Incidence of presumed cytomegalovirus retinitis in HIV-infected pediatric patients

Incidence of Presumed Cytomegalovirus Retinitis in HIV-Infected Pediatric Patients Lee T. Du, MD,a David K. Coats, MD,a Mark W. Kline, MD,b Howard M. Rosenblatt, MD,b Beverly Bohannon, RN, BSN,b Charles F. Contant, Jr, PhD,c Yi-Xi Zhong, MD,d Betty Brown, MS,b Paul G. Steinkuller, MD,a and Evelyn A. Paysse, MDa

Introduction: Large population studies of adult patients suggest an incidence of cytomegalovirus (CMV) retinitis as high as 19% to 20% as a late complication of adult HIV infection. We conducted this prospective study of a large cohort of HIV-infected children to determine the incidence of CMV retinitis in HIV-infected children. Methods: From January 1984 to August 1997, 173 HIV-infected children were followed up for an average of 55.3 months (13-164 months). The patients were seen in the Department of Pediatrics at least once every 6 months. Ophthalmologic examinations were initiated when a patient’s CD4 count dropped below 50 or sooner if required for ophthalmologic or other indications. Ophthalmologic examination was then repeated every 6 months. Results: A total of 116 (67%) of 173 patients underwent ophthalmologic examination. Four (3.4%) of 116 patients had CMV retinitis at a mean time of 17.3 months (8-38 months) after their CD4 counts dropped below 20. None of the 4 patients with CMV retinitis had subjective visual complaints despite advanced retinitis. Three patients had bilateral and 1 patient had unilateral CMV retinitis. Conclusions: CMV retinitis occurred infrequently in HIV-infected pediatric patients and was diagnosed only in patients with a CD4 count below 20. Routine ophthalmologic screening examinations may not be necessary in pediatric patients until the CD4 count is below 20. Because children may not complain of decreased vision, at-risk children should undergo frequent ophthalmologic examination. (J AAPOS 1999;3:245-9) ytomegalovirus (CMV) retinitis is the most common opportunistic ocular infection in adult HIVinfected patients and the leading cause of blindness associated with acquired immunodeficiency syndrome (AIDS) in adult patients.1-3 CMV retinitis is typically a late complication of AIDS with severe CD4 lymphocyte depletion common at diagnosis. CMV infection is easily recognized as a full-thickness retinal necrosis, appearing as a distinctly bordered yellowish opacification, associated with hemorrhages and hard exudates. The infection typically spreads along the major vascular arcades, but may begin anywhere in the retina. Untreated, the retinitis usually progresses relentlessly, ultimately resulting in irreversible

C

From the Baylor College of Medicine, Texas Children’s Hospital, Department of Ophthalmology,a Department of Pediatrics/Section of Allergy and Immunology,b and Department of Neurosurgery,c Houston, Texas; and the Human Genetics Center, School of Public Health, the University of Texas at Houston, Houston, Texas.d Supported in part by an unrestricted research grant from Research to Prevent Blindness, Inc, New York, New York. Presented at the Annual Meeting of the Association for Pediatric Ophthalmology and Strabismus in Palm Springs, California, April 4-8, 1998, and at the Association for Research in Vision Ophthalmology in Ft Lauderdale, Florida, May 10-15, 1998. Submitted April 8, 1998. Revision accepted November 28, 1998. Reprint requests: David K. Coats, MD, Department of Ophthalmology, Texas Children’s Hospital, 1102 Bates #300, MC 3-2700, Houston, TX 77030-2399 (e-mail: dcoats@ bcm.tmc.edu). Copyright © 1999 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/99 $8.00 + 0 75/1/99744

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blindness. Reported incidence of CMV retinitis in adult HIV-infected patients varies considerably from 6% to 34%.1-8 Most recent large population studies of adult patients suggest the incidence of CMV retinitis is about 19% to 20%.7,8 CMV retinitis as a complication of pediatric AIDS was first reported in 1986.9 Thereafter, several reports have appeared, with a 5-case report being the largest series.10-14 However, there have been little prospective data on large populations of HIV-positive children for a sufficiently long period of time to determine the incidence of CMV retinitis. We conducted this nonconcurrent prospective study (ie, ophthalmologic data were collected prospectively as a part of a larger HIV study that was not set up to specifically address ophthalmologic issues) of a large group of HIV-infected pediatric patients to determine the incidence and outcome of CMV retinitis in children.

SUBJECTS AND METHODS This study was conducted between January 1984 and August 1997, at Texas Children’s Hospital, Houston, Texas. All study subjects were children younger than 18 years at the time of HIV diagnosis. The Centers for Disease Control and Prevention (CDC) surveillance case definition for AIDS and the 1994 CDC revised classification system for HIV in children younger than 13 years were used to diagnose AIDS and HIV infection.15,16 A total of 241 HIV-positive pediatric patients were followed August 1999

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246 Du et al TABLE 2. Follow-up intervals

TABLE 1. Characteristics of the study population (N = 173)

Sex Male Female Race African American Latin American White Other Age at entry into study ≤1 y >1 y and ≤2 y >2 y and ≤6 y >6 y and ≤10 y >10 y Mode of HIV transmission Maternal-fetal Transfusion Hemophilia A Hemophilia B Heterosexual contact Homosexual contact Unknown Year of entry into study 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996

No. of subjects

Percentage (%)

81 92

46.8 53.2

104 33 31 5

60.1 19.1 17.9 2.9

81 20 39 14 19

46.8 11.6 22.5 8.1 11.0

137 21 5 2 5 2 1

79.2 12.1 2.9 1.2 2.9 1.2 0.6

3 3 13 16 12 9 23 21 17 16 14 16 11

1.7 1.7 7.5 9.2 6.9 5.2 13.3 12.1 9.8 9.2 8.1 9.2 6.4

Follow-up interval

No. of subjects

13 m to 24 m 25 m to 48 m 49 m to 72 m 73 m to 96 m ≥97 m Total

Percentage (%)

36 50 40 24 23 173

20.8 28.9 23.1 13.9 13.3 100

TABLE 3. CD4 counts at the initial and most recent evaluation

up, among which 173 patients met the minimum followup criterion of 12 months. Patients with follow-up of fewer than 12 months were excluded from the study because we wanted to have at least 2 clinical follow-up examinations at 6-month intervals to ensure consistent follow-up information. Failure to meet the follow-up requirements occurred in 68 patients for a variety of reasons including out-of-town move, early death, and loss to follow-up. The demographic characteristics of the study population are summarized in Table 1. Among the 173 patients studied, there were 81 male patients (46.8%) and 92 female patients (53.2%). The mean age at HIV-positive diagnosis was 35.5 months (0-215 months). The mean follow-up interval was 55.3 months (13-164 months), as tabulated in Table 2. The patients were evaluated by their HIV specialists every 6 months or more frequently, if the clinical situation required. A CD4 lymphocyte count was done at entry into the study and repeated every 6 months. The CD4 status

Initial evaluation CD4 ≤20 CD4 21-50 CD4 51-100 CD4 101-200 CD4 >200 Total

Most recent evaluation

No. of subjects

%

No. of subjects

%

7 5 6 7 148 173

4.0 2.9 3.5 4.0 85.5 100

41 13 11 19 89 173

23.7 7.5 6.4 11.0 51.4 100

was recorded as an absolute value and as a percentage of the total lymphocyte count. The CD4 lymphocyte to absolute lymphocyte count (ALC) ratio (CD4:ALC) corrects for the normal age-related decline in the absolute CD4 count. All the patients received other follow-up studies, diagnostic procedures, and treatments appropriate to their clinical situation. Ophthalmologic examinations were initiated when the CD4 count dropped below 50, on the basis of data from adult patients with HIV showing that CMV retinitis does not typically develop until the CD4 count falls below 50 (cells per millimeter).7,8 An ophthalmologic examination was also obtained on any patient with objective or subjective visual complaints. Ophthalmologic follow-up examinations were then repeated out every 6 months. Sixty-two patients received ophthalmologic examination despite a CD4 count greater than 50 because examination was requested by referring physicians, by the patient’s family, or as part of a larger systematic evaluation. Therefore, a total of 116 (67%) of 173 patients underwent ophthalmologic examination. Lymphocyte subsets were determined using standard 2color flow cytometry (before May 1995) or 3-color flow cytometry subsequent to that date. Monoclonal antibodies were purchased from Becton Dickinson Immunocytometry Systems (San Jose, Calif) and Coulter (Hialeah, Fla). All laboratory samples were run using the prevailing guidelines for CD4 T-cell determination as outlined by the Division of AIDS Research and the CDC. Gating for 2-color flow was based on forward and side scatter, whereas gating for 3-color flow was performed using a combination of light scatter and CD45 staining. CD4 determinations by 2-color and 3-color flow methodologies were comparable and related to each other. Absolute CD4 counts were calculated using the percentages of CD4 lym-

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TABLE 4. Pediatric HIV classification of CDC* Clinical categories Immunologic suppression 1: No 2. Moderate 3. Severe

N: No signs/ symptoms

A: Mild signs/ symptoms

B: Moderate signs/ symptoms

C: Severe signs/ symptoms

N1 N2 N3

A1 A2 A3

B1 B2 B3

C1 C2 C3

*The immunologic suppression is measured by the CD4 count and is age dependent. In any age group, severe immunologic suppression is indicated if CD4 count is less than 200. For clinical categories, a category A patient has 2 or more of the following: lymphadenopathy, hepatomegaly, splenomegaly, dermatitis, parotitis, and recurrent upper respiratory tract infection. A category C patient has any of the AIDS-defining conditions, such as serious bacterial infection, candidiasis, coccidioidomycosis, cryptococcosis, CMV infection, encephalopathy, Kaposi’s sarcoma, lymphoma, Mycobacterium tuberculosis, Pneumocystis carinii pneumonia, and wasting syndrome. A category B patient has conditions not listed in category A or category C.

TABLE 5. Characteristics of 4 children who had CMV retinitis Case no.

Age at HIV-postive diagnosis (months) Follow-up interval from entry into study to CMV diagnosis (months) Initial CD4 counts CD4 counts (CD4/ALC) at time of CMV retinitis diagnosis Interval between CD4 ≤20 and CMV retinitis diagnosis (months) Interval between CMV retinitis diagnosis and death (months) Involved eye(s)

phocytes and the ALC derived from the standard complete blood count performed on a Techincon Model H2 and a 100-cell manual differential.

RESULTS The CD4 counts of the study patients at the time of presentation and at the time of the most recent examination are tabulated in Table 3. Various degrees of decline of CD4 counts were shown in 136 (78.6%) patients during the study. Sixty-nine (39.9%) of the 173 patients died of complications of AIDS during the follow-up period. These 69 patients had a mean follow-up of 44.0 months (13-126 months). The diagnosis of CMV retinitis was presumed on the basis of the presence of typical findings of retinal necrosis associated with hemorrhage and exudates. CMV serologic reactions and cultures were not obtained. No patient had CMV retinitis at the time of initial ophthalmologic examination. Four (3.4%) of 116 patients who received an ophthalmologic examination had clinical features consistent with CMV retinitis during the follow-up period. All 4 patients were female, and all had AIDS-defining illnesses in the C3 category as defined by the CDC.16 The C3 disease category indicates the presence of severe AIDS-related signs and symptoms and laboratory evidence of severe immunologic suppression. The CDC pediatric HIV classification categories are reproduced in Table 4. None of the patients with CMV retinitis had subjective visual complaints at the time of CMV retinitis diagnosis. One patient with CMV retinitis with bilateral disease did not complain of visual problems, but had begun to bump

1

2

3

4

Mean

10 126 1815 6(1) 38 2 OU

30 22 47 16(0.8) 13 5 OU

152 44 92 2(0.1) 8 22 OD

65 22 16 6(1.4) 10 4 OU

64.3 53.0 492.5 10.0(0.82) 17.3 8.3

into walls in the weeks before CMV retinitis diagnosis. CMV retinitis developed at a mean interval of 17.3 months (8-38 months) after the CD4 count dropped below 20 and at a mean of 21.3 months (10-44 months) after the CD4 count dropped below 50. The 4 patients with CMV retinitis died at a mean interval of 8.3 months (2-22 months) after the diagnosis of CMV retinitis was made (Table 5). All were treated with ganciclovir. Bilateral involvement was present at the time of diagnosis in 3 of the 4 patients with CMV retinitis (Figure). Among the 3 bilateral cases, 2 patients (Cases 1 and 2) showed rapid progression of retinitis, developing widespread hemorrhage, exudates, and subsequent retinal detachment and blindness. Case Patient 4 was first noted to have bilateral exudative retinal lesions in the posterior pole of each eye in a perivascular distribution. She showed mild improvement of her retinitis on subsequent follow-up examination 2 months after initiation of ganciclovir, but died 4 months after the diagnosis of CMV retinitis was made. Only 1 patient with CMV retinitis (Case 3) had unilateral ocular involvement. When CMV retinitis was first diagnosed in her right eye, there were multiple areas of fluffy white infiltrates and necrosis along the superior arcade with large areas of intraretinal hemorrhage. Visual acuity of the involved eye at the time of diagnosis was 20/20. The retinitis gradually progressed and became more widespread. Visual acuity of the involved eye decreased to 20/100 at 9 months and to light perception at 11 months. She survived for 22 months after the diagnosis of CMV retinitis was made, the longest of the 4 patients

248 Du et al

Clinical photograph of severe CMV retinitis in Case 1.

with CMV retinitis. CMV retinitis did not develop in the contralateral eye. We compared the survival time from the first time the CD4 count was detected at or below 20 for the 4 patients with CMV retinitis and for the 50 patients without CMV retinitis. The mean survival time for the 4 patients with CMV retinitis was 8.3 months (2-22 months). Of the 50 patients without CMV retinitis, 33 patients died and 17 were still alive at the time the study ended. The mean survival time for the 33 patients who died was 16.3 months (155 months) (P = .81, Kaplan-Meir). Because the CD4 count fluctuates more in children than in adult patients with HIV and because the percentage of CD4 lymphocyte to the ALCs (CD4/ALC) is considered a more stable and consistent parameter for monitoring lymphocyte status in pediatric patients with HIV, we also used CD4/ALC to compare the life expectancy between the 4 patients with CMV retinitis and the 40 patients without CMV retinitis from the first time the CD4/ALC ratio was equal to or dropped below 2%. All 4 patients with CMV retinitis also had a CD4/ALC less than 2%. Of the 40 patients with a CD4/ALC below 2%, 26 patients died, whereas 14 patients were still alive at the end of the study period. The mean length of survival from the time the CD4/ALC was detected below 2% was 19.1 months (1-50 months) for the 26 patients who died (P = .87, Kaplan-Meier).

DISCUSSION Since CMV retinitis was first reported in 1986 as a complication of pediatric AIDS, sporadic reports have appeared in the literature.9-11 These reports suggested that the incidence of pediatric CMV retinitis as a complication of AIDS was lower than that of adult patients with HIV. No large, long-term prospective studies have been published to document the incidence of CMV retinitis in the pediatric population. Girard and Courpotin12 followed up

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33 HIV-positive children for a mean time of 2 years. Twenty-three of the children developed AIDS but none had CMV retinitis. Dennehy et al18 reported 2 cases of CMV retinitis among 40 pediatric patients with AIDS in a 14-month follow-up study for an incidence of 5%. These reports support the notion of a low incidence of CMV retinitis in pediatric HIV-infected patients. The lack of large, long-term studies makes extrapolation of these studies to the general population of HIV-infected children difficult. Mean follow-up time in this study was 55.3 months (range of 13-164 months) after HIV diagnosis, and we deem this sufficient to study the incidence of CMV retinitis in this patient group. The CD4 counts were below 20 in all 4 children at the time CMV retinitis was diagnosed. Kerr et al13 also observed extremely low CD4 counts (<10) in 2 pediatric patients with CMV retinitis. With the use of reference data from adult patients, mandatory ophthalmologic examinations were initiated when the CD4 count dropped below 50.6,7 The adult reference level was used because reference data for the pediatric population are unavailable in the literature. A CD4 count of less than or equal to 20 or a CD4/ALC percentage of less than 2% may be reasonable thresholds to initiate ophthalmologic screening examinations in pediatric patients with HIV, on the basis of the finding of this study. On the other hand, because none of the children with CMV retinitis spontaneously complained of vision loss, despite advanced retinitis, frequent ophthalmologic screening should be considered once these thresholds are reached to allow for earlier detection and treatment of the disease. The reason(s) why pediatric HIV-infected patients have a lower incidence of CMV retinitis and the reason(s) why CMV retinitis developed at a lower CD4 threshold are unclear. Pediatric HIV differs from adult HIV in several substantial ways. First, vertical transmission is the usual mode of transmission in infected children, compared with sexual transmission or percutaneous transmission from intravenous drug abuse in adult patients. Second, the immune status of an infected neonate is immature compared with that of the adult at the time of infection. Third, latent CMV infections are less likely to be present in children compared with adults who have frequently been exposed to the CMV virus; therefore, infection in children is more likely to be primary. Differences in disease expression and tolerance could occur on the basis of these and other unknown factors. A similar view has been advocated by Barrio et al.11 In conclusion, we confirmed a low incidence of CMV retinitis in HIV-infected children compared with HIVinfected adults. A reference CD4 count of less than 20 and a CD4/ALC ratio of less than 2% may be reasonable thresholds to trigger routine ophthalmologic examinations in HIV-infected children. Because children may not complain of vision loss and CMV retinitis may be advanced at the time of diagnosis, at-risk children should undergo ophthalmologic screening at frequent intervals once these immunologic thresholds have been reached.

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9. Daus W, Zimmer KP, Moller P. Bilateral cytomegalovirus retinitis in an infant with fatal congenital AIDS. Klinische Monatsblatter fur Augenheilkunde 1986;188:604-9. 10. Bremond-Gignac D, Aron-rosa D, Rohrlich P, Deplus S, Faye A, Vilmer E. Cytomegalovirus retinitis in children with AIDS acquired through materno-fetal transmission. J Francais d Ophalmologie 1995;18:91-5. 11. Barrio J, Carbonell P, Minguez E, Gracia-Casanova M, ParraFormento J. Cytomegalovirus retinitis in a pediatric AIDS patient. Revista de Neruologia 1997;25:1064-6. 12. Girard BP, Courpotin CLG. Ophthalmologic manifestations observed in a pediatric HIV-seropositive population. J Francais d Ophalmologie 1997;20:49-60. 13. Kerr NC, Livingston PG, Sullivan JL. Ocular disease in patients with vertically acquired pediatric AIDS. 23rd AAPOS Annual Meeting Abstract; 1997. p. 17. 14. Bergwerk K, Kodsi S, Schuval S, Weiss S. Ocular findings in HIV infected children. 23th AAPOS Annual Meeting Abstract; 1997. p. 16. 15. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morb Mortal Wkly Rep 1987:36:1-15s. 16. Centers for Disease Control and Prevention. Pediatric human immunodeficiency virus classification. MMWR Morb Mortal Wkly Rep 1994;43:RR-12, 1-6. 17. Aledort LM, Hilgartner MW, Pike MC, Gjerset GF, Koerper MA, Lian EY, et al. Variability in serial CD4 counts and relation to progression of HIV-I infection to AIDS in haemophilic patients: Transfusion Safety Study Group. BMJ 1992;304:212-6. 18. Dennehy PJ, Warman R, Flynn JT, Scott GW, Masgrucci MT. Ocular manifestations in pediatric patients with acquired immunodeficiency syndrome. Arch Ophthalmol 1989;107:978-82.

NOTICE On May 15, 1999, the Latin American Association for Pediatric Ophthalmology (SOPLA [Sociedad de Oftalmo Pediatria Latina Americana]) was founded in San Pablo, Brazil. There were delegates from Argentina, Brazil, Chile, Ecuador, Uruguay, and Paraguay. Its objectives are to improve infant visual health, share knowledge among members of the association, and raise the scientific standards of ophthalmologists who care for children. Charter members of SOPLA are Harley Bicas, Mauro Plut, Rosanna Da Cunha, Ana Teresa Moreira, Liana Ventura, Luis Ferreira de Sa, and Tomas Mendonca (Brazil); Delia Dauria (Uruguay); Andrea Molinari (Ecuador); Ximena Katz (Chile); and Versnica Hauviller (Argentina). Dr Hauviller was unanimously elected as president of SOPLA. The first meeting will be at Orlando at the Joint Meeting in October. For more information contact Dr Hauviller by e-mail: [email protected].