Treatment of symptomatic congenital cytomegalovirus infection with intravenous ganciclovir followed by long-term oral valganciclovir

Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Earlier studies showed that 6-weeks’ treatment with ganciclovir, starting in the neonatal period, prevented hearing deterioration at 6 months, but in one-fifth of the infants, the effect was not sustained at age 12 months. The aim of this preliminary retrospective study was to investigate the effectiveness and safety of long-term treatment with ganciclovir/valganciclovir for congenital cytomegalovirus infection. Twenty-three infants with culture-proven symptomatic congenital cytomegalovirus infection were treated with ganciclovir for 6 weeks followed by oral valganciclovir to age 12 months. Audiometry was performed at least three times in the first year, in addition to physical examination including neurological and developmental assessment. At age ≥1 year, hearing was normal in 76% of affected ears compared to baseline (54%). In 25 normal ears at birth no deterioration was found at ≥1 year. These results were significantly better than reported in a historical control group of similar infants treated for 6 weeks only (P= 0.001). Viral load monitoring demonstrated sustained virological response. Four of the children (18%) had mental retardation. The main side effect of treatment was transient neutropenia. In conclusion, prolonged therapy of symptomatic congenital CMV infection with intravenous ganciclovir followed by oral valganciclovir is safe, and it appears to lead to a better auditory outcome than short-term treatment.     

Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology

Aim: The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. Methods: The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. Results: Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA‐positive children were carriers of mutations of Cx26. Conclusion: Congenital CMV infection is a high risk factor in hearing impairment among children.     

Cytomegalovirus urinary excretion and long term outcome in children with congenital cytomegalovirus infection. Congenital CMV Longitudinal Study Group

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital infection, and both symptomatic and asymptomatic infants may have long term sequelae. Children with congenital CMV infection are chronically infected and excrete CMV in the urine for prolonged periods. However, the effect of prolonged viral replication on the long term outcome of these children is unknown. OBJECTIVE: To determine whether duration of CMV excretion is associated with outcome at 6 years of life in symptomatic and asymptomatic congenitally infected children. METHODS: Longitudinal cohort study. Children congenitally infected with CMV were identified at birth and followed prospectively in a study of long term effects of congenital CMV infection. The relationship between duration of CMV urinary excretion and growth, neurodevelopment and presence and progression of sensorineural hearing loss (SNHL) at 6 years of age was determined. RESULTS: There was no significant difference in the duration of viral urinary excretion between children born with asymptomatic (median, 4.55 years) and symptomatic (median, 2.97 years) congenital CMV infection (P = 0.11). Furthermore there was no association between long term growth or cognitive outcome and duration of viral excretion. However, a significantly greater proportion of children who excreted CMV for <4 years had SNHL and progressive SNHL compared with children with CMV excretion >4 years (P = 0.019, P = 0.009, respectively). CONCLUSIONS: Children congenitally infected with CMV are chronically infected for years, but the duration of CMV urinary excretion is not associated with abnormalities of growth, or neurodevelopmental deficits. However, SNHL and progressive SNHL were associated with a shorter duration of CMV excretion.     

先天性巨细胞病毒感染抗病毒治疗的效果和安全性观察

目的：观察更昔洛韦（GCV）和（或）缬更昔洛韦（VGCV）治疗先天性巨细胞病毒（ CMV）感染患儿的疗效和不良反应。 方法：回顾性纳入2012年3月1日至2017年5月31日在复旦大学附属儿科医院（我院）新生儿科住院、确诊为先天性CMV感染的患儿,随访至2017年12月31日。从病史资料中提取患儿的一般资料,抗CMV治疗的药物和疗程,新生儿期及1、 3和6月龄的肝脾触诊检查结果、胆红素和肝功能检查指标、CMV抗体和DNA检测结果、颅脑MRI、眼底检查结果和听力检测结果,治疗期间药物的不良反应。根据抗病毒治疗与否以及疗程长短分组,比较各组的临床特征和治疗反应。 结果：28例先天性CMV感染患儿进入本文分析,其中早产儿11例,男17例;无症状/轻度症状9例,未予抗病毒治疗;中重度症状19例,GCV和（或）VGCV治疗≤6周组11例,治疗6个月组8例。①6月龄时,除1例胆汁酸轻度升高外27例中枢神经系统以外的症状和体征、胆红素、肝功能和血常规均恢复正常。②无症状／轻度症状组1例在6月龄时出现左侧听力中度损失。治疗≤6周组中,2例CMV相关眼底病变于1月龄时消失; 颅脑MRI异常信号和听力损失者各5例,6月龄时分别有3例和2例无改善。治疗6个月组中,4例先天性CMV感染相关视网膜病变在随访中均消失;3例头颅MRI异常信号者和7例有听力损失者,6月龄时分别有2例和1例无改善。③治疗≤6周组和治疗6个月组在6月龄时中枢神经系统病变改善情况差异无统计学意义。④治疗过程中未发现与GCV和VGCV应用相关的粒细胞减少和肝功能异常。 结论：抗病毒治疗能改善感音神经性耳聋和脉络膜视网膜炎,GCV和（或）VGCV≤6周与6个月的治疗效果相近;建议对无临床症状先天性CMV感染患儿行眼底检查、脑干诱发电位和头颅MRI检查。     

Tratamiento prolongado con valganciclovir en un lactante con infección congénita por citomegalovirus

Treatment with intravenous ganciclovir for six weeks prevents hearing deterioration in children with symptomatic congenital cytomegalovirus (CMV) infection. Prolonged treatment might be more beneficial, but is associated with the potential side-effects of long-term use of intravenous lines. Oral valganciclovir could be an alternative because of its excellent bio-availability, reaching plasma concentrations similar to those achieved with intravenous ganciclovir in neonates with symptomatic CMV infection. We present a two-month-old girl with congenital CMV infection with central nervous disease involvement, who was treated with intravenous ganciclovir for 15 days followed by oral valganciclovir (30 mg/kg/day in 2 doses) for 6 months. Treatment resulted in adequate ganciclovir plasma levels, suppressed plasma viral load, prevention of hearing deterioration and was well tolerated, with no apparent side-effects.     

Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity

OBJECTIVE: To define hearing outcomes in children with congenital cytomegalovirus (CMV) infection born to mothers with non-primary CMV infection. STUDY DESIGN: A cohort of 300 children with congenital CMV infection identified by newborn virologic screening at the University of Alabama Hospital and a private community hospital in which the type of maternal infection could be classified constituted the study population. Maternal infections were categorized by analyzing serum samples. Children were followed prospectively and underwent serial audiologic evaluations. RESULTS: The frequency of hearing loss was not different between children born to mothers with non-primary infection (10%) and those with primary infection (11%). Significantly more children in the primary infection group had progressive and severe/profound hearing loss compared with children in the non-primary group. The frequency of bilateral, delayed onset, high-frequency, and fluctuating hearing loss was not different between the 2 groups. The mean age of diagnosis of hearing loss was 39 +/- 53 months for children born to mothers with non-primary infection and 13 +/- 21 months for the primary infection group (P = .16). CONCLUSIONS: Maternal preexisting seroimmunity to CMV does not provide complete protection against hearing loss in infants with congenital CMV infection.     

Antiviral therapy of congenital cytomegalovirus infection

Congenital infection caused by human cytomegalovirus (CMV) is a common occurrence, but its significance is underappreciated. In the developed world, congenital CMV infection confers a tremendous medical and economic burden on society. In recent years, appreciation of the scope of disability produced by such infections in newborns, which includes neurodevelopmental sequelae and sensorineural hearing loss (SNHL), has increased. Although much of the injury produced by infection in utero likely is irreversible, antiviral therapy of newborns with CMV infection is an option available to clinicians. Currently three antivirals are licensed for treatment of CMV: ganciclovir (and its prodrug, valganciclovir), foscarnet, and cidofovir. Novel antiviral therapies, which employ mechanisms of action that differ from these agents, also are in development. Experience with these agents in the setting of congenital and perinatal CMV infection is limited, but encouraging data come from a controlled clinical trial indicating that ganciclovir therapy may be of value in limiting the neurodevelopmental injury, particularly SNHL, caused by congenital infection. Newborn screening programs for CMV infection need to be developed and implemented. Infants with congenital CMV infection, once identified, could then be considered as candidates for antiviral therapy, and careful neurodevelopmental and hearing screening follow-up care plans could be established. CMV vaccines, once available, may ultimately be the best control strategy for this important public health problem.     

Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections.

Sensorineural hearing loss was present in ten of 59 (17%) patients with congenital cytomegalovirus (CMV) infection (three of eight born with symptomatic and seven of 51 born with subclinical infection). The defect was bilateral in eight, moderate to profound in eight, and of progressive nature in two. Hearing loss did not occur in 21 patients with natal CMV infection nor in seven of 12 patients with congenital toxoplasmosis. Histopathologic and immunofluorescent studies of the inner ear in two of three neonates who died with severe infection revealed that viral antigens were widely distributed in cochlear structures. Eye pathology was associated only with congenital Toxoplasma (nine of 12) and CMV (seven of 43) infections. Visual impairments were more prominent and severe in those born with symptomatic infections, exclusively so with CMV. However, ocular defects, in particular chorioretinitis, developed after birth in five of eight patients born with asymptomatic congenital toxoplasmosis. These data firmly establish clinically inapparent congenital CMV infection as a major public health problem and confirm the fact that congenital toxoplasmosis may be associated with late-appearing, debilitating chorioretinitis.     

Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection

OBJECTIVE: To determine the ability of neonatal clinical, audiologic, and computed tomography (CT) findings to predict long-term neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection. METHODS: Longitudinal cohort study of children (n = 41) with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. The performance of birth characteristics as predictors of long-term outcome were determined, and clinical and CT scoring systems were developed and correlated with intellectual outcome. RESULTS: Microcephaly was the most specific predictor of mental retardation (100%; 95% CI 84.5-100) and major motor disability (92.3%; 95% CI 74.8-99). An abnormality detected by CT was the most sensitive predictor for mental retardation (100%; 95% CI 82.3-100) and motor disability (100%; 95% CI 78.2-100). A highly significant (P <.001) positive correlation was found between head size at birth and the intelligence/developmental quotient (IQ/DQ). Approximately 29% of children had an IQ/DQ >90. There was no association between sensorineural hearing loss at birth and cognitive outcome. However, children with sensorineural hearing loss on follow-up (congenital and late-onset) had a lower IQ/DQ (P =.006) than those with normal hearing. CONCLUSIONS: The presence of microcephaly at birth was the most specific predictor of poor cognitive outcome in children with symptomatic congenital CMV infection, whereas children with normal findings on head CT and head circumference proportional to weight exhibited a good cognitive outcome.     

Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized,controlled trial

OBJECTIVE: To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease. STUDY DESIGN: Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). RESULTS: From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P=.06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P<.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and > or =1 year versus 13 (68%) of 19 control patients (P<.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P<.01). CONCLUSIONS: Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at > or =1 year. Almost two thirds of treated infants have significant neutropenia during therapy.     

Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) infection is a major public health problem because 30,000 to 40,000 neonates with the infection are born each year in the United States. Although 90% of the congenitally infected infants are asymptomatic at birth, evidence is accumulating that these infants are at risk for audiologic, neurologic, and developmental sequelae. The current study describes the audiologic outcome of 59 infants with asymptomatic congenital CMV infection compared with 26 control infants. Eight of 59 infected infants had congenital sensorineural hearing loss (SNHL) but none of the control subjects did. Longitudinal audiologic assessments revealed that 5 of the 8 infants had further deterioration of their SNHL; a ninth infant with initially normal hearing experienced a unilateral SNHL during the first year of life, with further deterioration subsequently. The frequency of SNHL was similar for infected infants born to mothers with recurrent CMV infections during pregnancy (2 of 9) and for those born to mothers who experienced primary CMV infections (5 of 26). There was a significant difference between the occurrence of hearing loss in infected infants with normal computed tomographic scans (2 of 40) compared with those with either periventricular radiolucencies (4 of 13) or calcifications (1 of 3). Children with SNHL often have no identified cause of the loss; thus, it is likely that many of these children had asymptomatic congenital CMV infection. Given the progressive nature of SNHL associated with asymptomatic congenital CMV infection, longitudinal audiologic assessments are mandatory.     

Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss

OBJECTIVE: To determine the relationship between the virus burden in infancy and hearing loss in congenital CMV infection. STUDY DESIGN: A cohort of 76 infants with congenital cytomegalovirus (CMV) infection identified by means of newborn virologic screening was monitored for outcome. The amount of infectious CMV was analyzed in urine specimens obtained during early infancy. Peripheral blood (PB) samples obtained during early infancy were available from 75 children and CMV DNA was quantitated with a real-time quantitative polymerase chain reaction. RESULTS: Infants with clinical abnormalities at birth (symptomatic congenital CMV infection) had higher amounts of CMV in urine (P = .005) and CMV DNA in PB (P = .001) than infants with no symptoms. Eight children with and 4 children without symptoms had hearing loss. Among children without symptoms, those with hearing loss had a significantly greater amount of CMV in urine (P = .03) and PB virus burden (P = .02) during infancy than those with normal hearing. Infants with < 5 x 10(3) pfu/mL of urine CMV and infants with < 1 x 10(4) copies/mL of viral DNA in PB were at a lower risk for hearing loss. CONCLUSION: In children with asymptomatic congenital CMV infection, hearing loss was associated with increased amounts of urine CMV and PB CMV DNA during early infancy.     

Safety and efficacy of prolonged cytomegalovirus prophylaxis with intravenous ganciclovir in pediatric and young adult lung transplant recipients

CMV infection causes morbidity and mortality after transplantation. Despite a wide range of prevention strategies among pediatric lung transplant programs, the optimal duration of prophylactic therapy against CMV infection in pediatric lung transplantation is unknown. To assess the feasibility, safety, and short-term efficacy of extending intravenous ganciclovir administration from six wk duration to 12 wk duration in pediatric lung transplant recipients. An open-label pilot study was performed in primary pediatric lung transplant recipients with donor and/or recipient CMV seropositivity. Intravenous ganciclovir was given for 12 wk post-transplantation. Subjects were tracked for protocol completion. Toxicities monitored included renal dysfunction, myelosuppression, gastrointestinal and neurological complications, as well as infection related to indwelling catheter placement. Serial CMV levels were measured to determine short-term efficacy of the intervention. Nine of nine subjects enrolled completed the pilot study. Subjects' ages ranged from six to 18 yr. Indications for lung transplantation included cystic fibrosis (n = 7), idiopathic pulmonary hypertension (n = 1), and complex congenital heart disease with pulmonary hypertension (n = 1). Seven subjects underwent deceased donor bilateral lung transplantation and two subjects underwent heart-lung transplantation. No subjects had protocol-defined drug toxicity. No episodes of neutropenia, thrombocytopenia, or renal toxicity occurred. Five subjects had catheter-related infections (three after week 12 of ganciclovir). Seven of nine subjects had CMV detected by PCR (four prior to ganciclovir completion) with only one subject having a positive viral culture for CMV viremia (prior to ganciclovir completion). No subjects had UL-97 mutation for ganciclovir resistance detected. The use of prolonged prophylactic administration of ganciclovir for 12 wk duration is a feasible, safe, and effective treatment to prevent CMV viremia based on viral culture in at risk pediatric lung transplant recipients. Further clinical studies are underway to determine optimal CMV prevention strategies.     

Congenital cytomegalovirus infection: a cause of sensorineural hearing loss.

Prospective studies have suggested that about 108 children with congenital cytomegalovirus (CMV) infection and bilateral sensorineural hearing loss are born each year in England and Wales; this represents about 12% of all children with congenital sensorineural hearing loss. Over a nine year period 1644 children aged between 6 months and 4 years who were attending the Nuffield Hearing and Speech Centre were screened for CMV infection. The prevalence of CMV in the urine of children with sensorineural hearing loss but no immediate family history of deafness was nearly twice that (13%) found in other children with impaired hearing and those with normal hearing (7%). These findings indicate the importance of CMV as a cause of hearing loss.     

Congenital cytomegalovirus infection

Congenital cytomegalovirus is the most common intrauterine infection and the leading non-genetic cause of sensorineural hearing loss. Worldwide, the birth prevalence is estimated at 7 per 1000 with the highest rates seen in developing countries. The highest intrauterine transmission rates and risk of neurodevelopmental sequelae are associated with primary maternal infections. Transmission occurs less frequently after non-primary maternal infections due to reactivation or reinfection. 10–15% of infected infants are symptomatic at birth with neurological symptoms present in two-thirds. Infants who are asymptomatic at birth may go on to develop late neurodevelopmental sequelae, with sensorineural hearing loss being the commonest late consequence. Prenatal, neonatal and retrospective diagnosis can be challenging. Early treatment of symptomatic neonates with the antiviral drug ganciclovir can reduce the long-term neurodevelopmental sequelae. Universal or targeted screening for congenital CMV is not currently advocated. The development of an effective vaccine appears to be some years away.     

Perinatal cytomegalovirus hepatitis: to treat or not to treat with ganciclovir

OBJECTIVE: The use on ganciclovir for perinatal cytomegalovirus (CMV) infection is controversial. We aim to evaluate the use of ganciclovir treatment for neonatal CMV hepatitis. METHODS: We present five infants with perinatally-acquired CMV hepatitis as a single organ manifestation of CMV infection. The three more severely affected children, i.e. those with cholestasis and elevation of serum hepatic enzymes to more than twice the normal values, were treated for 15 days with intravenous ganciclovir. RESULTS: The three treated infants improved clinically and CMV DNA in the blood disappeared during treatment. After cessation of ganciclovir treatment all of the patients had a relapse of the infection. The two untreated patients recovered completely. CONCLUSION: The long-term outcome of infants with CMV hepatitis is unpredictable. Some patients have persistent liver injury despite ganciclovir therapy. Ganciclovir therapy did not prevent chronic liver disease in any of the patients in our study. Owing to the possible serious side-effects the cost-benefit of ganciclovir treatment should be carefully evaluated.     

Häufigkeit der konnatalen Zytomegalie in der Bundesrepublik Deutschland

Introduction. Cytomegalovirus (CMV) is the leading cause of congenital infection. 90–95% of infected infants are free of symptoms at birth and 5–10% are suffering from symptomatic disease. Methods. Between 1.11.1997 and 31.10.1999 clinical, laboratory and demographic data were monthly collected from standardized case reports. A congenital CMV infection was documented by isolation of virus, antigen or DNA in the first or second week of life and serologically. Results. There were 65 infants with congenital symptomatic CMV disease and 32 infants with presumtive congenital CMV disease. 45 out of 97 children were foreigners. 34 patients were treated with ganciclovir. In 13 of them the indication for virostatic treatment did not seem to be correct. Conclusion. The prevalence rate of congenital CMV infection in Germany is about 2/1000 infants. A virostatic therapy should be initiated in children with symptomatic CMV disease within the first 2 weeks of life.     

Congenital cytomegalovirus infection

Congenital cytomegalovirus is the most common intrauterine infection and the leading non-genetic cause of sensorineural hearing loss. Worldwide, the birth prevalence is estimated at 7 per 1000 with the highest rates seen in developing countries. The highest intrauterine transmission rates and risk of neurodevelopmental sequelae are associated with primary maternal infections. Transmission occurs less frequently after non primary maternal infections due to reactivation or reinfection. 10–15% of infected infants are symptomatic at birth, with neurological symptoms present in two-thirds. Infants who are asymptomatic at birth may go on to develop late neurodevelopmental sequelae, with sensorineural hearing loss being the commonest late consequence. Prenatal, neonatal and retrospective diagnosis can be challenging. Early treatment of symptomatic neonates with the antiviral drug valganciclovir can reduce the long-term neurodevelopmental sequelae. Universal or targeted screening for congenital CMV is not currently advocated. The development of an effective vaccine appears to be some years away. This review highlights the important considerations for clinicians regarding the diagnosis, investigation and management of children with possible or confirmed congenital CMV infection.     

Outcome and management of newborns with congenital cytomegalovirus infection

Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of hearing loss and neurological disorder in children. Its overall prevalence is approximately 0.5% in Europe. In France, systematic screening during pregnancy is not recommended; screening is performed only if there are maternal or fetal symptoms suggestive of this infection. Approximately 90% of infected newborns are asymptomatic at birth, and among them the risk of neurosensory sequelae is 5–15%. By contrast, the prevalence of neurosensory impairment in symptomatic newborns at birth varies from 17% to 60%. Congenital CMV infection must be confirmed at birth before the 21st day of life by polymerase chain reaction (PCR) on saliva or urine samples. A complete clinical examination, blood tests (blood count, liver function test, CMV PCR), hearing tests, brain ultrasound and eye fundus examination should be performed. Neurological and auditory follow-up must be extended well beyond the neonatal period because the occurrence of neurosensory sequelae may be delayed. Oral valganciclovir is the recommended treatment in moderate or severe congenital CMV infections for a period of 6 weeks to 6 months; such treatment requires regular monitoring because of its possible side effects.