Congenital Cytomegalovirus Disease Research Articles

Assessment of patients’ characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease

IntroductionInsurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. Materials and methodsWe performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants’ baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. ResultsOf the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). ConclusionsInfants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Successful valganciclovir treatment initiated beyond 60 days of age in a preterm infant with congenital cytomegalovirus disease.

Successful valganciclovir treatment initiated beyond 60 days of age in a preterm infant with congenital cytomegalovirus disease.

Estimates of congenital cytomegalovirus-attributable infant mortality in high-income countries: A review.

As many as 5%-10% of infants with symptomatic congenital cytomegalovirus (cCMV) disease, or 0.4%-0.8% of all liveborn infants with cCMV infection, die in early infancy in high-income countries. However, estimates are uncertain due to several potential biases that can result from data limitations and study designs. First, infants with cCMV infections who die prior to diagnosis, which usually occurs at 1-4weeks after birth, may be excluded from both the count of deaths and the denominator of cCMV births, resulting in left truncation and immortal time biases. These 'biases' are features of the data and do not reflect bias on the part of researchers, but understanding the potential existence of threats to validity can help with interpretation of findings. Left truncation of infant deaths occurring prior to diagnosis of cCMV can result in understatement of the burden of infant deaths due to cCMV. Conversely, overestimation of infant deaths associated with symptomatic cCMV may occur in clinical case series owing to greater representation of relatively severely affected infants owing to ascertainment and referral biases. In this review, we summarise the characteristics of 26 studies that reported estimates of cCMV-associated infant deaths, including potential biases or limitations to which those estimates may have been subject. We discuss study designs whose implementation might generate improved estimates of infant deaths attributable to cCMV. More complete estimates of the overall public health impact of cCMV could inform current and future screening, prevention, and vaccine research.

1753. Neutropenia as a Function of Ganciclovir Exposure During Treatment of Congenital Cytomegalovirus Disease

Abstract Background Congenital cytomegalovirus (cCMV) infection is the leading cause of non-genetic sensorineural hearing loss (SNHL) in childhood. Treatment of infants with symptomatic cCMV disease with intravenous (IV) ganciclovir or oral valganciclovir improves audiologic outcomes when started in the first month of age. Neutropenia is the most common adverse event of antiviral treatment, occurring in 19-63% of infants. No correlation between ganciclovir drug exposure and development of neutropenia has been identified. Methods We utilized pharmacokinetic (PK), pharmacodynamic (PD), and hematologic data from three international, NIH-funded studies of IV ganciclovir or oral valganciclovir conducted by the Collaborative Antiviral Study Group (CASG) from 2002-2018. The minimum absolute neutrophil count (ANC) was used to classify each patient as life-threateningly, severely, moderately, mildly or never neutropenic, as defined in the Division of AIDS Toxicity Tables. The mean 12-hour area under the curve (AUC12) values of patients from each category were compared using ANOVA. The correlation between the minimum ANC value and the AUC value was estimated using Pearson correlation. Ordinal logistic regression determined if AUC was a significant predictor of neutropenia category. Results 139 subjects were included, with 18 (13%) developing an ANC below 500 prompting suspension of antiviral treatment. AUC12 exposure as a function of degree of neutropenia is presented in Figure 1. AUC12 weakly correlated with the ANC (p=0.02; R=0.20), suggesting that higher AUC values very weakly correlated with higher ANC values, the opposite of what was hypothesized. In comparison, the ANOVA showed no significant difference (P=0.72) between each group of subjects, meaning that each category of neutropenia status had equivalent drug exposure. Ordinal logistic regression did not show that AUC12 is a significant predictor of neutropenia category (P=0.62).Figure 1:AUC Values Across Five Categories of Neutropenia Conclusion We did not observe a high correlation between AUC12 and neutropenia. However, most participants only had one AUC12 result from time of study enrollment, so our results do not exclude the possibility that such a correlation exists. Future analyses will explore additional PK parameters, such as Cmax and half-life, as a function of ANC values. Disclosures Inmaculada Aban, PHD, Roche: Steering Committee Member David Kimberlin, MD, Gilead: Grant/Research Support|Gilead: Served as site PI on pediatric remdesivir study. All monies went directly to my university and not to me.

682 - Resolution of thrombocytopenia during treatment for symptomatic congenital cytomegalovirus disease

682 - Resolution of thrombocytopenia during treatment for symptomatic congenital cytomegalovirus disease

Healthcare costs of congenital cytomegalovirus (cCMV) disease in infants during the first two years of life: a retrospective German claims database analysis

BackgroundCongenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life.MethodsWe conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis (“representative” controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up (“healthy” controls). Due to missing data, mean imputation was applied for aids and remedies costs.ResultsWe identified 54 and 24 infants born 2014–2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. “representative” controls (€22,737 (€9759) vs. €3091 (€863), p < 0.001), with 87.2% inpatient costs. Healthcare costs for cCMV21-S cases compared to “healthy” controls were €34,498 (€20,924) vs. €680 (€569), p < 0.001. Differences decreased for both comparisons in the second year but remained statistically significant.ConclusionscCMV comprises a considerable economic burden for the German healthcare system (€19,646 to €33,818 higher mean costs for infants with recorded cCMV diagnosis in the first year of life). Attempts should be made to reduce this burden.

Congenital Cytomegalovirus Screening in Massachusetts Birth Hospitals: A Statewide Survey.

This study sought to assess the current state of screening for congenital cytomegalovirus infection in newborns among birth hospitals and newborn nurseries in the state of Massachusetts. A survey assessing hospital protocols for cytomegalovirus testing in newborns was distributed to all birth hospitals and newborn nurseries in Massachusetts from November 2020 to February 2021. 73.3% of hospitals responded to at least one survey question. Of these, fewer than half (48.5%) had any established approach for neonatal cytomegalovirus screening. Salivary polymerase chain reaction was the most common testing modality. Most hospitals did not perform confirmatory testing for positive test results. Most respondents (87.9%) did not know or did not answer how results of cCMV screening were reported to families and who was responsible for coordinating care for cCMV-infected infants. We conclude that congenital cytomegalovirus screening protocols are absent or incomplete in most Massachusetts birth hospitals and newborn nurseries. A cohesive strategy involving standardized education and screening guidelines is needed to reduce the incidence and burden of congenital cytomegalovirus disease on children and their families.

Oral Valganciclovir Therapy in Infants Aged ≤2 Months with Congenital Cytomegalovirus Disease: A Multicenter, Single-Arm, Open-Label Clinical Trial in Japan.

Our aims were to determine the clinical impact of oral valganciclovir (VGCV) in infants aged ≤2 months with congenital cytomegalovirus (CMV) disease and evaluate the efficacy of VGCV when initiated beyond the neonatal period. The multicenter, single-arm, open-label clinical trial was conducted in Japan. Twenty-five infants aged ≤2 months with congenital CMV disease involving the central nervous system were enrolled and treated with VGCV for 6 months. The primary endpoint was the change in the whole blood CMV load before and after treatment. The secondary endpoint was the change in the auditory brainstem response (ABR) before and after treatment. Changes in ABR were assessed between the younger and older age groups (≤ and >30 days at treatment initiation). Of the 25 patients, one was excluded owing to epilepsy before VGCV administration. The median change in the CMV DNA level in whole blood was −246.0 IU/mL. The best ear and total ear assessments based on ABR were categorized as (improved + unchanged) after treatment for 100% and 93.8%, respectively. No differences in hearing efficacy were observed between the younger and older age groups. Oral VGCV is a potential therapeutic option for treating infants aged ≤2 months with congenital CMV disease.

#62 Resolution of thrombocytopenia during treatment for symptomatic congenital cytomegalovirus disease

Abstract Background Congenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States (4.5 per 1000 live births) and is the leading non-genetic cause of sensorineural hearing loss and developmental disabilities in children worldwide. However, reliable estimates of time to resolution for manifestations of cCMV disease have not been fully elucidated. A better understanding of the resolution of laboratory abnormalities for cCMV is needed to guide decisions about frequency of platelet assessments following diagnosis and potentially optimize antiviral therapy. Method Data from 243 infants with symptomatic cCMV were retrospectively analyzed from four studies conducted by the NIH-funded Collaborative Antiviral Study Group over the years 1989-2011. Individuals were compared based on baseline platelet value, utilizing Division of AIDS Toxicity Scale categorization, and treatment received. Kinetics of the trend in platelets over time were compared between groups using Kaplan-Meier plots and binomial assessments of abnormal vs. normal. All analyses were conducted over the 6-week (45 day) time period. Results Predicted curves showed that the interaction between antiviral therapy and platelet value over time was found to be significant (p=0.0106) for individuals with normal baseline platelet counts (Grade 0, defined as ≥ 125,000). For individuals with Grades 1-4 thrombocytopenia at baseline, probability curves showed that both baseline grade (p=0.0006) and time (p&amp;lt;.0001) correlated with rate of resolution of thrombocytopenia, but antiviral treatment did not (p=0.1964). Kaplan-Meier plots of time to platelet count of ≥ 125,000 demonstrated that baseline platelet grade was significantly (p=0.0003) correlated with time to resolution of thrombocytopenia. Kaplan-Meier plots of time to platelet count of ≥ 100,000 demonstrated that baseline platelet grade was significantly (p=0.0056) correlated with time to Grade 1 thrombocytopenia. Conclusion For neonates with baseline thrombocytopenia from cCMV, antiviral therapy does not hasten time to resolution of thrombocytopenia. For neonates with normal baseline platelet values, antiviral therapy correlated with increasing platelet counts. Degree of baseline thrombocytopenia correlated with time to normalization of platelet count. Further understanding of the kinetics of resolution of laboratory abnormalities for symptomatic cCMV is needed to directly inform patient management decisions.

Congenital Cytomegalovirus Infection: Transmission, Diagnosis and Treatment.

Introduction: Cytomegalovirus (CMV) is a linear, dsDNA virus that is regarded as the prototype of the Betaherpesvirinae subfamily of viruses. It has an established endemic status in certain locations around the globe, and is also reported to be the most prevalently occurring congenital infection in humans. Furthermore, Cytomegalovirus is notorious for being a persistent lifelong pathogen that poses a threat of reactivation as well. Discussion: Congenital cytomegalovirus infection causes numerous ophthalmologic, and neurologic sequelae, and is also known for being the principal reason behind sensorineural hearing loss of non-genetic etiology in neonates. These symptoms, if present, may give rise to a premonition of congenital Cytomegalovirus disease, and so, a diagnosis can be established through serology, radiology, and PCR of salivary, urinary, or dried blood spot samples. Timely administration of ganciclovir or valganciclovir has proven to be effective in managing symptomatic cases of congenital CMV. Conclusion: A well-timed delivery of pharmacological and non-pharmacological interventions is necessary to achieve healthy developmental outcomes for the neonate. Moreover, there is still a need to study the role of antiviral therapy in silent cases since asymptomatic patients are at a risk of developing long-term clinical sequelae as well. Relevance: An estimated 60-90% of women of child-bearing age get infected with Cytomegalovirus, and Congenital CMV disease is reported in 0.2-2.4% of all live births. Therefore, in order to develop effective screening and management protocols, it is vital to educate healthcare professionals regarding the various aspects of this congenital infection.

Horizontal Transmission of Cytomegalovirus in a Rhesus Model Despite High-Level, Vaccine-Elicited Neutralizing Antibody and T-Cell Responses.

The development of a vaccine to prevent congenital human cytomegalovirus (HCMV) disease is a public health priority. We tested rhesus CMV (RhCMV) prototypes of HCMV vaccine candidates in a seronegative macaque oral challenge model. Immunogens included a recombinant pentameric complex (PC; gH/gL/pUL128/pUL130/pUL131A), a postfusion gB ectodomain, and a DNA plasmid that encodes pp65-2. Immunization with QS21-adjuvanted PC alone or with the other immunogens elicited neutralizing titers comparable to those elicited by RhCMV infection. Similarly, immunization with all 3 immunogens elicited pp65-specific cytotoxic T-cell responses comparable to those elicited by RhCMV infection. RhCMV readily infected immunized animals and was detected in saliva, blood, and urine after challenge in quantities similar to those in placebo-immunized animals. If HCMV evades vaccine-elicited immunity in humans as RhCMV evaded immunity in macaques, a HCMV vaccine must elicit immunity superior to, or different from, that elicited by the prototype RhCMV vaccine to block horizontal transmission.

Hearing Loss in Congenital CMV Disease Post-Ganciclovir

Source: Lanzieri TM, Caviness AC, Blum P, et al. Progressive, long-term hearing loss in congenital CMV disease after ganciclovir therapy. J Pediatric Infect Dis Soc. 2021;piab095. doi:10.1093/jpids/piab095Investigators from the CDC, Atlanta, GA, and Baylor College of Medicine, Houston, TX, conducted a study to assess long-term hearing outcomes in children with symptomatic congenital cytomegalovirus (CMV) infection, and the impact of ganciclovir therapy on hearing loss. For the study, they analyzed data from children born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. All study participants had CMV infection detected in urine samples in the first 3 weeks of life and had microcephaly, chorioretinitis, neurologic abnormalities or evidence of reticuloendothelial system involvement (eg, petechiae/purpura). Study children had longitudinal assessments of hearing with auditory brainstem response testing and behavioral audiometry; those with hearing thresholds >20 dB were classified as having sensorineural hearing loss (SNHL). SNHL was defined as congenital if diagnosed in the first month of life. Study children were placed into 3 groups: Group A included patients who had been enrolled in a clinical trial and received ganciclovir; group B included children with SNHL, microcephaly and/or chorioretinitis but who were untreated; and group C comprised those without any of these findings who also were not treated with ganciclovir. The primary study outcome was long-term assessment of hearing loss among children in these 3 groups.Data were analyzed on 76 children; 17 (22%) in group A, 27 (36%) in group B, and 32 (42%) in group C. Among the 17 children in group A, 16 had microcephaly, chorioretinitis, or congenital SNHL; median duration of ganciclovir treatment in these patients was 40 days. Overall, the most common findings in study patients when they were neonates were purpura/petechiae (82% of those in group A, 78% in group B, and 63% in group C); 71% and 70%, respectively, of those in groups A and B had microcephaly. Congenital SNHL was diagnosed in 65% of patients in group A and 56% for those in group B, although hearing was not assessed in the first month of life in all study participants. The median age at last hearing assessment was 13 years for children in groups A and C and 11 years for those in group B. At that time, 16 (94%) patients in group A, 24 (89%) children in group B, and 16 (50%) group C patients had SNHL. SNHL was categorized as severe (>70 dB) in 12 (71%), 16 (59%), and 7 (22%) children, respectively, in groups A, B, and C.The authors conclude that most children in this study with congenital CMV infection developed substantial SNHL with or without ganciclovir treatment.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The current investigators provide long-term hearing outcomes for infants born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. Participants were selected based on having severe disease as newborns.1,2 Not surprisingly, most developed substantial SNHL. As previously discussed, symptomatic congenital CMV infection at birth is a risk factor for SNHL. (See AAP Grand Rounds. 2019;42[5]:57.)3 Many infants also had microcephaly and/or head CT scan findings suggesting tissue destruction or dysplastic growth, which also are associated with an increased risk of SNHL.4 The results of early clinical trials of intravenous ganciclovir1,2 had suggested short-term stabilization or improvement in hearing at 6 months but were not borne out by the current investigation.With the introduction of oral valganciclovir, a phase III, randomized, placebo-controlled clinical trial, conducted during 2008– 2011, evaluated 6 weeks versus 6 months of therapy with valganciclovir.5 There was modest improvement in hearing and developmental outcomes at 12 and 24 months. Based on this trial, the AAP currently recommends 6 months of oral valganciclovir for infants with moderately to severely symptomatic congenital CMV infection who can start treatment in the first month of life.6 The current authors state that their findings cannot be extrapolated to infants who receive current standard of care therapy. Infants receiving valganciclovir are being followed to determine their long-term hearing outcomes.Another area that is not addressed is the role of valganciclovir for infants with congenital CMV infection who have isolated SNHL. The 2017 consensus guidelines do not routinely recommend valganciclovir for these infants based on insufficient evidence. Pasternak et al reported that 12 months of antiviral therapy for infants with congenital CMV infection and isolated SNHL led to improved hearing, but their study did not include a control group.(See AAP Grand Rounds. 2018;40[5]:55.)8Infants with congenital CMV infection are at risk for SNHL despite receipt of antiviral therapy. These infants deserve close audiology follow-up.The apparent lack of major benefit of antiviral therapy in children with symptomatic congenital CMV infection underscores the need for prevention. Neither CMV-IGIV nor investigational vaccines have yet proven efficacious.6

Hepatosplenomegaly and Periventricular Cyst in a Neonate with Direct Hyperbilirubinemia

Hepatosplenomegaly and Periventricular Cyst in a Neonate with Direct Hyperbilirubinemia

The association between maternal cytomegalovirus urinary excretion and congenital infection rate

BackgroundIn utero Cytomegalovirus (CMV) vertical transmission occurs predominantly during primary maternal infection. There are no known non-invasive methods for diagnosis of fetal infection before delivery, however some risk factors have been suggested. We aimed to evaluate the association between maternal CMV urinary excretion and congenital CMV infection.MethodsA retrospective cohort study of all women who were diagnosed with primary CMV infection during pregnancy in a single university affiliated tertiary medical center, between 2012 and 2016. We examined congenital CMV infection and disease rates among infants born to women with and without CMV urinary excretion.ResultsOverall, 126 women were included, 77 in the positive urinary excretion group, and 49 in the negative urinary excretion group. There was no difference in maternal symptoms between the groups. We found no difference in congenital CMV infection and disease rates between infants born to women with and without urinary excretion of CMV (congenital infection rate 37.1% vs. 24.4%, p = 0.209, congenital disease rate of 18.2% vs. 22.4%, p = 0.648). Women with positive urinary CMV excretion had lower IgG avidity values (36.7% vs 54.6%, p = 0.007), with no additional difference in serology pattern. Compared to asymptomatic women, those with CMV related symptoms did not have significantly higher rates of urinary excretion of CMV (70% vs. 60.5%, p = 0.38) or congenital infection rates (40.7% vs. 31.2%, p = 0.48).ConclusionAmong infants of women with primary CMV infection in pregnancy, we did not find an association between urinary excretion of CMV and congenital CMV infection.

Progressive, Long-Term Hearing Loss in Congenital CMV Disease After Ganciclovir Therapy.

Long-term hearing outcomes among children with symptomatic congenital cytomegalovirus (CMV) disease who received 6-week ganciclovir therapy early in life are unknown. Longitudinal study of 76 children with symptomatic congenital CMV disease, born 1983-2005, who were categorized into three groups: group A treated with ganciclovir; group B untreated who had microcephaly, chorioretinitis, or sensorineural hearing loss (SNHL; ≥25 dB) diagnosed in the first month of life (congenital); and group C untreated who did not meet criteria for group B. Patients in groups A (n = 17), B (n = 27), and C (n = 32) were followed to median age of 13, 11, and 13 years, respectively. In group A, patients received ganciclovir for median of 40 (range, 11-63) days; 7 (41%) had grade 3 or 4 neutropenia. Congenital SNHL was diagnosed in 11 (65%) patients in group A, 15 (56%) in group B, and none in group C. Early-onset SNHL was diagnosed between ages ≥1-12 months in an additional 4 (24%), 6 (22%), and 8 (25%) patients in groups A, B, and C, respectively. By the end of follow-up, 12 (71%), 16 (59%), and 7 (22%) of patients in groups A, B, and C, respectively, had severe (>70 dB) SNHL in the better-hearing ear. In this study, most patients with symptomatic congenital CMV disease and congenital or early-onset SNHL eventually developed hearing loss severe enough to have been potential candidates for cochlear implantation, with or without 6-week ganciclovir therapy. Understanding long-term hearing outcomes of patients treated with 6-month oral valganciclovir (current standard of care) is needed.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

Congenital Cytomegalovirus Infection: Transmission, Diagnosis and Treatment.

Introduction: Cytomegalovirus (CMV) is a linear, dsDNA virus that is regarded as the prototype of the Betaherpesvirinae subfamily of viruses. It has an established endemic status in certain locations around the globe, and is also reported to be the most prevalently occurring congenital infection in humans. Furthermore, Cytomegalovirus is notorious for being a persistent lifelong pathogen that poses a threat of reactivation as well. Discussion: Congenital cytomegalovirus infection causes numerous ophthalmologic, and neurologic sequelae, and is also known for being the principal reason behind sensorineural hearing loss of non-genetic etiology in neonates. These symptoms, if present, may give rise to a premonition of congenital Cytomegalovirus disease, and so, a diagnosis can be established through serology, radiology, and PCR of salivary, urinary, or dried blood spot samples. Timely administration of ganciclovir or valganciclovir has proven to be effective in managing symptomatic cases of congenital CMV. Conclusion: A well-timed delivery of pharmacological and non-pharmacological interventions is necessary to achieve healthy developmental outcomes for the neonate. Moreover, there is still a need to study the role of antiviral therapy in silent cases since asymptomatic patients are at a risk of developing long-term clinical sequelae as well. Relevance: An estimated 60-90% of women of child-bearing age get infected with Cytomegalovirus, and Congenital CMV disease is reported in 0.2-2.4% of all live births. Therefore, in order to develop effective screening and management protocols, it is vital to educate healthcare professionals regarding the various aspects of this congenital infection.

Труднощі добору специфічної терапії при тяжких формах вродженої цитомегаловірусної інфекції: погляд крізь час

The aim — to show the feasibility of using ganciclovir for congenital cytomegalovirus infection (CMVI) by demonstrating two clinical cases. Clinical cases. Over time, the approaches to the treatment of congenital CMVI have changed from the use of acyclovir to the appointment of ganciclovir. In 2011, a premature baby was diagnosed with congenital CMVI based on the presence of multiple organ lesions (lungs, liver, spleen, pancreas, eyes, central nervous system) and positive result of CMV PCR test in blood, urine and cerebrospinal fluid. Only acyclovir was used as an etiotropic drug due to the lack of evidence at that time on the safety of another antiviral drug — ganciclovir. Treatment was not completely effective: in the follow;up at the age of two the child has a grave violation hearing and vision and profound disability due to the residual effects on the central nervous system. In 2019, a newborn child with severe haemorrhagic syndrome, respiratory disorders and neurological symptoms was diagnosed with congenital CMVI by positive result of CMV PCR test and ganciclovir was prescribed at a dose of 6 mg/kg every 12 hours by an intravenous infusion under the control of a routine complete blood count (CBC) test. On the second week of treatment, positive dynamics was observed clinically, on the 6th week — negative result of CMV PCR test. The child was discharged on day 70th of treatment without residual effects on the central nervous system. At the age of 9 months, deafness of 2–3 degrees was diagnosed, but prosthetics were performed timely with complete restoration of hearing. At age of 12 month this child sits, rolls over, crawls; responds adequately to others; captures the gaze and keep an eye on items. Conclusions. Two clinical cases through the description of changes in approaches to specific therapy of congenital cytomegalovirus disease from acyclovir to ganciclovir and a clear demonstration of the difference in disease outcomes — from severe disability when ganciclovir was not prescribed, to complete rehabilitation with its use demonstrate the feasibility of prescribing ganciclovir. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: congenital cytomegalovirus infection, severe forms, treatment, acyclovir, ganciclovir.

Congenital Cytomegalovirus Infection Management-New Insights

Congenital Cytomegalovirus (CMV) infection is one of major public health concerns and one of the most frequent congenital infections worldwide. Congenital CMV infection is under-diagnosed in the majority of asymptomatic pregnant women due to its self-limited non-specific symptoms and unimplemented screening program. Primary CMV infections are associated with the highest in-utero transmission at estimated rates of 30–35%. Transmission rate occurs less frequently in secondary CMV maternal infections at approximately 1.1–1.7%. Congenital CMV infection can also go undetected at birth because the affected newborns are often asymptomatic, however, they manifest serious morbidities later in life. There are growing evidences that early diagnosis and treatment of newborns with congenital CMV infection can reduce sensorineural hearing loss (SNHL) and the subsequent long-term neurological and developmental disabilities. There is also increased interest in establishing a prophylactic CMV vaccine that can protect seronegative mothers from primary infection and augment the immune response in seropositive women, in order to prevent CMV reactivation or re-infection. Studies show that liquid-saliva polymerase chain reaction (PCR) assay has high sensitivity “100%" it is more advantageous than Dried blood spots (DBS) in detecting congenital CMV infection and it can be used to screen newborns in the first 3 weeks. Suggestive strategies to reduce the burden of congenital CMV disease are; establishing a screening programme for pregnant mothers, developing prophylactic CMV vaccine, early therapeutic intervention in pregnant women and newborns and use Saliva PCR assay as a new method for neonatal CMV screening.

Cytomegalovirus Genotype and Virulence in Infants with Congenital Infection

Abstract Objective Cytomegalovirus (CMV) virulence may depend on genetic variability in several regions of the genome. This study aimed to assess specific CMV genotypes' association with the severity of symptomatic congenital CMV disease at birth. Methods CMV glycoprotein B (gB), glycoprotein N (gN), glycoprotein H (gH), and UL144 strains were identified by nested polymerase chain reaction, restriction fragment length polymorphism, and heteroduplex mobility assay single-stranded conformation polymorphism in 50 infants infected congenitally and 25 asymptomatic infants. Results gN1 (p = 0.010) and UL144-B (p = 0.034) genotypes were associated, by logistic regression, with reduced risk of developing symptomatic congenital CMV infection. gN1 (p = 0.020) and gN3 (p = 0.022) genotypes were associated with reduced risk of severe symptomatic disease. Conversely, gB1 (p = 0.018) was the most virulent genotype and was associated with severe symptoms. Conclusion An association among gB1, gN1, gN3, and UL144-B genotypes of CMV and severity of congenital CMV disease might exist. gB, gN, and UL144 genotypes could be important virological markers of infant infection.