Cytomegalovirus (CMV) retinitis occurs in advanced human immunodeficiency virus (HIV) disease, alone, with disseminated CMV disease, or with immune reconstitution inflammatory syndrome.1 Diagnosis is made clinically through indirect fundoscopy, where features include retinal opacification, exudates, and hemorrhage. Extension occurs along the vascular arcades and may involve the optic nerve head. If untreated, the entire retina can become necrotic, leading to detachment, complete retinal destruction, and irreversible blindness.2 In the developed world, this disease is now infrequent because of screening, effective anti-CMV therapy, and immune recovery through highly active antiretroviral therapy (HAART). Previously, it affected up to one-third of adults,2 with a reported frequency of 0.5 per 100 child-years in children.1
In the developing world, there are few data describing CMV retinitis in HIV-infected children. Rates of 4% are reported where children have been screened,3 with higher rates for children with ocular symptoms and signs.4 Most studies describe data in older children.
The prevalence and clinical presentation of CMV retinitis in South African children is unknown. Retinal screening in HIV-infected children is not done routinely. This case series documents the clinical presentation, therapy, and outcome of 6 HIV-infected children with presumed CMV retinitis, diagnosed and managed in one institution.
MATERIALS AND METHODS
Between January 1, 2004 and April 21, 2009, a retrospective descriptive study of cases was conducted. Patients were identified from the Infectious Disease Clinic and inpatient databases. Demographic, clinical, and laboratory data were collected by review of patient records. Laboratory results were cross-referenced with National Health and Laboratory Services.
HIV infection was confirmed with 1 positive DNA or RNA PCR (COBAS, Roche) in children <18 months and 1 positive 4th generation Elisa for HIV antibodies (VIDAS HIV DUO Ultra, BioMérieux, Marcy-l'Etoile, France) in children >18 months.
CMV retinitis was clinically diagnosed by a single experienced ophthalmologist. Retinitis was considered inactive when retinal examination revealed only scarring, with no salvageable retina. HIV infection was staged according to the 2006 World Health Organization clinical and immunologic staging for HIV-infected children.
The study was approved by the committee for Human Research at Stellenbosch University.
A total of 6 cases (designated A through F) were identified. Table, Supplemental Digital Content 1, http://links.lww.com/INF/A713 shows the relevant clinical, laboratory, and diagnostic data. Children presented at young age (median, 6.7 [range, 2–40] months). All had clinically advanced HIV disease. Infant A had marked depletion of absolute CD4 count (884 cells/mm3), despite having only mild immunodeficiency by percentage criteria (30.8%).
Of the 6, 5 patients had visual signs, including nystagmus and an unfocused gaze at presentation. Patient D presented with left sixth nerve palsy and a relative afferent pupillary defect. Patient B had no visual signs; retinitis was identified through screening in a child already diagnosed with CMV pneumonia. Four children had bilateral eye disease and 4 had macula involvement. Retinal detachment had occurred in 3 cases.
Concomitant illness lacking definitive tissue diagnosis but suggestive of CMV, including pneumonia, encephalitis, and hepatitis, occurred in 5 patients.
Five patients received intravenous ganciclovir (GCV) 5 to 6 mg/kg twice daily at induction. The median treatment duration was 36.8 (3–79) days. Patient E had inactive retinal disease at diagnosis and was not treated. Patients A, C, and F received intravenous maintenance GCV (5 mg/kg once daily) for 10, 20, and 41 days, respectively, without progression of retinal disease after cessation of therapy. Patient A continued maintenance oral GCV for 16 months. Only patient F received oral valganciclovir for maintenance (40 days) until retinal disease appeared inactive.
Five patients received HAART. Patient D died before HAART could be commenced. Patients A and E presented with retinitis at 41 and 43 days, respectively, after commencing HAART, compatible with immune reconstitution inflammatory syndrome. However, baseline screening was not performed on anyone. Patients B, C, and F started GCV first; HAART commenced 8 or 9 days later.
The median length of hospitalization was 70 (15–133) days. Two patients died. Of these, 1 (patient D) had suspected disseminated CMV disease. The other died of bacterial sepsis. At final visual assessment, patient B, the only patient without visual signs at diagnosis, had appropriate vision for age.
Dual infection with CMV accelerates the progression of HIV disease.1,5 Poor access to HAART and early CMV infection are significant cofactors, especially in the developing world. In a study at our institution, 51% of HIV-infected children admitted to the pediatric intensive care unit (mean age, 4 months) had evidence of CMV infection. This prompted routine screening for CMV infection in symptomatic infants, and early initiation of GCV.6 The profound effect on younger infants is re-emphasized in our cohort, as 5 of the 6 cases were <1 year of age. Limited access to diagnostic modalities, intensive care, GCV, and HAART, with high early mortality in the developing world, may have caused selection biases toward older children in surveys done elsewhere.3,4
Screening presents a challenge for the developing world. Disease is often unsuspected, as there is little inflammation in the anterior segment of the eye. Visual signs and symptoms can occur late, and are usually not reported in infants and small children. A skilled clinician is required for diagnosis. The entire retina must be examined by indirect fundoscopy through a well-dilated pupil. In adults, systematic screening of asymptomatic, high-risk (CD4 count <50 cells) patients is more effective than limited screening of symptomatic patients. Once visual symptoms are present, disease is usually advanced and visual outcomes are poor.2 Therapy at this stage is nevertheless worthwhile to preserve residual vision.
Optimal therapy for CMV retinitis in children must still be determined. Practice is based on adult experience. Treatment in adults includes HAART and systemic anti-CMV medication at induction doses for 2 weeks, followed by maintenance therapy until immune reconstitution occurs.1,2 Successful treatment of retinitis in children, with systemic GCV either alone or in combination with foscarnet, is described.1,7
Local anti-CMV therapy in adults, comprising intraocular GCV implants and intravitreal GCV injections, is usually reserved for vision salvage when the macula and central vision are threatened.2 Implants are generally not available in South Africa, and are too large for the infant orbit. Successful intraocular implants have been described in older children in the developed world.1 Intravitreal GCV in infants and older children may be complicated by endophthalmitis or retinal detachment, and is technically difficult to instill.1,7,8
Children in this study were treated with induction doses of intravenous GCV for a minimum of 21 days (except in 1 case who died on day 3 of therapy). One case continued with oral GCV for maintenance therapy. This formulation is no longer available and has poor bioavailability.1 Due to high cost, only patient F was treated with valganciclovir, the oral prodrug for GCV. This alternative maintenance therapy would reduce hospitalization time as well as complications associated with intravenous therapy.2 In 2009, the Food and Drug Administration approved valganciclovir hydrochloride tablets and oral solution for children 4 months to 16 years of age who were undergoing kidney and heart transplants.9 Recent studies demonstrate that plasma concentrations in neonates treated for congenital CMV are comparable with intravenous GCV.10 However, cost and availability remain a problem in the developing world.2 In South Africa, tablets are used to create a suspension for small children, as the oral solution is awaiting Medical Control Council (MCC) approval (personal communication—Roche, South Africa).
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