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Intravitreal foscarnet for recurring CMV retinitis in a congenitally infected premature infant

2014; Elsevier BV; Volume: 18; Issue: 1 Linguagem: Inglês

10.1016/j.jaapos.2013.09.015

1528-3933

Kirstin L. Tawse, Caroline R. Baumal,

Neonatal Health and Biochemistry

A girl born at 32 weeks' gestational age was diagnosed at birth with congenital cytomegalovirus (CMV) infection without ocular involvement. On day 19 of life, retinal examination requested for retinopathy of prematurity (ROP) identified bilateral CMV retinitis and stage 1 ROP. Treatment of macular threatening CMV infection with intravitreal foscarnet injections and intravenous ganciclovir for 6 weeks led to quiescence of retinitis. Bilateral recurrence of CMV retinitis occurred on day 89 of life, requiring a second course of intravitreal foscarnet injections and intravenous ganciclovir. Both the initial presentation and reactivation of CMV retinitis were identified on examination for ROP and would have gone unrecognized had the infant not met ROP screening criteria. This case demonstrates delayed presentation of CMV retinitis after initial negative retinal examination in a premature infant with congenital infection and concurrent ROP. A girl born at 32 weeks' gestational age was diagnosed at birth with congenital cytomegalovirus (CMV) infection without ocular involvement. On day 19 of life, retinal examination requested for retinopathy of prematurity (ROP) identified bilateral CMV retinitis and stage 1 ROP. Treatment of macular threatening CMV infection with intravitreal foscarnet injections and intravenous ganciclovir for 6 weeks led to quiescence of retinitis. Bilateral recurrence of CMV retinitis occurred on day 89 of life, requiring a second course of intravitreal foscarnet injections and intravenous ganciclovir. Both the initial presentation and reactivation of CMV retinitis were identified on examination for ROP and would have gone unrecognized had the infant not met ROP screening criteria. This case demonstrates delayed presentation of CMV retinitis after initial negative retinal examination in a premature infant with congenital infection and concurrent ROP. A 1.446 kg girl born at 32 weeks' gestational age at the New England Eye Center at Tufts Medical Center was found to have petechiae, increased tone, and respiratory distress on day 1 of life. Prenatal ultrasound showed dilated ventricles and pericardial fluid. Pregnancy was complicated with intrauterine growth restriction and preterm labor. Infant urine and maternal serum confirmed symptomatic congenital cytomegalovirus (CMV) infection. Ophthalmologic examination on day 2 of life did not reveal retinitis, and no follow-up was scheduled. Treatment of systemic infection with intravenous ganciclovir was considered but not initiated because extensive brain calcification on imaging suggested longstanding chronic intrauterine infection with resultant central nervous system damage so severe that there was deemed to be little potential for benefit from antiviral therapy. No further monitoring of viral shedding was performed by the infectious disease service as there was felt to be no indication for treatment. On day 19 of life, retinal examination requested for ROP (indicated by birth weight <1500 g) revealed bilateral peripheral frosted branch angiitis and retinitis consistent with ocular CMV infection (Figure 1) as well as stage 1 ROP. Treatment with intravenous ganciclovir (6 mg/kg) was initiated and the dose was subsequently adjusted based on the absolute neutrophil count. After 1 week of therapy, worsening of retinitis bilaterally with macular extension in the left eye was observed (Figure 2). Given the risk of irreversible macular damage, intravitreal foscarnet (0.05 cc of 2.4 mg foscarnet/mL) was injected in the left eye. The retinitis improved in both eyes over the next 2.5 weeks after 3 injections in the left eye combined with intravenous gancyclovir. A 42-day course of intravenous ganciclovir was completed and follow-up was continued per protocol for stage 1 ROP.Fig 2Progression of frosted branch angiitis in the left eye with extension into the macula (circle) after 1 week of intravenous ganciclovir.View Large Image Figure ViewerDownload Hi-res image Download (PPT) On day 89 of life, reactivation of CMV retinitis was observed, with whitening at the margins of inactive lesions bilaterally and a new focus of perifoveal whitening in the left eye (Figure 3). Intravenous ganciclovir (14-day course) and additional intravitreal foscarnet injections (3 in each eye) were administered over the following 2 weeks, leading to complete resolution. After 2 years of follow-up, the lesions remain quiescent with macular scarring in the left eye. CMV is the most common congenital infection worldwide, affecting 1% of live births in the United States.1Kadambari S. Williams E.J. Luck S. Griffiths P.D. Sharland M. Evidence-based management guidelines for the detection and treatment of congenital CMV.Early Hum Dev. 2011; 87: 723-728Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Serious sequelae include hearing loss, microcephaly, mental retardation, and blindness. Treatment indications for congenital CMV infection include central nervous system or focal organ disease. Current regimens call for intravenous ganciclovir for 3-6 weeks, although only a complete course of 6 weeks has been studied in a single phase III randomized trial.2Kimberlin D.W. Lin C.Y. Sánchez P.J. et al.Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized controlled trial.J Pediatr. 2003; 143: 16-25Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar Given the frequent side effect of neutropenia, necessity of inpatient hospitalization and an indwelling catheter, the risks associated with intravenous ganciclover therapy may be prohibitive. Case series have described off-label oral valganciclovir and intravitreal ganciclovir to treat congenital CMV infection with retinitis.1Kadambari S. Williams E.J. Luck S. Griffiths P.D. Sharland M. Evidence-based management guidelines for the detection and treatment of congenital CMV.Early Hum Dev. 2011; 87: 723-728Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 3Lalezary M. Recchia F.M. Kim S.J. Treatment of congenital cytomegalovirus retinitis with intravitreous ganciclovir.Arch Ophthalmol. 2012; 130: 525-527Crossref PubMed Scopus (8) Google Scholar, 4Oschman Q. Kenneth Lord R. Kollipara R. Oluola O. Murthy V. Intravitreal ganciclovir for neonatal cytomegalovirus-associated retinitis: a case report.J Perinatol. 2013; 33: 329-331Crossref PubMed Scopus (5) Google Scholar To our knowledge, this is the first report of intravitreal foscarnet for active CMV retinitis in a congenitally infected premature infant. CMV retinitis may resolve on occasion without treatment with improved immune function. However, macular proximity, active progression, and uncertainty regarding immune recovery in this premature infant guided our decision to pursue targeted therapy with intravitreal injections in addition to intravenous ganciclovir. The choice of foscarnet was based on its known safety profile and efficacy in HIV-related CMV retinitis and potential synergistic effect with ganciclovir by differing mechanisms of action.5Diaz-Llopis M. España E. Muñoz G. et al.High dose intravitreal foscarnet in the treatment of cytomegalovirus in AIDS.Br J Ophthalmol. 1994; 78: 120-124Crossref PubMed Scopus (88) Google Scholar In cases of congenital infection with sight threatening lesions, intravitreal foscarnet may be an alternative as adjunctive therapy or as solo therapy if systemic therapy is not tolerated. The incidence of CMV retinitis in congenital infection has been reported in up to 25% of severely symptomatic cases and 1% of asymptomatic cases.6Coors L.E. Spencer R. Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection.Retina. 2010; 30: S59-S62Crossref PubMed Scopus (11) Google Scholar Current guidelines for ophthalmologic screening in congenital CMV infection include dilated retinal examination at initial diagnosis with no further examinations required if asymptomatic.2Kimberlin D.W. Lin C.Y. Sánchez P.J. et al.Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized controlled trial.J Pediatr. 2003; 143: 16-25Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar Had our patient not met ROP screening criteria and warranted close follow-up for concurrent ROP, identification of both the initial presentation and recurrence of retinitis may have been missed. In addition to this case, there are other reports of delayed presentation of CMV retinitis in congenital infection.6Coors L.E. Spencer R. Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection.Retina. 2010; 30: S59-S62Crossref PubMed Scopus (11) Google Scholar A small series demonstrated the risk of developing CMV retinitis was associated with positive viral cultures from the urine and nasopharynx.7Baumal C.R. Levin A.V. Kavalec C.C. Petric M. Khan H. Read S.E. Screening for cytomegalovirus retinitis in children.Arch Pediatr Adolesc Med. 1996; 150: 1186-1192Crossref PubMed Scopus (21) Google Scholar Infants with congenital CMV infection who are not receiving treatment in hopes of resolution following immune recovery should be monitored for CMV retinitis. More frequent ophthalmological examinations than current guidelines recommend may be indicated to ensure earliest diagnosis and treatment of this potentially blinding disease. PubMed (MEDLINE) was searched for English-language only articles from 1950 to 2013, using combinations of the terms intravitreal foscarnet and congenital cytomegalovirus.