplasmic chorioretinitis. Arch. Ophthalmol. 94:1485, 1976. 3. Masur, H., Jones, T. C , Lempert, J. A., and Cherubini, T. D.: Outbreak of toxoplasmosis in a family and documentation of acquired retinochoroid itis. Am. J. Med. 64:396, 1978. 4. Garcia, A. G. P.: Congenital toxoplasmosis in two successive sibs. Arch. Dis. Child. 43:705, 1968. 5. Desmonts, G., Couvreur, J., and Thulliez, P.: Congenital toxoplasmosis. Five cases with motherto-child transmission of pre-pregnancy infection. Presse Med. 19:1445, 1990. 6. Marx-Chemla, C , Puygauthier-Toubas, D., Foudrinier. F., Dorangeon, P. H., Leulier, J., Quereux, C , Leroux, B., and Pinon, J. M.: Should immu nologie monitoring of toxoplasmosis seronegative pregnant women stop at delivery? Presse Med. 19:367, 1990. 7. Feldman, H. A., and Miller, L. T.: Congenital human toxoplasmosis. Ann. N.Y. Acad. Sci. 64:180, 1956. 8. Desmonts, G., and Couvreur, J.: Congenital tox oplasmosis. A prospective study of 378 pregnancies. N. Engl. J. Med. 290:1110, 1974. 9. Stern, G. A., and Romano, P. E.: Congenital ocular toxoplasmosis. Arch. Ophthalmol. 96:615, 1978. 10. Lou, P., Kazdan, J., and Basu, P. K.: Ocular toxoplasmosis in three consecutive siblings. Arch. Ophthalmol. 96:613, 1978. 11. Silveira, C , Belfort, R., Jr., Burnier, M., Jr., and Nussenblatt, R.: Acquired toxoplasmic infection as the cause of toxoplasmic retinochoroiditis in fami lies. Am. J. Ophthalmol. 106:362, 1988. 12. Camargo, M. E.: Improved technique of indi rect immunofluorescence for serological diagnosis of toxoplasmosis. Rev. Inst. Med. Trop. Sao Paulo 6:117, 1964. 13. Smith, R. E., and Ganley, J. P.: Ophthalmic survey of a community. 1. Abnormalities of the ocular fundus. Am. J. Ophthalmol. 74:1126, 1972. 14. Maetz, H. M., Kleinstein, R. N., Federico, D., and Wayne, J.: Estimated prevalence of ocular toxo plasmosis and toxocariasis in Alabama. J. Infect. Dis. 156:414, 1987. 15. Koppe, J. G., Loewer-Sieger, D. H., and de Roever-Bonnet, H.: Results of 20-year follow-up of congenital toxoplasmosis. Lancet 1:254, 1986. 16. Wilson, C. B., Remington, J. S., Stagno, S., and Reynolds, D. W.: Development of adverse sequelae in children born with subclinical congenital toxoplasma infection. Pediatrics 66:767, 1980. 17. Stray-Pedersen, B.: A prospective study of ac quired toxoplasmosis among 8,043 pregnant women in the Oslo area. Am. J. Obstet. Gynecol. 136:399, 1980. 18. Kimball, A. C , Kean, B. H., and Fuchs, F.: Congenital toxoplasmosis. A prospective study of 4,048 obstetric patients. Am. J. Obstet. Gynecol. 111:211, 1971.
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19. Desmonts, G., Couvreur, ]., and Ben Rachid, M. S.: Le toxoplasme. La mère et l'enfant. Arch. Fr. Pediatr. 22:1183, 1965. 20. Martins, M. C , Silveira, C , Jamra, L. F., Barros, P. M., Belfort, R., Jr., Rigueiro, M. P., and Neves, R.: Isolamento de Toxoplasma gondii de carnes e derivados e olhos humanos, provenientes de regiäo endemica de toxoplasmose ocular—Erechim—RS. Arq. Bras. Oftalmol. 52:148, 1989.
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21. Brézin, A. P., Egwuagu, C. E., Burnier, M., Jr., Silveira, C , Mahdi, R. M., Gazzinelli, R. T., Belfort, R., Jr., and Nussenblatt, R. B.: Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am. J. Ophthalmol. 110:599, 1990. 22. O'Connor, G. R.: Manifestations and manage ment of ocular toxoplasmosis. Bull. N.Y. Acad. Med. 50:192, 1974.
OPHTHALMIC MINIATURE
Because the way these tests work is, whatever part of your body they claim they want to look at, they insist u p o n entering you via some OTHER part. If you have, for example, an ankle problem, they'll say, " W h a t we're going to do is insert this one-inch-diameter exploratory garden hose into your eye socket and r u n it the length of your body, so you might experience some discomfort." Dave Barry, Dave Barry Talks Back N e w York, Crown Publishers, 1991, p. 228
Accepted for publication May 5, 1992. From the Epidemiology and Biometry Branch, Divi sion of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (Drs. Glasner and Kaslow, and Ms. KruszonMoran); Clinica Silveira, Erechim, Rio Grande do Sul, Brazil (Drs. Silveira and Silveira); Departamento de Oftalmologia, Escola Paulista de Medicina, Sào Paulo, Brazil (Drs. Martins, Burnier, and Belfort); Departa mento de Immunologia, Laboratorio Fleury, Sào Paulo, Brazil (Dr. Camargo); and Laboratory of Immunology, National Eye Institute, Bethesda, Maryland (Dr. Nussen blatt). This study was supported by funds made avail able through the U.S.-Brazil Presidential Initiative for Science and Technology. Reprint requests to Peter D. Glasner, M.D., Epidemiol ogy and Biometry Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Solar Bldg., Rm. 3A24, Bethesda, MD 20892.
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quela of postnatal rather than congenital infection. O C U L A R TOXOPLASMOSIS has long been consid ered a sequela of congenital infection with Toxoplasma gondii1 and only infrequently has it been reported to follow infection acquired postnatally in an immunocompetent host. 13 Except for two cases described in offspring of immuno competent mothers attributed to prepregnancy infection 4,5 and two cases of infection in newboms attributed to perinatal infection, 6 large studies have shown that pregnant women with intact immune systems transmit to their chil dren only during the pregnancy in which infec tion first developed. 7,8 Accordingly, few cases of ocular toxoplasmosis have been described in siblings, presumably because of the infrequent development of ocular disease secondary to acquired infection. 910 These tenets have been challenged by the following: (1) the identification of over 150 families in southern Brazil in which multiple siblings had ocular toxoplasmosis, 11 and (2) the diagnosis of ocular toxoplasmosis in over 8,000 patients from this same region during the past 30 years (C.S., unpublished data, 1990). To determine the prevalence of this disease in the region, to estimate the relative proportion caused by congenital and acquired infection, and to identify potential risk factors for ocular disease, we initiated a population-based study in the rural area surrounding the city of Erechim in southern Brazil in 1990.
Subjects and Methods Selection of the study population—Erechim (population, 71,000) is in northern Rio Grande do Sul (population, 8,500,000), the most south-
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em state of Brazil that borders on Uruguay and Argentina. Southern Brazil is hilly with a tem perate climate and has been settled in large part by Italian, German, and Polish immigrants dur ing the early part of this century. In much of the rural area, the predominant lifestyle is based on subsistence family farming. The study was based at Clinica Silveira, a private ophthalmology clinic in Erechim. The two ophthalmologists at the clinic are among six ophthalmologists who serve a population of approximately 200,000 from the city of Erechim and the surrounding rural region. A greater proportion of patients with posterior uveitis than would be expected are seen at Clinica Silveira because it specializes in this type of ocular disease in southern Brazil. The study was confined to the rural region within an approximately 20-km radius sur rounding Erechim. This region was selected because of its proximity to personnel and facili ties in Erechim and because of the anecdotal suggestion of a higher prevalence of disease in the surrounding countryside than in the city. Using topographic maps, sections of the area along accessible rural roads were grouped into 40 segments, with an estimated 20 to 25 houses alongside the roads of each segment. To main tain the rural characteristics of the sample, roads close to the city of Erechim and to nearby villages with dense populations indicated on topographic maps were excluded from the seg ments. Less accessible roads, not reliably marked on the maps, were also excluded be cause the absence of road signs in the region would have made it extremely difficult to relo cate houses on these roads once they were selected. A random sample of 12 segments was selected from the previously mentioned 40 for inclusion in the study. Epidemiologie data—The study was per formed from July through September 1990. All households within the defined segments were invited to participate. Local residents accompa nied the interviewers to act as liaisons and to translate to Polish or Italian when requested. The number and ages of household members and whether anyone in the household had a history of eye problems or a history of having been seen by an ophthalmologist were recorded for all households, including those not agree ing to participate. An adult representative of each participating household was asked to enu merate individual household members and to provide general household information on de mographic and socioeconomic status, food
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preparation, sanitation, and farming practices. After obtaining informed consent, household members were scheduled for a visit to one of two local clinics for ophthalmic examination and blood testing. Ophthalmic examinations—After dilation, in dividuals were screened with indirect ophthalmoscopy for the presence of posterior uveitis by the identification of active inflammatory retinal lesions, or pigmented retinal or retinochoroidal lesions consistent with healed retinochoroiditis. Screening eye examinations were per formed by a team of five visiting ophthalmolo gists from the Escola Paulista de Medicina, Sâo Paulo. Individuals suspected of having posterior uveitis on the screening examination were re ferred for a detailed, definitive eye examination performed by one of us (C.S.). After dilation, using slit-lamp and indirect ophthalmoscopy, the size, number, and location of lesions, and inflammatory and vascular ocular disease were documented according to a standardized proto col. Individuals were classified as having possi ble ocular toxoplasmosis if they had the follow ing: (1) one or more healed, focal, pigmented retinal or retinochoroidal lesions with welldelineated margins, or (2) one or more active focal retinal lesions. Individuals considered to have possible ocular toxoplasmosis were fur ther graded by using a subjective scale of the probability of ocular toxoplasmosis ranging from 1 to 5 (1, definite ocular toxoplasmosis; 2, high probability; 3, moderate probability; 4, low probability; and 5, probably not ocular toxoplasmosis). Because no preestablished cri teria were available, these lesions were graded on the basis of the observer's judgment of the probability of ocular toxoplasmosis. The judg ment incorporated the location of the lesions (macular, bilateral, or satellite lesions, for ex ample), the degree and location of pigmenta tion, the size of the lesions, the number of lesions, and the degree of atrophy of the choroid and retina. All grading was done indepen dently of serologie results. The three most frequent reasons for exclusion at the screening eye examination were inability of the patient to cooperate with the examina tion, inability of the examiner to visualize the fundus completely (both occurring mostly in young children), and the patient's need to leave the clinic before being examined because of transportation requirements. Individuals who were not permanent residents of the selected households and those referred from the screen-
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ing examination because of posterior uveitis and who failed to complete the definitive eye examination were also excluded. Participants were defined as all those who completed the screening eye examination, and if indicated, the definitive eye examination. Fundus photography—Fundus photography was performed by using a Zeiss Yena retinal camera and Ektachrome 25 61m (Kodak, Roch ester, New York). Photographs of seven stan dard fields were attempted in all individuals who had a grade of 1 to 4 identified in the definitive eye examination. Photographs were limited to fields with typical lesions or were not completed when the following occurred: (1) there was difficulty in visualizing the posterior pole, (2) there were technical problems with equipment, or (3) an individual was unable to cooperate. All available fundus photographs were read by two of us (R.B.N. and C.S.), who were masked to each other's readings. The results of photographic readings were not used to con firm or alter the diagnosis made in the definitive eye examination. Selection of control subjects without posterior uveitis—For subsequent case-control analyses, a control group with an age distribution compa rable to the patients with posterior uveitis was identified at the stage of the screening examina tion. Selection of one age-matched control sub ject from the pool of participants for each individual who screened positive for posterior uveitis was attempted. Control subjects were required to be free of posterior uveitis and were matched within 5 years of age to each partici pant with posterior uveitis identified in the screening eye examination. Laboratory testing and quality control—Ve nous blood was drawn on all consenting indi viduals who were older than 4 years and able to cooperate. Initial determination of IgG antibodies to T. gondii was performed on all individuals with posterior uveitis and on agematched control subjects, using a standard immunofluorescence test.12 A titer of 1:16 or greater was considered positive. Testing was repeated on 28 samples randomly selected from those that originally tested positive and ten samples randomly selected from those that originally tested negative. One of the 28 sam ples (3.6%) that originally tested positive tested negative on the repeat test. There was complete concordance between the original and repeat measurements for all samples that originally tested negative. Eighteen of the 28 retested
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positive samples (64%) had the same titer; three (11%) had titer differences of one dilu tion; and six (21%) had titer differences of two or more dilutions. Study participants were not tested for syphi lis and tuberculosis because previous experi ence with testing of patients with posterior uveitis indicated the prevalence of syphilis and tuberculosis would be low. To verify these low rates, records of patients with posterior uveitis seen at Clinica Silveira were systematically re viewed. Diagnostic criteria—We restricted the diagno sis of ocular toxoplasmosis to those persons with a grade of 1 to 3 in the definitive eye examination. Although some individuals with grade 4 lesions possibly had ocular toxoplas mosis, we used a more conservative cutoff to avoid overestimating the true population prev alence. Using these criteria, all patients but one were seropositive. Analyses of risk factors for ocular toxoplasmosis were therefore based on cases with a moderate probability of ophthalmoscopically defined disease (grades 1 to 3) and control subjects with no evidence of pos terior uveitis. For determining interobserver variability, grades 1 to 5 were used. Review of patient records—The patient re cords at Clinica Silveira were searched to deter mine the frequency with which participants and nonparticipants had been seen at the clinic and had had posterior uveitis previously diag nosed. Statistical analysis—Analyses were perform ed using Statistical Analysis Software, version 5.18 (SAS Institute, Inc., Cary, North Carolina). To determine the representativeness of the sam ple, differences between participants and nonparticipants in the distributions of their epide miologie characteristics were analyzed using the chi-square or Fisher's exact test. Tests of association between IgG titer and posterior uveitis also using the chi-square or Fisher's exact test were performed to strengthen the clinical diagnosis. Confounding effects of age, gender, socioeconomic status, and segment on potential associations were evaluated by using stratified analyses and the Mantel-Haenszel chi-square test, when the potential confounder was known to be associated with both the exposure variable and the outcome variable of interest. The Mantel-Haenszel summary odds ratio was used in situations in which confound ing existed. Tests for a trend in the relationship between age and diagnosis of ocular toxoplas mosis were performed by using the extended
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Mantel-Haenszel chi-square test. A P value of less than .01 was considered significant; how ever, all P values greater than or equal to .001 were recorded.
Results Characteristics and representativeness of the study sample—Of 380 households (1,662 indi viduals) selected for study, 1,616 members from 366 of the households agreed to partici pate. Initial visits for the screening eye exami nation were made by 1,126 individuals from 327 households. Of these, we excluded 84, including two individuals with posterior uveitis identified on the screening eye examination who did not complete the definitive eye exami nation. Six (7.1%) of these individuals were specifically excluded because of the inability to visualize the fundus completely; five were younger than 6 years. The median age of those excluded was 4 years. The remaining 1,042 individuals constituted the study sample, with an overall participation rate of 63%. The participants were older and more fre quently women than the nonparticipants (P < .001). Among the participants, there was a relative underrepresentation of males younger than 30 years (24% of participants vs 38% of nonparticipants, P < .001) and a relative overrepresentation of women older than 30 years (26% of participants vs 16% of nonpartici pants, P < .001). A history of someone in the household having had eye problems and having been seen by an ophthalmologist was slightly more common among participants than nonparticipants (64% vs 58%). However, there was no significant difference between the propor tion of individuals who had previously been seen or in whom posterior uveitis or ocular toxoplasmosis had been diagnosed at Clinica Silveira. Socioeconomic measures, such as hav ing electricity, a telephone, and a car, were more prevalent in participants than in nonpar ticipants (P < .001). Frequency of ocular toxoplasmosis—Of the 1,042 participants, 215 (20.6%) had possible ocular toxoplasmosis. One hundred twentyeight participants (12.3%) had a grade of 1; 33 participants (3.2%) had a grade of 2; 23 partici pants (2.2%) had a grade of 3; 20 participants (1.9%) had a grade of 4; and 11 participants (1.1%) had a grade of 5. Six individuals (0.6%), all of whom had a grade of 1, had active lesions.
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Only five of ten individuals with a grade of 5 had anti-toxoplasma antibodies, as compared with 201 of 203 (99%) of those individuals with sera available and grades 1 to 4. The overall distribution of cases by age was determined by using the previously described definition (Fig. 1). The prevalence of ocular toxoplasmosis for the total sample was 17.7% (95% confidence interval, 15.4% to 20.1%). The prevalence of ocular toxoplasmosis increased with age. The prevalence was 0.9% (one pa tient) in 1- to 8-year-olds, 4.3% in 9- to 12year-olds, 14.3% in 13- to 16-year-olds, and 24.6% in 17- to 20-year-olds. The prevalence in 13- to 16-year-olds was significantly higher than in either of the two lowest age groups (P = .018). The prevalence of ocular toxoplasmosis appeared to increase from the 13- to 16-yearold age group to the 17- to 20-year-old age group; however, this was not statistically sig nificant by using trend analysis, by comparing to all older persons, or by comparing consecu tive five-year age groups. The overall preva lence of ocular toxoplasmosis in individuals 13 years or older was 21.3% (95% confidence in terval, 18.6% to 24.2%). There was no significant difference in preva lence between males (16.0%; 95% confidence interval, 12.9% to 19.6%) and females (19.1%; 95% confidence interval, 15.9% to 22.7%). However, analysis by age strata showed higher rates for females in the 13- to 16-year-old age group (22.9%) than males in this same age group (4.7%, P = .013). Photographic readings and interobserver variability—Photographs were available on 142 in-
0
5
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Fig. 1 (Glasner and associates). Prevalence of ocu lar toxoplasmosis (grades 1 through 3) by age group with 95% confidence intervals. Age groups are desig nated by the midpoint of the age interval.
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" -*&r Fig. 2 (Glasner and associates). Examples of fundus photographs of study participants that were graded concordantly on a scale of 1 to 4. Top left. Grade 1; top right, grade 2; bottom left, grade 3; and bottom right, grade 4. dividuals (103 individuals with a grade of 1 [80%], 22 individuals with a grade of 2 [67%], 11 individuals with a grade of 3 [48%], and six individuals with a grade of 4 [30%]). A compar ison of photographic readings by two of us (C.S. and R.B.N.) showed differences of one grade in 65 individuals (45.8%) and two grades in five individuals (3.5%). There was no consis tent trend toward upgrading or downgrading of lesions across grades, by using readings by one of us (C.S.) as a standard. Examples of fundus
photographs of study participants that were graded concordantly on a scale of 1 to 4 are shown in Figure 2. Case-control analyses (socioeconomic status and IgG)—There was a strong association be tween the presence of ocular toxoplasmosis and specific IgG antibodies to T. gondii. Of 184 cases, 183 cases (99.5%) had IgG antibodies to toxoplasmosis, compared with only 140 of the 181 age-matched control subjects (77.4%) (ageadjusted odds ratio, 13; P < .001). There was no
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confounding of this relationship by segment. No association was detected between ocular toxoplasmosis and the socioeconomic status measures (P > .05). Clinic survey of patients with posterior uveitis—Records of 200 patients with posterior uveitis at Clinica Silveira were surveyed; 50 had been tested for syphilis or tuberculosis. Testing consisted of VDRL and standard tuberculin skin tests performed at the local health department, and fluorescent treponemal antibody absorp tion tests performed by Laboratorio Fleury in Säo Paulo. (Twenty-seven patients were tested for both syphilis and tuberculosis, nine for syphilis alone, and 14 for tuberculosis alone.) None of the 24 tested for syphilis using VDRL tests or the 12 using fluorescent treponemal antibody absorption tests were positive. Four of the 41 patients with posterior uveitis (9.8%) tested for tuberculosis had areas of induration greater than 10 mm.
Discussion Population-based data on the prevalence of ocular toxoplasmosis in the world are sparse. The prevalence of ocular toxoplasmosis in the United States has been estimated to be 0.6% both in a community-based survey in Maryland and in a survey of cases by ophthalmologists in Louisiana. 1314 Estimates of the proportion of children with congenital infection who will develop retinochoroiditis vary from 80% by 20 years of age15 to 96% by 10 years of age.16 If one assumes that ocular toxoplasmosis secondary to ac quired infection is uncommon, incidence rates of congenital infection for a one-year birth cohort can be used to estimate the maximal eventual prevalence of retinochoroiditis scars in the same adult population. Estimates of the incidence of congenital infection range from 0.1% in Oslo17 and the United States 18 to 0.3% in France.19 Using these incidence estimates, the prevalence of ocular toxoplasmosis should be no higher than 0.1% to 0.3% for these regions. In our population-based study of this region of southern Brazil, 21.3% of examined individ uals 13 years or older had posterior uveitis attributed to toxoplasmosis on the basis of clinical appearance. This prevalence is over 30 times higher than previous estimates for ocular toxoplasmosis in other parts of the world. Be cause the grade 4 lesions were not included, the
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prevalence in the population is likely to be even greater. The study was designed to achieve a popula tion-based representative sample. Because of the poor quality of the unpaved rural roads and the difficulties in coordinating transportation to the clinics, the 63% participation rate was encouraging. The relative underrepresentation of boys and young adult men and overrepresentation of older women was expected because of the inability of farm laborers to leave farms unattended. As we were unable to detect a difference between the prevalence for men and women in our sample, the resultant gender differences between participants and nonparticipants were unlikely to have biased the over all estimate of the prevalence of ocular disease for the population. The older average age of the participants may have led to a slight overesti mate of the prevalence. Because of a lack of a demonstrated associa tion between ocular toxoplasmosis and socioeconomic status, no bias caused by the partici pants' higher socioeconomic status in our prevalence estimates was expected. Partici pants more frequently reported that someone in the household had had previous eye prob lems, and had been examined by an ophthal mologist. This potential bias may have resulted in a higher estimated prevalence of ocular dis ease. However, there were no differences be tween the proportions of participants and nonparticipants who had been seen at Clinica Silveira, or between the proportions with a previous diagnosis of ocular toxoplasmosis or other posterior uveitis. The higher socioeco nomic status of the participants may help ex plain this difference, because individuals from these households may have been better able to afford to visit an ophthalmologist. We were unable to estimate differences in visits to other ophthalmologists in the community. On the basis of this analysis, there was no evidence of a strong bias in the selection of our sample. Moreover, if all of the nonparticipants were actually free of posterior uveitis, the true preva lence for the sample would still be over 1 1 % — far in excess of any previous estimate. The correlation between physician diagnoses based on analysis of photographic readings was high (that is, differences of more than one grade were infrequent). This analysis served as a surrogate in confirming the diagnostic criteria used by one of us (C.S.) in the definitive eye examination. Even if differences of one grade were important, at most 23 of the 184 cases
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could be reclassified and the resulting estimat ed prevalence would still be over 15%. The results of photographic readings were not used to confirm or alter the diagnosis made by this observer (C.S.) in the definitive eye examination for several reasons. Photographs were not available for many individuals, and when they were available, there was a lack of direct comparability between the photographs and the ophthalmoscopic examination. Rea sons for this lack of comparability included the following: (1) both eyes were often affected but fundus photographs were available for only one eye, (2) sometimes lesions were seen in both the posterior pole and periphery, but only posterior pole lesions were photographed, and (3) photo graphs are not always able to detect subtle ophthalmoscopic findings that might influence grading. Several lines of evidence support the belief that T. gondii is the cause of the posterior uveitis occurring in this unusual epidemiologie pat tern. Toxoplasma organisms have been isolated from eyes that have characteristic lesions. 20 Histopathologic studies of 14 eviscerated or enu cleated eyes of 14 patients from this region of Brazil demonstrated viable and nonviable cysts associated with the characteristic eye lesions 11 (M.B., unpublished data, 1991). In some cases in which only nonviable cysts were observed, Toxoplasma organisms were demonstrated by the polymerase chain reaction. 21 No cysts have been found in contiguous normal-appearing retinal tissue in these same eyes (M.B., unpub lished data, 1991). The clinical appearance of lesions of ocular toxoplasmosis has long been considered to be specific.22 We initially relied solely on ophthal moscopic findings to diagnose disease for the following reasons: (1) we wished to determine the association of the ocular lesions seen with the presence of IgG antibodies to T. gondii, especially for less than characteristic lesions; (2) ocular toxoplasmosis and simultaneous low or undetectable levels of specific IgG antibodies have been described 22 ; and (3) so many individ uals were seropositive in this region of Brazil. For our study sample, serologie testing would not have assisted in making the diagnosis of ocular toxoplasmosis. Using our somewhat conservative clinical criteria, the probability of ocular toxoplasmosis for individuals with pos terior uveitis in this sample was 85.6%. A positive antibody test in someone with posteri or uveitis increased the probability of ocular toxoplasmosis only to 88.8%. That is, serologie
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testing contributed only marginally to the posi tive predictive value of ophthalmoscopic exam ination alone. Whether the single seronegative case was caused by misclassifkation or by un detectable levels of specific IgG antibodies has not yet been determined. Although clinically useful in making the di agnosis in Erechim, the extremely strong asso ciation of IgG antibodies with both posterior uveitis and clinically diagnosed ocular toxo plasmosis provides strong evidence that T. gondii is causally involved in inducing this posterior uveitis. The lesions seen in our study were generally considered to be typical of ocular toxoplasmo sis and had no characteristics suggesting other causes for the posterior uveitis. The essential absence of syphilis and low frequency of Mycobacterium tuberculosis infection in the surveyed patients with posterior uveitis virtually exclud ed these diseases as important causes of poster ior uveitis in this region. Moreover, the patients with posterior uveitis tested for these infections had atypical clinical signs and symptoms that raised a higher suspicion of tuberculous or syphilitic posterior uveitis. Although specific immunologie testing has not yet been per formed on the patients in our sample, no clini cal evidence exists that the population as a whole is immunosuppressed, or that other in fections suggestive of immunocompromise (cytomegalovirus, for example) are occurring at a higher than normal frequency. Congenital infection is an improbable expla nation for the high prevalence of ocular lesions in this region for several reasons. First, com pared with a prevalence of ocular disease in adults of over 20%, congenital infection with T. gondii appears to be relatively uncommon in this population. As mentioned before, clinical ly recognizable congenital toxoplasmosis has infrequently been observed by Erechim physi cians who were well aware of it (C.S., unpub lished data, 1991). Additionally, less than 1% of cord blood specimens collected from hospi tals in Erechim during 1990 tested positive for IgM antibodies to T. gondii (M.E.C., unpub lished data, 1991). Second, the epidemiologie pattern seen in this population was not consistent with the pattern expected of congenital infection. In the household survey, the prevalence of ocular tox oplasmosis was first noticed in the 9- to 12year-old age group. Most of the increase in prevalence occurred by the age of 17 to 20 years. The upper age limit of the infection
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pattern was consistent with previously de scribed patterns for retinochoroiditis in con genital toxoplasmosis 15 · 16 ; however, the paucity of scars in children younger than 9 years was not. Although the frequency has not yet been determined for our study sample, the occur rence of ocular lesions in multiple siblings from so many families in the region 11 could not be the sequela of congenital infection, under current assumptions that intrapartum infection confers lasting immunity. Although we did not find a statistically signif icant increase in the prevalence of ocular toxo plasmosis in patients older than 16 years, there appeared to be an increase in the prevalence in the 17- to 20-year-old age group. A larger sample size or mathematical modeling tech niques may be required to demonstrate this. The early age at which the prevalence of eye disease seems to stabilize suggests that the risk of developing ocular toxoplasmosis decreases for individuals infected at older ages. The in crease in prevalence at a younger age for fe males suggests a role of puberty in acquisition or pathogenesis of ocular lesions. This could be caused by hormonal effects or by a distinctive pattern of exposure to the infectious agent. The following hypotheses have been generat ed to explain the reasons for the unusually high prevalence of ocular toxoplasmosis in southern Brazil: (1) an early age of infection might be associated with a different host immune re sponse, (2) long-term and intense exposure to the organism may increase the chance that an individual with acquired infection will develop ocular complications, (3) strain differences may account for different manifestations of the dis ease (ocular tropism), (4) genetic or other host differences may predispose to the development of posterior uveitis, and (5) other agents or cofactors may interact with T. gondii infection to alter the natural course of the disease. Stud ies to address some of these hypothetical expla nations are in progress. ACKNOWLEDGMENT
George Reed, Ph.D., and Earl Bryant, Ph.D., assisted in statistical sampling design and analysis.
References 1. Perkins, E. S.: Ocular toxoplasmosis. Br. J. Ophthalmol. 57:1, 1973.
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2. Saari, M., Vuorre, I., Neiminen, H., and Räisänen, S.: Acquired toxoplasmic chorioretinitis. Arch. Ophthalmol. 94:1485, 1976. 3. Masur, H., Jones, T. C , Lempert, J. A., and Cherubini, T. D.: Outbreak of toxoplasmosis in a family and documentation of acquired retinochoroid itis. Am. J. Med. 64:396, 1978. 4. Garcia, A. G. P.: Congenital toxoplasmosis in two successive sibs. Arch. Dis. Child. 43:705, 1968. 5. Desmonts, G., Couvreur, J., and Thulliez, P.: Congenital toxoplasmosis. Five cases with motherto-child transmission of pre-pregnancy infection. Presse Med. 19:1445, 1990. 6. Marx-Chemla, C , Puygauthier-Toubas, D., Foudrinier. F., Dorangeon, P. H., Leulier, J., Quereux, C , Leroux, B., and Pinon, J. M.: Should immu nologie monitoring of toxoplasmosis seronegative pregnant women stop at delivery? Presse Med. 19:367, 1990. 7. Feldman, H. A., and Miller, L. T.: Congenital human toxoplasmosis. Ann. N.Y. Acad. Sci. 64:180, 1956. 8. Desmonts, G., and Couvreur, J.: Congenital tox oplasmosis. A prospective study of 378 pregnancies. N. Engl. J. Med. 290:1110, 1974. 9. Stern, G. A., and Romano, P. E.: Congenital ocular toxoplasmosis. Arch. Ophthalmol. 96:615, 1978. 10. Lou, P., Kazdan, J., and Basu, P. K.: Ocular toxoplasmosis in three consecutive siblings. Arch. Ophthalmol. 96:613, 1978. 11. Silveira, C , Belfort, R., Jr., Burnier, M., Jr., and Nussenblatt, R.: Acquired toxoplasmic infection as the cause of toxoplasmic retinochoroiditis in fami lies. Am. J. Ophthalmol. 106:362, 1988. 12. Camargo, M. E.: Improved technique of indi rect immunofluorescence for serological diagnosis of toxoplasmosis. Rev. Inst. Med. Trop. Sao Paulo 6:117, 1964. 13. Smith, R. E., and Ganley, J. P.: Ophthalmic survey of a community. 1. Abnormalities of the ocular fundus. Am. J. Ophthalmol. 74:1126, 1972. 14. Maetz, H. M., Kleinstein, R. N., Federico, D., and Wayne, J.: Estimated prevalence of ocular toxo plasmosis and toxocariasis in Alabama. J. Infect. Dis. 156:414, 1987. 15. Koppe, J. G., Loewer-Sieger, D. H., and de Roever-Bonnet, H.: Results of 20-year follow-up of congenital toxoplasmosis. Lancet 1:254, 1986. 16. Wilson, C. B., Remington, J. S., Stagno, S., and Reynolds, D. W.: Development of adverse sequelae in children born with subclinical congenital toxoplasma infection. Pediatrics 66:767, 1980. 17. Stray-Pedersen, B.: A prospective study of ac quired toxoplasmosis among 8,043 pregnant women in the Oslo area. Am. J. Obstet. Gynecol. 136:399, 1980. 18. Kimball, A. C , Kean, B. H., and Fuchs, F.: Congenital toxoplasmosis. A prospective study of 4,048 obstetric patients. Am. J. Obstet. Gynecol. 111:211, 1971.
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19. Desmonts, G., Couvreur, ]., and Ben Rachid, M. S.: Le toxoplasme. La mère et l'enfant. Arch. Fr. Pediatr. 22:1183, 1965. 20. Martins, M. C , Silveira, C , Jamra, L. F., Barros, P. M., Belfort, R., Jr., Rigueiro, M. P., and Neves, R.: Isolamento de Toxoplasma gondii de carnes e derivados e olhos humanos, provenientes de regiäo endemica de toxoplasmose ocular—Erechim—RS. Arq. Bras. Oftalmol. 52:148, 1989.
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21. Brézin, A. P., Egwuagu, C. E., Burnier, M., Jr., Silveira, C , Mahdi, R. M., Gazzinelli, R. T., Belfort, R., Jr., and Nussenblatt, R. B.: Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am. J. Ophthalmol. 110:599, 1990. 22. O'Connor, G. R.: Manifestations and manage ment of ocular toxoplasmosis. Bull. N.Y. Acad. Med. 50:192, 1974.
OPHTHALMIC MINIATURE
Because the way these tests work is, whatever part of your body they claim they want to look at, they insist u p o n entering you via some OTHER part. If you have, for example, an ankle problem, they'll say, " W h a t we're going to do is insert this one-inch-diameter exploratory garden hose into your eye socket and r u n it the length of your body, so you might experience some discomfort." Dave Barry, Dave Barry Talks Back N e w York, Crown Publishers, 1991, p. 228
