Journal of Perinatology (2006) 26, 648–649 r 2006 Nature Publishing Group All rights reserved. 0743-8346/06 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Successful treatment with oral valganciclovir in immunocompetent infant with gastrointestinal manifestations of cytomegalovirus infection PS Buonuomo1, P Maurizi1, P Valentini2, S Mastrangelo1, I Lazzareschi1, V Ridola1 and R Riccardi1 1Division of Pediatric Oncology, Department of Paediatrics, Universita` Cattolica del Sacro Cuore, Policlinico ‘A Gemelli’, Rome, Italy and 2Department of Paediatrics, Pediatric Infectious Disease, Universita` Cattolica del Sacro Cuore, Policlinico ‘A Gemelli’, Rome, Italy showed absence of IgM and IgG antibodies. Maternal A 3-month-old male infant was admitted to hospital with anemia. Follow- transplacental IgG for HSV (12.00 index) and CMV (1600 UA/ml) up controls revealed the presence of specific cytomegalovirus (CMV) were present. Urine and saliva cultures and serum PCR for antibodies. Virus was isolated from urine, blood, and saliva. At 7 months of CMV were negative. Chest and skull radiographs, cerebral age, he presented with melena. Polymerase chain reaction (PCR) of biopsy ultrasonography, and ophthalmologic examination were normal. samples from the duodenum was positive for CMV. Anemia resolved after Within 24 h, fever disappeared and the general condition rapidly starting antiviral therapy with oral valganciclovir. improved. Blood tests at discharge confirmed normocytic anemia Journal of Perinatology (2006) 26, 648–649. doi:10.1038/sj.jp.7211578 (hemoglobin 7.7 g/dl) with reticulocyte count of 3.4% and normal Keywords: cytomegalovirus; anemia; infant; failure to thrive; oral iron and folate values. valganciclovir After 13 days, at the age of about 3 months, he was admitted to our Onco-hematologic Pediatric Department; hemoglobin was 6.8 g/dl and on echocardiography, there was a mild septal Case report dyskinesia. A red blood cell transfusion was performed. Congenital erythrocyte defects (glucose-6-phosphate dehydrogenase deficiency, The patient was born in Rome, Italy, after an uncomplicated thalassemia, and hereditary spherocytosis) and vitamin E full-term pregnancy by spontaneous vaginal delivery with a birth deficiency were excluded. weight of 2690 g (10th percentile for gestational age). The After 4 weeks, at follow up, CMV-specific IgM and IgG antibodies perinatal course was uneventful, and the infant was thriving while were present (qualitative Enzygnost anti-CMV/IgM method; IgG being exclusively breast-fed. Maternal serology during pregnancy 8.400 UA/ml Enzygnost anti-CMV/IgG. DADE Behring Marburg revealed a protective immunoglobulin G (IgG) antibody titer GmbH, Marburg, Germany). Virus was cultured from urine, blood against cytomegalovirus (CMV) and herpes simplex virus (HSV). and saliva too. At the age of 8 weeks, he was hospitalized elsewhere for acute The baby was in good general condition, but was failing to onset of fever, pallor, and tachypnea. At that time, laboratory thrive (height and length <3rd percentile for age and sex) investigations revealed hemoglobin of 8 g/dl, platelet count of 3 3 and had persistent anemia. Screening for celiac disease 168 000/mm , and leukocyte count 4500/mm . Coagulation using antiendomysium antibody (EMA) IgA, IgA anti-tissue studies, renal function, transaminases, and albumin values were transglutaminase (tTGA), serum IgA and IgE titer, specific serum normal; hyperbilirubinemia was present with total serum bilirubin IgE to cow’s milk were normal; xylose absorption test was slightly concentration of 9.6 mg/dl and direct bilirubin level of 1.0 mg/dl. abnormal (19 mg/dl, normal>20). Direct Coombs test was negative. The patient was treated with At the age of 7 months, he presented with melena. An upper intravenous Ampicillin and Amikacin. Throat, urine, blood, and gastrointestinal endoscopy revealed a normal appearing esophagus cerebrospinal fluid cultures were all negative. Serologic tests for and stomach, but active bleeding in the duodenum that appeared Toxoplasma gondii, Parvovirus B19, Hepatitis A Virus, Hepatitis B grossly congested. Polymerase chain reaction performed by Q-CMV Virus, Hepatitis C Virus, and Human Immunodeficiency Virus AmplyMIX MIEA (Amplimedical-BIOLINE, Turin, Italy) for CMV on Correspondence: Dr PS Buonuomo, Division of Pediatric Oncology, Department of blood and biopsy specimens from the duodenum was positive. Virus Paediatrics, Universita` Cattolica del Sacro Cuore, Policlinico ‘A. Gemelli’, Largo ‘A. Gemelli’, was cultured again from urine and saliva. IgG-specific CMV 8, 00168 Rome, Italy. antibodies were 8700 UA/ml. Ophthalmologic examination showed E-mail: [email protected] Received 20 February 2006; revised 23 May 2006; accepted 28 June 2006 no evidence of chorioretinitis and audiologic tests were also Valganciclovir treatment in infant with CMV infection PS Buonuomo et al 649 normal. Histological studies on duodenal biopsies showed patchy of discontinuing drug administration. Although liquid villous atrophy and flattened surface cells, and an eosinophilic valganciclovir would be highly desirable, no commercial product is infiltrate in the lamina propria. available. According to the indication of Henkin et al.8 we obtained The infant became unwell with recurrent gross or occult blood a 60 mg/ml oral liquid valganciclovir preparation, compounded loss and persistent failure to thrive, so treatment with oral from crushed tablets in a 1:1 mixture of Ora-Plus and Ora-Sweet valganciclovir (15 mg/kg/dose thrice a day) was started. Oral (Paddock Laboratories, Minneapolis, MN USA). Ora-Plus is an valganciclovir was compounded from crushed tablets in a 1:1 aqueous-based vehicle consisting of a blend of suspending agents mixture of Ora-Plus and Ora-Sweet syrup (manufactured by that have a high degree of colloidal activity. When combined in a Paddock Laboratories, Minneapolis, MN USA). After 5 weeks 50/50 ratio with Ora-Sweet, the Ora-plus has increased palatability. of therapy, the baby presented neutropenia (leukocyte count The feasibility of oral administration represents a great 3190/mm3 with 0.25/mm3 polymorphonuclear leukocytes) and improvement for pediatric patients because it is possible to easily fever; blood sample revealed the presence of Streptococcus adjust the drug dosage on the basis of the child’s weight and to oralis infection, treated with a specific antibiotic (Cefepime). reduce the discomfort of the hospital stay. Valganciclovir therapy was discontinued. After 1 week, blood The reported case adds more elements to the clinical spectrum tests returned to normal values (hemoglobin b (Hgb) 10.8 g/dl, of perinatal CMV infection and, in so far as the current findings are reticulocyte count 1.4%, leukocyte count 6450/mm3 with 1500/ meaningful, it represents a good experience in the use of mm3 polymorphonuclear leukocytes). Xylose absorption test was valganciclovir in pediatric patients. The limitations of a single case normal (42 mg/dl). At 8 weeks after the therapy, multiple biopsies report with a relatively short follow-up emphasize the need for of the duodenum consistently showed a normal appearance of the further studies to evaluate pharmacokinetics, efficacy, and safety of intestinal mucosa and PCR was negative for CMV. oral valganciclovir therapy in pediatric age. At 14 months of age, the child is well with better growth parameters and is developmentally normal. Acknowledgments Discussion We thank Irene Scarano, MD, and Gaetano Mauro, MD, who prepared the oral CMV gastrointestinal disease secondary to perinatal infection is a liquid formulation of valganciclovir. rare condition in non-immunocompromised patients. We identified only a single published report,1 in which a 6-week-old male infant presented a large upper gastrointestinal hemorrhage due to CMV References infection. 1 Weinstein M, Ford-Jones E, Cutz E. Esophagitis and perinatal cytomegalovirus Currently, three antivirals are licensed for treatment of CMV: infection. Pediatr Infect Dis J 2001; 20: 545–546. ganciclovir and its prodrug, valganciclovir, foscarnet, and 2 Schleiss MR. Antiviral therapy of congenital cytomegalovirus infection. Semin 2–3 cidofovir. Pediatr Infect Dis 2005; 16: 50–59. Reports suggest that ganciclovir is being used to treat selected 3 Schleiss MR, McVoy MA. Overview of congenitally and perinatally acquired infants with CMV disease; however, because of the potential bone cytomegalovirus infections: recent advances in antiviral therapy. Exp Rev marrow suppression and the reported long-term effects, such as Anti-infective Ther 2004; 2: 389–403. testicular atrophy, it is recommended not to routinely use 4 Whitley RJ, Cloud G, Gruber W, Storch GA, Demonler GJ, Jacobs RF et al. ganciclovir.4–5 In addition, only parenteral administration is Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: possible. In March 2001, valganciclovir hydrochloride, the orally results of a phase II study. J Infect Dis 1997; 175: 1080–1086. administered valyl ester of ganciclovir, was approved for use in 5 Kimberlin DW. Antiviral therapy for cytomegalovirus infections in pediatric adults6 and some authors have used it for the treatment of patients. Semin Pediatr Infect Dis 2002; 13: 22–30. symptomatic congenital CMV infections.7 Valganciclovir is a 6 De Clercq E. Antiviral drugs in current clinical use. J Clin Virol 2004; 30: 115–133. prodrug that exists as a mixture of two diastereomers and is about 7 Meine Jansen CF, Toet MC, Rademaker CM, Ververs TF, Gerards LJ, van Loon 10 times more bioavailable than ganciclovir. The virustatic activity AM. Treatment of symptomatic congenital cytomegalovirus infection with of ganciclovir is owing to an inhibition of viral DNA synthesis. valganciclovir. J Perinat Med 2005; 33: 364–366. Cytopenia (neutropenia, anemia, and thrombocytopenia) may 8 Henkin C, Griener J, Ten Eick A. Stability of valganciclovir in occur at any time during treatment and may increase with extemporaneously compounded liquid formulations. Am J Health-Syst Pharm continued dosing, but usually begins to recover within 3 to 7 days 2003; 60: 687–690. Journal of Perinatology.